DE3619453A1 - 4-HYDROXY DERIVATIVES OF C-6 OR C-7 SUBSTITUTED STEROIDS, PHARMACEUTICAL AGENTS CONTAINING THEM, AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

The invention relates to new 4-hydroxy derivatives of C-6- or C-7 substituted 4-androsten-3,17-dione, pharmaceutical preparations containing them and a method of manufacturing the same.

The invention provides compounds of the following general Formula (I) available:

wherein
the symbol ---- represents a single or double bond;
R is hydrogen, C _1-6 alkyl, a hydroxy protecting group, a -CO-R ₄ group, wherein R ₄ represents: (a) hydrogen, (b) C _1-22 alkyl which is unsubstituted or is substituted with a substituent from the group consisting of carboxy, C _4-7 cycloalkyl, heterocyclyl or phenyl; or (c) phenyl which is unsubstituted or substituted with a substituent selected from C _1-4 alkyl, trifluoromethyl, halogen and C _1-4 alkoxy;
or R represents an -SO ₂ -R ₅ group, wherein R _{5 represents} C _1-6 alkyl or phenyl, the phenyl ring being unsubstituted or substituted by C _1-4 alkyl;
one of the substituents R ₁ and R _{2 is} hydrogen and the other is a substituent selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and phenyl, wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halogen, hydroxy,

wherein each R ₆ and R _{7 are} independently hydrogen or C _1-6 alkyl, and

wherein n represents an integer from 1 to 6, and each R ₈ and R ₉ , which may be the same or different, represent hydrogen or C _1-6 alkyl, or R ₈ and R ₉ together with the nitrogen atom to which they are attached are bound to form a heterocyclyl ring; and the pharmaceutically acceptable salts thereof.

In the formulas according to the present description the dashed lines (,,,) mean that the There are substituents in the α configuration, i.e. H. that they are below the ring level or the chain while the thick solid lines () point out that the substituents in the β configuration is present, i. H. itself over the ring plane or the chain; the wavy lines () mean that the groups are in the α configuration or may be in the β configuration.

The above for the compounds of the invention given formula includes all possible isomers, especially α and β isomers, both separately as well as their mixtures.

Examples of pharmaceutically acceptable salts of Compounds according to the invention are, for. B. those with inorganic acids, such as hydrochloric acid, sulfuric acid, Phosphoric acid, hydrobromic acid, nitric acid, or with organic acids, such as citric acid, Formic acid, maleic acid, malic acid, tartaric acid, Methanesulfonic acid.

The alkyl, alkenyl and alkynyl groups as well the other aliphatic components that are in others Substituents of the formula (I) can be branched or represent linear chains.

A C _1-6 alkyl group is preferably a C _1-4 alkyl group, especially methyl, ethyl, propyl or t-butyl. Methyl or ethyl are particularly preferred.

A hydroxy protecting group (i.e. ether group) is one Group operating under mild reaction conditions, e.g. B. Acid hydrolysis, can be converted into a hydroxy group can. Examples include acetal ethers, enol ethers and silyl ether. Preferred groups are:

wherein W represents -O- or -CH ₂ - and Alk represents a lower alkyl group; 2′-tetrahydropyranyl or trimethylsilyl are particularly preferred.

A C _1-22 alkyl group as defined above is preferably an unsubstituted C _1-12 alkyl group or a C _1-4 alkyl group; a C _1-3 alkyl group which is substituted by carboxy or phenyl or heterocyclyl or C _4-7 cycloalkyl is particularly preferred. A heterocyclic ring as a substituent of a C _1-22 alkyl chain is preferably a heteromonocyclic ring which contains one or two heteroatoms from the group consisting of nitrogen, oxygen and sulfur; furyl is particularly preferred.

A C _4-7 cycloalkyl ring as a substituent on a C _1-22 alkyl chain is preferably a C _5-6 cycloalkyl ring.

If R _{4 represents} a phenyl ring which is substituted as indicated above, it is preferably substituted by methoxy, chlorine or trifluoromethyl.

If R _{5 is} a C _1-6 alkyl group, it is preferably methyl or ethyl.

If R _{5 is} a phenyl substituted by C _1-4 alkyl, it is preferably tolyl.

The C _2-6 alkenyl group is bonded to the steroid ring B via a single bond, such as. B. with vinyl, ie CH ₂ = CH-, allyl, ie CH ₂ = CH-CH ₂ -, or 1-propenyl, ie CH ₃ -CH = CH-. Hence the symbol ---- can represent a single or a double bond. Preferred C _2-6 alkenyl radicals are vinyl, allyl, 1-propenyl, 1-butenyl and 2-butenyl, particularly preferably vinyl and allyl.

A C _2-6 alkynyl group is preferably a C _2-4 alkynyl group, particularly preferably ethynyl or propargyl.

A halogen atom is e.g. B. chlorine, fluorine or bromine.  

A

is z. For example: -NH ₂ , -NHCH ₃ , -NHC ₂ H ₅ , -N (CH ₃ ) ₂ or -N (C ₂ H ₅ ) ₂ , preferably -NH ₂ , -N (CH ₃ ) ₂ or -N (C ₂ H ₅ ) ₂ .

The integer n preferably represents 1, 2, 3 or 4, particularly preferably 1 or 2, and most preferably 2.

A

is z. E.g .: -NH ₂ , -NHCH ₃ , -N (C ₂ H ₅ ) ₂ or -NHC ₂ H ₅ , preferably -NH ₂ , -N (CH ₃ ) ₂ or -N (C ₂ H ₅ ) ₂ , or if R ₈ and R ₉ together with the nitrogen atom to which they are attached form a heterocyclyl ring, this is preferably a saturated ring which preferably contains from 2 to 6 carbon atoms and optionally a further hetero atom from the group, Has nitrogen, oxygen and sulfur; this heterocyclyl ring is preferably selected from the group consisting of aziridinyl, pyrrolidinyl and imidazolidinyl.

Preferred compounds according to the invention are compounds of the formula (I) in which
the symbol ---- represents a single or double bond;
R represents hydrogen, C _1-4 alkyl, a hydroxy protecting group or -CO-R ₄ , wherein R _{4 has} the meaning given above;
one of the substituents R ₁ and R _{2 is} hydrogen and the other has the following meaning: C _1-4 -alkyl, C _2-4 -alkenyl or phenyl, the phenyl ring being unsubstituted or substituted by a substituent selected from hydroxy, halogen ,

wherein each R ' ₆ and R' _{7 are} independently hydrogen or C _1-4 alkyl, and

wherein m is an integer from 1 to 4 and R ′ ₈ and R ′ ₉ , which are the same, represent hydrogen, methyl or ethyl, or R ′ ₈ and R ′ ₉ together with the nitrogen atom to which they are attached Form aziridinyl, pyrrolidinyl or imidazolidinyl ring; and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds according to the invention are compounds of the formula (I) in which:
the symbol ---- represents a single or double bond;
R represents hydrogen, C _1-4 alkyl, 2'-tetrahydropyranyl, trimethylsylyl or a -CO-R ₄ group which is selected from formyl, acetyl, propionyl, butyryl, n-hexanoyl, n-heptanoyl, n-octanoyl , n-dodecanoyl, semisuccinyl, (3'-cyclopentyl) propionyl, (3'-cyclohexyl) propionyl and benzoyl;
one of the substituents R ₁ and R _{2 is} hydrogen and the other is C _1-4 alkyl, C _2-4 alkenyl, or phenyl which is unsubstituted or substituted with a substituent selected from halogen, amino and dimethylamino; and the pharmaceutically acceptable salts thereof.

Examples of specific compounds according to the invention are:

4-hydroxy-6α-methyl-androst-4-en-3,17-dione;
4-hydroxy-6β-methyl-androst-4-en-3,17-dione;
4-hydroxy-7α-methyl-androst-4-en-3,17-dione;
4-hydroxy-7β-methyl-androst-4-en-3,17-dione;
4-hydroxy-6-methyl-androsta-4,6-diene-3,17-dione;

the corresponding 4-methoxy, 4-ethoxy and 4- (2'-tetrahydro-pyranyloxy) ether and the 4-formate, 4-acetate, 4-benzoate, 4-propionate, 4-butyrate, 4-heptanoate, 4-octanoate, 4- (3'-cyclopentyl propionate) -, 4- (3'-Cyclohexyl propionate) -, 4-dodecanoate and 4-Hemisuccinate ester of the above 4-hydroxy derivatives.

The compounds according to the invention and their salts can be obtained as follows:

• (a) hydrolyzing a compound of formula (II) wherein the symbol ---- and R ₁ and R _{2 have} the meanings given in claim 1, whereby - depending on the reaction conditions - a compound of the formula (I) is obtained in which R is hydrogen or C _1-6 -alkyl; or
• (b) hydrolyzing a compound of formula (III) wherein the symbol ---- and R ₁ and R _{2 have} the meanings given in claim 1 and Hal is halogen, to give a compound of the formula (I) in which R is hydrogen; or
• (c) oxidizing a compound of formula (IV) wherein the symbol ---- and R ₁ and R _{2 have} the meanings given in claim 1, giving a compound of the formula (I) in which R is hydrogen; and - if desired - acylating a compound of formula (I) in which R is hydrogen to give a compound of formula (I) in which R is a -CO-R ₄ - or -SO ₂ -R ₅ group , wherein R ₄ and R _{5 have} the meanings given in claim 1, and / or - if desired - etherifying a compound of the formula (I) in which R is hydrogen to give a compound of the formula (I) in which RC _1-6 alkyl or a hydroxy protecting group; and / or, if desired, converting a compound of formula (I) to another compound of formula (I), and / or, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof ; and / or - if desired - converting a salt into a free compound, and / or - if desired - separating a mixture of isomers of the compounds of formula (I) into the individual isomers.

The hydrolysis of a compound of formula (II) to Obtaining a compound of formula (I) wherein R is hydrogen represents z. B. by treatment with suitable organic acids or a mixture thereof be carried out at a temperature of approx. room temperature to the reflux temperature. The reaction is preferably carried out by treatment with  a mixture of glacial acetic acid and concentrated sulfuric acid at a temperature of about 10 to about 50 ° C, e.g. B. according to B. Camerino et al, 1956, Il Farmaco 7, 19, carried out.

The hydrolysis of a compound of formula (II) to obtain a compound of formula (I) wherein RC is _1-6 alkyl may e.g. B. by treatment with a suitable aqueous C _1-6 alkyl alcoholic alkali solution, the alkali preferably being NaOH, at a temperature in the range from about 20 ° C. to the reflux temperature, over a period of time of about 1 hour to about 48 hours, e.g. B. according to B. Camerino et al 1962, Gazz. Chim. It. 912, 709.

In a compound of formula (III), Hal is preferably chlorine. The hydrolysis of a compound of formula (III) can e.g. B. by treatment at reflux temperature with a suitable alcoholic alkali solution in an inert atmosphere, for. B. nitrogen atmosphere. Preferred alcohols are e.g. B. C _1-4 alkyl alcohols, especially t-butanol. A preferred alkali hydroxide is e.g. B. KOH.

A compound of formula (IV) is a 5β derivative or is a mixture of 5α, 5β derivatives in a ratio as is usually obtained in a reduction process of Δ4 double bond derivatives, according to generally known in organic chemistry Methods is followed. The oxidation of a compound of formula (IV) can e.g. B. in a suitable C _1-6 alcoholic medium, preferably t-butanol with potassium t-butoxide, in an air atmosphere or by introducing an oxygen or air stream over the stirred solution. The reaction temperature can go from approx. 10 ° C to the reflux temperature; reaction times can range from approx. 1 hour to a few days. A compound of formula (I) can - as indicated above - be converted into another compound of formula (I) by known methods. For example, a compound of formula (I) in which R represents hydrogen can be acylated to give a compound of formula (I) in which R represents -CO-R ₄ or -SO ₂ -R ₅ , where R ₄ and R ₅ have the meanings given above. This is done by treatment with a suitable acylation agent. This can e.g. B. represent a reactive derivative of a suitable carboxylic or sulfonylic acid, such as. B. a halide, preferably the chloride; the implementation takes place e.g. B. in the presence of a basic agent, preferably an organic base, such as. B. pyridine. The reaction can be carried out at a temperature from about room temperature to about 100 ° C.

A compound of formula (I) in which RC represents _1-6 alkyl can be converted into a compound of formula (I) in which R represents hydrogen by methods known per se, e.g. B. by treatment with pyridine hydrochloride or a strong acid such as HCl in organic solvents, e.g. B. Dioxane. In addition, an -OR radical can be converted as a free hydroxy group in the C ₄ position into a C _1-6 alkoxy group or into a protected hydroxy group or vice versa. This hydroxy protective group can be converted into a free hydroxy group by methods known per se.

Similarly, a compound of formula (I) in which the symbol ---- represents a single bond can be converted to another compound of formula (I) in which the symbol ---- represents a double bond, according to an known methods.

Furthermore, a connection of the Formula (I) in a salt or a corresponding salt in a free connection can be converted; can also a separation of an isomer mixture into the individual Isomers made by conventional methods will. For example, the separation of a mixture optical isomers into the individual isomers Salt formation with an optically active acid and subsequent fractional crystallization or by esterification with an optically active acid derivative and separation of the diastereoisomers.

Thus the separation of a mixture can be more geometric Isomer z. B. by fractional crystallization or carried out by separation using column chromatography will.

A compound of formula (II) can be obtained by epoxidation of a compound of formula (V)

wherein the symbol ---- and R ₁ and R _{2 have} the meanings given above.

The epoxidation of a compound of formula (V) can be carried out by treating it with a suitable oxidizing agent, preferably concentrated, e.g. B. 36% H ₂ O ₂ in alcoholic alkali hydroxide, preferably KOH or NaOH in methanol, at a temperature of about 0 ° C to room temperature within 2 hours to several days.

A compound of formula (III) can be obtained by halogenation of a compound of formula (V) according to known methods, using a Halogenating agent, e.g. B. sulfuryl chloride in Pyridine solution at a temperature of about 0 to about 50 ° C within a period of one to several Hours.

The compound of formula (IV) can e.g. B. can be obtained from a compound of formula (V) under reaction conditions as are known to those skilled in the art. For example, according to B. Camerino et al, Gazz. Chim. Ital., 1962, 92 / II, 676, the reduction with hydrogen at 5% Pd / C as catalyst in the presence of a base, e.g. B. triethylamine, in a solvent selected from the class of a C _1-6 alcohol, a C _3-10 ketone or a mixture thereof, e.g. B. t-butanol or acetone, at a hydrogen pressure of 1 to 10 atm and at temperatures which are preferably kept between 25 and 50 ° C.

The compounds of formula (V) are known Connections are and can be from known connections can be obtained by methods known per se.

If necessary, responsive functional groups in the compounds of the formulas (I), II), (III), (IV) and (V) with a suitable one Protective reagent to be protected after implementation with the help of known methods as they arise from the chemical literature can be removed.

The compounds according to the invention have one Aromatase inhibitory activity.

It is known to convert androgens too Estrogens take place when the A ring is in one 3-oxo-Δ4-10 methyl steroid (androstenedione and testosterone) is converted into an aromatic ring.

The final step in estrogen biosynthesis  is made possible by aromatase, a microsomal P 450 enzyme, causes, which acts on the androgenic substrate. This reaction does not only take place in the endocrine glands instead of like the ovaries, testis and adrenal glands, rather this reaction is over the whole organism spread.

There is a balance in a healthy body between androgens and estrogens; the flavoring serves to maintain this balance in the body, in the different tissues. It is also known that estrogens are the main hormone stimulator for the growth of hormone-dependent types of breast cancer represents; thus the enzyme aromatase plays both in the pathogenesis as well as in the treatment of hormone-dependent breast cancer play an important role. That's why the compounds according to the invention are suitable as an alternative to endocrine amputation, e.g. B. oophorectomy, Hypophysectomy, or adrenalectomy, during treatment of advanced, hormone-dependent breast cancer.

The aromatase inhibitors of the formula (I) can also used to control reproduction: one Indeed, decrease in estrogen levels in vivo results to inhibit gonadal activity and not adequate development of the uterus; Aromatase inhibitors can simultaneously represent implantation inhibitors.

Another application of the compounds according to the invention is the treatment of prostatic hypotrophy or hyperplasia associated with excessive  Estrogen production stops and leads to a shift the estrogen / androgen ratio after higher values. These compounds are also suitable for the treatment of Uterine, ovarian and pancreatic carcinoma.

The 6- or 7-substituted 4-hydroxy-androsten-3,17-dione derivatives according to the invention have an increased in vivo activity compared to the unsubstituted derivatives, which is due to their stability towards enzymatic metabolic processes. With regard to their high therapeutic index, the compounds according to the invention can be used with great certainty in medicine. The approximate acute toxicity ( LD ₅₀ ) of the compounds according to the invention, determined on the basis of a single administration of increasing doses and measured on the seventh day after the treatment, was found to be negligible in mice.

The compounds of the invention can in one A variety of forms of administration are given, e.g. B. orally, in the form of tablets and capsules, sugar or film coated tablets, liquid solutions or Suspensions; rectally, in the form of suppositories; parenterally, e.g. B. intramuscularly or by intravenous Injection or infusion.

The dose depends on the age, the weight, the Condition of patient and mode of administration; e.g. B. may be the one used for oral administration in adults Dose of about 10 to about 200 mg per dose, 1 to 5 times a day.  

The invention encompasses pharmaceutical preparations which a combination according to the invention in combination with a pharmaceutically acceptable excipient that represent a carrier or a diluent may contain.

The pharmaceutical preparations that the contain compounds according to the invention usually produced by conventional processes and administered in a pharmaceutically acceptable form.

For example, solid oral forms along with contain the active ingredient diluent, e.g. B. lactose, Dextrose, sucrose, cellulose, cornstarch and Potato starch; Lubricants, e.g. B. silicon oxide, talc, Stearic acid, magnesium or calcium stearate, and / or Polyethylene glycols; Binders, e.g. B. starches, gum arabic, Gelatin, methyl cellulose, carboxymethyl cellulose or Polyvinyl pyrrolidone; disintegrating agents, e.g. B. a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; Dyes; Sweeteners; moisturizing agents, such as lecithin, polysorbates, Lauryl sulfates; and generally non-toxic and pharmacologically inactive substances as described in pharmaceutical formulations can be used. The mentioned pharmaceutical preparations can after known methods are prepared, e.g. B. by mixing, Granulating, tableting, sugar coating or Film coating process. The liquid dispersions for oral administrations, e.g. B. syrups, emulsions and represent suspensions.  

The syrups can be used as a carrier e.g. B. sucrose or Sucrose with glycerin and / or mannitol and / or Sorbitol, included; in particular one can be diabetic Syrup to be administered to patients as a carrier only contain such products that are not in metabolism to glucose or only in very small amounts Glucose are broken down, e.g. B. Sorbitol.

The suspensions and emulsions can be used as carriers e.g. B. natural gum, agar, sodium alginate, pectin, Methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol contain.

The suspensions or solutions for intramuscular Injections can be combined with the active ingredient contain pharmaceutically acceptable carriers, e.g. B. sterile water, olive oil, ethyl oleate, glycols, e.g. B. Propylene glycol, and - if desired - an appropriate amount of lidocaine hydrochloride. The Solutions for intravenous injections or infusions can as a carrier z. B. contain sterile water; preferably they are in the form of sterile aqueous, isotonic saline solutions.

The suppositories can be combined with the active ingredient contain a pharmaceutically acceptable carrier, e.g. B. cocoa butter, polyethylene glycol, a polyoxyethylene Sorbitan fatty acid ester surfactant or Lecithin.

The following examples are intended to illustrate the invention without restricting it.

example 1

3.63 g of 4,5-epoxy-6α-methyl-androstane-3,17-dione were dropwise into a chilled mixture (100 ml) Glacial acetic acid and concentrated sulfuric acid (98: 2) added. The solution was allowed to rise to room temperature left standing and stirred for 20 hours.

The reaction mixture was then poured into ice water (900 ml), left to stand for 15 minutes and the solids filtered and dried. The crude mixture was purified on silica gel using ethyl acetate / methylene chloride (5:95) as the eluent; 0.5 g of pure 4-hydroxy-6α-methyl-androst-4-en-3,17-dione with a melting point of 210 ° C. was obtained. [ α ] _D = + 104 ° (C = 1 EtOH).

According to the method and described above starting from corresponding 4,5-epoxy-steroid derivatives the following connections were made:

4-hydroxy-6β-methyl-androst-4-en-3,17-dione,
F: 176-178 ° C, UV g max 280 nm, ε = 10750;
4-hydroxy-7α-methyl-androst-4-en-3,17-dione,
F: 168-170 ° C, [ α ] _D + 182 ° (C = 1 CHCl ₃ );
4-hydroxy-7β-methyl-androst-4-en-3,17-dione,
F: 154-156 ° C, [ α ] _D + 169 ° (C = 1 CHCl ₃ );
4-hydroxy-6-methyl-androsta-4,6-diene-3,17-dione;
4-hydroxy-7β-ethyl-androst-4-en-3,17-dione; and
4-hydroxy-7α-ethyl-androst-4-en-3,17-dione.

Example 2

To a solution obtained by dissolving of 4,5-epoxy-6α-methyl-androstane-3,17-dione (2 g) in 200 ml of methanol, 20 ml of 4 N sodium hydroxide solution added and the reaction mixture under 60 minutes Stirring kept under reflux. The solvent was removed in vacuo, dried, the aqueous Phase was diluted with 100 ml of water and the product extracted twice with 100 ml dichloromethane. The organic phase was washed, dried and the crude product obtained by evaporation of the solvent using flash chromatography with dichloromethane / diethyl ether purified in silica gel, 1.77 g of pure 4-Methoxy-6α-methyl-androst-4-en-3,17-dione obtained were.

The following compounds were made in an analogous manner produced:

4-methoxy-6β-methyl-androst-4-en-3,17-dione;
4-methoxy-7α-methyl-androst-4-en-3,17-dione;
4-methoxy-7β-methyl-androst-4-en-3,17-dione;
4-methoxy-6-methyl-androsta-4,6-diene-3,17-dione;
4-ethoxy-6β-methyl-androst-4-en-3,17-dione;
4-ethoxy-6α-methyl-androst-4-en-3,17-dione;
4-ethoxy-7α-methyl-androst-4-en-3,17-dione;
4-ethoxy-7β-methyl-androst-4-en-3,17-dione;
4-ethoxy-6-methyl-androsta-4,6-diene-3,17-dione;
4-butoxy-6β-methyl-androst-4-en-3,17-dione;
4-butoxy-6α-methyl-androst-4-en-3,17-dione;
4-butoxy-7α-methyl-androst-4-en-3,17-dione;
4-butoxy-7β-methyl-androst-4-en3,17-dione; and
4-butoxy-6-methyl-androsta-4,6-diene-3,17-dione.

Example 3

A solution became under a nitrogen atmosphere from 3.02 g of 4-chloro-7α, β-methyl-androst-4-en-3,17-dione in 100 ml of t-butanol at reflux temperature with the help heated by an external heat bath; then was under Stir a solution of 2.1 g of potassium hydroxide in 40 ml of water was added dropwise to the reaction mixture.

The solution was refluxed for 30 minutes then cooled to room temperature and with 2.5 ml Acetic acid neutralized.

The mixture was diluted with 100 ml of water and t-butanol was removed in vacuo; the residue was extracted with dichloromethane and the organic phase was dried and the solvent was distilled off in vacuo. The crude product was chromatographed on silica gel using hexane / ethyl ether as a gradient from 50:50 to a ratio of 10:90; 0.55 g of pure, rapidly migrating 4-hydroxy-7α-methyl-androst-4-en-3,17-dione with a melting point of 168 to 170 ° C., [ α ] _D + 182 ° (C = 1 CHCl ₃ ) and 1.50 g of pure, slower migrating 4-hydroxy-7β-methyl-androst-4-en-3,17-dione with a melting point of 154 to 156 ° C, [ α ] _D + 169 (C = 1 CHCl ₃ ) obtained.

According to the procedure given above, starting from of the corresponding 4-halo derivatives, the following Receive connections:

4-hydroxy-6α-methyl-androst-4-en-3,17-dione, m.p .: 210 ° C;
4-hydroxy-6β-methyl-androst-4-en-3,17-dione,
F: 176-178 ° C;
4-hydroxy-6-methyl-androsta-4,6-diene-3,17-dione;
4-hydroxy-6β-ethyl-androst-4-en-3,17-dione; and
4-hydroxy-7β-ethyl-androst-4-en-3,17-dione.

Example 4

A solution of 0.50 g of 4-chloro-7β-ethyl-androst-4-en-3,17-dione in 20 ml of t-butanol was refluxed in Treated nitrogen atmosphere and a solution Drop 0.35 g of potassium hydroxide in 5 ml of water added to the reaction mixture. The solution turned 30 Warmed for minutes, then cooled to room temperature and neutralized with acetic acid.

The mixture was diluted with 30 ml of water and the alcohol removed in vacuo; the residue was filtered and crystallized from diisopropyl ether to give 0.32 g of pure 4-hydroxy-7β-ethyl-androst-4-ene-3,17-dione, UV λ max 279 nm, ε = 12 240.

Following the same procedure, starting from the 7α isomer,  became 4-hydroxy-7α-ethyl-androst-4-en-3,17-dione produced.

Example 5

7β-methyl-androstane-3,17-dione (1.5 g) was dissolved in 30 ml dissolved t-butanol; the solution became 1.85 g Potassium t-butoxide implemented and in the presence of drier Air shaken while using the temperature an external cooling bath kept at 30 ° C for 7 hours has been.

The reaction mixture was then cooled to 25 ° C., neutralized with acetic acid and the solvent removed in vacuo. The crude product was purified on silica gel using hexane / diethyl ether (1: 1), whereby 0.85 g of pure 4-hydroxy-7β-methyl-androst-4-ene-3,17-dione with a melting point of 154 to 156 ° C was obtained. UV λ max 279 nm, ε = 12,000.

The following compounds were made in an analogous manner receive:

4-hydroxy-6α-methyl-androst-4-en-3,17-dione, F: 210 ° C, [ α ] _D + 104 ° (C = 1 EtOH);
4-hydroxy-6β-methyl-androst-4-en-3,17-dione;
4-hydroxy-7α-methyl-androst-4-en-3,17-dione,
F: 168-170 ° C, [ a ] _D + 182 ° (C = 1 CHCl ₃ );
4-hydroxy-7β-ethyl-androst-4-en-3,17-dione;
4-hydroxy-6-methyl-androsta-4,6-diene-3,17-dione; and
4-hydroxy-7α-ethyl-androst-4-en-3,17-dione.

Example 6

A solution of 2 g of 4-hydroxy-7β-methyl-androst-4-en-3,17-dione in 4 ml of dry dichloromethane and 15.6 ml of freshly distilled dihydropyran was cooled to 10 ° C. using an external cooling bath and 0. 14 ml of POCl _{3 are} added dropwise.

The mixture was allowed to rise to room temperature Let stand and then stir for 1 hour.

It was then neutralized with triethylamine, washed with water and with brine. The organic layer was dried with Na ₂ SO ₄ and the solvent removed in vacuo. The crude product was chromatographed on Al ₂ O ₃ using hexane / ethyl acetate (7: 3), 1.69 g of pure 4- (2′-tetrahydro-pyranyloxy) - 7β-methyl-androst-4-en-3, 17-dione were obtained. UV λ max 259, ε 12 500.

Following the same procedure, the following were Connections established:

4- (2'-tetrahydropyranyloxy) -6α-methyl-androst-4-ene-3,17-dione;
4- (2'-tetrahydropyranyloxy) -6β-methyl-androst-4-ene-3,17-dione;
4- (2'-tetrahydropyranyloxy) -7α-methyl-androst-4-ene-3,17-dione;
4- (2'-tetrahydropyranyloxy) -6-methyl-androsta-4,6-diene-3,17-one;
4- (2'-tetrahydropyranyloxy) -6β-ethyl-androst-4-ene-3,17-dione; and
4- (2'-tetrahydropyranyloxy) -6α-ethyl-androst-4-ene-3,17-dione.

Example 7

1 ml of acetic anhydride was added to a cooled solution of 0.40 g of 4-hydroxy-7β-methyl-androst-4-en-3,17-dione in 3 ml of dry pyridine and the mixture was cooled to 0 ° C. overnight. The solvent was removed in vacuo and the solid residue was washed four times with carbon tetrachloride; the crude product was recrystallized from methanol / acetone (50:40), using pure 4-acetoxy-7β-methyl-androst-4-en-3,17-dione (0.35 g) with a melting point of 178 to 180 ° C. were obtained. UV λ max 279 nm, ε 12 900.

According to the above procedure, the 4-formyloxy,  4-acetoxy, 4-propionyloxy, 4-butyryloxy, 4-heptanoyloxy-, 4-octanoyloxy-, 4- (3'-cyclohexyl-acetoxy) -, 4- (3'-Cyclopentyl-propionyloxy) -, 4- (3'-Cyclohexyl-propionyloxy) -, 4-dodecanoyloxy-, 4-hemisuccinyloxy-, 4-benzoyloxy-, 4- (p-methoxybenzoyloxy) -, 4- (p-chlorobenzoyloxy) - and 4- (p-trifluoromethylbenzoyloxy) derivatives of 4-hydroxy steroids, as used in Examples 1, 3, 4 and 5 occur.

Example 8

Tablets weighing 0.150 g containing 25 mg of active ingredient were made as follows:
androst-4-en-3,17-dione 250 g lactose 800 g corn starch 415 g talcum powder 30 g magnesium stearate 5 g

The 4-hydroxy-6α-methyl-androst-4-en-3,17-dione, the Lactose and half of the cornstarch were mixed together mixed; the mixture was then passed through a sieve 0.5 mm mesh size. Corn starch (10 g) was suspended in warm water (90 ml) and the obtained Paste used to granulate the powder. The Granules were dried on a 1.4 mm sieve  Mesh size applied, then the remaining amount Starch, talc and magnesium stearate added, carefully mixed and processed into tablets.

Example 9

Capsules, each weighing 0.200 g, containing 20 mg of active ingredient, were produced as follows:
4-en-3,17-dione-4-acetate 10 g lactose 80 g corn starch 5 g magnesium stearate 5 g

This formulation was divided into two-part hard gelatin capsules encapsulated, with 0.200 g being dosed into each capsule.

Claims (13)

1. Compound of the following formula (I) wherein
the symbol ---- means a single or double bond;
R represents hydrogen, C _11-6 alkyl, a hydroxy protecting group, a -CO-R ₄ group, wherein R _{4 represents} (a) hydrogen; (b) C _1-22 alkyl which is unsubstituted or substituted with a substituent from the group consisting of carboxy, C _4-7 cycloalkyl, heterocyclyl or phenyl; or (c) phenyl which is unsubstituted or substituted with a substituent from the group C _1-4 alkyl, trifluoromethyl, halogen and C _1-4 alkoxy; or R represents an -SO ₂ R ₆ group, wherein R _{5 represents} C _1-6 alkyl or phenyl, the phenyl ring being unsubstituted or substituted by C _1-4 alkyl;
one of the substituents R ₁ and R _{2 is} hydrogen and the other is a substituent which is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and phenyl, where the phenyl ring is unsubstituted or substituted with a substituent selected from halogen, hydroxy where each R ₆ and R ₇ independently of one another are hydrogen or C _1-6 alkyl, and wherein n is an integer from 1 to 6 and R ₈ and R ₉ , which are the same or different, each represent hydrogen or C _1-6 alkyl, or R ₈ and R ₉ together with the nitrogen atom to which they are attached , form a heterocyclyl ring, and the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein the symbol ---- represents a single or double bond; R represents hydrogen, C _1-4 alkyl, a hydroxy protecting group or -CO-R ₄ , where R _{4 has} the meaning given in claim 1; one of the substituents R ₁ and R _{2 is} hydrogen and the other is C _1-4 alkyl, C _2-4 alkenyl or phenyl, the phenyl ring being unsubstituted or substituted by a substituent selected from the group consisting of hydroxyl and halogen, wherein each R ' ₆ and R' _{7 are} independently hydrogen or C _1-4 alkyl, and wherein m represents an integer from 1 to 4 and R ′ ₈ and R ′ ₉ , which are the same, represent hydrogen, methyl or ethyl, or R ′ ₈ and R ′ ₉ together with the nitrogen atom to which they are attached one Form aziridinyl, pyrrolidinyl or imidazolidinyl ring; and the pharmaceutically acceptable salts thereof. 3. A compound according to claim 1, wherein the symbol ---- represents a single or double bond; R is hydrogen, C _1-4 alkyl, 2′-tetrahydropyranyl, trimethylsylyl or a -CO-R ₄ group selected from formyl, acetyl, propionyl, butyryl, n-hexanoyl, n-heptanoyl, n-octanoyl, n- Dodecanoyl, hemisuccinyl, (3'-cyclopentyl) propionyl, (3'-cyclohexyl) propionyl and benzyl; one of the substituents R ₁ and R _{2 is} hydrogen and the other is C _1-4 alkyl, C _2-4 alkenyl or phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of halogen, amino and dimethylamino ; and the pharmaceutically acceptable salts thereof. 4. Compound selected from the group: 4-hydroxy-6α-methyl-androst-4-en-3,17-dione;
4-hydroxy-6β-methyl-androst-4-en-3,17-dione;
4-hydroxy-7α-methyl-androst-4-en-3,17-dione;
4-hydroxy-7β-methyl-androst-4-en-3,17-dione;
4-hydroxy-6-methyl-androsta-4,6-diene-3,17-dione; the corresponding 4-methoxy, 4-ethoxy and 4- (2′-tetrahydro-pyranyloxy) ethers and the 4- Formate, 4-acetate, 4-benzoate, 4-propionate, 4-butyrate, 4-heptanoate, 4-octanoate, 4- (3′-cyclopentyl propionate) -, 4- (3 ′ -Cyclohexyl-propionate) -, 4-dodecanoate and 4-hemisuccinate esters of the aforementioned 4-hydroxy derivatives. 5. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, characterized by:

• (a) hydrolyzing a compound of formula (II) wherein the symbol ---- and R ₁ and R _{2 have} the meanings given in claim 1, whereby - depending on the reaction conditions - a compound of the formula (I) is obtained in which R is hydrogen or C _1-6 -alkyl; or
• (b) hydrolyzing a compound of formula (III) wherein the symbol ---- and R ₁ and R _{2 have} the meanings given in claim 1 and Hal is halogen, to give a compound of the formula (I) in which R is hydrogen; or
• (c) oxidizing a compound of formula (IV) wherein the symbol ---- and R ₁ and R _{2 have} the meanings given in claim 1, giving a compound of the formula (I) in which R is hydrogen; and - if desired - acylating a compound of formula (I) in which R is hydrogen to give a compound of formula (I) in which R is a -CO-R ₄ - or -SO ₂ -R ₅ group , wherein R ₄ and R _{5 have} the meanings given in claim 1, and / or - if desired - etherifying a compound of the formula (I) in which R is hydrogen to give a compound of the formula (I) in which RC _1-6 alkyl or a hydroxy protecting group; and / or, if desired, converting a compound of formula (I) to another compound of formula (I), and / or, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof ; and / or - if this is desired - converting a salt into a free compound, and / or - if this is desired - separating a mixture of isomers of the compounds of the formula (I) into the individual isomers:

6. Pharmaceutical preparation, thereby characterized as an active ingredient a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof together with a suitable carrier and / or Contains diluent.   7. Use of the compound according to formula (I) or a salt of the same as in one or defined several of the preceding claims is as an aromatase inhibitor. 8. Use of a compound according to formula (I) or a salt thereof, as in one or defined several of the preceding claims is in the treatment of advanced hormone-dependent breast cancer. 9. Use of a compound according to formula (I) or a salt thereof, as in one or more of the preceding claims is to control reproduction. 10. Use of a compound according to formula (I) or a salt thereof, as in one or defined several of the preceding claims is in the treatment of prostatic Hypertrophy or hyperplasia. 11. Use of a compound according to formula (I) or a salt thereof, as in one or defined several of the preceding claims is in the treatment of uterus, ovary or pancreatic cancer. 12. A process for producing a compound of Formula (I) as defined in claim 1 characterized in that  this is essentially one of Examples 1 to 7 corresponds. 13. Pharmaceutical preparation, thereby characterized that they are essentially corresponds to Examples 8 and 9.