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.
• This conversion may be accomplished by a number of methods, inclu ding the use of diazomethane or potassium carbonate-alkyl, i.e., R 3 (e.g. methyl) iodide in an aprotic solvent, such as acetone.
• R 3 e.g. methyl
• the reaction mixture is normally stirred at ambient temperature for about 48 to 96 hr, followed by refluxing for about 12 to 24 hrs.
• Compound 2 is recovered by removal of the solvent.
• Compound 3 is obtained, according to Step B, by treating Compound.2 with trimethylsilyl cyanide and zinc iodide at about ambient temperature in an inert atmosphere for about 12 to 36 hrs. The solvent is removed and the product, in most instances, may be used without further purification.
• Compound 4 is prepared, according to Step C, by treating Compound 3 with a reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as diethyl ether and/or tetrahydrofuran.
• a reducing agent such as lithium aluminum hydride
• an appropriate solvent such as diethyl ether and/or tetrahydrofuran.
• Compound 4 is obtained after treatment with sodium hydroxide solution, filtration and removal of solvent.
• Compound 5 is obtained, according to Step D, by treating Compound 4 with an organic acid, such as acetic acid, and sodium or potassium nitrite at about -10 to +10oC for about 1 to 24 hrs. After solvent removal and partitioning between ether/water, the ether layer is washed with water, sodium bicarbonate solution, dried and evaporated. Compound 5 is obtained in good yield.
• organic acid such as acetic acid
• sodium or potassium nitrite at about -10 to +10oC for about 1 to 24 hrs.
• the ether layer is washed with water, sodium bicarbonate solution, dried and evaporated.
• Compound 5 is obtained in good yield.
• Compound 6 is obtained, according to Step E, by treating Compound 5 with any agents which are useful to introduce a carbon-carbon double bond which is also conjugated with a ketone carbonyl group.
• agents which are useful to introduce a carbon-carbon double bond which is also conjugated with a ketone carbonyl group.
• These methods include treatment of Compound 5 with phenylselenenyl chloride at or about ambient temperature followed by treatment with hydrogen peroxide at ambient temperature. The solution is washed with water, saturated bicarbonate solution, water and dried. After chromatographic purification (usually preparative high, pressure liquid, chromatography, HPLC), Compound 6 is obtained.
• Compound 7 is obtained, according to Step F, by treatment of Compound 6 with a reducing agent such as lithium aluminum hydride in an appropriate solvent. After careful treatment: with water, a granular precipitate is obtained and. removed, by filtration. After the solution is washed, dried, and evaporated to dryness, Compound 7 is usually obtained in essentially a quantitative yield.
• a reducing agent such as lithium aluminum hydride in an appropriate solvent.
• 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.
• Compound 9 is obtained, according to Step H, by removal of the lower alkyl (or methyl) group at the 3-position of the A-ring of the steroid. This may be achieved by treatment with concentrated acid, such as hydrochloric acid, for about 0.5 to 25 hr at about -10 to 50oC and neutralized. The aqueous solution is extracted with diethyl ether, and the ether portions are washed with water and evaporated to dryness. The residue is purified using preparative HPLC.
• concentrated acid such as hydrochloric acid
• step (b) reacting the product of step (a) with a trialkyl or arylsilyl cyanide to add across the 17-keto group;
• step (c) reducing the product of step (b) with a reducing agent to produce the 17-hydroxy-17-methylamine derivative
• step (e) reacting the product of step (e) with phenylselenenyl chloride and hydrogen peroxide;
• step (f) reducing the product of step (e);
• step (g) reacting the product of step (f) with a strong reducing agent to partially reduce the aromatic ring A; th) reacting the product of step (g) with acid to dealkylate the 3-alkoxy group to produce the compound of formula I where R 1 is hydrogen;
• the starting material and reagents used in this invention are readily available or may be prepared by methods known, in the art,, see, for example Chemical Sources, published by Directories Publishing Company, Inc., Flemington, New Jersey in 1979 or Organic Chemical Reagents by L. Fieser and M. Fieser, published by John Wiley and Sons, Inc. of New York, New York in 1967.
• Reaction Sequence 2 describes an alternative procedure to obtain the compounds of formula I.
• Compound 10 is prepared synthetically, as reported by J. Gutzwiller et al., Helv. Chim. Acta., Vol. 61, pp 2397 ff (1978) which is incorporated herein by reference.
• Compound 10 is converted, according to Step A 2 , to the 4,6-diene derivative, Compound 11, by treatment first with bromine followed by treatment with a mixture of lithium bromide and lithium carbonate. The reaction is conducted at about 0 to 80oC for about 1 to 10 hr.
• Compound 11 is obtained by filtration and removal of the solvent.
• Step B 2 Compound 12 is obtained by dissolving Compound 11 in an inert solvent and treatment with lithium dimethyl copper at about -10o to 100oC for about 0.5 to 25 hr.
• the 7 ⁇ -methyl derivative 12 is obtained upon purification and removal of the solvent.
• R 4 OH where R 4 is lower alkyl containing 1 to 6 carbon atoms (e.g. methanol in Reaction Sequence 2), in the presence of a small amount of acid, such as sulfuric acid or p-toluenesulfonic acid.
• Compound 13 is obtained after washing with water, bicarbonate, and brine, drying and evaporation of the solvent.
• Compound 14 is obtained, according to Step D 2 , by dissolving Compound 13 in an inert solvent, such as methylene dichloride, and treatment with chromic oxide for about 1 to 10 hr at about -10o to 100oC. Compound 14 is obtained after washing with water, bicarbonate and brine, drying and evaporation of the solvent.
• an inert solvent such as methylene dichloride
• Compound 15, according to Step E 2 is obtained by treating Compound 14 with phenylselenenyl chloride in ethyl acetate followed by reaction with hydrogen peroxide in tetrahydrofuran (See the preparation and purification of Compound 6 in Reaction Sequence 1 above).
• Step F 2 Compound 16, according to Step F 2 , is obtained by reducing Compound 15 using lithium aluminum hydride in dry tetrahydrofuran. After purification as described for Step D in Reaction Sequence 1, Compound 16 is obtained in essentially quantitatively yield.
• Compound I may be obtained from Compound 16 by two different routes.
• the first route combines Steps G 2 and K 2 . These steps are performed in essentially the same manner as Steps H and J in Reaction Sequence 1 with the same result.
• Compound I may also be obtained, according to Steps H 2 and J 2 , by treatment with acyl anhydride as is described for Step J in Reaction Sequence 1, followed by mild treatment with water and acid as is also described in Step H in Reaction Sequence 1.
• step (b) reacting the product of step (a) with lithium dimethyl copper to produce the 4-ene-7 ⁇ -methyl derivative
• step (c) reacting the product of step (b) with an alcohol and acid to produce the 3,3-dialkoxy derivative
• step (d) oxidizing selectively the product of step (c) to produce the 17ct-keto derivative
• 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 (g) hydrolyzing the product of step (f) with acid to produce the 3-keto derivative, which is the compound of formula I where R 1 is hydrogen.
• step (i) reacting the product of step (f) with acyl anhydride or acyl halide to produce the 3,3-dialkoxy derivative and
• step (g) may be further hydrolyzed using water, heat and mild acid to produce the 17 a ⁇ -hydroxy derivative, which is the compound of formula I where R 1 is hydrogen.
• Reaction Sequence 3 desribes an additional alternative procedure to obtain the compounds of formula I.
• Compound 20 which is available according to the methods described by J.A. Zedric et al., Steroids, Vol. 1, p 233 (1963).
• Step A 3 Compound 20 is converted to the 7o-methyl derivative, Compound 21, using lithium dimethyl copper.
• the reaction is performed in an inert solvent for about 1 to 25 hr. at about -10 to 100oC. After purification involving washing with water, bicarbonate and brine, drying and removal of the solvent, Compound 21 is obtained in good yield.
• Compound 22 is obtained, according to Step B 3 , by reaction with Compound 21 with ethylene glycol and acid, such as sulfuric acid or p-toluenesulfonic acid. After purification by washing with water, bicarbonate, and brine, drying and evaporation of the solvent. Compound 22 is obtained in good yield.
• acid such as sulfuric acid or p-toluenesulfonic acid.
• Compound 23 is obtained, according to Step C 3 , by treatment of Compound 22 with chromic oxide in methylene chloride. The reaction is performed at about -10 to +45oC for about 1 to 25 hrs. Compound 23 is obtained after washing with water, bicarbonate and brine, drying and evaporation of the solvent.
• Compound 24 is obtained, according to Step D 3 , by treatment of the 17-keto derivative, Compound 23, with trimethylsilyl cyanide and zinc iodide in methylene chloride. After work up as is described above for Step B in Reaction Sequence 1, Compound 24 may be used without further purification.
• 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 14 is obtained, according to Step G 3 , by treating Compound 26 with methanol and acid such as sulfuric acid or p-toluenesulfonic acid.
• Compound 14 is purified by successive washing with water, sodium bicarbonate, and brine solution, drying and evaporating the solvent.
• 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 (b) reacting the product of step (a) with ethylene glycol to produce the 1, 3-dioxolane derivative at the 3-position of the steroid; (c) oxidizing the product of step (b) with chromic oxide to produce the 17-keto derivative;
• step (d) reacting the product of step (c) with trimethylsilyl cyanide in the presence of zinc iodide to produce the corresponding 17-ether-17-nitrile;
• step (e) reducing of the nitrile of step (d) to produce the 17-ether-17-methyleneamine derivative
• 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;
• step (i) reducing the product of step (h), the 17 ⁇ -keto derivative, to the 17 a ⁇ -hydroxy derivative;
• step (j) reacting the product of step (i) with acyl anhydride or acyl halide to produce the 3,3- dialkoxy-17 a ⁇ ester;
• step (k) hydrolyzing the product of step (j) in the presence of mild acid to produce the compound of formula I, where R 1 is acyl as is defined herein.
• ester of step (k) may be subsequently hydrolyzed with acid and water to produce the compound of formula I, where R 1 is hydrogen.
• step (1) reacting the 17 a ⁇ -hydroxy product of step (1) with acyl anhydride or acyl halide to produce the compound of formula I, where R 1 is acyl and R 2 is as defined herein.
• 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 compound of formula I where R 1 is ethyl when tested in rats, was found to have 40 times the androgenic activity of testosterone via subcutaneous injection and 6 times the activity of 17 ⁇ -methyltestosterone when orally administered. Further, the androgenic effect of this compound when orally administered was 6 times the effect for methyl testosterone.
• 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.
• compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages.
• the compositions will include a conventional pharmaceutical excipient and an active compound of formula I or the pharmaceutically acceptable salts thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
• 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.
• composition or formulation to be administered will, in any event, contain a quantitiy of the active compound(s), a therapeutically effective amount, i.e. in an amount effective to achieve the desired fertility control in the subject being treated.
• a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients described above.
• Such compositions take. the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
• Such compositions may contain 1%-95% active ingredient, preferably 1-70%.
• Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as. emulsions.
• Suitable, excipients are, for example water, saline, dextrose, glycerol, ethanol or the like.
• the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
• a more recently revised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795, which is incorporated herein by reference.
• 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
• EXAMPLE 17 An oral suspension 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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• 1985
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  • 1985-04-08 WO PCT/US1985/000609 patent/WO1985005361A1/en not_active Application Discontinuation
• 1986
  • 1986-01-20 NO NO860177A patent/NO860177L/no unknown
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