NO860177L - 17A-BETA-HYDROXY-7 ALFA-METHYL-D-HOMO-19-NORANDROST-4,16-DIEN-3-ON- AND 17A-BETA-HYDROXYESTERS THEREOF, THEIR PREPARATION AND APPLICATIONS. - Google Patents

Description

Background for the invention

The invention described herein was made while working under a contract fromU.S. National Institutes of Health No. N01-HD-O-2828, Department of Health and Human Resources.

Field of the invention

The present invention belongs to the field of steroid chemistry. More particularly, it relates to 17α|3-hydroxy-7α-methyl-D-homo-19-norandrost-4,16-dien-.3-one and its 17αØ-hydroxy esters, their preparation and their use in regulation of fertility in male mammals, especially humans. These compounds combine gonadotropic, anti-gonadotropic and androgenic properties in the same compound.

Related Science

The use of substituted steroids for the regulation of conception in female mammals has been known for some time; see for example G. Pincus et al. in Science, vol. 124, p.890 (1956); J. Rock et al. in Science, vol. 124, pp. 891 ff (1956); G. Pincus, The Control of Fertility, Academic Press, New York, New York, published 1965; and C. Djerassi, Science, vol. 151, p. 3716 (1966).

The lack of a similar antifertility "pill" for the male has stimulated research into the regulation of male fertility. Male fertility is a function of spermatogenesis. Since spermatogenesis is under hormonal regulation, the possibility of disruption of spermatogenesis by suppressive gonadotropins has been investigated; see, for example, D.J. Patanelli (ed.) "Hormonal Control of Male Fertility" in Department of Health, Education and Welfare Publication, NIH 78-1097, Bethesda, Maryland, published November 1977.

F. Newman et al., reported in the International Journal of Andrology, Supplement 2, pages 147-154, (1978), that the A 1 6-D-homo-19-nortestosterone propionate had an activity 50% that of the testosterone propionate as an androgen and was ten times as potent as testosterone propionate in reducing testicular weight in rats when administered subcutaneously. Newman also reported that all orally active androgens are 17-alkyl derivatives of testosterone, and there is a real fear that long-term administration of these 17-alkyl derivatives may cause liver damage.

Didolkar et al., compare in International Journal of Andrology, vol. 5, (1982) pages 413-424, Antispermatogenic effects of a new D-homo-steroid and testosterone in rabbits. They conclude that 18p-hydroxy-18a-methyl-16a,17a-methylene-D-homo-5a-androstan-3-one suppresses spermatogenesis and increases the weight of the accessory gonads in doses where testosterone is still ineffective. In rabbits, the new steroid thus proves to be a more potent androgen than testosterone, but a connection between antigonadotropic and androgenic properties has not been observed.

W. Lotz compares in Journal of Steroid Biochemistry, vol. 13. pages 1261-1264, published in 1980 the tropic effects and the reducing effects on serum luteinizing hormone (LH) in testosterone, 19-nortestosterone, 5a-dihydrotestosterone and their corresponding D-homo-A 1 6 analogs in rats. He concludes that the shape of the D-ring is important for the 5a-reductase's ability to act on these compounds. Furthermore, 5a-reduction in the 5-position is most important for the negative effect on LH release, less important for tropic activity on the accessory genital organs, and of less importance for the myotropic (anabolic) activity.

Additional references describing compounds that are related to either the structure of the compounds or the biological activity of the present invention include R. Riley, Sexual Medicine Today, pages 14-19, January 1983 and US Pat. No. 2 819,276, 3,278,528 and 4,087,524, German Patent No. 606,113 and Dutch Patent No. 7,701,872.

All of the above references are incorporated herein by reference.

Summary of the invention

In one aspect, this invention relates to steroid derivatives of the general formula:

where

R 1 is hydrogen or an acyl substituent of the formula:

where

R 2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkylene, haloalkyl, aryl, haloaryl or arylalkylene.

These compounds can be administered orally and are suitable for regulating female fertility and at the same time have androgenic activity. These uses and pharmaceutical preparations therefore constitute further aspects of this invention. Other aspects of this invention include methods for preparing the compounds according to formula I and the new intermediates for these, which are described in more detail below.

Detailed description of the invention The compounds according to this invention are defined by the general formula I where R 1 is hydrogen or an acyl substituent with the formula -(C=0)-R 2 , where R 2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkylene, haloalkyl, aryl, haloaryl or arylalkylene group.

"Acyl" denotes a group of the structure -(C=O)-R<2>, where R<2> is as described herein. 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-tetra-

dekynoyl, 2-chloropentanoyl, 2-chlorotetracosanyl, 3-bromo-2-methacryloyl, benzoyl, 1- and 2-naphthoyl, phenylacetyl, 6-phenylhexylene-oyl and the like.

"Alkenyl" denotes a branched or unbranched unsaturated hydrocarbon group having 2-24 carbon atoms and one or more unsaturated carbon-carbon bonds, such as, for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, octenyl, dekenyl,

8 11

tetradecenyl, N'-heptadecadienyl, hexadecenyl, eicosenyl, tetracosenyl and the like.

"Alkyl" denotes a branched or unbranched saturated hydrocarbon group of 1-24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and such.

"Alkylene" denotes a difunctional saturated branched or unbranched hydrocarbon chain containing 1-6 carbon atoms, and includes, for example, methylene (-CH^-), ethylene (-CH^-CH^-), propylene (-CH2-CH2~ CH2-), 2-methylpropylene [-CH2"CH(CH3)-CH2"], hexylene [-(CH„),-3 and the like.

£b

"Alkynyl" denotes a branched or unbranched acetylenically unsaturated hydrocarbon group of 2-24 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, octynyl, dekynyl, tetradecenyl, hexadecynyl, eicosynyl, tetracosynyl and the like.

"Aryl" denotes a phenyl or 1- or 2-naphthyl group. These groups are optionally substituted with 1-4 lower alkyl groups (with 1-6 carbon atoms).

"Arylalkylene" means an aryl group as defined herein which is attached to one end of an alkylene group as 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.

"Cycloalkyl" denotes a saturated hydrocarbon ring group with 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclohexyl, methylcyclohexyl, cyclooctyl and the like.

"Cycloalkylalkylene" denotes a saturated hydrocarbon containing a cycloalkyl group as defined herein and an alkylene group as defined herein. The designation

includes, for example, cyclopropylmethylene, cyclobutylethylene, 3-cyclohexyl-2-methylpropylene, 6-cyclooctylhexylene and the like.

"Halogen" denotes fluorine, chlorine, bromine or iodine, usually with respect to the substitution of a hydrogen atom by halogen in an organic compound.

"Haloalkyl" denotes an "alkyl" group in which 1-4, especially one of its hydrogen atoms, is substituted with a "halogen" group.

"Halogenaryl" denotes an "aryl" group substituted with 1-4 halogen groups.

"Possible" or "eventually" means that the subsequently described case or condition may or may not occur and that the description includes examples where said case or condition occurs and examples where it does not occur. For example, "optionally substituted phenyl" means that the phenyl may or may not be substituted and that the description includes both unsubstituted phenyl and phenyl where there is substitution.

The compounds of the present invention are usually named according to IUPAC's or Chemical Abstracts Service's nomenclature system. The substituents on the ring system

is as stated above in the summary of the invention. When, for example, the group attached to the 17a carbon atom in the steroid is acyloxy, i.e. -0-(C=0)-R 2 , and R 2 is ethyl, the compound of formula I is named 17ap-hydroxy-7a-methyl -D-homo-19-norandrost-4,16-dien-3-one-propionate or 7α-methyl-17αØ-propionyloxy-D-homo-19-norandrost-4,16-dien-3-one, and is shown below:

The five- or six-membered rings in the steroid molecule are often designated A, B, C and D, as shown just above.

Preferred compounds according to the present invention are such compounds according to formula I where R 2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkylene, aryl or an arylalkylene. A more preferred subgroup includes such compounds when R 2 is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylene group. Even more preferred subgroups include such compounds according to formula I where 2 2 R is alkyl, especially normal (or straight chain) alkyl, where R contains 1-16 carbon atoms. Particularly preferred compounds are those where R 2 is ethyl, n-hexyl, n-nonyl or n-tridecyl.

Further preferred compounds are those where R 2 is aryl, especially phenyl or arylalkylene, especially 2-phenylethylene.

Method of manufacture

Reaction sequences 1, 2 and 3 shown below can be used for the preparation of compounds according to formula I.

In the reaction sequences, the first structure and the last structure in each sequence will show (CH^-) for the 18-methyl group and (H-) for the 19-nor group. The intermediate structures may not show these groups in an attempt to indicate a less complex reaction sequence.

In reaction sequences 2 and 3 for certain steroid structures, a dotted line connecting the carbon atoms C(10), C(5) and C(6) is also shown. This dotted line indicates for these intermediates that the exact position of a double bond is not known with certainty or that a mixture of the unsaturated C(10)-C(5) and C(5)-C(6) compounds exists present. Regardless of the position of these double bonds, the C(4)-C(5) double bond is introduced with certainty at the end of reaction sequences 2 and 3.

Reaction sequence 1

The compounds according to formula I are prepared according to step A, starting with 7α-methylestrone, compound 1, and alkylating (for example methylating) the hydroxyl group in the 3-position of the A group to form the corresponding ether, compound 2. R<3> in reaction sequence 1 is usually lower alkyl with 1-6 carbon atoms, and alkyl is as described herein. This conversion can be carried out by a number of methods including the use of diazomethane or potassium carbonate alkyl, i.e. R' 3-(for example methyl) iodide in an aprotic solvent such as acetone. The reaction mixture is usually stirred at ambient temperature for approx. 48-96 hours followed by boiling under reflux for approx. 12-24 hours. 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 approximately ambient temperature in an inert atmosphere for approx. 12-36 hours. The solvent is removed and the product can in most cases 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 a suitable 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 approx. -10 - +10°C for approx. 1-24 hours. After removal of solvent and separation between ether and water, the ether layer is washed with water and 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 suitable for introducing 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 around ambient temperature, followed by treatment with hydrogen peroxide at ambient temperature. The solution is washed with water, saturated bicarbonate solution and 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 treating compound 6 with a reducing agent such as lithium aluminum hydride in a suitable solvent. After careful treatment with water, a granular precipitate is obtained which is removed by filtration. After the solution is washed, dried and evaporated to dryness, compound 7 is usually obtained in practically quantitative yield.

Compound 8 is obtained according to step G by treating compound 7 with 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 removing the lower alkyl (or methyl) group in the 3-position of the A ring in the steroid. This can be achieved by treatment with concentrated acid such as hydrochloric acid for approx. 0.5-25 hours at approx. -10-50°C and neutralization. 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.

Compounds according to formula I are obtained according to step J by treating compound 9 with the acyl anhydride, for example the R 2 -(C=0)-0-(C=0)-R 2 anhydride or mixed acyl anhydrides corresponding to the desired R 2 in the presence of an organic base such as pyridine at ca. ambient temperature for approx. 0.5-25 hours. After neutralization and purification, the compound according to formula I is obtained in good yield. Alternatively, the acyl anhydride in this reaction can be substituted with an acyl halide, R 2-(C=0)-X, where X is halogen

2

and R is as described herein.

In summary, the compounds according to formula I are then prepared in the following steps: (a) the 3-hydroxyl group in 7a-methylestrone is alkylated (or methylated); (b) the product of step (a) is reacted with a trialkyl or arylsilyl cyanide during addition over the 17-keto group; (c) the product of step (b) is reduced with a reducing agent to form the 17-hydroxy-17-methylamine derivative; (d) the amine is reacted with nitrite during expansion of ring D in the steroid molecule; (e) reacting the product from step (e) with phenylselenenyl chloride and hydrogen peroxide; (f) the product of step (e) is reduced; (g) reacting the product of step (f) with a strong reducing agent during partial reduction of the aromatic ring A; (h) the product from step (g) is reacted with acid during de-alkylation of the 3-hydroxy group to form the compound according to formula I where R 1 is hydrogen; and

(i) then reacting the product from step (h) with an acyl anhydride or acyl halide to form the compound

1 2 2

according to formula I where R is -(C=O)-R and R is as described herein.

Reactions describing the conversion of steroid compounds to numerous derivatives have been described by C. Djerassi (ed.) in Steroid Reactions: An Outline for the Organic Chemist, published by Holden-Day Publishing Company, Inc., Belmont, California in 1964 and by J. Fried and J. Edwards, Organic Reactions In Steroid Chemistry, vol. I and II, von Nostrand Reinhold Co., New York, New York, (1973), which are incorporated herein by reference.

The starting materials and reagents used in this invention are readily available or can be prepared by methods known in the field; 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., New York, New York in 1967.

Reaction sequence 2

Reaction sequence 2 describes an alternative method for obtaining the compounds according to formula I.

Compound 10 is prepared synthetically, as reported by

J. Gutzwiller et al., Heiv. Chim. Acta., vol. 61, pages 2397 ff

(1978), which is incorporated herein by reference. Compound 10 is converted stepwise to the 4,6-diene derivative, compound 11, by first treating it with bromine followed by treatment with a mixture of lithium bromide and lithium carbonate. The reaction is carried out at approx. 0-80°C for approx. 1-10 hours. Compound 11 is obtained by filtration and removal of the solvent.

In step B, compound 12 is obtained by dissolving compound 11 in an inert solvent and treating with lithium dimethyl copper at approx. -10 - 100°C for approx. 0.5-25 hours. The 7α-methyl derivative 12 is obtained by purification and removal of the solvent.

Compound 13 is obtained according to step C„ by treating 4 4

compound 12 with lower alcohol, R 0H, where R is lower alkyl containing 1-6 carbon atoms (for example 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 salt solution, drying and evaporation of the solvent.

Compound 14 is obtained according to steps by dissolving compound 13 in an inert solvent such as methylene dichloride and treating with chromium oxide for approx. 1-10 hours at approx. -10 - 100°C. Compound 14 is obtained after washing with water, bicarbonate and salt solution, drying and evaporation of the solvent.

Compound 15 is obtained according to steps by treating compound 14 with phenylselenenyl chloride in ethyl acetate followed by reaction with hydrogen peroxide in tetrahydrofuran (see preparation and purification of compound 6 in reaction sequence 1 above).

Compound 16 is obtained stepwise 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 practically quantitative yield.

Compound I can be obtained from compound 16 in two different ways. The first path combines steps and ■ These steps are carried out in essentially the same way as steps H and J in reaction sequence 1 with the same result. Compound I can also be obtained according to steps and J_ by treatment with acyl anhydride as described for step J in reaction sequence 1, followed by mild treatment with water and acid, which is also described in step H in reaction sequence 1.

In summary, the compounds according to formula I are then prepared by the following steps: (a) D-homotestosterone is brominated followed by dehalogenation to form the 4,6-diene; (b) the product of step (a) is reacted with lithium-dimethyl-copper to form the 4-ene-7a-methyl derivative; (c) reacting the product of step (b) with an alcohol and acid to form the 3,3-dimethoxy derivative; (d) the product of step (c) is selectively oxidized to form the 17α-keto derivative; (e) the product of step (d) is oxidized using phenylselenenyl chloride followed by hydrogen peroxide to form the 4,16-diene derivative; (f) the product of step (e) is reduced to form the 17α|3-hydroxy derivative; (g) the product of step (f) is hydrolyzed with acid to form the 3-keto derivative, which is the compound of formula I where is hydrogen; (h) the product from step (g) is reacted with acyl anhydride or acyl halide to form the compound according to formula I where

1 2 2

R is acyl according to the formula -(C=O)-R and R is as described herein.

A variation of this reaction sequence is to omit steps (g) and (h) above and replace them with the following steps: (i) the product from step (f) is reacted with acyl anhydride or acyl halide to form the 3,3-dimethoxy derivative and

(j) the product from step (i) is hydrolyzed with acid to form the compound according to formula I, where R 1 is acyl according to the formula -(C=0)-R 2 and R 2 is as described herein.

Optionally, the product from step (g) can be further hydrolysed using water, heat and mild acid to form the 17a(3-hydroxy-derivative, which is the compound according to formula I where R 1 is hydrogen.

Reaction sequence 3

Reaction sequence 3 describes a further alternative method for obtaining the compounds according to formula I.

One starts with compound 20, which is available according to the methods described by J.A. Zedric et al., Steroids, vol. 1, p. 233 (1963). In step A, compound 20 is converted to the 7α-methyl derivative, compound 21, using lithium dimethyl copper. The reaction is carried out in an inert solvent for approx. 1-25 hours at approx. -10 - 100°C. After purification including washing with water, bicarbonate and saline, drying and removal of the solvent, compound 21 is obtained in good yield.

Compound 22 is obtained according to steps by reacting compound 21 with ethylene glycol and acid such as sulfuric acid or p-toluenesulfonic acid. After purification by washing with water, bicarbonate and salt solution, drying and evaporation of the solvent, compound 22 is obtained in good yield.

Compound 23 is obtained according to steps by treating compound 22 with chromium oxide in methylene chloride. The reaction is carried out at approx. -10 - +45°C for approx. 1-25 hours. Compound 23 is obtained after washing with water, bicarbonate and salt solution, drying and evaporation of the solvent.

Compound 24 is obtained according to steps by treating the 17-keto derivative, compound 23, with trimethylsilyl cyanide and zinc iodide in methylene chloride. After work-up as described above for step B in reaction sequence 1, compound 24 can be used without further purification.

Compound 25 is obtained according to step E^ by reduction using lithium aluminum hydride in tetrahydrofuran-diethyl ether and purification as described for step C in reaction sequence 1.

Compound 26 is obtained according to step F^ by oxidation of 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 in reaction sequence 1.

Compound 14 is obtained according to steps 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 salt solution, drying and evaporation of the solvent.

Compound I is then obtained by performing the steps

H^, J3, K_ and in the same way as described for steps E^ r F^, H2 and J2 in reaction sequence 2, respectively.

Alternatively, compound I is also obtained by carrying out the steps , , M-. and in the same way as described for steps E^, F^ in H2 and J2 in reaction sequence 2, respectively.

In summary, the compounds according to formula I are then prepared in the following steps: (a) 6-ene-testosterone is reacted with lithium dimethyl copper to form the 7a-methyl derivative; (b) the product from step (a) is reacted with ethylene glycol to form the 1,3-dioxolane derivative in the 3-position of the steroid; (c) the product of step (b) is oxidized with chromium oxide to form the 17-keto derivative; (d) the product of step (c) is reacted with trimethylsilyl cyanide in the presence of zinc iodide to form the corresponding 17-ether-17-nitrile; (e) the nitrile from step (d) is reduced to form the 17-ether-17-methyleneamine derivative; (f) reacting the product of step (e) with nitrite to form the D-homo-17α-keto derivative; (g) the product from step (f) is reacted with alcohol and acid to form the 3,3-dimethoxy derivative; (h) reacting the product from step (g) with phenylselenenyl chloride and hydrogen peroxide to form the 16-ene derivative; (i) the product of step (h), the 17α-keto derivative, is reduced to the 17α(3-hydroxy derivative;

(j) the product from step (i) is reacted with acyl anhydride or acyl halide to form the 3,3-dihydroxy-17aO-ester; and

(k) the product of step (j) is hydrolysed in the presence of mild acid to form the compound of formula I wherein R<1> is acyl as described herein.

Optionally, the ester from step (k) can then be hydrolysed with acid and water to form the compound according to formula I where R 1 is hydrogen.

A variation of this method substitutes sub-steps (j) and (k) above with the following steps: (1) the product of step (i) is hydrolysed in the presence of acid to form the compound of formula I wherein R 1 is hydrogen; and optionally: (m) the 17ap-hydroxy product from step (1) is reacted with acyl anhydride or acyl halide to form the compound

1 2

according to formula I where R is acyl and R is as described herein.

Application of the compounds

Another embodiment of the present invention includes a method suitable for regulating fertility in male mammals, especially humans, which method comprises administering to an individual in need of such treatment a therapeutically effective amount of the compound according to formula I, especially where R 1 is hydrogen. A preferred method involves oral administration of the compound of formula I, especially where R 2 is ethyl.

A preferred preparation includes preparations comprising compounds according to formula I for oral administration to a human, especially where R 1 is hydroxyl, and furthermore where R 1 is

2

acyl and R is ethyl.

Applicability and administration

The compounds according to this invention have been shown to be effective in animal models in terms of antigonadotropic effect and in regulating spermatogenesis in male mammals. These compounds are, in large doses, suitable for contraception in male mammals, especially humans, while maintaining the male's libido. In smaller doses, a paradoxical result has been observed in that these compounds increase spermatogenesis while maintaining the male's libido.

For example, the compound of formula I wherein R 1 is ethyl when tested in rats was found to have four times the androgenic activity of testosterone by subcutaneous injection and six times the activity of 17o-methyltestosterone by oral administration. Furthermore, the androgenic effect of this compound when administered orally was six times that of methyltestosterone.

Although not fully understood at this time, the compounds of this invention exhibit potent anti-gonadotropic-androgenic activity in the same compound when administered orally. These compounds are shown to have anti-gonadotropic activity that interferes with spermatogenesis at the testicular level by suppressing testosterone synthesis via affect regulation and also have androgenic activity with up-maintenance of libido and secondary sex characteristics.

Administration of the active compounds and salts described herein may be by any of the approved routes of administration for therapeutic agents. These methods include oral, rectal, parenteral, transdermal, subcutaneous and other systems. The preferred method of administration is oral, except in such cases where the individual is not able to digest any drug himself. In such cases, it may be necessary to administer the preparation parenterally.

Depending on the intended method, the preparations can be in solid, semi-solid or liquid dosage form, such as

tablets, suppositories, pills, capsules, powders, liquids, suspensions or the like, preferably in unit dosage forms suitable for easy administration of precise dosages. The preparations will include a conventional pharmaceutical excipient and an active compound according to formula I or the pharmaceutically satisfactory salts thereof and may additionally include other medicinal agents, pharmaceutical agents, carriers, excipients, diluents, etc.

The amount of active compound that is administered will, of course, depend on the individual being treated, the individual's weight, the severity of the disorder, the method of administration and the prescribing physician's assessment. However, an effective dosage for reducing spermatogenesis is in the range of approx. 1-10 mg/kg per day, preferably approx. 6 mg/kg per day. For an average person of 70 kg, this would amount to approx. 70-700 mg/day or preferably approx. 420 mg/day.

An effective dosage for increasing spermatogenesis is in the range of approx. 0.01-0.99 mg/kg per day, preferably approx. 0.5 mg/kg per day. For an average person of 70 kg, this would amount to approx. 0.7-69 mg/day, preferably approx. 35/mg/day.

For solid preparations, conventional non-toxic solids can be used including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like. The active compound as described above can be designed as suppositories using, for example, polyalkylene glycols, for example propylene glycol, as a carrier. Liquid pharmaceutically administrable preparations can, for example, be prepared by dissolving, dispersing, etc., an active compound as described above, and any pharmaceutical excipients in an excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, as thereby forming a solution or suspension. If desired, the pharmaceutical preparation to be administered can also contain smaller amounts of non-toxic excipients such as wetting agents or emulsifiers, pH buffering agents and the like, for example sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamino oleate, etc. Existing methods for the preparation of such dosage forms is known, or will be obvious, to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mark Publishing Company, Easton, Pennsylvania, 15th ed., 1975. The preparation or formulation to be administered will in all cases contain a quantity of the active compound(s), a therapeutically effective amount, i.e. in an amount that is effective in achieving the desired fertility regulation in the individual being treated.

For oral administration, a pharmaceutically satisfactory non-toxic preparation is formed by incorporating any of the commonly used excipients described above. Such preparations take the form of solutions, suspensions, tablets, pills, capsules, powders, preparations with prolonged release and the like. Such preparations may contain 1-95% active ingredient, preferably 1-70%.

Parenteral administration is, if used, generally characterized by intravenous injection, either subcutaneously, intramuscularly or intravenously. Injectable preparations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. If desired, the pharmaceutical preparations to be administered can also contain smaller amounts of non-toxic excipients 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 method of parenteral administration utilizes the implantation of a slow-release or sustained-release system so that a constant dosage level is maintained. See, for example, US Patent No. 3,710,795, which is incorporated herein by reference.

The following examples serve to illustrate the invention. They should not be understood as curtailing it or as limiting its scope. The steps A, B, C, etc., discussed in the examples refer to the corresponding steps in reaction sequence 1.

EXAMPLE 1

7a- metvlestron- metvleter

(Step A for the formation of compound 2)

A slurry of 14.94 g of 7α-methylestrone (compound 1, prepared according to J. Kalvoda et al., Heiv. Chim. Acta. vol. 50, pages 281-288 (1967)) and 28 g of anhydrous potassium carbonate in 600 ml of acetone and 100 ml of methyl iodide are stirred under argon at ambient temperature and pressure for 3 days. Thin layer chromatography analysis indicates that the reaction is approximately 90% complete. The mixture is then heated to a gentle reflux (oil bath temperature 70°C) and refluxed for 24 hours, after which time the reaction is complete. The solvent is removed under reduced pressure and the residue is dissolved in methylene chloride (500 ml) and water (200 ml). The layers are separated and the aqueous layer is washed twice with 150 ml portions of methylene chloride. The combined methylene chloride extracts are combined and washed twice with 200 ml portions of water, dried using sulfate and evaporated to dryness using reduced pressure. 14.8 g (approx. 100% yield) of 4-methoxy-7a-methylestrone is obtained, which has the following spectral properties:

Proton magnetic resonance spectrum (in CDCl^):

0.88 (d, Y = 6 Hz, C 7 CH 3 ); 0.91 (C 18 CH 3 ); 3.76 (OHCH 3 );

6.60 (C 4 H); 6.72 (dd, Y = 9 Hz, Y = 3 Hz, C 2 H); 7.21 6 (d, Y = 9 Hz, CH) .

EXAMPLE 2

17-cyano-3-methoxy-7α-methyl-17-trimethylsilyloxyestra-1,3,5(10)-triene

(Step B for the formation of compound 3)

A mixture of 10.74 g of compound 2 (from Example 1), 10 ml of chloroform, 14 ml of trimethylsilyl cyanide and 40 mg of zinc iodide is stirred at ambient temperature and pressure under argon for 19 hours. The solvent and excess reagent are removed using reduced pressure, and the residue is dissolved in a mixture of ether (300 mL) and water (100 mL). The layers are separated and the aqueous layer is extracted twice with ether (150 ml). The combined ether extracts are washed twice with water (100 ml), dried over sodium sulfate and evaporated to dryness using reduced pressure. A practically quantitative yield (14.45 g) of compound 3 is obtained, which is used in example 3 without further purification. The structure of compound 3 is confirmed by the following spectral data: film Infrared spectrum: Å ^ = 4.5 (C=N); 6,20 and

6.40 µm (aromatic).

Proton magnetic resonance spectrum (in CCl^):

0.22 (0TMS); 0.81 (C 18 CH 3 ); 0.92 (d, Y = 7 Hz, C?CH 3 );

3.73 (OHCH 3 ); 6.52 (C₂H); 6.52 (dd, Y = 9 Hz, Y = 3 Hz;

C2H); 7.13 6 (d, Y = 9 Hz), C^H).

EXAMPLE 3

17-hydroxy-3-methyl-7a-methyl-17-aminomethylestra- 1, 3. 5( 10)- triene

(Step C for the formation of compound 4)

To a slurry of lithium aluminum hydride, 50 ml of anhydrous diethyl ether and 50 ml of anhydrous tetrahydrofuran (which has been dried by distillation from methylmagnesium bromide and stored over molecular sieves) is added under argon a solution of 14.45 g of compound 3 (from Example 2) in 50 ml of dry tetrahydrofuran. The reaction mixture is cooled during the addition in an ice-water bath. After the solution containing compound 3 has been added, the ice bath is removed and the reaction mixture is stirred at ambient temperature for 3 hours. To the reaction mixture, 4.5 ml of water is added dropwise with vigorous stirring, followed by 4.5 ml of 15% sodium hydroxide solution. Upon further stirring, a white, granular precipitate is formed. The solution is filtered and the precipitate is washed with several 50 ml portions of diethyl ether. The combined ether solutions are dried over sodium sulfate and evaporated to dryness under reduced pressure to give 10.8 g (about 91% yield) of a crystalline product which was used in the following example without further purification. The structure of compound 4 is confirmed by the following spectral data:

Infrared spectrum: X ^ks^ : 3.05' 3.15 and 3.25

(OH), NH2); 6.20 and 6.35 pm (aromatic).

Proton magnetic resonance spectrum (in CCl^, CD^OD; 1:1):

0.80 (d, Y = 7 Hz, C 7 CH 3 ); 0.88 (C 18 CH 3 ); 3.70 (OHCH 3 );

6.53 (C 4 H); 6.60 (dd, Y = 8 Hz, Y = 2 Hz, C 2 H); 7.14 6 (d, Y = 8 Hz, CjH).

EXAMPLE 4

17a-keto-3-methoxy-7a-methyl-D-homoestra-1, 3.5(10)-triene

(Step D for the formation of compound 5)

To a solution of 10.8 g of compound 4 in 300 ml of glacial acetic acid and 50 ml of water, a solution of 5.9 g of sodium nitrite in 50 ml of water is added dropwise over 30 minutes while the reaction mixture is cooled in an ice-water bath . After stirring for 2 hours at ice-water temperature, the solution is heated to ambient temperature and stirred for 18 hours. The reaction mixture is cooled to ice-water temperature and a further 5.9 g of sodium nitrite is added with vigorous stirring. The mixture is stirred for 1 hour at ice-water temperature followed by stirring at ambient temperature for 4 hours. The solvent is evaporated at below ambient temperature using a lyophilizer, 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 and once with 250 ml of water, dried over sodium sulfate and evaporated to dryness using reduced pressure.

The 20 g of yellow solid which. is obtained, chromatographed using a Waters 500 preparative high pressure liquid chromatograph (HPLC) using a normal phase silica gel cartridge with elution using 5% ethyl acetate/petroleum ether (b.p. 31-60°C). 4.51 g of pure compound 5 is obtained (55% yield) with the following analytical and spectral data:

Infrared spectrum: Å ^ks"<1>5.85 (C=0) ; 6.20 and

6.35 µm (aromatic).

Proton magnetic resonance spectrum (in CDCl^):

0.80 (d, Y = 7 Hz, C?CH 3 ); 1.08 (C₂CH₂); 3.79 (OHCH 3 );

6.53 (C 4 H); 6.65 (dd, Y = 8 Hz, Y = 2 Hz, C 2 H); 7.18 6 (d, Y = 8 Hz).

High-resolution mass spectrum:

Calculated for c2i<H>28°2<:><3>12.2089

Found : 312.2075

EXAMPLE 5

17α-keto-3-methoxy-7α-methyl-D-homoestra-1. 3, 5(10). 16- tetraene

(Step E for the formation of compound 6)

To a solution of 5.68 g of compound 5 (from example 4) in 130 ml of ethyl acetate, 4.38 g of phenylselenenyl chloride are added under argon. After stirring at ambient temperature for 3 hours, 1.44 g of further phenylselenenyl chloride is added with continued stirring for a further 1 hour. Water (45 ml) is added and the mixture is stirred vigorously for 5 minutes and transferred to a separatory funnel. The aqueous layer is removed and the ethyl acetate layer is washed three times with 30 ml of water. 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 hour and diluted to a volume of approx. 300 ml of 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. The residue (6.67 g) is chromatographed using a Waters 500 preparative high pressure liquid chromatograph (HPLC) using a normal phase silica gel cartridge. Elution from the column takes place using 6% ethyl acetate/petroleum ether (b.p. 35-60°C) and gives 3.1 g of compound 6 (55% yield). The following analytical and spectral data are consistent with the proposed structure:

Infrared spectrum: XnU?°1: 5.95 (=C-C=0); 6.20

and 6.35 (aromatic).

Proton magnetic resonance spectrum (in CDCl^):

0.80 (d, Y 1 Hz, C?CH 3 ); 1.02 (C 18 CH 3 ); 3.77 (OHCH 3 );

5.90 (dd, Y = 9 Hz, Y = 2 Hz, C₂H); 6.60 (C 4 H); 6.72 (dd, Y = 8 Hz, Y = 2 Hz); 6.8 (m, C1gH); 7.20 6 (C 1 H).

EXAMPLE 6

17αp-hydroxy-3-methoxy-7α-methyl-D-homoestra-1. 3.5(10). 16- tetraene

(Step F for the formation of compound 7)

Compound 6 (from Example 5), 3.79 g, is dissolved in 50 ml of anhydrous diethyl ether and 100 ml of dry tetrahydrofuran (dried by distillation from methylmagnesium bromide and stored over molecular sieves). The mixture is cooled under a blanket of argon to approx. 0°C using an ice-water bath, and 589 mg of lithium aluminum hydride is added in small portions to keep foaming under control. The solution is stirred at ice-water temperature for 45 minutes, and 10 ml of water is added dropwise with vigorous stirring until a white, granular precipitate is formed. The precipitate is filtered off and washed three times with 50 ml of diethyl ether. The filtrate is mixed with the washing solutions and the combined solution is dried using anhydrous sodium sulfate, filtered and evaporated to dryness using reduced pressure. Compound 7 (3.85 g, 100% yield) is used in the next step without further purification. The structure of compound 7 is confirmed by the following spectral data:

Infrared spectrum: max"1<:>2.9 (0H) '6.20°g

6.35 µm (aromatic).

Proton magnetic resonance spectrum (in CDCl^):

0.80 (d, Y = 7 Hz, C 7 CH 3 ); 0.85 (C 18 CH 3 ); 3.77 (OHCH 3 );

5.57 (d, Y = 7 Hz, C1?H); 5.72 (dm, C₂H); 6.57 (C 4 H);

6.63 (dd, Y = 8 Hz, C 2 H); 7.19 5 (d, Y = 8 Hz, CjH).

EXAMPLE 7

17αp-hydroxy-3-methoxy-7α-methyl-D-homoestra-2, 5( 10). 16- trien

(Step G for the formation of compound 8)

Liquid ammonia (20 ml) is condensed into a flame-dried reaction flask under argon at dry ice-acetone temperature. Small pieces of lithium wire with 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 minutes at dry ice-acetone temperature. A mixture of 22 ml of absolute ethanol and 33 ml of tetrahydrofuran is added dropwise over 15 minutes. The cooling bath is removed and the still blue solution is stirred. At this point, no more dry ice is added to the dry ice condenser. The blue color disappears after 20 minutes, the ammonia is allowed to evaporate and the residual solution is diluted with 300 ml of ether and 200 ml of water. The layers are separated and the aqueous layer is extracted twice

100 ml of diethyl ether. The combined ether solutions are washed twice

with water, dried over sodium sulfate and evaporated to dryness using reduced pressure. A crude product residue, compound 8, weighing 3.38 g is obtained, and this is used in the next step without further purification.

The following spectral data are consistent with the proposed structure:

Infrared spectrum: X ^^g<1>: 3.1 (OH) ; 5, 9 and

6.0 µm (C=C).

Proton magnetic resonance spectrum (in CDCl^):

0.74 (d, Y = 8 Hz, C 7 CH 3 ); 0.80 (C₂CH₂; 3.60 (OCH₃);

4.64 (C 2 H); 5.47 (d, Y = 7 Hz, C1?H); 5.68 6 (dm, Y =

7 Hz, C1gH).

EXAMPLE 8

1 7a|3-hydroxy-7a-methyl-D- homo- 19- norandrost- 4, 16- diene- 3- one

(Step H for the formation of compound 9)

To a solution of 3.38 g of compound 8 (from example 7) in 50 ml of 80% aqueous methanol, 1.25 ml of concentrated hydrochloric acid is added. The solution is stirred at reflux temperature for 20 minutes and cooled to ambient temperature. After neutralization using solid sodium acetate, the mixture is added to a saturated sodium chloride solution. The precipitate is extracted using three 250 ml portions of diethyl ether. The combined ether extracts are washed with 160 ml of water, dried using sodium sulphate and evaporated to dryness using reduced pressure. The crude product residue of 4 g is chromatographed using a preparative HPLC instrument of the type Waters 500 using a normal phase silica gel cartridge. Elution with 5% ethyl acetate/chloroform gives 2.22 g of pure compound 9 (total yield 58%, for examples 6, 7 and 8). The structure of compound 9 (which is the compound according to formula I where R 1 is hydrogen) is confirmed by the following spectral data:

Infrared spectrum-. X ^£™ 2.95 (OH) ; 6.0 and

6.25 µm (=C-C=0).

Proton magnetic resonance spectrum (in CDCl^):

0.80 (d, Y = 7 Hz, C 7 CH 3 ); 0.88 (C 18 CH 3 ); 3.94 (b, C1α<H>); 5.41 (d, Y = 8 Hz, C₂H); 5.71 (dm, C₂H); 5.71 (dm, C1gH); 5.82 and (C4~H).

EXAMPLE 9

7α-methyl-17α|3-propionyloxy-D-homo-19-norandrost-4. 1 6- diene- 3- on

(Step J for the formation of compound I

1 2

where R— is acyl and R~ is ethyl)

(a) To a solution of 1.0 g of compound 9 (from

step H) and 20 ml of dry pyridine (dried over potassium hydroxide pellets) are added 3 ml of propionic anhydride followed by stirring at ambient temperature for 42 hours. The mixture is added to 150 ml of a 3% hydrochloric acid solution and the precipitate is extracted in three 80 ml portions of diethyl ether. The combined ether extracts are washed once with 100 ml of water, dried using anhydrous sodium sulfate and evaporated to dryness using reduced pressure. A crystalline residue consisting of 1.1 g of compound I is obtained, which is recrystallized from ether-hexane to form an analytical sample. 1 2 The structure of compound I where R is acyl and R is ethyl is confirmed by the following spectral data:

Infrared spectrum: max"1 5.75 (0-c=0) ' 6'00°9

6.25 pm (=C-C=0).

Proton magnetic resonance spectrum (in CDCl3):

0.72 (d,C?CH 3 ); 0.91 (<C>18CH3); 5.12 (b, C^<H>)<;><5.>41 (d, Y = 9 Hz, C1gH); 5.76 (dm, C15H); 5.88 6 (C4H).

High-resolution mass spectrum:

Calculated for C23H32°3<:><3>56.2351

Found: 356.2323

(b) In a similar manner, proceeding as in sub-part (a) above, but substituting propionic anhydride with a stoichiometrically equivalent amount of

acetic anhydride;

butyric anhydride;

isosaroic anhydride;

n-octanoic anhydride;

dodecanoic anhydride;

hexadecanoic anhydride;

eicosanoic anhydride;

tetracosanoic anhydride;

acrylic anhydride;

methacrylic anhydride;

3-methylacrylic anhydride;

2-octenoylan anhydride;

2-hexadecenoylan anhydride;

2-tetracosenoic anhydride;

propionic anhydride;

2-hexynoic anhydride;

2-hexadequinoyl anhydride;

2-tetracosynoyl anhydride;

2- chloroacetic anhydride;

3- bromopropionyl anhydride;

2-chlorohexanoyl anhydride;

2-chlorohexadecanoylan anhydride;

2-chlorotetracosanoyl anhydride;

benzoyl anhydride;

4- chlorobenzoyl anhydride;

4-methylbenzoyl anhydride;

2- naphthoic anhydride;

4-chloro-2-naphthoyl anhydride;

6-bromo-2-naphthoyl anhydride;

phenylacetic anhydride;

3- phenylpropionic anhydride or

6-phenylhexanoyl anhydride, the following esters of compound 9 are obtained: 7a-methyl-17aø-acetyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-butanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-isobutanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α|3-n-octanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-dodecanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α[3-hexadecanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-eicosanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-tetracosanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-acryloyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α(3-me tacryloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-(3-methylacryloyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-(2-octenoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α(3-(2-hexadecenoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-tetracosenoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α(3-propynyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α|3-(2-hexynyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-hexadecynyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-tetracosynyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-chloroacetyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-(3-bromopropionyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-chlorohexanoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-(2-chlorohexadecanoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-chlorotetracosanoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-benzoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17β-(4-chlorobenzoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17β-(4-methylbenzoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-(2-naphthoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17β-(4-chloro-2-naphthoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17β-(6-bromo-2-naphthoyloxy)-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-phenylacetyloxy-D-homo-19-norandrost-4,16-dien-3-one;

70-methyl-17ap-(3-phenylpropionoyloxy)-D-homo-19-norandrost-4,16-dien-3-one; or

7α-methyl-17αβ-(6-phenylhexanoyloxy)-D-homo-19-norandrost-4,16-dien-3-one.

(c) In a similar manner, proceeding as in subpart (a) above, but substituting propionyl anhydride with a stoichiometric equivalent amount of

acetyl chloride;

propionyl chloride;

n-octanoyl chloride;

eicosanoyl chloride;

acryloyl chloride;

methacryloyl chloride;

2-tetracosenoyl chloride;

propynoyl chloride;

2-tetracosynoyl chloride;

2-chloroacetyl chloride;

2-chlorotetracosanoyl chloride;

benzoyl chloride;.

4-chlorobenzoyl chloride;

4-methylbenzoyl chloride;

2- naphthoyl chloride;

6-bromo-2-naphthoyl chloride;

phenylacetyl chloride;

3- phenylpropionyl chloride; or

6-phenylhexanoyl chloride, the following esters of compound 9 are obtained: 7α-methyl-17α-acetyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-propionyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17ap-n-octanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-eicosanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-acryloyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-methacryloyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-2-tetracosenyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17α-propynoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-2-tetracosynoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-2-chloroacetyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-2-chlorotetracosanoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αβ-benzoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-4-chlorobenzoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-4-methylbenzoyl-D-homo-19-norandrost-4,16-dien-3-one;

7α-methyl-17αp-2-naphthoyloxy-D-homo-19-norandrost-4,16-dien-3-one;

70-methyl- 1 7a 0-6-bromo-2-naphthoyloxy-D-homo -1 9-no rand rost-4,16-dien-3-one;

7a-methyl-1 7a|3-phenylacetyloxy-D-homo-1 9-norandrost-4,16-dien-3-one;

7α-methyl-17αp-3-phenylpropionoyloxy-D-homo-19-norandrost-4,16-dien-3-one; or

7α-methyl-1 7α(3-6-phenylhexanoyloxy-D-homo-19-norandrost-4,16-dien-3-one.

Example 10

The following example illustrates the preparation of representative pharmaceutical formulations containing an active compound according to formula I, for example 7α-methyl-17α(3-propionyloxy-D-homo-19-norandrost-4,16-dien-3-one.

I. V. design

In examples 11-17, the active ingredient is 7a-methyl-17a(3-propionyloxy-D-homo-19-norandrost-4,16-dien-3-one. Other compounds according to formula I can be substituted in this.

Example 11

The above ingredients are mixed thoroughly and pressed into single-shaped tablets.

Example 12

The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

Example 13

The above ingredients are intimately mixed and pressed into single-shaped tablets.

Example 14

The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

Example 15

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 with the following composition:

Constituents

Example 17

An oral suspension is prepared with the following composition:

Constituents

Although the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention.

Claims (46)

1. Compound according to the formula: where: R 1 is hydrogen or an acyl substituent of the formula: -(C=0 )-R <2> where: R 2 is an organic substituent selected from the group consisting of alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkylalkylenes, haloalkyls, aryls, haloaryls and arylalkylenes. 2. Compound according to claim 1, where R 1 is hydrogen. 3. Compound according to claim 1, where R 2 is selected from among alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkylalkylenes, aryls and arylalkylenes. 4. Compound according to claim 3, where R 2 is alkyl. 5. Compound according to claim 4, where R 2 is alkyl containing 1-16 carbon atoms. 6. Compound according to claim 5, wherein said alkyl is normal-alkyl. 2 7. Compound according to claim 6, where R is ethyl. 8. Compound according to claim 6, where R 2 is n-hexyl. 2 9. Compound according to claim 6, where R is n-nonyl. 10. Compound according to claim 6, where R 2 is n-tridecyl. 11. Compound according to claim 3, where R 2 is aryl. 12. Compound according to claim 11, where R 2 is phenyl. 13. Compound according to claim 3, where R 2 is arylalkylene. 14. Compound according to claim 13, where R 2 is 2-phenylethylene. 15. Compound according to the formula: where: 3 R is lower alkyl. 16. Compound according to the formula: where: 3 R is lower alkyl. 17. Compound according to the formula: where: 3 R is lower alkyl. 18. Compound according to the formula: where: 3 R is lower alkyl. 19. Compound according to the formula: 20. Compound according to the formula: where: 4 R is lower alkyl. 21. Compound according to the formula: where: 4 R is lower alkyl. 22. Compound according to the formula: where: 4 R is lower alkyl. 23. Compound according to the formula: where: 4 R is lower alkyl. 24. Compound according to the formula: where -. 4 R is lower alkyl. 25. Compound according to the formula: 26. A pharmaceutical composition suitable for regulating fertility in a male mammal while maintaining the male's libido, comprising a fertility-effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient. 27. Preparation, according to claim 26, where the preparation is administered orally. 28. Preparation according to claim 27, where the mammal is a human. 29. Preparation according to claim 28, where R 1 is acyl and R 2 is ethyl in the compound according to formula I. 30. Method for reducing fertility in a male mammal, which method comprises administering to said mammal an effective spermatogenesis-reducing amount of the compound according to claim 1. 31. Method according to claim 30, wherein said mammal is a human. 32. Method according to claim 31, where the spermatogenesis-reducing amount is an amount of from approx. 1-10 mg/kg per day. 1 2 33. Method according to claim 32, where R is acyl and R is ethyl in the compound according to formula I. 34. Method for increasing spermatogenesis in a male mammal, which method comprises administering to the mammal an effective spermatogenesis-increasing amount of the compound according to claim 1. 35. Method according to claim 34, wherein the mammal is a human. 36. Method according to claim 35, where the spermatogenesis-increasing amount is an amount of from approx. 0.01-0.99 mg/kg per day. 37. Method according to claim 36, where R 1 is acyl and R 2 is ethyl in the compound according to formula I. 38. Method for preparing a compound according to the formula: which procedure includes: (a) the 3-hydroxyl group in 7α-methylestrone is alkylated; (b) the product of step (a) is reacted with a trialkyl or triarylsilyl cyanide; (c) reacting the product of step (b) with a reducing agent to form the 17β-hydroxy-17-methylamine derivative; (d) reacting the product from step (c) with alkali nitrite; (e) reacting the product from step (d) with phenylselenium chloride and hydrogen peroxide; (f) the product from step (e) is reacted with a reducing agent; (g) reacting the product of step (f) with a strong reducing agent during partial reduction of the aromatic ring A; and (h) the product from step (g) is reacted with acid during de-alkylation of the 3-position on the A ring to form the 17aØ-hydroxy compound. 39. Method according to claim 38, where: (a) the alkylation in step (a) is carried out using methyl iodide; (b) the cyanide in step (b) is trimethylsilyl cyanide; (c) the reducing agent in step (c) is lithium aluminum hydride; (d) the nitrite in step (d) is formed by the combination of nitric acid and acetic acid; (e) said phenylselenyl chloride and hydrogen peroxide are used in step (e); (f) the reducing agent in step (f) is lithium aluminum hydride; (g) the strong reducing agent in step (g) is lithium in ammonia; and (h) the acid in step (h) is concentrated hydrochloric acid. 40. Process for the preparation of compounds according to the formula where: R 1 is an acyl substituent according to the formula: -(C=0)-R <2> where: R 2 is an organic substituent selected from the group consisting of alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkylenes, haloalkyls, aryls, haloaryls and arylalkylenes, which method comprises: (a) the compound according to the formula: is reacted with an acyl anhydride or an acyl halide. 41. Method according to claim 40, where the acyl anhydride in step (a) is propionic anhydride. 42. Process for the preparation of a compound according to the formula: which procedure includes: (a) bromination of D-homotestosterone followed by dehalogenation to form the 4,6-diene; (b) reacting the product of step (a) with lithium dimethyl copper to form the 4-ene-7α-methyl derivative; (c) reacting the product of step (b) with an alcohol and acid to form the 3,3-dihydroxy derivative; (d) selective oxidation of the product of step (c) to form the 17α-keto derivative; (e) oxidizing the product of step (d) with phenylselenenyl chloride followed by hydrogen peroxide to form the 4,16-diene derivative; (f) reducing the product from step (e) to form the 17ap-hydroxy derivative; and (g) hydrolyzing the product of step (f) with acid to form the 17ap-hydroxy compound. 43. Process for the preparation of compounds according to the formula: where: R 1 is an acyl substituent according to the formula: -(C=0 )-R<2> where: R 2 is an organic substituent selected from the group consisting of alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkylenes, haloalkyls, aryls, haloaryls and arylalkylenes, which method comprises: (a) bromination of D-homotestosterone followed by dehalogenation to form the 4,6-diene; (b) reacting the product of step (a) with lithium dimethyl copper to form the 4-ene-7α-methyl derivative; (c) reacting the product of step (b) with an alcohol and acid to form the 3,3-dihydroxy derivative; (d) selective oxidation of the product of step (c) to form the 17α-keto derivative; (e) oxidizing the product of step (d) using phenylselenenyl chloride followed by hydrogen peroxide to form the 4,16-diene derivative; (f) reducing the product from step (e) to form the 17ap-hydroxy derivative; (g) reacting the product of step (f) with acyl anhydride or acyl halide to form the 3,3-dimethoxy derivative; and (h) hydrolyzing the product from step (g) with acid to form the compound of formula I wherein R i is acyl. 44. Process for the preparation of a compound according to the formula: which method comprises: (a) hydrolyzing a compound according to the formula where: R<1> is an acyl substituent according to the formula: -(C-O)-R <2> where: R 2 is an organic substituent selected from the group consisting of alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkylenes, haloalkyls, aryls, haloaryls and arylalkylenes, which method comprises: (a) said acyl compound is reacted with aqueous acid. 45. Process for the preparation of compounds according to the formula: where -. R 1 is an acyl substituent according to the formula: -(C=0)-R <2> where: R 2 is an organic substituent selected from the group consisting of alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkenes, haloalkyls, aryls, haloaryls and arylalkylenes, which method comprises: (a) The 6-ene-testosterone is reacted with lithium dimethyl copper to form the 7α-methyl derivative; (b) the product from step (a) is reacted with ethylene glycol to form the 1,3-dioxolane derivative in the 3-position of the steroid; (c) the product of step (b) is oxidized with chromium oxide to form the 17-keto derivative; (d) the product of step (c) is reacted with trimethylsilyl cyanide in the presence of zinc iodide to form the corresponding 17-ether-17-nitrile; (e) the nitrile from step (d) is reduced to form the 17-ether-17-methyleneamine derivative; (f) reacting the product of step (e) with nitrite to form the D-homo-17α-keto derivative; (g) the product from step (f) is reacted with alcohol and acid to form the 3,3-dimethoxy derivative; (h) reacting the product from step (g) with phenylselenenyl chloride and hydrogen peroxide to form the 16-ene derivative; (i) the product of step (h), the 17α-keto derivative, is reduced to the 17α|3-hydroxy derivative; (j) the product from step (i) is reacted with acyl anhydride or acyl halide to form the 3,3-dihydroxy-17aO-ester; and (k) the product of step (j) is hydrolyzed in the presence of mild acid. 46. Method for preparing the compounds according to the formula: where: R 1 is an acyl substituent according to the formula: -(C=0)-R <2> where: R 2 is an organic substituent selected from the group consisting of alkyls, alkenyls, alkynyls, cycloalkyls, cycloalkylenes, haloalkyls, aryls, haloaryls and arylalkylenes, which method comprises: (a) The 6-ene-testosterone is reacted with lithium dimethyl copper to form the 7α-methyl derivative; (b) the product from step (a) is reacted with ethylene glycol to form the 1,3-dioxolane derivative in the 3-position of the steroid; (c) the product of step (b) is oxidized with chromium oxide to form the 17-keto derivative; (d) the product of step (c) is reacted with trimethylsilyl cyanide in the presence of zinc iodide to form the corresponding 17-ether-17-nitrile; (e) the nitrile from step (d) is reduced to form the 17-ether-17-methyleneamine derivative; (f) reacting the product of step (e) with nitrite to form the D-homo-17α-keto derivative; (g) the product from step (f) is reacted with alcohol and acid to form the 3,3-dimethoxy derivative; (h) reacting the product from step (g) with phenylselenenyl chloride and hydrogen peroxide to form the 16-ene derivative; (i) the product of step (h), the 17α-keto derivative, is reduced to the 17α|3-hydroxy derivative; (j) the product of step (i) is hydrolysed in the presence of aqueous acid.