WO1985005361A1 - 17abeta-HYDROXY-7alpha-METHYL-D-HOMO-19-NORANDROST-4,16-DIENE-3-ONE AND THE 17-ESTERS THEREOF: METHODS OF PREPARATION AND USES - Google Patents
17abeta-HYDROXY-7alpha-METHYL-D-HOMO-19-NORANDROST-4,16-DIENE-3-ONE AND THE 17-ESTERS THEREOF: METHODS OF PREPARATION AND USES Download PDFInfo
- Publication number
- WO1985005361A1 WO1985005361A1 PCT/US1985/000609 US8500609W WO8505361A1 WO 1985005361 A1 WO1985005361 A1 WO 1985005361A1 US 8500609 W US8500609 W US 8500609W WO 8505361 A1 WO8505361 A1 WO 8505361A1
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- compound
- product
- produce
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- 0 C[C@](Cc1c2)C(C(CC=C3)C(C)(CC4)C3=O)C4c1ccc2O* Chemical compound C[C@](Cc1c2)C(C(CC=C3)C(C)(CC4)C3=O)C4c1ccc2O* 0.000 description 2
- VOJRARKVVVBEAI-MLTBTBTASA-N C[C@H](CC(C(CC1)C2CC3)=CC1=O)C2C(CCC1)C3(C)C1O Chemical compound C[C@H](CC(C(CC1)C2CC3)=CC1=O)C2C(CCC1)C3(C)C1O VOJRARKVVVBEAI-MLTBTBTASA-N 0.000 description 1
Classifications
-
- 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
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- 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
- C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Definitions
- the present invention is in the field of steroid chemistry. More particularly, it concerns 17 a ⁇ -hydroxy-7 ⁇ -methyl-D-homo-19-norandrost-4,16- diene-3-one and its 17 a ⁇ -hydroxy esters, their preparation and their use in the control of male fertility in mammals, particularly male human beings. These compounds combine gonadotropic, antigonadotropic and androgenic properties in the same compound.
- this invention concerns steroid derivatives of the general formula:
- R 2 is an alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkylene, haloalkyl, aryl, haloaryl or arylalkylene.
- Acyl therefore, includes such groups as, for example, acetyl, propanoyl (or propionyl), isopropanoyl, n-butanoyl (or n-butyryl), octanoyl, eicosanoyl, propenoyl (or acryloyl), 2-methylpropenoyl (or methacryloyl), octanoyl, tetradecenoyl, eicosenoyl, tetracosenoyl, propynoyl,. n-butynoyl, i-butynoyl, n-2-octynoyl, n-2-tetradecynoyl, 2-chloropentanoyl,
- Alkenyl refers to a branched or unbranched unsaturated hydrocarbon group of 2 to 24 carbon atoms and one or more unsaturated carbon-carbon bonds, such as for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, ⁇ 8,11 -heptadecadienyl, hexadecenyl, eicosenyl, tetracosenyl and the like.
- Alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
- Alkylene refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 6 carbon atoms, and includes, for example, methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), propylene (-CH 2 -CH 2 -CH 2 -), 2-methyl ⁇ ropylene C-CH 2 - CH(CH 3 )-CH 2 -3, hexylene [-(CH 2 ) 6 -] and the like.
- Alkynyl refers to a branched or unbranched acetylenically unsaturated hydrocarbon group of 2 to 24 carbon atoms such as ethynyl, 1- ⁇ ropynyl, 2-propynyl, 1-butynyl, 2-butynyl, octynyl, decynyl, tetradecenyl, hexadecynyl, eicosynyl, tetracosynyl and the like.
- Aryl refers to a phenyl or 1- or 2- naphthyl group. Optionally, these groups are substituted with one to four lower alkyl groups (having from one to six carbon atoms).
- Arylalkylene refers to an aryl group as is defined herein which is attached to one end of an alkylene group as is defined herein. As used herein, the other end of the alkylene group is attached to the carbon of the carbonyl group to form the acyl group.
- Cycloaikyl refers to a saturated hydrocarbon ring group having from 3 to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclohexyl, methyleyelohexyl, cyclooctyl, and the like.
- Cycloalkylalkylene refers to a saturated hydrocarbon containing a cycloaikyl group as is defined herein and an alkylene group as is defined herein.
- the term includes for example cyclopropylmethylene, cyclobutylethylene, 3-cyclohexyl-2-methylpropylene, 6-cyclooctylhexylene, and the like.
- Halo or halogen refers to fluoro, chloro, bromo or iodo, usually regarding halo substitution for a hydrogen atom in an organic compound.
- Haloalkyl refers to an "alkyl” group in which one to four, especially one of its hydrogen atoms, is substituted by a "halogen” group.
- Haloaryl refers to an “aryl” group substituted with from one to four halogen groups.
- Optional or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- optionally substituted phenyl means that the phenyl may or may not be substituted and that the description includes both unsubstituted phenyl and phenyl wherein there is substitution.
- the compounds of the present invention are generally named according to the IUPAC or Chemical Abstracts Service nomenclature system.
- the substituents on the ring system are as depicted above in the Summary of the Invention.
- the compound of formula I is named 17 a ⁇ -hydroxy-7 ⁇ -methyl-
- the five or six membered rings of the steroid molecule are often designated A, B, C and D as is shown immediately above.
- Preferred compounds of the present invention are those compounds of formula I wherein R 2 is an alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkylene, aryl, or an arylalkylene.
- a more preferred subgroup includes those compounds when R 2 is an alkyl, alkenyl, alkynyl, cycloaikyl or cycloalkylene group.
- Yet more preferred subgroups include those compounds of formula I wherein R 2 is alkyl, particularly normal (or straight chain) alkyl, where R 2 contains from 1 to 16 carbon atoms.
- Particular preferred compounds are those where R 2 is ethyl, n-hexyl, n-nonyl, or n-tridecyl.
- R 2 is aryl, particularly phenyl or arylalkylene, particularly 2-phenylethylene.
- the first structure and the last structure of each sequence will show the (CH 3 -) for the 18-methyl group and (H-) for the 19-nor group.
- the intermediate structures may not show these groups in an attempt to depict a less complex reaction sequence.
- Reaction Sequence 1 is usually lower alkyl of one to six carbon atoms and alkyl as is described herein.
- Compound 8 is obtained, according to Step G, by treatment of Compound 7 with a strong reducing agent, such as lithium in liquid ammonia.
- a strong reducing agent such as lithium in liquid ammonia.
- the crude solution is partitioned between ether and water, and the ether layer is washed, dried and evaporated to dryness. The residue is used without further purification.
- step (e) oxidizing the product of step (d) using phenylselenenyl chloride followed by hydrogen peroxide to produce the 4,16-diene-derivative; (f) reducing the product of step (e) to produce the 17 a ⁇ -hydroxy derivative;
- step (i) reacting the product of step (f) with acyl anhydride or acyl halide to produce the 3,3-dialkoxy derivative and
- Compound 25 is obtained, according to Step E 3 , by reducing using lithium aluminum hydride in tetrahydrofuran-diethyl ether, and purified as is described for Step C of Reaction Sequence 1.
- Compound 26 is obtained, according to Step F 3 , by oxidizing the 17-hydroxy derivative, Compound 25, using acetic acid and nitrite ion, followed by purification, in a manner similar to that described above for Step D of Reaction Sequence 1.
- Compound I is also obtained by performing Steps H 3 , J 3 , M 3 and N 3 in the same manner as is described for Steps E 2 , F 2 , H 2 and J 2 , respectively, in Reaction Sequence 2.
- step (f) reacting the product of step (e) with nitrite to produce the D-homo-l7 a -keto derivative;
- step (g) reacting the product of step (f) with alcohol and acid to form the 3,3-dialkoxy derivative;
- step (h) reacting the product of step (g) with phenylselenenyl chloride and hydrogen peroxide to produce the 16-ene derivative;
- Another embodiment of the present invention involves a method useful in the control of male fertility in a mammal, particularly a human being, which method comprises administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula I, particularly where R 1 is hydrogen.
- a preferred method includes oral adminis tration of the compound of formula I, particularly where R 2 is ethyl.
- a preferred composition includes compositions comprising compounds of formula I for oral administration to a human being, particularly where R 1 is hydroxyl, and also where R 1 is acyl and R 2 is ethyl.
- the compounds of this invention have been shown to be effective in animal models for antigonadotropic effect and, in the control of spermatogenesis in male mammals. These compounds are in large doses, useful in male contraception, in a mammal, particularly a human being, while maintaining the male libido. In smaller doses, a paradoxical result is observed in that these compounds increase spermatogenesis, while maintaining male libido.
- the compounds of this invention exhibit potent antigonadoptropic-androgenic activity in the same compound when orally administered. These compounds appear to have antigonadoptropic activity which interferes with spermatogenesis at the testicular level by supressing testosterone synthesis via feedback control and also have androgenic activity to maintain libido and secondary sex characteristics.
- Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include oral, rectal, parenteral, transdermal, subcutaneous and other system modes. The preferred method of administration is oral, except in those cases where the subject is unable to ingest, by himself, any medication. In those instances it may be necessary to administer the composition parenterally.
- an effective dosage for reduction of spermatogenesis is in the range of about 1-10 mg/kg/day, preferably about 6 mg/kg/day. For an average 70 kg human, this would amount to about 70-700 mg/day, or preferably about 420 mg/day.
- An effective dosage for increasing spermatogenesis is in the range of about 0.01 to 0.99 mg/kg/day, preferably about 0.5 mg/kg/day. For an average 70 kg human this would amount to about 0.7 to 69 mg/day, preferably about 35/mg/day.
- nontoxic solids include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
- the active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
- Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc.
- an active compound as defined above and optional pharmaceutical adjuvants in a excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
- a excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
- the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
- wetting or emulsifying agents such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
- CD 3 OD; 1:1): 0.80 (d, Y 7 Hz, C 7 CH 3 ); 0.88 (C 18 CH 3 ); 3.70 (OCH 3 ); 6.53 (C 4 H); 6.60 (dd,
- the solvent is evaporated below ambient temperature using a lyophizer, and the residue is dissolved in 500 ml of diethyl ether and 200 ml of water.
- the layers are separated, and the aqueous layer is extracted with two 150 ml portions of diethyl ether.
- the combined ether extracts are washed twice with 250 ml of water, twice with 250 ml of saturated sodium bicarbonate solution, once with 250 ml of water, dried over sodium sulfate and evaporated to dryness using reduced pressure.
- the ethyl acetate layer is returned to the reaction flask and diluted with 45 ml of tetrahydrofuran. This mixture is cooled using an ice-water bath and 4.1 ml of 30% aqueous hydrogen peroxide is added. The mixture is stirred at ambient temperature for 1 hr and diluted to a volume of approximately 300 ml with diethyl ether. The solution is washed twice with 100 ml of water, twice with 100 ml of saturated sodium bicarbonate solution and once with 100 ml of water, dried using sodium sulfate and evaporated to dryness using reduced pressure.
- Liquid ammonia (20 ml) is condensed into a flame-dried reaction flask under argon at Dry Iceacetone temperature. Small pieces of lithium wire, a total weight of 1.01 g, are dissolved in the ammonia.
- Compound 7, 3.85 g (from Example 6), is dissolved in 130 ml of dry tetrahydrofuran (dried by distillation from methylmagnesium bromide and stored over molecular sieves), added to the ammonia solution, and stirred for 45 min at Dry Ice-acetone temperature. A mixture of 22 ml of absolute ethanol and 33- ml of tetrahydrofuran is added dropwise over 15 min. The cooling bath is removed, and the still-blue solution is stirred.
- Example 10 The following example illustrates the preparation of representative pharmaceutical formulations containing an active compound of formula I, e.g. 7 ⁇ -methyl-17 a ⁇ -propionyloxy-D-homo-19-norandrost- 4,16-dien-3-one.
- an active compound of formula I e.g. 7 ⁇ -methyl-17 a ⁇ -propionyloxy-D-homo-19-norandrost- 4,16-dien-3-one.
- the active ingredient is 7 ⁇ -methyl-17cl ⁇ -propionyloxy-D-homo-19- norandrost-4, 16-dien-3-one.
- Other compounds of formula I may be substituted therein.
- Active ingredient 10 cornstarch 20 lactose, spray-dried 153 magnesium stearate 2
- Active ingredient 5 lactose, spray-dried 148 magneisum stearate 2
- Active ingredient 0.5 cornstarch 50 lactose 145 magnesium stearate 5
- the above ingredients are mixed and introduced into a hard-shell gelatin capsule.
- the above ingredients are mixed and introduced into a hard-shell gelatin capsule.
- EXAMPLE 16 An injectable preparation buffered to a pH of 7 is prepared having the following composition: Ingredients
- Active ingredient 0.1 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.1 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
- Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI860253A FI860253A (fi) | 1984-05-21 | 1986-01-20 | 17a -hydroxi-7 -metyl-d-homo -19-norandrost-4,16-dien-3-on och dess 17a -estrar och foerfarande foer framstaellning av dessa foereningar. |
DK27286A DK27286A (da) | 1984-05-21 | 1986-01-20 | 17a beta-hydroxy-7alfa-methyl-d-homo-19-norandrost-4,16-dien-3-on og 17-estrene deraf, fremstillingsmaader og anvendelser |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61241584A | 1984-05-21 | 1984-05-21 | |
US612,415 | 1984-05-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1985005361A1 true WO1985005361A1 (en) | 1985-12-05 |
Family
ID=24453058
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1985/000609 WO1985005361A1 (en) | 1984-05-21 | 1985-04-08 | 17abeta-HYDROXY-7alpha-METHYL-D-HOMO-19-NORANDROST-4,16-DIENE-3-ONE AND THE 17-ESTERS THEREOF: METHODS OF PREPARATION AND USES |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0182808A1 (fi) |
JP (1) | JPS61502186A (fi) |
DK (1) | DK27286A (fi) |
FI (1) | FI860253A (fi) |
NO (1) | NO860177L (fi) |
WO (1) | WO1985005361A1 (fi) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005061528A2 (en) * | 2003-12-22 | 2005-07-07 | Akzo Nobel N.V. | Steroids having a mixed androgenic and progestagenic profile |
US6949561B1 (en) | 1997-12-04 | 2005-09-27 | Sterix Limited | Steroid 3-O-sulphamate derivatives as inhibitors of oestrone sulphatase |
WO2006134167A1 (en) * | 2005-06-17 | 2006-12-21 | N.V. Organon | Steroids having a mixed androgenic and progestagenic profile |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2546613A1 (de) * | 1974-10-18 | 1976-04-22 | Hoffmann La Roche | Neue d-homosteroide |
DE2706860A1 (de) * | 1976-02-23 | 1977-08-25 | Hoffmann La Roche | Neue d-homosteroide |
US4155918A (en) * | 1976-10-28 | 1979-05-22 | Hoffmann-La Roche Inc. | Novel D-homosteroids |
-
1985
- 1985-04-08 EP EP85902235A patent/EP0182808A1/en active Pending
- 1985-04-08 WO PCT/US1985/000609 patent/WO1985005361A1/en not_active Application Discontinuation
- 1985-04-08 JP JP60501806A patent/JPS61502186A/ja active Pending
-
1986
- 1986-01-20 NO NO860177A patent/NO860177L/no unknown
- 1986-01-20 FI FI860253A patent/FI860253A/fi not_active Application Discontinuation
- 1986-01-20 DK DK27286A patent/DK27286A/da not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2546613A1 (de) * | 1974-10-18 | 1976-04-22 | Hoffmann La Roche | Neue d-homosteroide |
DE2706860A1 (de) * | 1976-02-23 | 1977-08-25 | Hoffmann La Roche | Neue d-homosteroide |
US4155918A (en) * | 1976-10-28 | 1979-05-22 | Hoffmann-La Roche Inc. | Novel D-homosteroids |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6949561B1 (en) | 1997-12-04 | 2005-09-27 | Sterix Limited | Steroid 3-O-sulphamate derivatives as inhibitors of oestrone sulphatase |
WO2005061528A2 (en) * | 2003-12-22 | 2005-07-07 | Akzo Nobel N.V. | Steroids having a mixed androgenic and progestagenic profile |
WO2005061528A3 (en) * | 2003-12-22 | 2005-09-09 | Akzo Nobel Nv | Steroids having a mixed androgenic and progestagenic profile |
JP2007515455A (ja) * | 2003-12-22 | 2007-06-14 | アクゾ・ノベル・エヌ・ベー | 混合された男性ホルモン及び黄体ホルモン特性を有するステロイド |
US7582622B2 (en) | 2003-12-22 | 2009-09-01 | N.V. Organon | Steroids having a mixed androgenic and progestagenic profile |
WO2006134167A1 (en) * | 2005-06-17 | 2006-12-21 | N.V. Organon | Steroids having a mixed androgenic and progestagenic profile |
Also Published As
Publication number | Publication date |
---|---|
NO860177L (no) | 1986-01-20 |
FI860253A0 (fi) | 1986-01-20 |
FI860253A (fi) | 1986-01-20 |
DK27286D0 (da) | 1986-01-20 |
EP0182808A1 (en) | 1986-06-04 |
DK27286A (da) | 1986-01-20 |
JPS61502186A (ja) | 1986-10-02 |
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