CA2069956C - Process for the production of 17-oxosteroids - Google Patents
Process for the production of 17-oxosteroids Download PDFInfo
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- CA2069956C CA2069956C CA002069956A CA2069956A CA2069956C CA 2069956 C CA2069956 C CA 2069956C CA 002069956 A CA002069956 A CA 002069956A CA 2069956 A CA2069956 A CA 2069956A CA 2069956 C CA2069956 C CA 2069956C
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
- C12P33/12—Acting on D ring
- C12P33/16—Acting at 17 position
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- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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Abstract
A process for the production of 17-oxosteroids by fermentative oxidation of 17.beta.-hydroxy steroids is described, which is characterized in that for the fermentation, a bacterial culture of the species Mycobacterium spec. NRRL B-3805, Mycobacterium spec. NRRL B-3683, Mycobacterium phlei NRRL B-8154 or Mycobacterium fortuitum NRRL B-8153 is used.
Description
:L
Process far the Production of 17-Oxo~teroids The invention relates 'to a process for the productian of 17 -oxasteroids by fermentative oxidation of 17Q-hydroxy steroids.
Processes far fermentative production of 17-axosteroids have been known for a long time. As early as 1938, A. Vercellane and L. Momoli describe a process for the productian of 4-androstene- -.
3,17-dione -by fermentation of 5-andrastene-3~,17(~-diol (Ber. 71, 1938, 152-155). This process provides high yields of process product, when the suitable microorganisms are selected (Czech 87.068; ref. C.A. 54, 1960, 2441). There are also a great number of publications in which is described that 17-oxosteraids (such as 4-androstene-3,17-dione, 1,4-androstadiene-3,17-diane or 3-hydroxy-1,3,5(10)-estratrien-1-one) can be produced while achieving high yields by fermentative side chain catabolism of substrates, which carry a hydrocarbon chain in 17~-position.
Only vary little is known about processes with whose help it is possible to oxidize 17~-hydroxy steroids microbiologically in good yield to 17-oxysteroids, without an additianal conversion of the steroid taking place. M. Welsh and C. Heusghem describe a process that is to make it passable to convert estradiol with a yield of 95o to estrane, but this process cannot be done over.
again, since the microorganism used by these authors is not available to the public (Campt. Rend. Sac. Biol., 142, 1948, 1074).
But there is a cansiderable demand fox making such a fermentative process available, since the chemical processes for oxidation are quite.expensive. In addition, these chemical ?~~~~~-~
processe~~ suffer from the shortcoming that they are performed by reagents such as pyridine and sulfur trioxide, whose environment-compatible disposal is quite problematical.
It has nom been found that 17-oxosteroids surprisingly can be produced in high yields from 17~-hydroxy steroids, if bacterial cultures of the species Mycobacterium spec. NRRL B- --3805, Mycobacterium spec. NRRL B-3683, Mycobacterium phlei NRRL
B-8154 or Mycobacterium fortuitum NRRL B-8153 are used far fermentation of the 17~-hydroxy steroids. y The process according to the invention is performed under the same fermentation conditions, which are also used with these bacterial cultures in the known microbiological conversions.
Under the culture conditions usually used fox these bacterial cultures, submerged cultures are cultivated in a suitable nutrient medium with aeratian. Then, the substrate (dissolved in a suitable solvent or in emulsified form) is added to the cultures and fermented, until a maximum substrate conversion is reached.
Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylfox-mamide or dimethylsulfoxide. The emulsification of the substrate can be brought about, for example, by the latter being sprayed in micronized form or dissolved in a water-miscible solvent (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethylformamide or dimethylsulfoxide) under strong turbulence in (preferably decalcified) water, which contains the usual emulsifying aids. Suitable emulsifying aids are nonionogenic DC1-3299~t s emulsifiers, such as, for example, ethylenoxy adducts or fatty acid esters of polyglycols. As suitable emulsifiers, the commercially available wetting agents Tegin~R~, TweentR~ and Span~R~ can be mentioned as examples.
The optimum substrate concentratian, substrate addition time and fermentation period depend on 'the type of substrate and -microorganism used and fermentation conditions. These values, as is generally necessary in microbiological steroid conversions, have to be determined in the individual case by preliminary tests, as they are familiar to one skilled in the art.
To perform the process according to the invention, 17~-hydroxy steroids of general formula I
o~
st ~ ~I) in which R1 represents a hydrogen atom or a methyl group and St symbolizes the radical of an estran-1a~3-of derivative, containing up to 5 noncumulated double bonds, substituted ~in the 3-position by a phenolic hydroxy group, a lower alkoxy group,.a lower 1-alkoxy-alkoxy group, a 2-tetrahydropyranyloxy group, or a lower alkylenedioxy group, as well as optionally in 5,10-position by an epoxy group and in 19-position optionally by a methyl group, are preferably used as substrates.
Hy a lower alkoxy group is preferably to be understood a group which carries up to 4 carbon atoms. Suitable alkoxy groups are, for example, the methoxy group or the tert-butyloxy group.
Dy a lower l-alkoxy-alkoxy group is preferably to be understood a lower alkoxy-methoxy group with an alkoxy group having up to 4 carbon atoms. For example, the 1-methoxy-methoxy group can be mentioned. By a lower alkylenedioxy group is preferably to be understood a grouping having 2 to 6 carbon atoms such as, for example, the ethylenedioxy group or the 2,2-dimethyl- -prapylenedioxy group.
Substrates, which are suitable to perform 'the process according to the invention are, for example, estran-17~-0l derivatives of general formula Ia (1a1, RZO
in which Rl has the above-mentioned meaning, R2 represents a hydrogen atom or an alkyl group containing up to 4 carbon atoms and l -A-B-C-D° symbolizes a grouping of partial formula i i ~ ~ i ~
-CHZ-CH2-CH-Cfi-, CH2-CH=C-Cii- or -CH=CEI-C=C-.
The estran-17-one derivatives formed from these substrates or the 3-hydroxy compounds obtained from this by ether cleavage are, as is known, pharmacologically effective and can; moreover, as is known, be reduced to,the corresponding l7rx-hydroxy compounds or be converted to the corresponding 173-hydroxy-17a-ethinyl compounds.
Further, suitable substrates are estrane derivatives of general formula 7Cb in which symbolizes a single bond or a double bond, R1 has the above-mentioned meaning, R3 represents an alkyl group with at most ~ carbon atpms.
The 17-oxosteroids formed from these compounds can, as is known, be used, for example, to produce the pharmacologically effective 17a-ethinyl-17~-hydroxy-4-estren-3-one or its 18-methyl homologs.
Substrates worth mentioning are also those of general t formula Ic cj~) , R 5 .., R
in which R3 has the above-mentioned meaning, R4 represents a hydrogen atom or a methyl group, R5 and R6 together symbolize a lower alkyldio:xy 'group or R5 means a hydrogen atom and R6 represents a lower alkoxy group, a lower 1-alkoxyalkoxy group or a 2-tetrahydropyranyl group.
The 17-oxosteroids obtained from these compounds can be further processed in the same way as those of the es~tran-17~i-of derivatives of general formula Ica but, on the other hand, they can also be used for the production of pregnane derivatives, as is well known to one skilled in the art.
Finally, also worth mentioning are estran-17~-0l derivatives of general formula Id ~Id), in which R1 has the above-mentioned meaning, R9 symbolizes a hydrogen atom and R~ and R$ together symbolize a lower alkylenediaxy group or R~ and R9 mean two hydrogen atoms or together mean a carbon-carbon bond and --R8 represents a lower alkoxy group, a lower 1-alkoxyalkoxy group or a 2--tetrahydropyranyloxy group.
The ketones obtained from these compounds can be converted to antigestagenically active steroids according to the process, as described in EP-A 0129499.
The following embodiments are used to explain the process according to the invention in more detail.
r Example 1 a) A 500 ml Erlenmeyer with 100 ml of sterile nutrient medium containing 1 s yeast extract 0.45 % Na2HP04 ' 2H20 0.34 a KH2P04 _ 0.2 % Tween 80 with a pH of 6.7 is inoculated with a suspension of a Mycobacterium spec. NRRL B-3683 culture and shaken for 72-hours at 30°C with 180 revolutions per minute.
b) 50 Erlenmeyers (100 ml) with 20 ml of sterile nutrient medium each containing 0.5 % carn steep liquor 0.05 % glucose monohydrate 0.2 % yeast extract -° adjusted to pH 7.0 --are inoculated with 1 ml of Mycobacterium-spec.-growing culture each and incubated for 24 hours on a rotaxy shaker with 220 revolutions per minute at 30°C.
Then, 0.02 g of 3,3-(2,2-dimethyltrimethylenedioxy)-5~,.10~s-epoxy--5~c-estr-9 ( 11 ) -en-17 ~-of dissolved in 0 . 2 ml of dimethylformamide and sterilized by filtration is added to each culture and fermented for another 48 hours at 30°C.
c) The combined cultures are extracted with methyl isobutyl ketone and the ext~'act is concentrated by evaporation under vacuum in a rotary evaporator at a maximum of 50°C. Then, a purification takes place by chromatography on a silica gel column.
0.85 g of 3,3-(2,2-dimethyltrimethylenedioxy)-5,10a-epoxy-Sec-estr-9{11)-en-17~-one, which is identical with an authentic sample according to HPLC, is thus obtained.
Example 2 a) The production of the growing culture takes place as indicated in example 1a).
b) 50 Erlenmeyers (100 ml) with 20 ml of sterile nutrient medium each containing 2.5 % corn steep liquor 0.25 % soybean flour 0.3 0 (NH4)2HP04 0.25 % Tween 80 -- adjusted to pH 6.5 --are inoculated with 1 ml of the Mycobacterium-spec.-growing culture each and incubated for 24 hours on a rotary shaker with 220 revolutions per minute at 30°C.
Then, 0.002 g of ~-equilol dissolved in 0.2 ml of dimethylformamide and s~terili~ed by filtration is added to each culture and fermented for another 72 hours at 30°C.
c) The isolation of the product takes place as described under 1c).
0.095 g of equilin, which is identical wit~a an authentic sample according to HPLC, is thus obtained. '
Process far the Production of 17-Oxo~teroids The invention relates 'to a process for the productian of 17 -oxasteroids by fermentative oxidation of 17Q-hydroxy steroids.
Processes far fermentative production of 17-axosteroids have been known for a long time. As early as 1938, A. Vercellane and L. Momoli describe a process for the productian of 4-androstene- -.
3,17-dione -by fermentation of 5-andrastene-3~,17(~-diol (Ber. 71, 1938, 152-155). This process provides high yields of process product, when the suitable microorganisms are selected (Czech 87.068; ref. C.A. 54, 1960, 2441). There are also a great number of publications in which is described that 17-oxosteraids (such as 4-androstene-3,17-dione, 1,4-androstadiene-3,17-diane or 3-hydroxy-1,3,5(10)-estratrien-1-one) can be produced while achieving high yields by fermentative side chain catabolism of substrates, which carry a hydrocarbon chain in 17~-position.
Only vary little is known about processes with whose help it is possible to oxidize 17~-hydroxy steroids microbiologically in good yield to 17-oxysteroids, without an additianal conversion of the steroid taking place. M. Welsh and C. Heusghem describe a process that is to make it passable to convert estradiol with a yield of 95o to estrane, but this process cannot be done over.
again, since the microorganism used by these authors is not available to the public (Campt. Rend. Sac. Biol., 142, 1948, 1074).
But there is a cansiderable demand fox making such a fermentative process available, since the chemical processes for oxidation are quite.expensive. In addition, these chemical ?~~~~~-~
processe~~ suffer from the shortcoming that they are performed by reagents such as pyridine and sulfur trioxide, whose environment-compatible disposal is quite problematical.
It has nom been found that 17-oxosteroids surprisingly can be produced in high yields from 17~-hydroxy steroids, if bacterial cultures of the species Mycobacterium spec. NRRL B- --3805, Mycobacterium spec. NRRL B-3683, Mycobacterium phlei NRRL
B-8154 or Mycobacterium fortuitum NRRL B-8153 are used far fermentation of the 17~-hydroxy steroids. y The process according to the invention is performed under the same fermentation conditions, which are also used with these bacterial cultures in the known microbiological conversions.
Under the culture conditions usually used fox these bacterial cultures, submerged cultures are cultivated in a suitable nutrient medium with aeratian. Then, the substrate (dissolved in a suitable solvent or in emulsified form) is added to the cultures and fermented, until a maximum substrate conversion is reached.
Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylfox-mamide or dimethylsulfoxide. The emulsification of the substrate can be brought about, for example, by the latter being sprayed in micronized form or dissolved in a water-miscible solvent (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethylformamide or dimethylsulfoxide) under strong turbulence in (preferably decalcified) water, which contains the usual emulsifying aids. Suitable emulsifying aids are nonionogenic DC1-3299~t s emulsifiers, such as, for example, ethylenoxy adducts or fatty acid esters of polyglycols. As suitable emulsifiers, the commercially available wetting agents Tegin~R~, TweentR~ and Span~R~ can be mentioned as examples.
The optimum substrate concentratian, substrate addition time and fermentation period depend on 'the type of substrate and -microorganism used and fermentation conditions. These values, as is generally necessary in microbiological steroid conversions, have to be determined in the individual case by preliminary tests, as they are familiar to one skilled in the art.
To perform the process according to the invention, 17~-hydroxy steroids of general formula I
o~
st ~ ~I) in which R1 represents a hydrogen atom or a methyl group and St symbolizes the radical of an estran-1a~3-of derivative, containing up to 5 noncumulated double bonds, substituted ~in the 3-position by a phenolic hydroxy group, a lower alkoxy group,.a lower 1-alkoxy-alkoxy group, a 2-tetrahydropyranyloxy group, or a lower alkylenedioxy group, as well as optionally in 5,10-position by an epoxy group and in 19-position optionally by a methyl group, are preferably used as substrates.
Hy a lower alkoxy group is preferably to be understood a group which carries up to 4 carbon atoms. Suitable alkoxy groups are, for example, the methoxy group or the tert-butyloxy group.
Dy a lower l-alkoxy-alkoxy group is preferably to be understood a lower alkoxy-methoxy group with an alkoxy group having up to 4 carbon atoms. For example, the 1-methoxy-methoxy group can be mentioned. By a lower alkylenedioxy group is preferably to be understood a grouping having 2 to 6 carbon atoms such as, for example, the ethylenedioxy group or the 2,2-dimethyl- -prapylenedioxy group.
Substrates, which are suitable to perform 'the process according to the invention are, for example, estran-17~-0l derivatives of general formula Ia (1a1, RZO
in which Rl has the above-mentioned meaning, R2 represents a hydrogen atom or an alkyl group containing up to 4 carbon atoms and l -A-B-C-D° symbolizes a grouping of partial formula i i ~ ~ i ~
-CHZ-CH2-CH-Cfi-, CH2-CH=C-Cii- or -CH=CEI-C=C-.
The estran-17-one derivatives formed from these substrates or the 3-hydroxy compounds obtained from this by ether cleavage are, as is known, pharmacologically effective and can; moreover, as is known, be reduced to,the corresponding l7rx-hydroxy compounds or be converted to the corresponding 173-hydroxy-17a-ethinyl compounds.
Further, suitable substrates are estrane derivatives of general formula 7Cb in which symbolizes a single bond or a double bond, R1 has the above-mentioned meaning, R3 represents an alkyl group with at most ~ carbon atpms.
The 17-oxosteroids formed from these compounds can, as is known, be used, for example, to produce the pharmacologically effective 17a-ethinyl-17~-hydroxy-4-estren-3-one or its 18-methyl homologs.
Substrates worth mentioning are also those of general t formula Ic cj~) , R 5 .., R
in which R3 has the above-mentioned meaning, R4 represents a hydrogen atom or a methyl group, R5 and R6 together symbolize a lower alkyldio:xy 'group or R5 means a hydrogen atom and R6 represents a lower alkoxy group, a lower 1-alkoxyalkoxy group or a 2-tetrahydropyranyl group.
The 17-oxosteroids obtained from these compounds can be further processed in the same way as those of the es~tran-17~i-of derivatives of general formula Ica but, on the other hand, they can also be used for the production of pregnane derivatives, as is well known to one skilled in the art.
Finally, also worth mentioning are estran-17~-0l derivatives of general formula Id ~Id), in which R1 has the above-mentioned meaning, R9 symbolizes a hydrogen atom and R~ and R$ together symbolize a lower alkylenediaxy group or R~ and R9 mean two hydrogen atoms or together mean a carbon-carbon bond and --R8 represents a lower alkoxy group, a lower 1-alkoxyalkoxy group or a 2--tetrahydropyranyloxy group.
The ketones obtained from these compounds can be converted to antigestagenically active steroids according to the process, as described in EP-A 0129499.
The following embodiments are used to explain the process according to the invention in more detail.
r Example 1 a) A 500 ml Erlenmeyer with 100 ml of sterile nutrient medium containing 1 s yeast extract 0.45 % Na2HP04 ' 2H20 0.34 a KH2P04 _ 0.2 % Tween 80 with a pH of 6.7 is inoculated with a suspension of a Mycobacterium spec. NRRL B-3683 culture and shaken for 72-hours at 30°C with 180 revolutions per minute.
b) 50 Erlenmeyers (100 ml) with 20 ml of sterile nutrient medium each containing 0.5 % carn steep liquor 0.05 % glucose monohydrate 0.2 % yeast extract -° adjusted to pH 7.0 --are inoculated with 1 ml of Mycobacterium-spec.-growing culture each and incubated for 24 hours on a rotaxy shaker with 220 revolutions per minute at 30°C.
Then, 0.02 g of 3,3-(2,2-dimethyltrimethylenedioxy)-5~,.10~s-epoxy--5~c-estr-9 ( 11 ) -en-17 ~-of dissolved in 0 . 2 ml of dimethylformamide and sterilized by filtration is added to each culture and fermented for another 48 hours at 30°C.
c) The combined cultures are extracted with methyl isobutyl ketone and the ext~'act is concentrated by evaporation under vacuum in a rotary evaporator at a maximum of 50°C. Then, a purification takes place by chromatography on a silica gel column.
0.85 g of 3,3-(2,2-dimethyltrimethylenedioxy)-5,10a-epoxy-Sec-estr-9{11)-en-17~-one, which is identical with an authentic sample according to HPLC, is thus obtained.
Example 2 a) The production of the growing culture takes place as indicated in example 1a).
b) 50 Erlenmeyers (100 ml) with 20 ml of sterile nutrient medium each containing 2.5 % corn steep liquor 0.25 % soybean flour 0.3 0 (NH4)2HP04 0.25 % Tween 80 -- adjusted to pH 6.5 --are inoculated with 1 ml of the Mycobacterium-spec.-growing culture each and incubated for 24 hours on a rotary shaker with 220 revolutions per minute at 30°C.
Then, 0.002 g of ~-equilol dissolved in 0.2 ml of dimethylformamide and s~terili~ed by filtration is added to each culture and fermented for another 72 hours at 30°C.
c) The isolation of the product takes place as described under 1c).
0.095 g of equilin, which is identical wit~a an authentic sample according to HPLC, is thus obtained. '
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the production of 17-oxosteroids by fermentative oxidation of 17.beta.-hydroxy steroids, characterized in that for the fermentation, a bacterial culture of the species Mycobacterium spec. NRRL B-3805, Mycobacterium spec. NRRL B-3683, Mycobacterium phlei NRRL B-8154 or Mycobacterium fortuitum NRRL
B-8153 is used.
B-8153 is used.
2. Process for the production of 17-oxosteroids by fermentative oxidation of 17.beta.-hydroxy steroids according to claim 1, wherein a 17.beta.-hydroxy steroid of general formula I
in which R1 represents a hydrogen atom ar a methyl group and St symbolizes the radical of an estran-17.beta.-ol derivative, containing up to 5 noncumulated double bonds, substituted in the
in which R1 represents a hydrogen atom ar a methyl group and St symbolizes the radical of an estran-17.beta.-ol derivative, containing up to 5 noncumulated double bonds, substituted in the
3-position by a phenolic hydroxy group, a lower alkoxy group, a lower 1-alkoxy-alkoxy group, a 2-tetrahydropyranyloxy group, or a lower alkylenedioxy group, as well as optionally in 5,10-position by an epoxy group and in 19-position optionally by a methyl group, is oxidized.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4026462 | 1990-08-18 | ||
| DEP4026462.9 | 1990-08-18 | ||
| PCT/DE1991/000628 WO1992003572A1 (en) | 1990-08-18 | 1991-08-01 | Method of preparing 17-oxosteroids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2069956A1 CA2069956A1 (en) | 1992-02-19 |
| CA2069956C true CA2069956C (en) | 2001-05-08 |
Family
ID=6412643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002069956A Expired - Fee Related CA2069956C (en) | 1990-08-18 | 1991-08-01 | Process for the production of 17-oxosteroids |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0496846B1 (en) |
| JP (1) | JP3137645B2 (en) |
| AT (1) | ATE152773T1 (en) |
| AU (1) | AU650467B2 (en) |
| CA (1) | CA2069956C (en) |
| CZ (1) | CZ279575B6 (en) |
| DE (1) | DE59108700D1 (en) |
| DK (1) | DK0496846T3 (en) |
| ES (1) | ES2103818T3 (en) |
| FI (1) | FI102973B1 (en) |
| GR (1) | GR3024188T3 (en) |
| HU (1) | HU213017B (en) |
| RU (1) | RU2082762C1 (en) |
| SK (1) | SK279666B6 (en) |
| WO (1) | WO1992003572A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7335650B2 (en) | 2000-01-14 | 2008-02-26 | Sterix Limited | Composition |
| US6593321B2 (en) * | 2001-06-11 | 2003-07-15 | Southwest Foundation For Biomedical Research | 2-alkoxyestradiol analogs with antiproliferative and antimitotic activity |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3386890A (en) * | 1965-07-12 | 1968-06-04 | American Home Prod | Process for preparing equilin |
| ES8502612A1 (en) * | 1983-06-15 | 1985-02-01 | Schering Ag | 13-Alpha-alkyl gonanes, their preparation and pharmaceutical compositions containing them. |
| DE3876769T2 (en) * | 1987-12-23 | 1993-06-09 | Roussel Uclaf | MICROBIOLOGICAL PRODUCTION OF 9-ALPHA-HYDROXY-17-KETO-STEROIDS. |
-
1991
- 1991-08-01 JP JP03512503A patent/JP3137645B2/en not_active Expired - Fee Related
- 1991-08-01 DE DE59108700T patent/DE59108700D1/en not_active Expired - Lifetime
- 1991-08-01 ES ES91913348T patent/ES2103818T3/en not_active Expired - Lifetime
- 1991-08-01 WO PCT/DE1991/000628 patent/WO1992003572A1/en active IP Right Grant
- 1991-08-01 DK DK91913348.8T patent/DK0496846T3/en active
- 1991-08-01 AT AT91913348T patent/ATE152773T1/en not_active IP Right Cessation
- 1991-08-01 EP EP91913348A patent/EP0496846B1/en not_active Expired - Lifetime
- 1991-08-01 CA CA002069956A patent/CA2069956C/en not_active Expired - Fee Related
- 1991-08-01 AU AU82284/91A patent/AU650467B2/en not_active Ceased
- 1991-08-01 RU SU915011897A patent/RU2082762C1/en not_active IP Right Cessation
- 1991-08-01 HU HU9201646A patent/HU213017B/en not_active IP Right Cessation
- 1991-08-16 SK SK2549-91A patent/SK279666B6/en unknown
- 1991-08-16 CZ CS912549A patent/CZ279575B6/en not_active IP Right Cessation
-
1992
- 1992-04-15 FI FI921697A patent/FI102973B1/en not_active IP Right Cessation
-
1997
- 1997-07-22 GR GR970401833T patent/GR3024188T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI102973B (en) | 1999-03-31 |
| DK0496846T3 (en) | 1997-12-01 |
| JPH05503218A (en) | 1993-06-03 |
| EP0496846A1 (en) | 1992-08-05 |
| FI102973B1 (en) | 1999-03-31 |
| HU9201646D0 (en) | 1992-08-28 |
| RU2082762C1 (en) | 1997-06-27 |
| GR3024188T3 (en) | 1997-10-31 |
| HUT64603A (en) | 1994-01-28 |
| ATE152773T1 (en) | 1997-05-15 |
| WO1992003572A1 (en) | 1992-03-05 |
| ES2103818T3 (en) | 1997-10-01 |
| CS254991A3 (en) | 1992-02-19 |
| FI921697A0 (en) | 1992-04-15 |
| DE59108700D1 (en) | 1997-06-12 |
| AU650467B2 (en) | 1994-06-23 |
| HU213017B (en) | 1997-01-28 |
| SK279666B6 (en) | 1999-02-11 |
| EP0496846B1 (en) | 1997-05-07 |
| CA2069956A1 (en) | 1992-02-19 |
| CZ279575B6 (en) | 1995-05-17 |
| JP3137645B2 (en) | 2001-02-26 |
| AU8228491A (en) | 1992-03-17 |
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