DE19805965C1 - New seco-D-steroid carboxylic acid dialkylaminoalkyl esters, used for treating cardiovascular disorders such as hypertonia or cardiac insufficiency - Google Patents

Abstract

Dialkylaminoalkyl 3 beta -hydroxy-14-oxo-14,15-seco-pregn-20-ene-21-carboxylates (I) are new. Seco-D-steroid derivatives of formula (I) (where the double bond can have E- or Z-configuration) and their stereoisomers (including mixtures) and salts are new. R1 = methyl, ethyl or propyl; R2, R3 = H or 1-4C alkyl; or NR2R3 = saturated, monocyclic, 5- or 6-membered heterocycle; n = 2-4. An Independent claim is included for the preparation of (I).

Description

This invention relates to new seco-D steroid derivatives which are useful for the cardiovascular system is active, a procedure too their manufacture and pharmaceutical compositions which these contain. The compounds described herein are for the treatment of cardiovascular diseases such as Heart failure and hypertension are useful.

The claimed compounds show high binding affinity for the digitalis receptor site at the Na ⁺ , K ⁺ -ATPase and are active for the cardiovascular system, although they do not have some structural requirements which are of fundamental importance for the natural digitalis compounds such as digoxin, ouabain and digitoxigenin were viewed.

These requirements are: the cyclopentaperhydrophenanthrene skeleton and the cis bond between the A / B and C / D rings (Repke KRH, Schönfeld W. (1984); Na ⁺ / K ⁺ -ATPase as the digitalis receptor; Trends Pharmacol Sci. 5: 393-397; Thomas R., Gray P., Andrews J. (1990); Digitalis: Its mode of action, receptor and structure-activity relationships; Adv. Drug Res. 19: 312-562).

This invention relates to compounds of general formula I.

in which mean:
the symbol that the hydrogen in position 5 and the substituent R ¹ in position 17 can have an α or β configuration and the double bond can have an E or Z configuration;
R ^{1 is} methyl, ethyl or propyl;
R ² , R ³ independently represent hydrogen, C1-C4-alkyl or wherein R ² and R ³ together and the nitrogen to which they are attached form a saturated, 5- or 6-membered monoheterocyclic ring;
n 2, 3 or 4
as well as stereoisomers and mixtures thereof.

Likewise, the pharmaceutically acceptable salts of Compounds of general formula I to the extent of this Invention included.  

Pharmaceutically acceptable salts of I are salts that the maintain biological activity of the base and differ from such known pharmacologically acceptable acids as Hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, fumaric acid, succinic acid, oxalic acid, Malic acid, tartaric acid, maleic acid, citric acid, Derive methanesulfonic acid or benzoic acid.

The alkyl groups can be branched or straight-chain groups his.

The C1-C4 alkyl group is preferably methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, tert-butyl.

The NR ² R ³ group is preferably amino, methylamino, dimethylamino, ethylamino, diethylamino, 1-pyrrolidinyl, piperidino.

Preferred examples of specific compounds of this invention are:

2-aminoethyl (E) -3β-hydroxy-14-oxo-5β, 17β-14.15-seco-pregn-20-en-21-carboxylate
3-aminopropyl (E) -3β-hydroxy-14-oxo-5β, 17β-14.15-seco-pregn-20-en-21-carboxylate
2-Dimethylaminoethyl (E) -3β-hydroxy-14-oxo-5β, 17β-14.15-sec-pregn-20-en-21-carboxylate
3-Dimethylaminopropyl (E) -3β-hydroxy-14-oxo-5β, 17β-14.15-sec-pregn-20-en-21-carboxylate
2-aminoethyl (E) -3β-hydroxy-14-oxo-5β, 17α-14.15-seco-pregn-20-en-21-carboxylate
3-aminopropyl (E) -3β-hydroxy-14-oxo-5β, 17α-14.15-seco-pregn-20-en-21-carboxylate
2-Dimethylaminoethyl (E) -3β-hydroxy-14-oxo-5β, 17α-14.15-sec-pregn-20-en-21-carboxylate
3-Dimethylaminopropyl (E) -3β-hydroxy-14-oxo-5β, 17α-14.15-sec-pregn-20-en-21-carboxylate

Preferred compounds are also the corresponding ones (Z) isomer derivatives and the (EZ) mixtures.

This invention further provides a process for the preparation of the compounds of general formula I, comprising a condensation reaction of compounds of formula II:

where the symbol

and the substituent R ^{1 are} as defined above, with a compound of the general formula III

(EtO) ₂ POCH ₂ COO (CH ₂ ) _n NR ² R ³ (III)

wherein R ² , R ³ and n are as defined above, to obtain compounds of general formula I after hydrolysis of the acetoxy group in position 3.

The condensation reaction can be carried out in a solvent such as Tetrahydrofuran or toluene or a mixture of these Solvent at a temperature between -78 ° C and Room temperature in the presence of a base such as sodium hydride, Potassium hydride or butyllithium can be performed.

Compounds of the general formula II in which the symbol

and the substituent R ^{1 are} as defined above, can be prepared from compounds of general formula IV by subsequent reaction with acetic anhydride and ozonolysis.

The reaction with acetic anhydride can take place in the presence of Triethylamine in a solvent such as tetrahydrofuran, Chloroform, methylene dichloride or mixtures of the Solvent at a temperature between -30 ° C and that Boiling point of the solvent or mixtures of the Solvents are carried out to obtain the Enol acetate of aldehyde, which in turn is treated with ozone becomes.

The ozonolysis reaction can be carried out in a solvent such as Ethanol, methanol, dioxane, tetrahydrofuran, chloroform, Methylene dichloride or mixtures of solvents in one Temperature between -78 ° C and room temperature  become. The ozonide obtained can be converted into the desired product by treating the reaction mixture with a Reducing agents such as zinc in the presence of acetic acid, Dimethyl sulfide, sodium sulfite, thiourea, Trimethyl phosphite or triethyl phosphite at one temperature be reduced between -30 ° C and room temperatures. The Ozonide can also be isolated from the reaction mixture and then by dissolving in a solvent like ethanol, Methanol, dioxane, tetrahydrofuran, chloroform, Methylene dichloride or mixtures of solvents and by Reaction with a reducing agent as described above, be isolated.

Compounds of general formula IV can by Ozonolysis of the general formula V, wherein the symbol

and the substituent R ^{1 are} as defined above, are prepared under the conditions described above.

Compounds of the general formula V, in which the symbol

and the substituent R ¹ as defined above are derived from compounds of general formula VI, wherein the symbol

and the substituent R ^{1 are} as defined above, by reaction with SOCl ₂ in pyridine or POCl ₃ in pyridine at a temperature between 0 ° C. and room temperature or by reaction with dilute mineral acids such as hydrochloric acid or sulfuric acid in methanol / water or ethanol / water Room temperature or p-toluenesulfonic acid in toluene at a temperature between room temperature and the boiling point of the solvent.

Compounds of the general formula VI, in which R ^{1 is} methyl, can be derived from compounds of the general formula VII in which the symbol

as defined above and R ^{4 is} Ac, can be prepared by deoxygenation of the oxo function of compounds of general formula VII.

The reaction can be carried out by treating a compound of general formula VII dissolved in a polar protic solvent such as methanol, ethanol, acetic acid or a mixture of the solvents with p-toluenesulfonic acid hydrazide at a temperature between room temperature and the boiling point of the above-mentioned solvents or mixtures thereof become. The p-toluenesulfonic acid hydrazone obtained was again reduced by adding a reducing agent such as NaBH ₄ or NaCNBH _3, optionally in the presence of a catalytic amount of zinc iodide or zinc chloride, to the reaction mixture at a temperature between room temperature and the boiling point of the above-mentioned solvents or their mixtures. Alternatively, the resulting p-toluenesulfonic acid hydrazone was isolated from the reaction mixture and reduced by dissolving it in a polar protic solvent such as methanol, ethanol, acetic acid or a mixture of the solvents and with a reducing agent such as NaBH ₄ or NaCNBH _3, optionally in the presence of a catalytic amount of zinc iodide or Treated zinc chloride at a temperature between room temperature and the boiling point of the above-mentioned solvents or their mixtures.

Compounds of the general formula VI in which the symbol

as defined above and the substituent R ^{1 is} ethyl, are prepared by deoxygenation of the oxo function of compounds of the general formula VIII as described above for the preparation of compounds of the general formula VI in which R ^{1 is} methyl:

Compounds of the general formula VI, in which the symbol

as defined above and the substituent R ^{1 is} propyl, of compounds of general formula VII, wherein R ^{4 is} t-butyldimethylsilyl, by reaction with EtMgBr in solvents such as ether or THF or a mixture of solvents, at a temperature between room temperature and the boiling point of the above-mentioned solvents and mixtures thereof. The secondary alcohols obtained were again deoxygenated using Barton's procedure (Barton DHR et al. J. Chem. Soc. Perkin. I, 1975, 1574) to give the desired compounds. The t-butyldimethylsilyl group can be removed by conventional methods and the 3β-OH group can be protected again as an acetate by conventional methods.

Compounds of general formula VII, wherein R ^{4 is} H or Ac, are known compounds: 5β, 17β (Boutagy J. and Thomas R. Aust. J. Chem., 1971, 24, 2723); 5β, 17α (Boutagy J. and Thomas R. Aust. J. Pharm. Sc., 1973, NS2, 9). The 5β, 17β derivative is prepared from the commercially available uzarigenin according to the procedure described by Boutagy for the analog transformation of digitoxigenin (Boutagy J. and Thomas R. Aust. J. Chem., 1971, 24, 2723); the 5α, 17α derivative is prepared from the corresponding 5α, 17β-epimeric compound by isomerization under alkaline conditions.

Compounds of the general formula VIII are known Compounds: 5β, 17β (Donovan S. F, et al. Tetrahedron Lett. 1979, 35, 3287), 5α, 17β (Nambara T. et al. Chem. Pharm. Bull. 1970, 18, 453); 5α, 17α (Weiss e. Et al. Helv. Chim. Acta 1969, 52, 2583). The unknown compound 5ß, 17α is from of the corresponding 5β, 17β-epimeric compound Isomerization produced under alkaline conditions.

Compounds of general formula III are by Esterification of diethylphosphonoacetic acid and the  adequate alcohol, e.g. B. by esterification with DCC as Condensing agents, generally commercially available or of known compounds by known methods producible, manufactured.

All chemical reactions described above are Examples of general approaches to organic Chemistry (e.g.: J. March "Advanced Organic Chemistry", J. Wiley 6 Sons, 1985; D. Barton and W. D. Ollis "Comprehensive Organic Chemistry ", Pergamon Press, 1979).

Compounds of general formula I which according to this Invention are made, and their pharmaceutical acceptable salts are useful agents for the treatment of cardiovascular diseases such as heart failure and Hypertension.

Compounds of the general formula I which are prepared according to the invention and their pharmaceutically acceptable salts have a better therapeutic index in comparison with the known positive inotropic agents such as digoxin and digitoxin. These compounds I show a good affinity for the receptor site of the Na ⁺ , K ⁺ -ATPase.

To investigate the affinity for the Na ⁺ , K ⁺ -ATPase receptor site and the inhibitory activity on the enzyme, the following experiments were used:

• a) Shift of the specific ³ H-ouabain bond from the Na ⁺ , K ⁺ -ATPase receptor, purified according to Jorghensen (Jorghensen P., BBA, 1974, 356, 36) and Erdmann (Erdmann E. et al., Arzneimittel. Forsh ., 1984, 34, 1314);
• b) Inhibition of the activity of the purified Na ⁺ , K ⁺ -ATPase, measured as% hydrolysis of ³² P-ATP in the presence and absence of the compound under investigation (Doucet A, et al., Am. J. Physiol., 1986, 251, F851).

To study antihypertensive activity, the following test applied:

Systolic blood pressure (SBP) and heart rate (HR) were measured through the tail cuff procedure in boys Prepyertonic male rats (MHS or SHR) strains before developing hypertension (4 weeks old) to Record basal values measured by SBP. Groups of 7 Rats were raised and in control and treated Groups divided. The compound suspended with Methocel 0.5% (w / v) was taken orally daily for at least 5 weeks treated groups administered. The control group received only methocel.

SBP and HR were weekly 6 and 24 hours after treatment measured. After 5 weeks of treatment, was considered the Hypertension in the control group (9 weeks old) complete was developed with a washout for at least 1 week started to verify whether the treatment was blood pressure kept low or restored basal values.

The validity of this approach to identifying a Hypertonic activity had previously been studied for β-blockers that did not produce a hypotonic effect when they acute hypertensive rats (SHR) were administered, however have been effective in preventing the development of Hypertension when starting from weaning more than 5 weeks (Takeda K. et al., Japan  J. Pharmacol., 1979, 29, 171; Takeda K. et al. Japan J. Pharmacol., 1982, 32, 283; Richer C. et al. Eur. J. Pharmacol, 1978; 47,393).

The inotropic activity was in the electrically strained left antechamber of a guinea pig according to Bova (Bova S. et al., Hypertension, 1991, 17,944).

The pharmacological profile of some compounds of the general formula I in the experiments mentioned above shown in the following tables:

Binding affinity and inhibitory activity in Na ⁺ , K ⁺ -ATPase

Effect of 5-week treatment in spontaneously hypertensive rats (MHS) in the development of hypertension

The following examples illustrate this invention without it to restrict.  

example 1 (EZ) 2-dimethylaminoethyl-3β-hydroxy-14-oxo-5β, 17β-14.15- seco-pregn-20-en-21-carboxylate (I-a)

A solution of 1.10 g of 2- (N, N-dimethylamino) ethyldiethoxyphosphorylacetate in THF (6 ml) was added dropwise to a suspension of 0.156 g of NaH (55% suspension in oil) in THF (4 ml) in 10 min admitted. After stirring for 20 minutes, a solution of 1.00 g of 3β-acetoxy-14-oxo-17β-formyl-14.15-seco-5β-androstane (II-a, prep. 1) in THF (10 ml) was added dropwise . The mixture was stirred for an additional 30 minutes, then quenched by the addition of ice / 5% NaH ₂ PO ₄ (100 ml) and extracted with CHCl ₃ . The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was dissolved in dioxane (5 ml) and 5% aqueous HCl (2 ml). After 6 days at room temperature, dioxane was concentrated and the aqueous solution extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was chromatographed on silica gel using CHCl ₃ / MeOH 96: 4 as eluent to give the target compound (I-a) as an E / Z (4: 1) mixture, viscous oil.
E isomer: ¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 1.02 (3H, s); 1.18 (3H, s); 2.30 (6H, s); 2.51 (2H, m); 4.10 (1H, m); 4.23 (2H, m); 5.83 (1H, d); 6.79 (1H, dd).
Z isomer: ¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 1.02 (3H, s); 1.16 (3H, s); 2.30 (6H, s); 2.51 (2H, m); 4.10 (1H, m); 4.23 (2H, m); 5.93 (1H, d); 6.20 (1H, t).

Example 2 (EZ) 2-dimethylaminoethyl-3β-hydroxy-14-oxo-5β, 17α-14.15- seco-pregn-20-en-21-carboxylate (I-b)

The target compound was, as in Example 1, starting from 3β-acetoxy-14-oxo-17α-formyl-14.15-seco-5β-androstane (II-b, prep. 2) as an E / Z (4: 1) Blend, viscous oil, manufactured.
E isomer: ¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 1.02 (3H, s); 1.08 (3H, s); 2.38 (6H, s); 2.48 (2H, s); 2.72 (2H, m); 4.12 (1H, m); 4.30 (2H, m); 5.89 (1H, d); 6.79 (1H, dd).
Z isomer: ¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 1.02 (3H, s); 1.06 (3H, s); 2.38 (6H, s); 2.48 (2H, s); 2.72 (2H, m); 4.12 (1H, m); 4.30 (2H, m); 5.95 (1H, d); 6.15 (1H, dd).

Preparation 1 3β-acetoxy-14-oxo-17β-formyl-14,15-seco-5β-androstane (II-a)

A solution of 10.0 g of 3β-acetoxy-5β-pregn-14-en-20-one (Bach, G. et al., Can. J. Chem. 1968, 46, 733) and K ₂ CO ₃ (25 , 0 g) in MeOH / water (160 ml / 80 ml) was stirred at room temperature for 2 h; the organic solvent was evaporated to dryness under reduced pressure and the aqueous suspension obtained was extracted with CH ₂ Cl ₂ ; the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure; the crude 3β-acetoxy-5β, 17α-pregn-14-en-20-one obtained was used for the next step without further purification.

A solution of the crude intermediate and p-toluenesulphonyl hydrazide (11.1 g) in AcOH (300 ml) was stirred at room temperature for 12 h. NaBH ₄ (7.8 g) was added in portions to this solution; after 2 h the reaction mixture was poured into water / ice and the aqueous suspension obtained was extracted with EtOAc and neutralized with 0.1 N NaOH; the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ) using n-hexane / ethyl acetate 1/1 as eluent to give 7.0 g of 3β-acetoxy-5β, 17α-pregn-14-ene as a white solid.
¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 0.90 (3H, t); 1.01 (3H, s); 1.06 (3H, s); 2.06 (3H, s); 2.54 (1H, m); 5.05 (1H, bs); 5.10 (1H, bs).

A solution of 10.0 g of 3β-acetoxy-5β, 17α-pregn-14-ene in methylene chloride (200 ml) was cooled at -78 ° C and an ozone stream was passed through until the reaction was complete (approx. 1 h ). The excess ozone was removed by a stream of nitrogen, then zinc (200 g) and AcOH (300 ml) were added slowly and the temperature was allowed to warm to room temperature. After stirring for 3 hours, the mixture was filtered, the solid washed with CH ₂ Cl ₂ and the solution evaporated to dryness under reduced pressure. The rest was dissolved in EtOAc and washed with a saturated aqueous solution of disodium hydrogenphosphate; the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to give 9.2 g of 3β-acetoxy-14.15-dioxo-17α-ethyl-14.15-seco-5β-androstane as a white solid.
¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 0.92 (3H, t); 1.03 (3H, s); 1.18 (3H, s); 2.06 (3H, s); 2.56 (1H, m); 5.05 (1H, bs); 9.76 (1H, bs).

A solution of 5.0 g of 3β-acetoxy-14.15-dioxo-17α-ethyl-14.15-seco-5β-androstane, Ac ₂ O (16.1 ml), TEA (16.1 ml) and DMAP (0.4 g) in methylene chloride (100 ml) was stirred at room temperature for 9 hours. The excess Ac ₂ O was decomposed with EtOH (15 ml) and the solution poured into water / crushed ice. The mixture was extracted with ethyl ether, the organic layer washed with a 5% aqueous solution of NaHCO ₃ , dried over anhydrous sodium sulfate and concentrated to dryness. The rest was purified by flash chromatography (SiO ₂ ) using n-hexane / ethyl ether 90/10 to 80/20 as an eluent to give 3.1 g of the 15-en-15-ol acetate.

A solution of 3.0 g of the enol acetate in methylene chloride (25 ml) was cooled at -78 ° C and an ozone stream was passed through until the reaction was complete (approx. 1 h). The excess ozone was removed by a stream of nitrogen, then dimethyl sulfide (1.7 ml) was added dropwise and the temperature was allowed to warm to room temperature. After stirring for 48 hours, the solution was concentrated to dryness under reduced pressure and purified by flash chromatography (SiO ₂ ) using n-hexane / ethyl acetate 80/20 as an eluent, to obtain 2.0 g of 3β-acetoxy-14- oxo-17β-formyl-14,15-seco-5β-androstane as a white solid.
¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 0.94 (3H, t); 1.05 (3H, s); 1.15 (3H, s); 2.12 (3H, s); 5.06 (1H, bs); 9.87 (1H, t).

Preparation 2 3β-acetoxy-14-oxo-17α-formyl-14,15-seco-5β-androstane (II-b)

A solution of 27.4 g of 3β-acetoxy-5β-pregn-14-en-20-one (Bach, G. et al. Can. J. Chem. 1968, 46, 733) and p-toluenesulphonylhydrazide (17.1 g) in AcOH (50 ml) was stirred at room temperature for 4 h. The solvent was evaporated to dryness under reduced pressure. The residue obtained was dissolved in MeOH (600 ml) and zinc iodide (3.0 g) was added. Sodium cyanoborohydride (14.4 g) was added in portions to this solution and the temperature was raised to the boiling point of the reaction mixture. After 4 h the solvent was evaporated to dryness under reduced pressure, the crude product was dissolved in ethyl acetate and neutralized with 0.1 N NaOH; the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The rest were purified by flash chromatography (SiO ₂ ) using n-hexane / ethyl acetate 95/5 as eluent to give 18.2 g of 3β-acetoxy-5β-pregn-14-ene as a white solid.
¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 0.84 (3H, s); 0.92 (3H, t); 1.01 (3H, s); 2.06 (3H, s); 5.04 (1H, bs); 5.17 (1H, bs).

A solution of 16.0 g of 3β-acetoxy-5β-pregn-14-ene in methylene chloride (800 ml) was cooled at -78 ° C and an ozone stream was bubbled through until the reaction was complete (approx. 1 h). The excess ozone was removed by a stream of nitrogen, then zinc (63.0 g) and AcOH (90.0 ml) were added slowly and the temperature was allowed to warm to room temperature. After stirring for 3 hours, the mixture was filtered, the solid washed with CH ₂ Cl ₂ and the solution evaporated to dryness under reduced pressure. The rest was dissolved in EtOAc and washed with a saturated aqueous solution of disodium hydrogenphosphate; the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to give 17.1 g of 3β-acetoxy-14.15-dioxo-17β-ethyl-14.15-seco-5β-androstane as a white solid.
¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 0.90 (3H, t); 1.04 (3H, s); 1.12 (3H, s); 2.06 (3H, s); 5.06 (1H, m); 9.82 (1H, t).

A solution of 30.4 g of 3β-acetoxy-14.15-dioxo-17β-ethyl-14.15-seco-5β-androstane, Ac ₂ O (94.0 ml), TEA (94.0 ml) and DMAP (1.0 g) in methylene chloride (400 ml) was stirred at room temperature for 8 h. The excess Ac ₂ O was decomposed with EtOH (100 ml) and the solution poured into water / crushed ice. The mixture was extracted with ethyl ether, the organic layer was washed with a 5% aqueous solution of NaHCO ₃ , dried over anhydrous sodium sulfate and concentrated to dryness. The rest was purified by flash chromatography (SiO ₂ ) using n-hexane / ethyl ether 90/10 to 80/20 as an eluent to give 17.5 g of the 15-en-15-ol acetate.

A solution of 17.0 g of the enol acetate in methylene chloride (500 ml) was cooled at -78 ° C. and an ozone stream was passed through until the reaction was complete (approx. 1 h). The excess ozone was removed by a stream of nitrogen, then dimethyl sulfide (6.0 ml) was added dropwise and the temperature was allowed to rise to room temperature. After stirring for 48 hours, the solution was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography (SiO ₂ ) using n-hexane / ethyl acetate 80/20 as an eluent, to obtain 13.1 g of 3β-acetoxy-14-oxo -17α-formyl-14,15-seco-5β-androstane as a white solid.
¹ H NMR (300 MHz, CDCl ₃ , ppm from TMS): 0.94 (3H, t); 1.06 (3H, s); 1.30 (3H, s); 2.09 (3H, s); 5.03 (1H, bs); 9.90 (1H, t).

Claims (4)

1. Seco-D steroid derivatives of the general formula I
in which mean:
the symbol that the hydrogen in position 5 and the substituent R ¹ in position 17 can have an α or β configuration and the double bond can have an E or Z configuration;
R ^{1 is} methyl, ethyl or propyl;
R ² , R ³ independently represent hydrogen, C1-C4-alkyl or wherein R ² and R ³ together and the nitrogen to which they are attached form a saturated, 5- or 6-membered monoheterocyclic ring;
n 2, 3 or 4, where the alkyl groups can be branched or straight-chain and stereoisomers and mixtures thereof and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1 selected from:
(EZ) -2-dimethylaminoethyl-3β-hydroxy-14-oxo-5β, 17β-14.15-seco-pregn-20-en-21-carboxylate
(EZ) -2-dimethylaminoethyl-3β-hydroxy-14-oxo-5β, 17α-14.15-seco-pregn-20-en-21-carboxylate. 3. A process for the preparation of the compounds of general formula I as defined in claim 1, comprising the condensation reaction of a compound of general formula II:
wherein the symbol and the substituent R ^{1 are} as defined in claim 1, with a compound of general formula III
(EtO) ₂ POCH ₂ COO (CH ₂ ) _n NR ² R ³ (III)
wherein R ² , R ³ and n are as defined above, to obtain compounds of general formula I after hydrolysis of the acetoxy group in position 3. 4. A pharmaceutical composition comprising a A compound of general formula I as in claim 1 or 2 defined, with a pharmaceutically acceptable carrier and / or diluents.