New 6-hydroxy and 6-oxo-androstane derivatives active on the cardiovascular system and pharmaceutical compositions containing same

Abstract: 6-Hydroxy and 6-oxo-androstane derivatives having the general formula (I): wherein the symbol represents a single or a double bond and A, R 1 and R 2 have the meanings given in the description; a pharmaceutical composition comprising the same and their use for the preparation of a medicament useful for the treatment of cardiovascular disorders such as heart failure and hypertension are disclosed.

Description: The present invention relates to new 6-hydroxy and 6-oxo-androstane derivatives and to pharmaceutical compositions containing same for the treatment of cardiovascular disorders such as heart failure and hypertension. The compounds of the invention have the following general formula ( I ): wherein: the symbol A represents CH-OR, C=N-OR, CH-CH=N-OR and C=CH-CH=N-OR, where: R represents a C2-C6 alkyl group substituted by NR 3 R 4 , NHC(NH)NHR 5 , C(NH)NR 6 R 7 or -O-(C2-C4-alkyl)-NR 3 R 4 groups, wherein R 3 and R 4 , which may be the same or different, are H, C1-C6 lower alkyl group, benzyl or phenyl or R 3 and R 4 , taken together with the nitrogen atom, form an unsubstituted or substituted saturated or unsaturated mono-heterocyclic 5- or 6-membered ring optionally containing another heteroatom chosen from oxygen, sulphur or nitrogen, R 5 , R 6 and R 7 , which are the same or different, may be H or C1-C4 lower alkyl; the symbol ---· in position 6 and in position 17 represents independently a single or a double bond; when the symbol ---· represents a single bond R 1 represents H, C1-C4 lower alkyl and C2-C6 acyl groups; R 2 represents H, methyl, C2-C6 alkyl group unsubstituted or substituted by NR 3 R 4 , C2-C6 acyl groups, benzoyl, benzoyl substituted by one or more hydroxy, methoxy, amino, chloro, fluoro, methylmercapto groups. when the symbol ---· represent a double bond, it means a keto group and no R 1 or R 2 is present. Also included in this invention are pharmaceutically acceptable salts of ( I ), which retain the biological activity of the base and are derived from known acids such as, for example, hydrochloric, sulphuric, phosphoric, malic, tartaric, maleic, citric, methanesulfonic, benzoic acid or other acids used in the art. The alkyl and alkenyl groups may be branched or straight chain groups. The C2-C6 alkyl group is preferably a C2-C4 alkyl group, e.g. ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl. The C2-C6 acyl is preferably a C2-C4 acyl group, e.g. acetyl, propionyl, butyryl. The NR 3 R 4 group is preferably amino, methylamino, ethylamino, n-propylamino, iso-propylamino, allylamino, propargylamino, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-iso-propylamino, pyrrolidinyl, piperidino, morpholino, 4-methyl-piperazin-1-yl, 1-imidazolyl. The -O-C2-C4-alkyl-NNR 3 R 4 group is preferably 2-amino-ethoxy, 2-N,N-dimethylamino-ethoxy, 2-(1-pyrrolidinyl)ethoxy. Preferred examples of specific compounds ( I ) according to the present invention are: 3β-(4-N-ethylaminobutoxy)-5α-androstan-6,17-dione 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-6,17-dione 3α-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione 3β-(4-N,N-dimethylaminobutoxy)-5α-androstan-6,17-dione 3β-(2-N-pyrrolidinylethoxy)-5α-androstan-6,17-dione 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6,17-dione 3β-[2-(2-N-pyrrolidinylethoxy)ethoxy]-5α-androstan-6,17-dione 3β-(2-N-imidazolylethoxy)-5α-androstan-6,17-dione 3β-(3-N-imidazolylpropoxy)-5α-androstan-6,17-dione 3β-(2-N-piperidinoethoxy)-5α-androstan-6,17-dione 3β-[2-(4-methylpiperazin-1-yl)ethoxy)]-5α-androstan-6,17-dione 3β-(2-aminoethoxy)-5α-androstan-6α,17β-diol 3β-(3-aminopropoxy)-5α-androstan-6α,17β-diol 3β-(3-N-methylaminopropoxy)-5α-androstan-6α,17β-diol 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-6α,17β-diol 3α-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α,17β-diol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α,17β-diol 3β-(4-N,N-dimethylaminobutoxy)-5α-androstan-6α,17β-diol 3β-(2-N-pyrrolidinylethoxy)-5α-androstan-6α,17β-diol 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6α,17β-diol 3β-[2-(2-N-pyrrolidinylethoxy)ethoxy]-5α-androstan-6α,17β-diol 3β-(2-aminoethoxy)-5α-androstan-6β,17β-diol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6β,17β-diol 3β-(2-guanidinoethoxy)-5α-androstan-6α,17β-diol 3β-(3-guanidinopropoxy)-5α-androstan-6β,17β-diol 3β-(2-guanidinoethoxy)-5α-androstan-6β,17β-diol 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6β,17β-diol 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-17β-acetate-6α-ol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-17β-acetate-6α-ol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-17β-benzoate-6α-ol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-17β-(2-N,N-dimethylaminoethoxy)-6α-ol 3β-(2-aminoethoxy)-5α-androstan-6α-hydroxy-17-one 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α-hydroxy-17-one 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-17β-hydroxy-6-one (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione (E)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione (Z)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione (E)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6,17-dione (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6,17-dione (E)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6,17-dione (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6,17-dione (E)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6,17-dione (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6,17-dione (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6,17-dione (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6,17-dione (E)-3-[2-(2-N,N,dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6,17-dione (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6,17-dione (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6α,17β-diol (E)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (E)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (E)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol (E,Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol 6-Hydroxy steroids are steroid metabolites produced both in humans and in animals such as rat, dog or baboon (Derks H.J.G.M. and Drayer N.M., Steroids 1978 , 289; Setchell K.D., FEBS Lett. 1976 , 70, 197; Miyabo S., Kishida S., Asato T. and Saito Z., Nippon Naibumpi Gakkai Zasshi 1976, 52 , 630; Jellink H.P. and Galraith A.R., J. Steroid Biochem. Mol. Biol. 1991 , 39, 947). The main function of 6-hydroxylation process is supposed to be the elimination of the parent steroid (Jellink H.P. loc.cit., Orlowski J. and Clark A.F., Endocrinology 1991 , 128 , 872). Simple 6-hydroxy and 6-oxo-androstane, such as for example 5α-androstane-3β,6α,17β-triol or 3β,17β-diacetoxy-5α-androstan-6-one are known compounds (Isaacs J.T., McDermott I.R. and Coffey D. S., Steroids 1979, 33 , 639). Also known compounds are pregnane derivatives such as 17α-acetate-3α,6α-dihydroxy-5α-pregnan-20-one or 3β,17α-diacetate-5α-pregnan-6,20-dione (Templeton J.F. and Kumar V.P.S., J.Chem.Soc., Perkin Trans. I 1987, 1361). Said derivatives are described as devoid of pharmacological activity (Isaacs J.T. loc. cit.; Templeton J.F. loc. cit.; Templeton J.F., Kumar V.P.S., Kim S.R. and LaBella F.S., Steroids 1987, 383; Celotti F., Avogadri N., Ferraboschi P., Motta M., Negri-Cesi P. and Santaniello E., J. Steroid Biochem. 1983 , 397) and indeed they are usually prepared as intermediate for the synthesis of derivatives in which the group linked to position 6 is different from oxygen ( e.g. : methyl, methylene, fluorine, chlorine, bromine. See for example: Templeton J.F. loc. cit.; Buzzetti F., Longo A., Crugnola A., Di Salle E., WO 93 14,105). Structural as well as pharmacobiological differences between the compounds ( I ) of the present invention and the already known 6-oxo and 6-hydroxyandrostanes are evident. EP-A-590,489 discloses 6-unsubstituted 17-α aryl androstane derivatives with cardio-activity. The invention furthermore provides a process for the preparation of compounds of general formula ( I ) which comprises the condensation of compounds of general formula ( II ): where the symbol B represents CH-OH, C=O, CH-CH=O or C=CH-CH=O, the symbol ---· represents a single o double bond and R 1a has the same meanings of R 1 or it represents a hydroxy protecting group such as a silyl group, R 2a has the same meanings of R 2 or it represents a hydroxy protecting group such as a silyl group, with a compound of general formula ( III ) when B represents CH-OH, R-X III where R is as already defined, and where X is a good leaving group such as halogen, mesyloxy, tosyloxy or trifluoroacetoxy group and with a compound of general formula ( IV ) when B represents C=O, CH-CH=O or C=CH-CH=O R-ONH 2 IV where R is as already defined with, if desired, the free hydroxy and/or the amino groups optionally present in R, R 1a and/or R 2a are protected with methods well known by those skilled in the art, to give, if necessary after removal of known protective groups possibly present in R, R 1a and/or R 2a , a compound of general formula ( I ) which may be converted into another compound of general formula ( I ) and/or, if desired, subjected to salification and/or isomer separation. The reaction between a compound of general formula ( II ) and a compound of general formula ( III ) is best carried out in an inert solvent, such as tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxyde, benzene, toluene, dichloromethane, chloroform or their mixtures in the presence of a condensing agent such as a strong base (e.g.: sodium or potassium hydride), or an acid (e.g.: p-toluensulfonic acid, hydrogen chloride, trifluoroacetic acid) or a heavy metal salt (e.g.: silver carbonate, silver oxide, silver triflate, mercury oxide or mercury tetrafluoborate) at a temperature ranging from -10 °C to the reflux temperature of the reaction mixture. The reaction between a compound of general formula ( II ) and a compound of general formula ( IV ) is best carried out in a solvent such as tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, benzene, toluene, dichloromethane, methanol, ethanol, water or their mixtures, at a temperature ranging from 0 °C to the reflux temperature of the reaction mixtures. The reaction may be performed in the presence of a base, such as sodium or potassium hydroxide, sodium or potassium carbonate, or in presence of an acid such as, hydrochloric acid, hydrobromic acid or acetic acid. The reaction time varies from a few minutes to several hours. All said transformations are only examples of well established procedures described in Organic Chemistry (see for example: J. March "Advanced Organic Chemistry", J. Wiley & Sons, 1992; D. Barton and W. D. Ollis "Comprehensive Organic Chemistry", Pergamon Press, 1979) well known to those skilled in the art. The compounds of general formula ( II ) are prepared from prasterone ( V ): by a series of known chemical transformation that comprise for example the oxidation of hydroxy group into a keto group, the oxidation of a double bond to alcohol, the transformation of a keto group into the homologous aldehyde, the transformation of a keto group into the vinilogous ester and reduction of an ester to the corresponding aldehyde or alcohol, as well as protection and deprotection of hydroxy and keto groups, by standard methods well known by those skilled in the art. Compounds of general formula ( III ) and ( IV ) are known compounds, often commercially available or preparable from commercially available compounds by standard procedures. Prasterone ( V ) is commercially available. We have found that the derivatives ( I ), prepared according to the invention, and their pharmaceutically acceptable salts are useful agents for the treatment of cardiovascular disorders, such as heart failure and hypertension. Moreover said compounds show affinity and inhibit the enzymatic activity of the Na + ,K + -ATPase. To test the affinity for the receptor site of the Na + ,K + -ATPase and the inhibitory activity on the enzyme, the following tests were used: a ) displacement of the specific 3H-ouabain binding from the Na + ,K + -ATPase receptor purified according to Jorghensen (Jorghensen P., BBA, 1974, 356, 36) and Erdmann (Erdmann E. et al., Arzneim.Forsh., 1984 , 34, 1314); b ) inhibition of the activity of the purified Na + ,K + -ATPase measured as % of hydrolysis of 32P-ATP in presence and in absence of the tested compound (Mall F. et al., Biochem.Pharmacol., 1984 , 33, 47). Moreover the compounds of the invention possesses positive inotropic features, as shown in electrically paced guinea pig left atrium according to Bova (Bova S., Blaustein M.P., Ludens J.H., Harries D.W., Ducharme D.W. and Hamlyn J.M. Hypertension 1991 , 17, 944). Finally, the compounds of the invention have a low toxicity when compared with standard cardiotonic steroids. Nine hours food deprived mice were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LD 50 ) was assessed on the seventh day after the treatment. The activity of some compounds of general formula ( I ) on the above mentioned tests are shown in the following Table 1. Example n ° Binding to Na,K-ATPase EC 50 (µM) Inhibition of Na,K-ATPase IC 50 (µM) Inotropic activity in vitro EC 50 (µM) Acute toxicity mouse oral LD 50 (mg/kg) Digoxin 0.06 0.5 0.5 18 I-a 0.10 1.6 2.5 > 600 I-d 0.13 1.6 10.5 > 600 I-e 0.16 2.0 5.6 > 600 I-f 0.10 1.0 0.8 560 I-h 0.02 0.3 0.6 520 I-i 0.50 12.0 7.1 > 1000 I-k 0.32 3.2 12.6 > 600 I-m 1.30 50.0 20.0 > 1000 To obtain the desired therapeutic effect, the compounds of the invention of general formula ( I ) may be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion; in the form of a depot preparation administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. The dosage depends on the age, weight, conditions of the patient and administration route; for example, the dosage adopted for adult humans (of approximately 70 kg body weight) is 0.01 to 10 mg per dose, from 1 to 3 times daily for oral administration and 0.01 to 50 mg per dose, from 1 to 3 times daily for parenteral administration. The oral rote is employed, in general, for all conditions requiring such compounds. Preference is given to the parenteral route, e.g. intravenous injection or infusion, for the treatment of acute hypertension. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response. The invention includes a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent). The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch, lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures: dyestuffs: sweeteners; wetting agents, for instance, lecithin, polysorbates. laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by mean of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions, suspensions and solutions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amounts to glucose. such as, sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose. carboxymethylcellulose, or polyvinyl alcohol. The solutions for oral administration may contain as carrier, for example, water, ethanol, propylene glycol, glicerine, saccharose and, possibly, pharmaceutically acceptable salts. The solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water, ethanol, propylene glycol and, possibly, pharmaceutically acceptable salts to prepare sterile aqueous Isotonic saline solutions. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate the invention without limiting it. Example 1 (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6α,17β-diol oxalate (I-a) A solution of O-(2-aminoethyl)-hydroxylamine dihydrochloride (350 mg) in water (4 mL) was added to a solution of 3-oxo-5α-androstan-6α,17β-diol ( II-b, Prep. 2, 500 mg) in dioxane (4 mL) and the resulting mixture was stirred for 2 hrs. Sodium hydroxide (1N) was added to pH = 9 and the mixture was extracted with chloroform (5x20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO 2 , chloroform/methanol/ ammonia 90/10/1) to give 460 mg of (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6α,17β-diol, that were dissolved in ethyl acetate/ methanol 70/30 (5 mL) and treated with oxalic acid (110 mg) to give 510 mg of (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6α,17β-diol oxalate ( I-a ), as a white podwer mp 151-156 °C. Example 2 (E)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (I-b) (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (I-c) A solution O-(2-N,N-dimethylaminoethyl)-hydroxylamine dihydrochloride (425 mg) in water (5 mL) was added to a solution of 3-oxo-5α-androstan-6α,17β-diol ( II-b, Prep. 2 , 500 mg) in dioxane (15 mL). Hydrochloric acid (IN) was added to pH = 1 and the resulting mixture was stirred overnight. Sodium hydroxide (4N) was added to pH = 10.5 and the mixture extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue (640 mg) was purified by flash chromatography (SiO 2 , chloroform/methanol/ ammonia 90/10/1) to give 240 mg of a fraction A and 180 mg of afraction B. Fraction A crystallized from ethyl acetate/methanol 70/30 to give 46 mg of (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (I-c), as a white podwer mp 117-120 °C. Fraction B crystallized from ethyl acetate/diethyl ether 50/50 to give 33 mg of (E)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol ( I-b ), as a white podwer mp 102-106 °C. Example 3 (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol oxalate (I-d) A solution of 3-formyl-5α-androstan-6α,17β-diol ( II-c, Prep. 3, 240 mg) in dioxane/water (2/1, 30 mL) was treated with sodium hydroxide (0.1 N) to pH = 13-14 and stirred for 15 minutes, then a solution O-(2-aminoethyl)-hydroxylamine dihydrochloride (170 mg) in water (3 mL) was poured in. After 1 hr, the organic solvent was distilled off and the acqueous solution was extracted with chloroform (5x20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO 2 , chloroform/methanol/ammonia 90/10/1) to give (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol, wich was dissolved in ethyl acetate/methanol 70/30 and treated with oxalic acid to give 85 mg of (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol oxalate ( I-d ) as a white solid mp 190-192 °C. Example 4 (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol oxalate (I-e) Using the same reaction conditions described in Ex. 3, and starting from 3-formyl-5α-androstan-6α,17β-diol ( II-c, Prep. 3 ) and O-(2-N,N-dimethylaminoethyl)-hydroxylamine dihydrochloride the title compound (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol oxalate ( I-e ), mp 113-114 °C, was obtained in 42% yield. Example 5 (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol (I-f) A solution of O-(2-N,N-dimethylaminoethyl)-hydroxylamine dihydrochloride (215 mg) in "pH 7 buffer solution" (Janssen 25.859.57, 5 mL) was slowly dropped into a solution of (E)-3-formylmethylen-5α-androstan-6α,17β-diol ( II-d, Prep. 4 , 240 mg) in dioxane (20 mL) and "pH 7 buffer solution" (5 mL). During the addidition of the reactant, the pH of the reaction mixture was kept between 4 and 6.5 by addition of sodium hydroxide (0.1 N). After 2 hrs, sodium hydroxide (4N) was added to pH = 7.5 and the mixture extracted with chloroform (3x50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue (304 mg) was purified by flash chromatography (SiO 2 , chloroform/methanol/ammonia 95/5/0.1) to give, after trituration with diisopropyl ether, 100 mg of (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol ( I-f ) as a pale white solid mp 110-115 °C. Example 6 (E,Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol (I-g) A solution of O-(2-N,N-dimethylaminoethyl)-hydroxylamine dihydrochloride (215 mg) in "pH 10 buffer solution" (Janssen 25.860.58, 10 mL) was slowly dropped into a solution of (Z)-3-formylmethylen-5α-androstan-6α,17β-diol (II-e, Prep. 4, 240 mg) in dioxane (12 mL) and "pH 10 buffer solution" (5 mL). After 36 hrs the mixture was extracted with chloroform (3x70 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue (285 mg) was purified by flash chromatography (SiO 2 , chloroform/methanol/ammonia 95/5/0.1) to give after trituration in diisopropylether 70 mg of (E,Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol - ( I-g ), as a white podwer mp 111-114 °C. Example 7 (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione emioxalate (I-h) o -Iodoxybenzoic acid (560 mg) was added in one portion to a solution of (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6α,17β-diol ( I-a , 290 mg) and trifluoroacetic acid (60 µL) in dimethylsulfoxide (9 mL). The reaction mixture was stirred overnight, then it was diluted with sodium hydroxide (0.1 N) and extracted with chloroform (3x50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO 2 , chloroform/methanol/ ammonia 90/10/1) and treated with oxalic acid to give 250 mg of (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione emioxalate ( I-h ), mp 148-151 °C. Example 8 (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6,17-dione (I-i) o -Iodoxybenzoic acid (300 mg) was added in one portion to a solution of (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol ( I-c , 140 mg) in dimethylsulfoxide (4 mL). The reaction mixture was stirred overnight, then it was diluted with sodium hydroxide (0.1 N) and extracted with ethyl acetate (3x20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue (160 mg) was purified by flash chromatography (SiO 2 , chloroform/methanol/ammonia 90/10/1) to give 100 mg of (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6,17-dione ( I-i ), as a light yellow solid, mp 141-145 °C. Example 9 (E)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6,17-dione oxalate (I-j) Using the same reaction conditions described in Ex. 8, and starting from (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol ( I-e, Ex. 4 ) the title compound (E,Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6,17-dione oxalte ( I-j ) was obtained as a solid mp 162-164 °C. Example 10 (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6,17-dione oxalate- (I-k) Using the same reaction conditions described in Ex. 8, and starting from (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol ( I-f; Ex; 5 ) the title compound (E,Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6,17-dione oxalate ( I-k ) was obtained as a solid mp 177-178°C. Example 11 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α,17β-diol (I-l) Sodium hydride (300 mg, 60 % dispersion in oil) was added to a solution of 6α,17β-diethoxymethoxy-5α-androstan-3β-ol ( II-f, Prep. 5 , 1.8 g) and 3-N,N-dimethylamino-1-chloropropane (1.7 g) in 25 ml of anhydrous tetrahydrofuran, under argon atmosphere at room temperature. The mixture was refluxed for 32 hrs, then it was cooled to room temperature, brine and ethyl acetate were added, the organic layer separated and extracted several times with HCl 1N. The collected aqueous phase was neutralised with potassium hydroxide 4N and extracted with chloroform to give, after workup, a brown-yellowish oil which was dissolved in acetonitrile/water (85/15, 60 mL). p-Toluensulfonic acid was added to pH=0.9 and the reaction mixture stirred for 24 hrs. After usual work-up the residue was purified by flash chromatography (SiO 2 , chloroform/methanol/ ammonia 90/10/1) to give 400 mg of 3β-(3-N,N-dimethylamino propoxy)-5α-androstan-6α,17β-diol ( I-l ) as a white solid, mp 117-123 °C. Example 12 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione (I-m) o -Iodoxybenzoic acid (500 mg) was added in one portion to a solution of 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α,17β-diol ( I-l , 200 mg) in dimethylsulfoxide (8 mL), and the reaction mixture stirred overnight. It was diluted with sodium hydroxide (0.1 N) and extracted with chloroform (3x30 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO 2 , chloroform/methanol/ammonia 90/10/1) to give 140 mg 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione ( I-m ) as a light yellow solid, mp 124-125 °C. Example 13 3β-(2-N-pyrrolidinylethoxy)-5α-androstan-6,17-dione (I-n) Using the same reaction conditions described in Exs. 11 and 12 , and starting from 6α,17β-diethoxymethoxy-5α-androstan-3β-ol ( II-f, Prep. 5 ) and N-(2-chloroethyl)-pyrrolidine the title compound 3β-(2-N-pyrrolidinylethoxy)-5α-androstan-6,17-dione ( I-n ) was obtained 136-140 °C. Example 14 3β-(4-N,N-dimethylaminobutoxy)-5α-androstan-6,17-dione (I-o) Using the same reaction conditions described in Exs. 11 and 12, and starting from 6α,17β-diethoxymethoxy-5α-androstan-3β-ol ( II-f, Prep. 5 ) and 4-N,N-dimethylamino-1-chlorobutane the title compound 3β-(4-N,N-dimethylaminobutoxy)-5α-androstan-6,17-dione ( I-o ) was obtained as a viscous oil. 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 3.60-3.40 (4H, m), 3.25 (1H, m), 2.55-1.20 (30H, m) 0.90 (3H, s), 0.78 (3H, s). Example 15 3β-[2-(2-N-pyrrolidinylethoxy)ethoxy]-5α-androstan-6,17-dione oxalate (I-p) Using the same reaction conditions described in Exs. 11 and 12, and starting from 6α,17β-diethoxymethoxy-5α-androstan-3β-ol ( II-f, Prep . 5 ) and 2-(2-N-pyrrolidinyl)ethoxy-1-chloroethane the title compound 3β-[2-(2-N-pyrrolidinylethoxy)ethoxy]-5a-androstan-6,17-dione was obtained and purified as oxalate salt ( I-p ) mp 69-73 °C Example 16 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6,17-dione (I-q) Using the same reaction conditions described in Exs. 11 and 12 , and starting from 6α,17β-diethoxymethoxy-5α-androstan-3β-ol ( II-f, Prep. 5 ) and 2-(2-N,N-dimethylamino)ethoxy-1-chloroethane the title compound 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6,17-dione ( I-q ) was obtained as an amorphous solid. 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 3.80-3.50 (8H, m), 3.25 (1H, m), 2.60-1.20 (26H, m) 0.90 (3H, s), 0.78 (3H, s). Example 17 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6β,17β-diol (I-r) Sodium borohydride (70 mg) was added to a solution of 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione ( I-m, Ex. 12, 350 mg) in methanol (10 mL) and the reaction mixture was stirred overnight at room temperature. Glacial acetic acid was added and the reaction mixture is evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO 2 , chloroform/methanol/ammonia 90/10/1) to give 320 mg 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6β,17β-diol, mp 161-166 °C. Example 18 Tablets, each weighing 100 mg and containing 1 mg of the active substance can be manufactured as follows: Composition (for 10.000 tablets): (E,Z)-3-(2-Aminoethoxyimino)-5α-androstane-6,17-dione emioxalate ( I-h ) 10.0 g Lactose 700.0 g Corn starch 240.0 g Talc powder 35.0 g Magnesium stearate 15.0 g The active ingredient is sieved through a suitable sieve and blended with lactose and corn starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with talc and magnesium stearate. The granules are then compressed in the tablets using 7 mm diameter punches. Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit. Example 19 Solutions for oral administration containing 5 mg of the active substance can be manufactured by dissolving 5 mg of [E,Z)-3-(2-Aminoethoxyimino)-5α-androstane-6,17-dione emioxalate ( I-h ) in 10 ml of 70% ethanol. Suitable number of drops can be diluted in water. Example 20 Ampoules for intramuscular injections containing 0.1 mg of the active substance can be manufactured as follows: Composition (for 10,000 ampoules): ((E,Z)-3-(2-Aminoethoxyimino)-5α-androstane-6,17-dione emioxalate ( I-h ) 1.0 g Sterile water 10.0 L The active ingredient was dissolved in sterile water. The solution was sterilized by filtration through a suitable filter and filled into the ampoules. Preparation 1 3β- tert -Butyldimethylsilyloxy-5α-androstan-6α,17β-diol (II-a) tert -Butyldimethylsilylchloride (9.72 g) was added, at room temperature, to a solution of prasterone ( V , 15 g) in pyridine (60 mL). After 24 hrs, the reaction mixture was poured into iced water (600 mL). Ethyl acetate was added, the two layers were separated, the organic layer washed with sodium bicarbonate (5%), sodium dihydrogenphosphate (5%) and brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude residue, [3β- tert -butyldimethylsilyloxy-androst-5-en-17-one, g 23.9; 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 5.32 (1H, d), 3.48 (1H, hept), 2.49 (1H, dd), 2.35-0.8 (33H, m), 0.03 (6H, s)] was dissolved in diethyl ether/ethanol (335 mL/250 mL), cooled to 0 °C and treated with sodium borohydride (4 g). The reaction mixture was stirred at room temperature for 1 hr, then quenched with 1N hydrochloric acid to pH = 7, diluted with brine (300 mL) and extracted with diethyl ether. The organic layer was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude residue, [3β- tert -butyldimethylsilyloxyandrost-5-en-17β-ol, g 21; 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 5.32 (1H, m), 3.62 (1H, m), 3.48 (1H, hept), 2.35-0.8 (34H, m), 0.03 (6H, s)] was dissolved in tetrahydrofurane (850 mL), cooled to 0 °C and treated with borane-dimethylsulfide complex (THF, 1M, 155 mL). The reaction mixture was stirred at room temperature for 2 hrs, then it was cooled to 0 °C and quenched with water (300 mL), and sodium perborate tetrahydrate (43 g). The mixture was stirred overnight at room temperature, ammonium chloride (30%, 300 mL) was added, the two layers were separated, the organic one dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by flash-chromatography (SiO 2 ; n-hexane/ethyl acetate 75/25) to give to give 18 g of the title compound ( II-a ) as a foam. 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 3.68 (1H, t), 3.52 (1H, hept), 3.42 (1H, dd), 2.20-0.6 (35H, m), 0.03 (6H, s). Preparation 2 3-oxo-5α-androstan-6α,17β-diol (II-b) A solution of 3β- tert -butyldimethylsilyloxy-5α-androstan-6α,17β-diol (II-a, Prep. 1) (20 g) and acetic anhydride (25 mL) in anhydrous pyridine (50 mL) was stirred at room temperature 24 hrs. The mixture was then poured into ice and water and extracted with ethyl acetate to give after usual workup crude 3β- tert -butyldimethylsilyloxy-6α,17β-diacetoxy-5α-androstane, [23 g, 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 4.67 (1H, dd), 4.58 (1H, t), 3.50 (1H, hept)], used as such in the next reaction without further purification. This intermediate was deprotected with tetrabutylammonium fluoride (21 g) in THF (350 mL), to give 6a,17β-diacetoxy-5α-androstan-3β-ol [18 g, 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 4.67 (1H, dd), 4.58 (1H, t), 3.55 (1H, hept)], used as such in the next reaction without further purification. A solution of 6α,17β-diacetoxy-5α-androstan-3β-ol (18 g) and o -iodoxybenzoic acid (27 g) in dimethylsulfoxide (180 mL) was stirred at room temperature overnight, then diluted with water (1.5 L) and diethyl ether (400 mL) and filtered. The two layers were separated, the waters extracted with diethyl ether (3x200 mL), the combined organic layers dried over sodium sulfate and evaporated to dryness under reduced pressure, to give 17 g of 6α,17β-diacetoxy-5α-androstan-3-one. The crude residue was dissolved in methanol (380 mL) and sodium hydroxide (4N, 125 mL), was stirred at room temperature for 1 hr. It was then evaporated to dryness under reduced pressure, the residue dissolved in dichloromethane (600 mL) and water (5000 mL). The two layers were separated and the water extracted with dichloromethane (3x100 mL). The combined organic layers were washed with hydrocloric acid (1N) and water, dried over sodium sulfate and evaporated under reduced pressure to give 15 g of a crude residue, that was purified by flash-chromatography (SiO 2 ; chloroform/methanol 99/1) to give 12 g of 3-oxo-5α-androstan-6α,17β-diol ( II-b ) as a white solid, mp 195-205 °C. Preparation 3 3-Formyl-5α-androstan-6α,17β-diol (II-c) Sodium hydride (50% in mineral oil, 640 mg) was carefully washed with n-hexane, under nitrogen atmosphere. Then anhydrous dimethylsulfoxide (160 mL) and trimethylsolfoxonium iodide (2.9 g) were added and the reaction mixture was stirred to complete dissolution. 3-Oxo-5α-androstan-6α,17β-diol ( II-b, Prep. 2 , 600 mg) was added and the reaction mixture stirred at room temperature for 2 hrs, then poured into ice and water and extracted with ethyl acetate to give, after usual workup, 3-spiro-oxirane-5α-androstan-6α,17β-diol [590 mg, 1 H-NMR [ 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 3.65 (1H, t), 3.39 (1H, m), 2.70-2.60 (2H, m)]. Freshly distilled borontrifluoride-diethylether complex (300 µL) was added to a solution of crude 3-spiro-oxirane-5α-androstan-6α,17β-diol (590 mg) in anhydrous tetrahydrofurane (25 mL) at -30° C, under nitrogen atmosphere. After 70 minutes, the reaction mixture was poured into disodium hydrogen phosphate (5%), extracted with chloroform (3x50 mL), the combined organic layers were separated and dried over anhydrous sodium sulfate to give, after evaporation to dryness, 530 mg of crude 3-formyl-5α-androstan-6α,17β-diol ( II-c ) as an amorphous solid (3α-formyl/3β-formyl = 1/6 determined by 1 H-NMR). 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 9.71 (1H, s), 9.67 (1H, s), 3.75 (1H, m), 3.65 (1H, t), 3.50 (1H, m), 2.40-0.6 (25H, m). Preparation 4 (E)-3-Formylmethylen-5α-androstan-6α,17β-diol (II-d) and (Z)-3-formylmethylen-5α-androstan-6α,17β-diol (II-e) Trimethyl phosphonoacetate (1.9 mL) was added to a mixture of sodium hydride (50%, 500 mg) in anhydrous tetrahydrofurane (25 mL), and the mixture was stirred at room temperature under nitrogen atmosphere for 15 min, then 3-oxo-5α-androstan-6α,17β-diol ( II-b, Prep. 2.0 g) dissolved in anhydrous tetrahydrofurane (5 mL) was added. After 1 hr the reaction was quenched with sodium dihydrogen phosphate (5%). The mixture was extracted several times with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude residue was purified by chromatography (SiO 2 ; n-hexane/ethyl acetate 50/50) to give 780 mg of (E)-3-methoxycarbonylmethylen-5α-androstan-6α,17β-diol and 1.04 g of (Z)-3-methoxycarbonylmethylen-5α-androstan-6α,17β-diol as amorphous solids. (E)-3-methoxycarbonylmethylen-5α-androstan-6α,17β-diol 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 5.65 (1H, bs), 3.75 (1H, m), 3.65 (3H, s), 3.52 (1H, t), 3.48 (1H, ddd), 2.55 (1H, m), 2.20-0.6 (24H, m). (Z)-3-methoxycarbonylmethylen-5α-androstan-6α,17β-diol 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 5.62 (1H, bs), 4.10 (1H, m), 3.65 (3H, s), 3.52 (1H, t), 3.48 (1H, ddd), 2.40-0.6 (25H, m). Diisobutylaluminum hydride (1M in hexane, 10 mL) was added at -78 °C to a solution of (E)-3-methoxycarbonylmethylen-5α-androstan-6α,17β-diol (700 mg) in anhydrous tetrahydrofurane (25 mL) under nitrogen atmosphere. The mixture was stirred overnight, then it was quenched (-78 °C) with sulfuric acid (0.1 N, to pH = 3-4) and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO 2 , n-hexane/chloroform/acetone 10/45/45) to give 640 mg of (E)-3-(2-hydroxyethylen)-5α-androstan-6α,17β-diol. 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 5.35 (1H, m), 4.10 (2H, m), 3.52 (1H, t), 3.48 (1H, m), 2.55 (1H, m), 2.20-0.6 (25H, m). A mixture of (E)-3-(2-hydroxyethylen)-5α-androstan-6α,17β-diol (630 mg) and manganese dioxide (3 g) in dioxane (60 mL) was stirred at room temperature for 40 hrs, then it was filtered on a celite pad. The organic solution was dried over sodium sulfate and evaporated to dryness under reduced pressure. to give 530 mg of (E)-3-formylmethylen-5α-androstan-6α,17β-diol ( II-d ) 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 10.03 (1H, d), 5.90 (1H, m) 3.65 (1H, t), 3.48 (1H, m), 3.28 (1H, m), 2.55 (1H, m), 2.20-0.6 (24H, m). Similarly, starting from (Z)-3-methoxycarbonylmethylen-5α-androstan-6α,17β-diol and using the experimental conditions above described it was possible to prepare (Z)-3-formylmethylen-5α-androstan-6α,17β-diol ( II-e ) 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 10.08 (1H, d), 5.82 (1H, m) 3.65 (1H, t), 3.52 (1H, m), 2.50-0.6 (26H, m). Preparation 5 6α,17β-Diethoxymethoxy-5α-androstan-3β-ol (II-f) A solution of 3β- tert -butyldimethylsilyloxy-5α-androstan-6α,17β-diol ( II-a, Prep. 1, 10 g ), chloromethyl ethyl ether (16 mL) and di-iso-propylethylamine (120 mL) in dry dichloromethane (500 mL) was stirred overnight at 0 °C. Citric acid (10% water solution, 1.5 L) was added, the organic layer separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography (hexane/ethyl acetate 85/15) to give 10.8 g of 3β- tert -butyldimethylsilyloxy-6α,17β-di-ethoxymethoxy-5α-androstane. 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 4.60 (4H, m), 3.70-3.40 (7H, m), 2.20-0.6 (41H, m), 0.03 (6H, s). This intermediate was deprotected with tetrabutylammonium fluoride (12 g) in THF (100 ml), to give 7.7 g of 6α,17β-di-ethoxymethoxy-5α-androstan-3β-ol as an amorphous solid. 1 H-NMR (300 MHz, CDCl 3 , ppm from TMS): 4.62 (4H, m), 3.70-3.40 (7H, m), 2.20-0.6 (32H, m).

Claims: Compounds of general formula (I) wherein: the symbol A represents CH-OR, C=N-OR, CH-CH=N-OR and C=CH-CH=N-OR, where: R represents a C2-C6 alkyl group substituted by NR 3 R 4 , NHC(NH)NHR 5 , C(NH)NR 6 R 7 or -O-(C2-C4-alkyl)-NR 3 R 4 groups, wherein R 3 and R 4 , which may be the same or different, are H, C1-C6 lower alkyl group, benzyl or phenyl or R 3 and R 4 , taken together with the nitrogen atom, form an unsubstituted or substituted saturated or unsaturated mono-heterocyclic 5- or 6-membered ring optionally containing another heteroatom chosen from oxygen, sulphur or nitrogen, R 5 , R 6 and R 7 , which are the same or different, may be H or C1-C4 lower alkyl; the symbol ---· in position 6 and in position 17 represents independently a single or a double bond; when the symbol ---· represents a single bond R 1 represents H, C1-C4 lower alkyl and C2-C6 acyl groups; R 2 represents H, methyl, C2-C6 alkyl group unsubstituted or substituted by NR 3 R 4 , C2-C6 acyl groups, benzoyl, benzoyl substituted by one or more hydroxy, methoxy, amino, chloro, fluoro, methylmercapto groups. when the symbol ---· represent a double bond, it means a keto group and no R 1 or R 2 is present, or the pharmaceutically acceptable salts thereof. A compound of formula (I) according to claim 1 selected from: 3β-(4-N-ethylaminobutoxy)-5α-androstan-6,17-dione 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-6,17-dione 3α-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6,17-dione 3β-(4-N,N-dimethylaminobutoxy)-5α-androstan-6,17-dione 3β-(2-N-pyrrolidinylethoxy)-5α-androstan-6,17-dione 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6,17-dione 3β-[2-(2-N-pyrrolidinylethoxy)ethoxy]-5α-androstan-6,17-dione 3β-(2-N-imidazolylethoxy)-5α-androstan-6,17-dione 3β-(3-N-imidazolylpropoxy)-5α-androstan-6,17-dione 3β-(2-N-piperidinoethoxy)-5α-androstan-6,17-dione 3β-[2-(4-methylpiperazin-1-yl)ethoxy)]-5α-androstan-6,17-dione 3β-(2-aminoethoxy)-5α-androstan-6α,17β-diol 3β-(3-aminopropoxy)-5α-androstan-6α,17β-diol 3β-(3-N-methylaminopropoxy)-5α-androstan-6α,17β-diol 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-6α,17β-diol 3α-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α,17β-diol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α,17β-diol 3β-(4-N,N-dimethylaminobutoxy)-5α-androstan-6α,17β-diol 3β-(2-N-pyrrolidinylethoxy)-5α-androstan-6α,17β-diol 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6α,17β-diol 3β-[2-(2-N-pyrrolidinylethoxy)ethoxy]-5α-androstan-6α,17β-diol 3β-(2-aminoethoxy)-5α-androstan-6β,17β-diol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6β,17β-diol 3β-(2-guanidinoethoxy)-5α-androstan-6α,17β-diol 3β-(3-guanidinopropoxy)-5α-androstan-6β,17β-diol 3β-(2-guanidinoethoxy)-5α-androstan-6β,17β-diol 3β-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-5α-androstan-6β,17β-diol 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-17β-acetate-6α-ol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-17β-acetate-6α-ol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-17β-benzoate-6α-ol 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-17β-(2-N,N-dimethylaminoethoxy)-6α-ol 3β-(2-aminoethoxy)-5α-androstan-6α-hydroxy-17-one 3β-(3-N,N-dimethylaminopropoxy)-5α-androstan-6α-hydroxy-17-one 3β-(2-N,N-dimethylaminoethoxy)-5α-androstan-17β-hydroxy-6-one (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione (E)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione (Z)-3-(2-aminoethoxyimino)-5α-androstan-6,17-dione (E)-3-(2-N.N-dimethylaminoethoxyimino)-5α-androstan-6,17-dione (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6,17-dione (E)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6,17-dione (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6,17-dione (E)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6,17-dione (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6,17-dione (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6,17-dione (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6,17-dione (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6,17-dione (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6,17-dione (E,Z)-3-(2-aminoethoxyimino)-5α-androstan-6α,17β-diol (E)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (Z)-3-(2-N,N-dimethylaminoethoxyimino)-5α-androstan-6α,17β-diol (E)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (E)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (Z)-3β-(2-N,N-dimethylaminoethoxyiminomethyl)-5α-androstan-6α,17β-diol (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(E)-ethylidene)-5α-androstan-6α,17β-diol (E,Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol (E)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol (Z)-3-[2-(2-N,N-dimethylaminoethoxyimino)(Z)-ethylidene)-5α-androstan-6α,17β-diol A pharmaceutical composition comprising a compound of claim 1 or 2 or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient therefor. Use of a compound of claim 1 or 2 or its pharmaceutically acceptable salt in the preparation of a medicament useful for the treatment of cardiovascular disorders. The use according to claim 4 wherein the cardiovascular disorders are heart failure or hypertension.

Inventors: DE MUNARI SERGIO, FOLPINI ELENA, FRIGERIO MARCO, MELLONI PIERO, SERRA FULVIO, SPUTORE SIMONA, DE MUNARI, SERGIO, FOLPINI, ELENA, FRIGERIO, MARCO, MELLONI, PIERO, SERRA, FULVIO, SPUTORE, SIMONA
Applicants: SIGMA TAU IND FARMACEUTI, SIGMA-TAU INDUSTRIE
Application year: 1997
Main classification: C07J41
IPC codes: A61K31, A61P9, C07J1, C07J43, C07J41