WO1996030390A2 - METHOD FOR PREPARING 17α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES USEFUL IN THE METHOD, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES. - Google Patents
METHOD FOR PREPARING 17α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES USEFUL IN THE METHOD, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES. Download PDFInfo
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- WO1996030390A2 WO1996030390A2 PCT/US1996/003660 US9603660W WO9630390A2 WO 1996030390 A2 WO1996030390 A2 WO 1996030390A2 US 9603660 W US9603660 W US 9603660W WO 9630390 A2 WO9630390 A2 WO 9630390A2
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- 0 CC1([C@@](CC2)([C@]3(C)C2C(CCCCOCCOCCC*OC2)C2=CC3)O)OCCO1 Chemical compound CC1([C@@](CC2)([C@]3(C)C2C(CCCCOCCOCCC*OC2)C2=CC3)O)OCCO1 0.000 description 3
- ZMWJDTZKIGRECX-YYTJNDDGSA-N CC(C)c1ccc([C@@H](C[C@@](C)(C(CC2)C3CC4)[C@]2(C(C)=O)O)C3=C(CC2)C4=CC2=O)cc1 Chemical compound CC(C)c1ccc([C@@H](C[C@@](C)(C(CC2)C3CC4)[C@]2(C(C)=O)O)C3=C(CC2)C4=CC2=O)cc1 ZMWJDTZKIGRECX-YYTJNDDGSA-N 0.000 description 1
- HKDLNTKNLJPAIY-FJUZNJMPSA-N C[C@](C[C@@H]1c(cc2)ccc2N(C)C)(C(CC2)C(CC3)C1=C(CC1)C3=CC1=O)[C@]2(C(C)=O)O Chemical compound C[C@](C[C@@H]1c(cc2)ccc2N(C)C)(C(CC2)C(CC3)C1=C(CC1)C3=CC1=O)[C@]2(C(C)=O)O HKDLNTKNLJPAIY-FJUZNJMPSA-N 0.000 description 1
- ITBGBOBQGVJJRT-GUMHCPJTSA-N C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)[C@]2(C#N)O Chemical compound C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)[C@]2(C#N)O ITBGBOBQGVJJRT-GUMHCPJTSA-N 0.000 description 1
- ZMKWHHGPMUNNND-BBITVKMKSA-N C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)[C@]2(C#N)O[Si](C)(C)CCl Chemical compound C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)[C@]2(C#N)O[Si](C)(C)CCl ZMKWHHGPMUNNND-BBITVKMKSA-N 0.000 description 1
- BBGHGDZCXNGJAE-YZLYJHIHSA-N C[C@]1(C(CC2)C(CC[C@]3(C4)O[C@@]33CCC44OCCO4)C3=CC1)[C@]2(C1(C)OCCO1)O Chemical compound C[C@]1(C(CC2)C(CC[C@]3(C4)O[C@@]33CCC44OCCO4)C3=CC1)[C@]2(C1(C)OCCO1)O BBGHGDZCXNGJAE-YZLYJHIHSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- 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
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
-
- 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
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
Definitions
- the present invention relates generally to steroids and, in particular, to methods for the preparation of 17 ⁇ -acetoxy-ll3-(4-N,N-dimethylaminophenyl)-19- norpregna-4,9-diene-3,20-dione, intermediates useful in those methods, and methods for the preparation of such intermediates.
- Swern oxidation is then used to convert the dienone 6 to compound T_, with compound 7 being ketalized to provide a ketal 8.
- the ketal ⁇ _ is then epoxidized using m- chloroperbenzoic acid to provide an epoxide 9.
- the epoxide then undergoes conjugate ring-opening using a copper (I) catalyzed Grignard reagent generated by the reaction of 4-bromo-N,N dimethylaniline with magnesium in the presence of copper (I) to provide compound ip_.
- the foregoing procedure can be used to provide the 19-norprogesterone of formula I, certain drawbacks are inherent therein. More specifically, the foregoing procedure includes processing steps which are hazardous and/or not readily amenable to the preparation of relatively large quantities of the desired 19-norprogesterone, e.g., the use of highly toxic and expensive Os0 4 to effect hydroxylation, effecting Birch reduction using lithium and ammonia, as well as bromination-dehydrobromination and Swern oxidation procedures. Moreover, many of the steps require chromatographic purification for the isolation of the intermediates. Further, the overall yield provided by this known process is relatively low.
- One aspect of the present invention provides methods for the preparation of the 19-norprogesterone of formula I and its intermediates which are relatively safer and more efficient, and which further provide those compounds in relatively high quantities and purity levels, as compared to known methods.
- the present invention comprises protecting the hydroxyl group in the compound of formula II
- protecting group B which protecting group comprises a halo ethyl functional group
- Another aspect of the present invention provides methods for the preparation of several of the intermediates useful in the foregoing method for the preparation of the 19-norprogesterone of formula I.
- Yet another aspect of the present invention provides crystalline forms of the 19-norprogesterone of formula I, as well as certain of the aforesaid intermediates, i.e., the compounds of formulas V, VI, VII, and VIII, as well as of Ilia (which is formula III in which B is -Si(CH 3 ) 2 CH 2 Cl)
- Figure 2 sets forth the method for the preparation of the 19-norprogesterone of formula I in accordance with the present invention.
- One aspect of the present invention provides a method for preparing the compound of formula I
- the starting material i.e., the compound of formula II
- This compound is commercially available from Roussel-Uclaf (Paris, France) .
- the reaction preferably proceeds by reacting the compound of formula II with that protecting group in a suitable anhydrous solvent.
- solvents suitable for this reaction include, but are not limited to, tetrahydrofuran (THF) , diethyl ether, acetonitrile, dichloromethane, dioxane, and the like, with THF being a preferred solvent.
- the protecting reaction is preferably further conducted in the presence of a base, the base functioning to scavenge the acid by-product.
- a base the base functioning to scavenge the acid by-product.
- suitable bases include triethyla ine and pyridine.
- the protecting reaction is further conducted in the presence of a silylation catalyst, e.g., 4-N,N-dimethylaminopyridine (DMAP) , which is typically present in a substoichiometric amount.
- a silylation catalyst e.g., 4-N,N-dimethylaminopyridine (DMAP)
- DMAP 4-N,N-dimethylaminopyridine
- the reactants are advantageously maintained at a temperature of from about 0°C to about 40°C, and preferably at a temperature of about 25°C.
- the reaction mixture is diluted with a non-polar solvent or mixture of such solvents, e.g., pentanes and hexanes, to precipitate the amine hydrochloride byproduct.
- the precipitate may then be removed by any known method, e.g., filtration.
- the filtrate may then be concentrated by evaporation, and subsequently diluted with a solvent, e.g., diethyl ether, in order to be able to subject it to further purification. It is preferred that the solution be kept under a dry atmosphere, such as a nitrogen atmosphere.
- the solution is then preferably passed through a silica gel column to obtain the compound of formula Ilia (assuming the protecting group is -Si(CH 3 ) 2 CH 2 Cl) as a crystal (m.p. 80° to 82°C) in 98% yield.
- the protected compound of formula III is then reacted in a single-step with an alkali or alkaline earth metal anion radical comprised of an alkali or alkaline earth metal and a radical anion. It is believed that, during the reaction, the nucleophilic carbon atom of the halomethyl functional group in the protecting group intra olecularly attacks the nitrile group and forms a cyclic structure therewith. Therefore, selection of the alkali or alakaline earth metal anion radical should be based upon the ability of the radical to initiate the aforementioned intramolecular attack.
- suitable alkali metals that can be used in the practice of the present invention include lithium, sodium, potassium, and rubidium, with lithium being preferred. Calcium is a preferred alkaline earth metal.
- Examples of compounds suitable for forming the radical anion include naphthalene, di-tert-butylnaphthalene, di-tert- butylbiphenyl (DBB) , anthracene, naphthacene, benzanthrene, benzophenone, 1,3,5-trinitrobenzene, dimethylaminonaphthalene, diisopropylamide, hexamethyl phosphoric triamide, ammonia, and 18-crown-6.
- DBB di-tert-butylnaphthalene
- DBB di-tert-butylbiphenyl
- the resulting reaction mixture which includes the aforedescribed compound having the two cyclic structures, i.e., the cyclic ketal group and the cyclic structure formed by the previously described intramolecular attack, is then quenched with an excess of acid, advantageously an aqueous acid, and the compound having the said two cyclic structures is concomitantly hydrolyzed, to provide the compound of formula IV
- the aforesaid resulting reaction mixture is quenched with CH 2 C1 2 to destroy any excess alkali metal or alkaline metal anion radical present in that mixture prior to the acid quenching step.
- the reaction of the alkali metal with DBB is preferably conducted in the presence of a solvent, e.g., THF.
- a solvent e.g., THF.
- the alkali metal/DBB complex is highly sensitive to oxygen and moisture, care should be exercised in handling this complex. Subsequently, the alkali metal/DBB complex is reacted with the compound of formula III.
- the reactants should advantageously be contacted with one another at a low temperature, preferably at about -75°C to about -30°C, due to the instability of the reaction intermediates.
- this building of the pregnane side chain is advantageously completed using a single-step procedure known as the Silicon Nucleophilic Annealation Process (SNAP) .
- SNAP Silicon Nucleophilic Annealation Process
- the compound of formula III (wherein B is -Si(CH 3 ) 2 CH 2 X, wherein X is preferably Cl) is reacted with the DBB anion radical generated from DBB and the alkali metal (e.g., lithium) in a solvent, e.g., THF.
- a solvent e.g., THF.
- Subsequent acid hydrolysis of this intermediate provides the I7 ⁇ -hydroxy-20-ketone moiety, and concomitant deketalization provides the compound of formula IV.
- the ketalization step may be conducted in any suitable manner, but is preferably undertaken by reacting the compound of formula IV with a diol in the presence of an acid.
- Any suitable acid may be used in the foregoing reaction, as long as it functions to catalyze the formation of the ketal.
- Suitable acids for this purpose include sulfur-based organic acids, e.g., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid, with toluenesulfonic acid being preferred.
- Any suitable diol may be used in the reaction, provided that it is able to provide a cyclic ketal. Such diol should further be provided in excess with respect to the carbonyl groups being ketalized, such so as to favor the formation of the cyclic ketal.
- a preferred diol for this reaction is ethylene glycol.
- orthoesters are suitable for use in the foregoing reaction, the orthoesters functioning to chemically remove the water from the reaction and drive the reaction to completion.
- Orthoformate esters are advantageously utilized because they provide high yields.
- Preferred orthoformateesters include triisobutyl orthoformate and triisopropyl orthoformate, with triethyl orthoformate being most preferred.
- This reaction is advantageously accomplished by reacting the compound of formula V with an adduct formed from the reaction of a halogenated acetone and a peroxide in the presence of an inorganic phosphate.
- a peroxide or peracid
- suitable peroxides include hydrogen peroxide, sodium peroxide, potassium peroxide, benzoyl peroxide, and acetyl peroxide, with the preferred peroxide being 30 wt.% hydrogen peroxide in water.
- the halogenated acetone may comprise any such acetone which provides the desired results.
- a hexahalogenated acetone is used, e.g.
- hexafluoroacetone hexachloroacetone and hexabromoacetone
- hexafluoroacetone is preferred.
- Such hexahalogenated acetones provide the 5 ⁇ ,10 / 3-epoxide in the greatest yield.
- the reaction is preferably carried out in the presence of an inorganic base.
- suitable bases include di- and tri-basic sodium and potassium phosphate, sodium and potassium carbonate, and sodium and potassium bicarbonate, with dibasic sodium phosphate being preferred.
- dibasic sodium phosphate is especially preferred.
- dibasic sodium phosphate in combination with the 30 wt.% hydrogen peroxide and hexafluoroacetone.
- the reaction is further advantageously conducted in the presence of a solvent.
- the solvent should advantageously be a halogenated solvent. Suitable solvents include chloroform, methylene chloride. dichloroethane, and trichloroethane, with a preferred solvent being methylene chloride.
- the compound of formula VI can be crystallized (m.p. 188.5°C to 191.5°C) using an ether, e.g., diethyl ether, isopropyl ether, isobutyl ether, and n-butyl ether, with diethyl ether being preferred.
- an ether e.g., diethyl ether, isopropyl ether, isobutyl ether, and n-butyl ether, with diethyl ether being preferred.
- the epoxide in the compound of formula VI undergoes a conjugate ring-opening reaction, and a N,N- dimethylaminophenyl functional group may be substituted in the axial position of C ⁇ , to provide the compound of formula VII
- reaction may be carried out with about a five-fold excess of Grignard reagent over the epoxide as opposed to the nearly eight-fold excess used in the process described in the '490 patent.
- the crystalline form of compound VI further permits the use of a relatively small amount of the cuprous halide reagent. More specifically, the conjugate ring opening reaction of the 5 ⁇ ,100-epoxide can be carried with the molar ratio of the cuprous halide to the
- Compound VII is further advantageously obtained in crystalline form (m.p. 236°C to 240°C) by crystallization from an ether, preferably, diethyl ether.
- the first step comprises the conversion of the compound of formula VII to the compound of formula VIII by reaction with a dilute alcoholic acid solution.
- the acid serves the dual function of hydrlyzing the ketal group (i.e., deketalization) and removing the hydroxyl at C 5 position (i.e., dehydration). Any acid which functions to hydrolyze the ketal group is suitable for use, including sulfuric acid, hydrochloric acid, and phosphoric acid.
- the compound of formula VIII may be crystallized (m.p.: softens at 103°C and foams at 125°C to 128°C) from ether in high yield and in high purity.
- the compound of formula I may then be prepared from the compound of formula VIII, advantageously its crystalline form, by acetylation.
- any suitable reactants may be utilized to complete the acetylation, advantageously, a mixed anhydride procedure employing a trifluoroacetic anhydride/acetic acid mixture is used. This procedure has been found to provide the compound of formula I in high purity and yield from the compound of formula VIII without resort to chromatography.
- the compound of formula I can be purified by crystallization from ether in high yield and high purity (m.p.: 183°C to 185°C) .
- the inventive method for preparing the compound of formula I from the compound of formula VII in two steps was surprisingly found to provide a greater yield of the desired product than the one step method described in the '490 patent, i.e., a net yield of about 68% as compared to about 16% as calculated from the yields reported in the '490 patent. From an overall perspective, the inventive method provides a much greater yield of the final product of formula I as compared to that provided by the '490 patent, and also avoids many of the problems of the reaction scheme described in the '490 patent, such as the use of synthetic procedures which are unreasonably hazardous and/or not readily amenable to scale-up.
- the instant invention further allows one to prepare any of the intermediates described herein starting from the compound of formula II, or any other preceding intermediate, as well as the compound of formula I starting from any of the aforesaid.
- FTIR (KBr, diffuse reflectance): y max 3034, 2977, 2947, 2865, 2230 (CN) , 1546, 1473, 1431, 1383, 1346, 1322, 1256 & 1235 (O- CH 2 CH 2 -0) , 1173, 1158, 1131 (Si-0-CH 2 ) , 1099, 1058, 1041, 1010 cm '1 ; ! H NMR (CDC1 3 ) : ⁇ 0.47 (s, 0Si(CH 3 ) 2 ), 0.90 (s, 18-CH 3 ) , 2.88 (s, OSiCH 2 Cl) , 3.99 (br. S, 3-0(CH 2 ) 2 0-) , 5.60 (br.
- Li/DBB mixture was stirred at room temperature for 2 hours. After chilling the flask to -70°C, 2,400 mL of a THF solution containing 898 g of the compound of formula (Ilia) were added to the Li/DBB mixture at a rate designed to maintain the blue color throughout the addition. Upon completion of the addition, dichloroethane (400 mL) was added slowly to destroy excess anion-radical. 4,000 mL of 6 N aqueous HC1 were then added slowly, and the reaction mixture was allowed to warm to room temperature and was stirred overnight.
- reaction mixture was evaporated in vacuo to remove the THF, and the resulting aqueous mixture was extracted with methylene chloride. Following washes with water and brine, the methylene chloride extracts were combined and dried over sodium sulfate. Evaporation of the solvent gave a solid.
- the solid was partitioned between hexanes and 90% methanol (3 x 2500 mL Hex/ 3 x 2500 mL, 90% MeOH) .
- the combined methanol layers were evaporated to remove the methanol, and the aqueous mixture was extracted with methylene chloride.
- the methylene chloride extracts were washed with water and brine, combined, and dried over sodium sulfate. Evaporation of the solvent gave 572 g of a diketone, i.e., the compound of formula (IV) in 91% yield.
- the diketone of formula (IV) was a 4:1 mixture of 4,9(10)- and 5(10) ,9(11)-dienedione. The mixture was converted, without purification, to the 3,20-diketal (i.e., the compound of formula (V)) as described in
- Example 3 Evaporation of the hexane extracts allowed for the recovery of the DBB. NMR (CDC1 3 ) ⁇ 0.83 (s, 18-CH 3 ) , 2.30 (s, 21-CH 3 ) , 5.70 (br.s, C-4 H) .
- the mixture was diluted with 2,150 mL of saturated sodium bicarbonate solution and stirred for 10 minutes.
- the methylene chloride layer was washed with water (2x) and brine.
- the aqueous washes were extracted with additional methylene chloride.
- the methylene chloride extracts were combined and dried over sodium sulfate.
- the methylene chloride solution was concentrated to a thick syrup.
- Approximately 2,000 mL of methanol containing 0.5 vol% pyridine was drawn into the evaporation flask and the evaporative removal of the methylene chloride was continued.
- the flask was removed from the roto-vap, and additional methanol with 0.5 vol.% pyridine was added.
- the flask was chilled to 4°C.
- reaction mixture was quenched with the cautious addition of a 4.5 N potassium carbonate solution until the pH was in the range of 7.0 - 7.5.
- the reaction mixture was diluted with water and extracted with methylene chloride. The methylene chloride extracts were washed with water and brine, combined, and dried over sodium sulfate. Evaporation of the solvent gave the acetate of formula (I) as a thick syrup.
Abstract
Description
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU53145/96A AU716894B2 (en) | 1995-03-30 | 1996-03-18 | Method for preparing 17alpha-acetoxy-11beta-(4-N,N-dimethyla minophenyl)-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the method, and methods for the preparation of such intermediates |
EP96909749A EP0817793A2 (en) | 1995-03-30 | 1996-03-18 | Method for preparing 17alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the method, and methods for the preparation of such intermediates. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/413,755 | 1995-03-30 | ||
US08/413,755 US5929262A (en) | 1995-03-30 | 1995-03-30 | Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates |
Publications (2)
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WO1996030390A2 true WO1996030390A2 (en) | 1996-10-03 |
WO1996030390A3 WO1996030390A3 (en) | 1997-01-09 |
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PCT/US1996/003660 WO1996030390A2 (en) | 1995-03-30 | 1996-03-18 | METHOD FOR PREPARING 17α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES USEFUL IN THE METHOD, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES. |
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US (1) | US5929262A (en) |
EP (1) | EP0817793A2 (en) |
AU (1) | AU716894B2 (en) |
CA (1) | CA2216737A1 (en) |
WO (1) | WO1996030390A2 (en) |
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US5962444A (en) * | 1998-05-29 | 1999-10-05 | Research Triangle Institute | 17β-nitro-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
US6020328A (en) * | 1998-03-06 | 2000-02-01 | Research Triangle Institute | 20-keto-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
US6262042B1 (en) | 1998-05-29 | 2001-07-17 | Research Triangle Institute | 17β-amino and hydroxylamino-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
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US20060247452A1 (en) * | 2004-01-21 | 2006-11-02 | Guisasola Luis Octavio S | Method for obtaining 17sg(a)-acetoxy-11$g(b)-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione |
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US8569276B2 (en) | 1996-05-01 | 2013-10-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents |
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Also Published As
Publication number | Publication date |
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AU5314596A (en) | 1996-10-16 |
EP0817793A2 (en) | 1998-01-14 |
US5929262A (en) | 1999-07-27 |
AU716894B2 (en) | 2000-03-09 |
CA2216737A1 (en) | 1996-10-03 |
WO1996030390A3 (en) | 1997-01-09 |
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