CA2492079A1 - Microbiological processes for the production of 7 alpha-substituted 11 alpha-hydroxy steroids - Google Patents
Microbiological processes for the production of 7 alpha-substituted 11 alpha-hydroxy steroids Download PDFInfo
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- C12P33/00—Preparation of steroids
- C12P33/06—Hydroxylating
- C12P33/08—Hydroxylating at 11 position
- C12P33/10—Hydroxylating at 11 position at 11 alpha-position
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- C12P33/12—Acting on D ring
- C12P33/16—Acting at 17 position
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Abstract
Disclosed is a new synthetic pathway for the production of precursors for th e production of compounds having general formula (8,10,12). During said synthesis, compounds of general formal (4,B) are produced in a microbiologic al reaction. The meanings of radicals R7, R10, R11, R13, R17 and R17' and group U- V-W-X-Y-Z are defined in the patent claims.
Claims (27)
1. Microbiological process for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids with general formula 4,B:
in which R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene, and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R10 can be in .alpha.- or .beta.-position and stands for H, CH3 or CF3, and R13 is methyl or ethyl, in which a 7.alpha.-substituted steroid with general formula 3,A:
in which R7, R10 and R13 have the same meanings as indicated above, is hydroxylated and oxidized with use of a microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Glomerella sp., Gnomonia sp., Haplosporella sp. and Rhizopus sp.
in which R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene, and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R10 can be in .alpha.- or .beta.-position and stands for H, CH3 or CF3, and R13 is methyl or ethyl, in which a 7.alpha.-substituted steroid with general formula 3,A:
in which R7, R10 and R13 have the same meanings as indicated above, is hydroxylated and oxidized with use of a microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Glomerella sp., Gnomonia sp., Haplosporella sp. and Rhizopus sp.
2. Process according to claim 1, characterized in that the microorganism is selected from the group that comprises Aspergillus awamori, Aspergillus fischeri, Aspergillus malignus, Aspergillus niger, Beauveria bassiana, Glomerella cingulata, Gnomonia cingulata, Haplosporella hesperedica and Rhizopus stolonifer.
3. Microbiological process for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids with general formula 4,B:
in which R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R10 can be in .alpha.- or .beta.-position and stands for H, CH3 or CF3, and R13 is methyl or ethyl, in which a 7.alpha.-substituted steroid with general formula 3,A:
in which R7, R10 and R13 have the same meanings as previously indicated, is hydroxylated in 11.alpha.-position in a first microbiological process step with use of a first microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Gibberella sp., Glomerella sp., Gnomonia sp., Metarrhizium sp., Nigrospora sp., Rhizopus sp. and Verticillium sp., with the formation of a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula C:
in which R7, R10 and R13 have the same meanings as indicated above, and the 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula C that is produced is then oxidized in a second microbiological process step with use of a second microorganism that is selected from the group that comprises Bacillus sp., Mycobacterium sp., Nocardia sp. and Pseudomonas sp., with the formation of the 7.alpha.-substituted steroid with general formula 4,B.
in which R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R10 can be in .alpha.- or .beta.-position and stands for H, CH3 or CF3, and R13 is methyl or ethyl, in which a 7.alpha.-substituted steroid with general formula 3,A:
in which R7, R10 and R13 have the same meanings as previously indicated, is hydroxylated in 11.alpha.-position in a first microbiological process step with use of a first microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Gibberella sp., Glomerella sp., Gnomonia sp., Metarrhizium sp., Nigrospora sp., Rhizopus sp. and Verticillium sp., with the formation of a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula C:
in which R7, R10 and R13 have the same meanings as indicated above, and the 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula C that is produced is then oxidized in a second microbiological process step with use of a second microorganism that is selected from the group that comprises Bacillus sp., Mycobacterium sp., Nocardia sp. and Pseudomonas sp., with the formation of the 7.alpha.-substituted steroid with general formula 4,B.
4. Process according to claim 3, wherein the first microorganism is selected from the group that comprises Aspergillus malignus, Aspergillus melleus, Aspergillus niger, Aspergillus ochraceus, Beauveria bassiana, Gibberella fujikuroi, Gibberella zeae, Glomerella cingulata, Glomerella fusaroides, Gnomonia cingulata, Metarrhizium anisopliae, Nigrospora sphaerica, Rhizopus oryzae, Rhizopus stolonifer and Verticillium dahliae.
5. Process according to one of claims 3 and 4, wherein the second microorganism is selected from the group that comprises Bacillus lactimorbus, Bacillus sphaericus, Mycobacterium neoaurum, Mycobacterium smegmatis, Nocardia corallina, Nocardia globerula, Nocardia minima, Nocardia restrictus, Nocardia rubropertincta, Nocardia salmonicolor and Pseudomonas testosteroni.
6. Microbiological process for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids with general formula 4,B:
in which R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R10 stands for H, CH3 or CF3, and R13 is methyl or ethyl, in which 7.alpha.-substituted steroids with general formula D:
in which R7, R10 and R13 have the same meanings as indicated above, are hydroxylated with use of a microorganism that is selected from the group that comprises Beauveria sp., Curvularia sp., Gibberella sp., Glomerella sp., Gnomonia sp., Haplosporella sp., Helicostylum sp., Nigrospora sp., and Syncephalastrum sp.
in which R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R10 stands for H, CH3 or CF3, and R13 is methyl or ethyl, in which 7.alpha.-substituted steroids with general formula D:
in which R7, R10 and R13 have the same meanings as indicated above, are hydroxylated with use of a microorganism that is selected from the group that comprises Beauveria sp., Curvularia sp., Gibberella sp., Glomerella sp., Gnomonia sp., Haplosporella sp., Helicostylum sp., Nigrospora sp., and Syncephalastrum sp.
7. Process according to claim 6, wherein the microorganism is selected from the group that comprises Beauveria bassiana, Curvularia lunata, Gibberella zeae, Glomerella cingulata, Glomerella fusaroides, Gnomonia cingulata, Haplosporella hesperedica, Helicostylum piriformae, Nigrospora sphaerica, and Syncephalastrum racemosum.
8. Microbiological process according to one of claims 1 to 7, wherein R7 stands for CH3.
9. Microbiological process according to one of claims 1 to 8, wherein R10 stands for H.
10. Microbiological process according to one of claims 1 to 9, wherein R13 stands for CH3.
11. 7.alpha.,17.alpha.-Substituted 11.beta.-halogen steroids with general formula 8, 10, 12:
in which U-V-W-X-Y-Z stands for one of ring structures C1-C2-C3-C4=C5-C10, C1-C2-C3-C4-C5=C10 or C1-C2-C3-C4-C5-C10, whereby in this case, an oxo group (=O) is bonded to W (=C3), or for ring structure C1=C2-C3=C4-C5=C6, whereby in this case radical OR3 is bonded to W (=C3), R3 stands for H, C1- to C4-alkyl, C1- to C4-alkanoyl or a cyclic C3- to C7-ether with the O-atom of the OR3-radical, R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and grouping P-Q is bonded via P to the steroid skeleton, R10 can be in .alpha.- or .beta.-position and stands for H, CH3 or CF3, and is present only if X-Y-Z is not C4-CS=C10, R11 is a halogen, R13 is methyl or ethyl, R17 stands for H, C1- to C18-alkyl, alicyclic C1- to C18-alkyl, C1- to C18-alkenyl, alicyclic C1- to C18-alkenyl, C1- to C18-alkinyl, C1- to C18-alkylaryl, C1- to C8-alkylenenitrile or for the grouping P-Q, whereby the grouping P-Q has the above-mentioned meaning, R17' stands for H, C1- to C18-alkyl, alicyclic C1- to C18-alkyl, C1- to C18-alkenyl, alicyclic C1- to C18-alkenyl, C1- to C18-alkinyl or C1- to C18-alkylaryl, whereby R17' also can be bonded via a keto group to the 17.beta.-oxy group, and whereby R17' also in addition can be substituted with one or more groups NR18R19 or one or more groups SOXR20, whereby x = 0,1 or 2 and R18, R19 and R20 in each case independently of one another can have the same meaning as R17, as well as their pharmaceutically compatible addition salts, esters and amides.
in which U-V-W-X-Y-Z stands for one of ring structures C1-C2-C3-C4=C5-C10, C1-C2-C3-C4-C5=C10 or C1-C2-C3-C4-C5-C10, whereby in this case, an oxo group (=O) is bonded to W (=C3), or for ring structure C1=C2-C3=C4-C5=C6, whereby in this case radical OR3 is bonded to W (=C3), R3 stands for H, C1- to C4-alkyl, C1- to C4-alkanoyl or a cyclic C3- to C7-ether with the O-atom of the OR3-radical, R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and grouping P-Q is bonded via P to the steroid skeleton, R10 can be in .alpha.- or .beta.-position and stands for H, CH3 or CF3, and is present only if X-Y-Z is not C4-CS=C10, R11 is a halogen, R13 is methyl or ethyl, R17 stands for H, C1- to C18-alkyl, alicyclic C1- to C18-alkyl, C1- to C18-alkenyl, alicyclic C1- to C18-alkenyl, C1- to C18-alkinyl, C1- to C18-alkylaryl, C1- to C8-alkylenenitrile or for the grouping P-Q, whereby the grouping P-Q has the above-mentioned meaning, R17' stands for H, C1- to C18-alkyl, alicyclic C1- to C18-alkyl, C1- to C18-alkenyl, alicyclic C1- to C18-alkenyl, C1- to C18-alkinyl or C1- to C18-alkylaryl, whereby R17' also can be bonded via a keto group to the 17.beta.-oxy group, and whereby R17' also in addition can be substituted with one or more groups NR18R19 or one or more groups SOXR20, whereby x = 0,1 or 2 and R18, R19 and R20 in each case independently of one another can have the same meaning as R17, as well as their pharmaceutically compatible addition salts, esters and amides.
12. 7.alpha.,17.alpha.-Substituted 11.delta.-halogen steroids according to claim 11, wherein U-V-W-X-Y-Z stands for ring structure C1-C2-C3-C4=C5-C10 or C1-C2-C3-C4-C5=C10 or C1=C2-C3=C4-C5=C10
13. 7.alpha.,17.alpha.-Substituted 11.beta.-halogen steroids according to one of claims 11 and 12, wherein R1 stands for H.
14. 7.alpha.,17.alpha.-Substituted 11.beta.-halogen steroids according to one of claims 11 to 13, wherein R7 stands for CH3.
15. 7.alpha.,17.alpha.-Substituted 11.beta.-halogen steroids according to one of claims 11 to 14, wherein R11 stands for fluorine.
16. 7.alpha., 17.alpha.-Substituted 11.beta.-halogen steroids according to one of claims 11 to 15, wherein R13 stands for CH3.
17. 7.alpha.,17.alpha.-Substituted 11 .beta.-halogen steroids according to one of claims I I to 16, wherein R17 stands for H, CH3, C1-to C18-alkinyl, CH2CN or CF3.
18. 7.alpha.,17.alpha.-Substituted 11 .beta.-halogen steroids according to one of claims I I to 17, wherein R17' is ethinyl.
19. 7.alpha., 17a-Substituted 11 .beta.-halogen steroids according to one of claims 11 to 18, wherein R17' stands for H.
20. 7.alpha.,17.alpha.-Substituted 11 .beta.-halogen steroids according to one of claims 11 to 19, namely 17.alpha.-Ethinyl-11.beta.-fluoro-17.beta.-hydroxy-7.alpha.-methylestr-4-en-3-one 17-Ethinyl-11 .beta.-fluoro-17.beta.-hydroxy-7.alpha.-methylestr-5(10)-en-3-one 17.alpha.-Ethinyl-11.beta.-fluoro-7.alpha.-methylestra- 1, 3, 5 (10)-triene-3,17 .beta.-diol.
21. 7.alpha.-Substituted 11.beta.-haloestra-1,3,5(10)-trienes with general formula 6:
in which R3 stands for H, C1- to C4-alkyl, C1- to C4-alkanoyl or a cyclic C3- to C7-ether with the O-atom of the OR3-radical, R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R11 is a halogen;
R13 is methyl or ethyl, as well as their pharmaceutically compatible addition salts, esters and amides.
in which R3 stands for H, C1- to C4-alkyl, C1- to C4-alkanoyl or a cyclic C3- to C7-ether with the O-atom of the OR3-radical, R7 is the grouping P-Q, whereby P represents a C1- to C4-alkylene and Q represents a hydrogen, C1- to C4-alkyl- or C1- to C4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, R11 is a halogen;
R13 is methyl or ethyl, as well as their pharmaceutically compatible addition salts, esters and amides.
22. 7.alpha.-Substituted 11 .beta.-haloestra-1,3,5(10)-trienes according to claim 21, namely 11.beta.-Fluoro-3-hydroxy-7.alpha.-methylestra-1,3,5(10)-trim- 17-one.
23. Process for the production of 7.alpha., 17.alpha.-substituted 11.beta.-halogen steroids with general formula 10 according to one of claims 11 to 20, in which U-V-W-X-Y-Z
stands for the ring structure C1-C2-C3-C4=C5-C10, with the following process steps:
- Nucleophilic substitution in a 7.alpha.-substituted 11 .alpha.-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent;
- Reaction of the 7.alpha.-substituted 11.beta.-halogen steroid that is produced in this case with an alkylating agent in a selective manner on the C17 atom of the ring skeleton to form the 7.alpha., 17.alpha.-substituted 1.beta.-halogen steroid with general formula 10.
stands for the ring structure C1-C2-C3-C4=C5-C10, with the following process steps:
- Nucleophilic substitution in a 7.alpha.-substituted 11 .alpha.-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent;
- Reaction of the 7.alpha.-substituted 11.beta.-halogen steroid that is produced in this case with an alkylating agent in a selective manner on the C17 atom of the ring skeleton to form the 7.alpha., 17.alpha.-substituted 1.beta.-halogen steroid with general formula 10.
24. Process for the production of 7.alpha., 17.alpha.-substituted 11.beta.-halogen steroids with general formula 12 according to one of claims 11 to 20, in which U-V-W-X-Y-Z
stands for the ring structure C1-C2-C3-C4-C5=C10, with the following process steps:
- Nucleophilic substitution in a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent, - Reaction of the 7a-substituted 11.beta.-halogen steroid that is produced in this case with an alkylating agent in a selective manner on the C17 atom of the ring skeleton to form the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula 10, - Isomerization of the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula to form the corresponding isomer with general formula 12, in which U-V-W-X-Y-Z stands for the ring structure C1-C2-C3-C4-C5 =C10
stands for the ring structure C1-C2-C3-C4-C5=C10, with the following process steps:
- Nucleophilic substitution in a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent, - Reaction of the 7a-substituted 11.beta.-halogen steroid that is produced in this case with an alkylating agent in a selective manner on the C17 atom of the ring skeleton to form the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula 10, - Isomerization of the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula to form the corresponding isomer with general formula 12, in which U-V-W-X-Y-Z stands for the ring structure C1-C2-C3-C4-C5 =C10
25. Process for the production of 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroids with general formula 8 according to one of claims 11 to 20, in which U-V-W-X-Y-Z
stands for the ring structure C1=C2-C3 =C4-C5=C6 with the following process steps:
- Nucleophilic substitution in a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent, - Oxidizing of the 7.alpha.-substituted 11.beta.-halogen steroid that is produced in this case to form 7.alpha.-substituted estra-1,3,5(10)-triene with general formula 6 according to one of claims 17 and 18;
- Reaction of the 7.alpha.-substituted estra-1,3,5(10)-triene with general formula 6 with an alkylating agent in a selective manner on the C17 atom of the ring skeleton to form the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula 8.
stands for the ring structure C1=C2-C3 =C4-C5=C6 with the following process steps:
- Nucleophilic substitution in a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent, - Oxidizing of the 7.alpha.-substituted 11.beta.-halogen steroid that is produced in this case to form 7.alpha.-substituted estra-1,3,5(10)-triene with general formula 6 according to one of claims 17 and 18;
- Reaction of the 7.alpha.-substituted estra-1,3,5(10)-triene with general formula 6 with an alkylating agent in a selective manner on the C17 atom of the ring skeleton to form the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula 8.
26. Use of the 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroids with general formula 8, 10, 12 according to one of claims 11 to 20 for the production of pharmaceutical agents.
27. Pharmaceutical preparations that contain at least one 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroid with general formula 8, 10, 12 according to one of claims 11 to 20 as well as at least one pharmaceutically compatible vehicle.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10233723A DE10233723A1 (en) | 2002-07-24 | 2002-07-24 | Preparation of 7 alpha-substituted 11 alpha-hydroxy-steroids, useful as precursors for new androgenic 7 alpha,17 alpha-substituted 11 beta-halo-steroids, by microbiological conversion of 7 alpha-substituted steroids |
| DE10233723.3 | 2002-07-24 | ||
| US40295302P | 2002-08-14 | 2002-08-14 | |
| US60/402,953 | 2002-08-14 | ||
| PCT/EP2003/008111 WO2004011663A2 (en) | 2002-07-24 | 2003-07-24 | Microbiological method for the production of 7 alpha-substituted 11 alpha-hydroxysteroids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2492079A1 true CA2492079A1 (en) | 2004-02-05 |
| CA2492079C CA2492079C (en) | 2012-01-10 |
Family
ID=31189296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2492079A Expired - Fee Related CA2492079C (en) | 2002-07-24 | 2003-07-24 | Microbiological processes for the production of 7 alpha-substituted 11 alpha-hydroxy steroids |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1523568A2 (en) |
| JP (1) | JP4417838B2 (en) |
| KR (1) | KR101041328B1 (en) |
| CN (1) | CN100339486C (en) |
| BR (1) | BR0313210A (en) |
| CA (1) | CA2492079C (en) |
| CO (1) | CO5690563A2 (en) |
| CR (1) | CR7672A (en) |
| EA (2) | EA010572B1 (en) |
| EC (1) | ECSP055630A (en) |
| HK (1) | HK1081999A1 (en) |
| HR (1) | HRP20050172A2 (en) |
| IL (1) | IL166358A0 (en) |
| MX (1) | MXPA05001024A (en) |
| NO (1) | NO20050980L (en) |
| NZ (2) | NZ549529A (en) |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101296936B (en) * | 2005-10-27 | 2011-06-22 | 大鹏药品工业株式会社 | Process for production of steroid compound |
| CN103834712B (en) * | 2012-11-26 | 2016-03-30 | 复旦大学 | The optimization method of desogestrel intermediate nanometer liposome bio-transformation |
| CN103214543B (en) * | 2012-12-25 | 2015-09-02 | 中国人民解放军海军医学研究所 | New Crategolic acid derivative, its preparation method and the application in antitumor drug thereof |
| CN104862323B (en) * | 2015-06-02 | 2018-01-16 | 中国农业科学院生物技术研究所 | Modify the '-hydroxylase gene of diphenol compounds |
Family Cites Families (16)
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|---|---|---|---|---|
| NL75841C (en) | 1949-06-11 | |||
| US2658023A (en) * | 1953-04-21 | 1953-11-03 | Pfizer & Co C | Oxygenation of steroids |
| US2985563A (en) * | 1958-11-13 | 1961-05-23 | Schering Corp | 11alpha-hydroxylation of steroids by glomerella |
| US3004047A (en) * | 1959-03-13 | 1961-10-10 | Olin Mathieson | 6alpha-halo-11alpha-hydroxy steroids of the pregnane series and esters thereof |
| US3341557A (en) * | 1961-06-05 | 1967-09-12 | Upjohn Co | 7-methyltestosterones |
| US3203869A (en) * | 1962-10-11 | 1965-08-31 | Syntex Corp | 11alpha-hydroxylation of 6-substituted-11-desoxy steroids with microorganisms of thegenus fusarium, liseola section |
| US5342834A (en) | 1989-04-07 | 1994-08-30 | The Population Council, Inc. | Method for androgen supplementation |
| EP1167381A3 (en) * | 1995-12-11 | 2004-09-29 | G.D. Searle & Co. | Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and Intermediates useful therein |
| GB9525194D0 (en) | 1995-12-12 | 1996-02-07 | Zeneca Ltd | Pharmaceutical composition |
| CN1138861C (en) * | 1995-12-12 | 2004-02-18 | 阿克佐诺贝尔公司 | Microbial 11 'alpha'-hydroxylation of steroids |
| US20020012694A1 (en) * | 1997-09-17 | 2002-01-31 | Alfred J. Moo-Young | Transdermal administration of ment |
| US6767902B2 (en) | 1997-09-17 | 2004-07-27 | The Population Council, Inc. | Androgen as a male contraceptive and non-contraceptive androgen replacement |
| US5952319A (en) | 1997-11-26 | 1999-09-14 | Research Triangle Institute | Androgenic steroid compounds and a method of making and using the same |
| SI1267885T1 (en) | 2000-02-15 | 2007-08-31 | Bayer Schering Pharma Ag | Male contraceptive formulation comprising norethisterone and testosterone undecanoate |
| DE10104327A1 (en) * | 2001-01-24 | 2002-07-25 | Schering Ag | New 11beta-halo-testosterone derivatives useful in male hormone replacement therapy and in male fertility control |
| ES2299735T3 (en) * | 2002-07-25 | 2008-06-01 | Bayer Schering Pharma Aktiengesellschaft | COMPOSITION, CONTAINING AN ANDROGEN 11-BETA-HALOGEN-STEROID AND A GESTAGEN, AS WELL AS A MALE ANTI-CONCEPT ON THE BASIS OF THIS COMPOSITION. |
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2003
- 2003-07-24 CN CNB038176963A patent/CN100339486C/en not_active Expired - Fee Related
- 2003-07-24 EP EP03740474A patent/EP1523568A2/en not_active Withdrawn
- 2003-07-24 CA CA2492079A patent/CA2492079C/en not_active Expired - Fee Related
- 2003-07-24 EA EA200601030A patent/EA010572B1/en not_active IP Right Cessation
- 2003-07-24 JP JP2004523777A patent/JP4417838B2/en not_active Expired - Fee Related
- 2003-07-24 WO PCT/EP2003/008111 patent/WO2004011663A2/en active Application Filing
- 2003-07-24 EA EA200500224A patent/EA008147B1/en not_active IP Right Cessation
- 2003-07-24 BR BR0313210-2A patent/BR0313210A/en not_active IP Right Cessation
- 2003-07-24 KR KR1020057001140A patent/KR101041328B1/en not_active IP Right Cessation
- 2003-07-24 NZ NZ549529A patent/NZ549529A/en not_active IP Right Cessation
- 2003-07-24 RS YU20050045A patent/RS51855B/en unknown
- 2003-07-24 PL PL03373808A patent/PL373808A1/en not_active Application Discontinuation
- 2003-07-24 MX MXPA05001024A patent/MXPA05001024A/en active IP Right Grant
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2005
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- 2005-02-23 NO NO20050980A patent/NO20050980L/en not_active Application Discontinuation
- 2005-02-24 EC EC2005005630A patent/ECSP055630A/en unknown
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2006
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| RS20050045A (en) | 2007-06-04 |
| EA200601030A1 (en) | 2006-10-27 |
| PL373808A1 (en) | 2005-09-19 |
| CO5690563A2 (en) | 2006-10-31 |
| EA200500224A1 (en) | 2005-08-25 |
| CN100339486C (en) | 2007-09-26 |
| PH12005500143B1 (en) | 2011-03-25 |
| EA008147B1 (en) | 2007-04-27 |
| BR0313210A (en) | 2005-06-28 |
| NO20050980L (en) | 2005-02-23 |
| RS51855B (en) | 2012-02-29 |
| JP2006503813A (en) | 2006-02-02 |
| JP4417838B2 (en) | 2010-02-17 |
| MX260952B (en) | 2008-10-01 |
| EP1523568A2 (en) | 2005-04-20 |
| KR101041328B1 (en) | 2011-06-14 |
| AU2003281677A1 (en) | 2004-02-16 |
| MXPA05001024A (en) | 2005-05-16 |
| HK1081999A1 (en) | 2006-05-26 |
| KR20050026507A (en) | 2005-03-15 |
| IL166358A0 (en) | 2006-01-16 |
| NZ549529A (en) | 2008-04-30 |
| CA2492079C (en) | 2012-01-10 |
| ECSP055630A (en) | 2005-04-18 |
| CN1671858A (en) | 2005-09-21 |
| WO2004011663A9 (en) | 2004-05-06 |
| WO2004011663A3 (en) | 2004-07-15 |
| WO2004011663A2 (en) | 2004-02-05 |
| HRP20050172A2 (en) | 2005-04-30 |
| EA010572B1 (en) | 2008-10-30 |
| CR7672A (en) | 2006-05-29 |
| NZ537871A (en) | 2006-10-27 |
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