MXPA98001428A - Steroid compounds that have anticonceptive and anti-osteoporo activity - Google Patents

Abstract

The invention relates to a steroidal compound having the formula (I), which comprises an E-ring, said ring sharing carbon atoms in position 16 and 17 with the five-ring D and being alpha with respect to said ring D. In addition, the carbon atom at position 17 is substituted with a group comprising an oxygen atom through a CO bond. The invention also relates to a pharmaceutical composition comprising said steroidal compound. The steroidal compounds of the present invention are well suited for use in the prevention or treatment of peri-menopausal or menopausal complaints, most preferably for the prevention or treatment of osteoporosis. In addition, the steroidal compounds of the present invention can be used for contraceptive purposes

Description

STEROIDAL COMPOUNDS THAT HAVE ANTICONCEPTIVE ACTIVITY AND ANTI-OSTEOPOROSIS DESCRIPTION OF THE INVENTION The present invention relates to a new class of steroidal compounds, and in particular to a steroidal compound having the formula (I), Formula (I) where: - . R3 is = O; -OH; = NOR; -OR or -OOCR, wherein R is an alkyl group having from 1 to 6 carbon atoms; R6 is H; = CH2 or - (CH) mH, m is 1 or 2, wherein the steroidal compound optionally may have one or more double bonds selected from the group consisting of? 9 (10); 5 (10); 4 (5); ? 11 (12); ? 14 (5); or any of the rings A or B can be aromatic. The presence or absence of hydrogen atoms that can not be represented, depends on whether a given ring is saturated, unsaturated or aromatic, and is immediately apparent to those skilled in the art. R7 is H; C1 alkyl-; C2-5 alkenyl or C2-s alkynyl, wherein the alkyl, alkenyl or alkynyl group can be substituted with 1 to 3 halogen atoms independently selected from the group consisting of fluorine or chlorine atoms; Rn is H; C? alkyl?; C2.4 alkenyl; C2-4 alkynyl or C? -4 alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene group can be substituted with 1 to 3 halogen atoms independently selected from the group of fluorine or chlorine atoms; E represents, including the 16 and 17 carbon atoms of the D ring, a ring of four to seven members, said ring being a with respect to ring D, substituted with RE and optionally comprising one or two endocyclic double bonds. The position a of the E-ring vis-à-vis the D ring is essential, since the corresponding steroids having an E ring in the β position do not possess the required biological activity. It should be noted that, for reasons of nomenclature, some compounds according to the invention have a name, which includes a reference to substituents 16β and / or 17β. However, without considering this, in all the compounds of the invention, ring E as a whole is a. RE is H; C-? 6 alkyl; C2-β alkenyl; C2-e alkynyl; alkylidene of C? -6; C2-6 cycloalkyl-spiro bent; -OR; -MR; -OOCR; -N HR; -NRR; -N HCOR, wherein R (and in the case of RE being -NRR, each R independently of the other) is an alkyl of 1 to 6 carbon atoms; -NCO; - (CH2) "- N3 or - (CH2)" - CN, with n from 0 to 5, wherein the alkyl, alkenyl, alkynyl, alkylidene or cycloalkyl group can be substituted with 1 to 3 substituents independently selected from the group consisting of from -OR; -MR; -OOCR; -NH R; -NRR; and -NHCOR, R being defined above, fluorine atoms and chlorine atoms; R17 is -OH; -OCH2OR; -OR or -OOCR, wherein R is an alkyl with 1 to 6 carbon atoms; any of the alkyl, alkenyl, alkynyl and alkylidene groups in the steroidal compound having the formula (I) may be branched or unbranched. If R3, Re or Rn is connected to the steroidal skeleton via an individual bond, the substituted carbon atom of the steroid skeleton both comprises a hydrogen atom as it is involved in a carbon-carbon double bond. RE is connected to ring E through an individual bond, the carbon atom substituted for ring E also comprises a hydrogen atom. Surprisingly it was found that the steroidal compounds of the present invention have excellent estrogenic and / or progestagenic and interesting properties. Due to these specific characteristics, the steroidal compounds of the present invention are very suitable for use in the prevention or treatment of peri-menopausal or post-menopausal complaints, including climacteric symptoms, such as hot flashes and mood disorders, urogenital disorders such as incontinence atrophy of the skin (and epithelium of the vagina), and other symptoms associated with estrogen deficiency or removal of estrogen, such as osteoporosis, atherosclerosis, and Alzheimer's disease. The steroidal compounds according to the invention are very suitable for the prevention or treatment of osteoporosis resulting from estrogen deficiency. In addition, the steroidal compounds of the present invention can be used for contraceptive purposes. Steroidal compounds having substitution in ring 16, 17 have been described. Chemical Abstracts 89: 215660p (Kamemitskii AV et al.) Discloses a steroidal compound comprising a ring of 5 or 6 members ringed in 16, 17 and an acetyl group in position 17. The compounds described in this publication, however, differ from the steroidal compounds according to the present invention in that the carbon atom at the 1 1 position carries a hydrogen atom. Chemical Abstracts 123: 285604p (Wang J. Et al.) Describes steroidal compounds having a 10-membered E-ring with two triple bonds, a hydroxyl group at position 17, and a hydrogen atom at position 1 1. EP 41 1 .733 (Schering AG) discloses a steroidal compound having an E-ring of 6 members, the carbon atom at position 17 being involved in a CO bond. The compounds described in EP 41 1 733, however, differ from the steroidal compounds according to the present invention in that the carbon atom at the 1 1 position carries an aryl group (substituted). These compounds are written as being competitive antagonists for progesterone. Thus, none of the references of the prior art discloses the steroidal compounds according to the present invention. The steroidal compounds according to the present invention differ from those described in the state of the art by the substitution at the 1 1, 16 and 17 position. Particularly, the steroidal compounds according to the invention comprise an E ring, sharing hydrogen atoms. carbon at position 16 and 17 with ring D of five members and where a with respect to said ring D. In addition, the carbon atom at position 17 is substituted with a group comprising an oxygen atom through a bond of CO. The carbon atom in the 1 1 position does not carry any aryl group. In addition, none of the publications suggests the pharmaceutical properties of interest of the steroidal compounds according to the present invention. Therefore, the steroidal compounds according to the present invention form a novel class of steroidal compounds, as defined by their in vitro and in vivo activity. Specifically, to obtain selective estrogen activities, in the steroidal compounds according to the invention, ring E suitably is a five-membered ring. It is preferred that ring E be a six-membered ring, in view of the favorable estrogen / progesterone profiles of the compounds, which include both potent selective oestrogens and potent mixed estrogen / progesterone compounds. According to a preferred embodiment, ring A is aromatic and the remaining rings are saturated, wherein it is further preferred that R7 is α-propyl. The highly preferred compound, encoded Org 38515, further is characterized in that R3 and R17 are OH, and R6, Rn and RE are H. The present invention also relates to a pharmaceutical composition comprising the steroidal compound according to the invention mixed with a pharmaceutically acceptable auxiliary, as described in the standard reference, Gennaro et al. , Remmington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). The mixture of the steroidal compounds according to the invention and the pharmaceutically acceptable auxiliary can be compressed into solid dose units, such as pills, tablets, or can be processed into capsules or suppositories. Through pharmaceutically acceptable liquids, the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion or a spray, for example, nasal spray. To make dosage units, for example, tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive, which does not interfere with the function of the active compounds, can be used.

The steroidal compounds of the invention can also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release. Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts. Furthermore, the invention relates to the use of the steroidal compound according to the invention for the manufacture of a medicament having activity to alleviate per- and / or post-menopausal complaints, in particular an anti-osteoporosis activity. Thus, the invention also relates to the medical indications of per- and / or post-menopausal (climacteric) complaints and osteoporosis, that is, a treatment method in the field of H RT (hormone replacement therapy), which comprises administration to a patient, being a woman, of a compound as described above (in a suitable pharmaceutical dosage form). In addition, the invention relates to the use of the steroidal compound according to the invention for the manufacture of a medicament having contraceptive activity. Thus, the invention also relates to the medical indication of contraception, that is, a contraceptive method comprising the administration to a subject, being a female or a female animal, of a compound as described above (in a form of appropriate pharmaceutical dosage).

Finally, the invention relates to the use of the steroidal compound for the manufacture of a medicament having selective estrogenic activity, such as a medicament that is generally suitable in the area of HRT (hormone replacement therapy). The 16a, 17a-ringed steroid synthesis is generally achieved by first attaching a C3 or C4 fragment suitably functionalized to the C6 position of the steroid (for the formation of 5-membered or 6-membered rings, respectively). To facilitate this procedure, the 17-keto function is generally converted first to a dimethylhydrazone, which is split again after the assembly of the required side-chain functionality. Ring closure can be achieved through organometallic techniques, such as the treatment of iodoalkyl derivatives with transition metals such as samarium (in the case of 5-membered rings, illustrated in Example I), or by the formation of organolithium derivatives through the use of reagents such as r-butyllithium (illustrated in the formation of 6-membered rings in Example II). Alternatively, the formation of five-membered rings can be achieved through the generation of anions through the fluoride-assisted cleavage of silicon groups on β-silyl side chains, as found in example III ,. The α-acetylenes can serve similarly well as substrates for ring closure reactions in reactions mediated with radical anion, using elements such as sodium or lithium, as illustrated in example IV.

A completely different aspect consists in the formation of ringed rings applying olefin metathesis techniques, using catalysts derived from transition metals such as ruthenium, molybdenum or tungsten. At this point, the dialkenylated steroids 16a, 17a serve as substrates. These are readily available through the alkylation of steroidal ketones at C-16, followed by the introduction of an alkene fragment via anionic organometallic derivatives (lithiates, etc.). As an example of such a reaction, the formation of both 5-membered and 6-membered rings has been demonstrated in example V. Thus, in addition to the above compounds of the invention and the various uses of these compounds, the invention also provides the above methods for making ringed steroids 16, 17, generating a ring added to a steroidal skeleton, said ring includes carbon atoms 16 and 17 of said skeleton. These methods, which have not been applied in the technique of steroidal chemistry, allow to make a wide scale of ringed steroids 16, 17. For example, in DE 19709870 (not pre-published), a method is described, which has serious restrictions with respect to the specific compounds that can be synthesized. The method involves a cycloaddition reaction [4 + 2] of butadiene or dimethylbutadiene with a strongly activated double bond in C? 6-17- This means that in C? 7 a strong electron withdrawing substituent must always be present, such as -CN or -acilo, which severely limits the number of options. Furthermore, the method allows to make only 6-membered rings, allows a limited number and a variety of compounds, and requires a symmetrical butadiene structure, since the methods lack regioselectivity. The methods of the invention do not have these restrictions, and allow the stereoselective and regioselective synthesis of a wide variety of ringed steroids 16, 17 of 5 or 6-membered rings, as described above. These methods thus make an inventive contribution to the field of steroidal chemistry. The present invention will be described through the following Figures (schemes) and Examples without necessarily being restricted to the specific modalities described therein.

FIGURES (SCHEMES) Scheme 1: schematic representation (2-13) of a process for the synthesis of two spheroidal compounds (12 and 13) according to the present invention as described in Example I. Scheme 2: schematic representation (14 -21) of a process for the synthesis of three steroidal compounds (19, 20 and 21) according to the present invention as described in Example II. Scheme 3: schematic representation of a procedure (22-23) for the synthesis of two steroidal compounds (30 and 33) according to the present invention as described in Example 11. Scheme 4: schematic representation of a procedure (34-39) for the synthesis of a steroidal compound (39) according to the present invention as described in Example IV. Scheme 5: schematic representation of a procedure (40-44) for the synthesis of a steroidal compound (44) according to the present invention as described in Example V. Scheme 6: Schematic representation of a process (40-47) for the synthesis of a steroidal compound ( 47) according to the present invention as described in Example VI. The numbers in parentheses refer to the corresponding structural formula of the compounds represented in the scheme.

EXAMPLE 1 Although the substrate can be easily synthesized by the dehydrogenation of steroids in C6C7 according to literature methods (for example, through the use of chloranil or DDQ) a new method was developed, which allows the use of a variety of 17-a-ethynyl, 17-β-hydroxy steroids, as well as substrates to access appropriate 17-keto steroids. These can be deethinylated through the treatment with copper carbonate precipitated on Celite. Although a similar conversion has been described in the literature using silver carbonate, the currently described method has the advantage of using a much less expensive reagent. A batch of CuCO3 on Celite was prepared as follows. 100 g of Celite were purified by stirring in a mixture of 500 ml of methanol and 100 ml of 6N HCl for 15 minutes. The mixture was filtered and washed several times with water until neutral. The material thus obtained was slurried to a solution of 60 g of Cu (NO3) 2.3H2O in 400 ml of water. Then a solution of 30 g of Na 2 CO 3 was added dropwise with sufficient stirring. H20 in 200 ml of water. After stirring for an additional 15 minutes, the material was filtered and washed with water (in order to remove most of the water before drying, the material was made a slurry in acetone and filtered and subsequently washed with pentane) . Finally, the vacuum drying was carried out at 80 ° overnight, to yield 160 g of a reagent. 4 g of (17β) -17-hydroxypregna-4,6-dien-20-yn-3-one and 20 g of CuCO3-Celite in 100 ml of toluene were suspended. The mixture was refluxed for about 6 hours with a Dean-Stark trap to remove some of the residual water. The progress of the reaction was verified through TLC. After the end of the reaction, the reaction mixture was filtered over Celite. The filtrate was concentrated and the residue was treated with isopropyl ether-hexane to provide 2.4 g of pregna-4,6-dien-20-yn-3-one, m.p. 182-184. The reduction of this with sodium borohydride provided the required 17 β alcohol, which after acetylation with acetic anhydride provided the required substrate 1_. 7-alpha.17-beta) -17-facethyloxy) -7-propylestr-4-en-3-one 12) A solution of propyl-lithium (prepared from 1.4 g of Li and 9 ml of propyl bromide in 60 ml of ether at -20 ° C) was added at -40 ° C to 7.6 g of Cul in 60 ml of THF dry. After stirring for a further 0.5 hours, a solution of 5.2 g of (17 beta) -17- (acetyloxy) estra-4 was added dropwise., 6-dien-3-one (1) in 20 ml of TH F, at -40 ° C. After stirring for an additional 15 minutes, the reaction was complete, and the mixture was poured into 300 ml of a saturated NH 4 Cl solution, followed by extraction with ethyl acetate. The organic material, isolated after washing, drying and evaporating the solvent, was taken up in 30 ml of THF and stirred in the presence of 3 ml of 6N H2SO4 to isomerize some of the? 5,6 isomer to the? 4, 5 isomer. After one hour, the mixture was neutralized with a NaHCO3 solution and extracted with ethyl acetate. Chromatography of the crude product on silica gel (heptane / ethyl acetate 8/2) provided 2.1 g of 2, m.p. 97-100 ° C. 17-Acetate (7-alpha.17-beta) -7-propylestra-1.3.5110) -trien-3.17-diol (3) To a solution of 15 g of 2 in 300 ml of acetonitrile was added 12 g of CuBr2. The mixture was stirred for 20 hours, while the reaction was verified by TLC (tic plates were purchased from Merck A.G., Germany). The reaction was then poured into water and extracted with ethyl acetate. Chromatography of the crude product on a short silica gel column (heptane / ethyl acetate 4/1 as eluent) provided 13.5 g of 3 as a white amorphous material. Rf 0.57 (hept./etilac 7/3).

Acetate (7-alpha 17-beta) -3-methoxy-7-propylestra-1.3.5 (10 rien-17-Ql (4) To a solution of 13.5 g of 3 in 60 ml of DMF was added 2.4 g of NaH (60% dispersion in mineral oil) in portions After stirring for 1 hour, the evolution of hydrogen was lowered, then 3 ml of methyl iodide was added dropwise after one hour of stirring at room temperature. At room temperature, the reaction mixture was poured into 300 ml of water, and the product was extracted with ethyl acetate.The residue, which remained after evaporation of the volatiles, was taken up in 20 ml of THF and a solution was introduced of 4 g of NaOH in 80 ml of CH3OH After stirring for 1 hour, the saponification was complete.The reaction mixture was neutralized through the addition of 1 N H2SO4, and the product was extracted into ethyl acetate, provide 1 1 .5 g of 4, Rf 0.34 (hept./etilac 7/3).

M 7-alpha) -3-methoxy-7-propylestra-1 .3.5 (10) -trien-17-one (5) To a solution of 10.4 g of 3-O-methyl, 7a-propyl estradiol 4 in 50 ml of methylene chloride were subsequently added 15 g of sodium acetate powder, 30 g of silica gel and 32 g of pyridinium chlorochromate. After stirring for 1 hour, the oxidation was complete. The excess reagent was destroyed through the addition of 1 ml of isopropanol, followed by 150 ml of hexane 10 minutes later. All the precipitates were filtered on Celite, and the filtrate was concentrated to dryness. This provided 9.6 g of essentially pure ketone 5; Rf 0.54 (hept. / Ethyl acetate 7/3). (7-alpha) -3-methoxy-7-propylestra-1.3.5 (10) -trien-17-on-dimethyl-hydrazone (6) To a solution of 11.1 g of 7a-propyl-3-O Methyltrone 5 in 60 ml of toluene was added 6 ml of dimethylhydrazine and 0.5 ml of trifluoroacetic acid. The mixture was refluxed for 1.5 hours. After cooling to room temperature, the reaction mixture was neutralized with 5% NaHCO3 and the organic layer was washed several times with water and dried over sodium sulfate. After concentration and chromatography, 1 1 .4 g of the hydrozone 6 remained as an oil; Rf (hept./etilac 7/3). r7-alpha.16-alpha (SH-16-r3-rrdimethylM .1 -dimethylenesilypoxy1-2-rnetyl-propy-3-methoxy-7-propyl-r-1, 3.5 (10) -trien-17- on-d imeti I-hydrazone (7) To a solution of 2.6 g of 6 in 30 ml of dry THF were added, at -40 ° C, 5.6 ml of BuLi (1.5 N of solution in hexane).

After stirring for 0.5 hour at this temperature, 2.7 g of ether (2R) -2-methyl-3-iodopropanol-0-ter were introduced. butyldimethylsilyl (TBDMS) in 5 ml of THF. After stirring for an additional hour at -20 ° C, the reaction mixture was poured into water and extracted. Then the chromatography provided 4.6 of 7; Rf 0.50 (hept./etilac 7/3 0.50). 7-alpha ri. 16-alpha (S) 1-1 ß- (3-hydroxy-2-methylpropyl) -3-7-propylestra-1.3.5 (10) -trien-17-on-deimetilhid ratio (8) A solution of 4.6 g from 7 to 5 ml of THF was treated with 15 ml of 1 M TBAF for one hour at 50 ° C. The mixture was diluted with 100 ml of water and extracted with ethyl acetate. After passing the product through a column of short silica gel, 3.1 g of 8 were obtained as an oil; Rf 0.18 (hept./etilac 7/3).

RI 7-alpha.16-alpha (S11-16-r2-methy1-3-rr (4-methylphenyl) sulfoninoxy1propin -7-propylestra-1.3.5 (10) -tri-17- ona (10) A solution of 2.8 g of 9 in 7 ml of pyridine was treated at 0 ° C with 2.6 g of tosyl chloride.After stirring for 2 hours, the excess reagent was decomposed by stirring with ice for 0.5 hours. The product was extracted through ethyl acetate and purified by chromatography to provide 3.2 g of ^ 0 as a colorless oil, Rf 0.35 (hept./etilac 7/3). α7-alpha a.16-alpha (S) M 6- (3-hydroxy-2-methylpropyl-3-methoxy-7-propyl-estra-1, 3,5 (10) -trien-17- One (9) A mixture of 3.1 g of 8 in 30 ml of acetone and 3 ml of water was treated with 3 g of acidic resin Amberlyst-15 (Fuka AG) for 2 hours at 55 ° C. The reaction was filtered and concentrated to provide 2.8 g of 9 as an oil, Rf 0.75 (heptane / acetone 1/1). r7-alpha-16-alpha (S 1-16- (3-vodo-2-methylpropin-7-propiclestra-1.3.5) (10) -trien-17-one (11) A mixture of 3.2 g of 10. and 10 g of sodium iodide in 30 ml of acetone was heated at 65 ° C for 1 hour. After the reaction was quenched in water and extraction with ethyl acetate yielded 2.9 g of the iodide 11; Rf ° - 55 (hept./etilac 7/3). r4'S.7-alpha.16-beta.17-beta) -3.4'.5M 6-tetrahydro-3-methoxy-4'-methyl-7-propyl-17H-cyclopentaMβ.171estra-1.3.5 (10 ) -trien-17-lo (12) A solution of Sml2 was prepared from 3 g of samarium metal and 4.7 g of 1,2-diiodoethane in 70 ml of dry THF. To this solution was added, at 0 ° C, 2 mg of tris (dibenzoylmetamate) -fiber, followed by a solution of 2.8 g of H in 10 ml of THF. After stirring for an additional hour, the mixture was poured into water, acidified with 2N H2SO4 and extracted with ether. The crude product thus obtained was chromatographed to remove some of the 16, 17-beta isomer, and provided 1.6 g of 12; Rf 0.32 (hept./etilac 7/3). The related beta isomer has an Rf value of 0.37. f4, .7-alpha.1 ß-beta.17-beta) -3'.4'.5'.16-tetrahydro-4'-methyl-7-propyl-17H-cyclopentari 6.17lestra-1.3 , 5 (10) -trien-3.17-diol (13) To a solution of 700 mg of 12 in 5 ml of toluene was added 15 ml of DI BAL (1 M in toluene). The mixture was refluxed for 3 hours to effect cleavage of the ether. The excess reagent was destroyed by the addition of water, followed by a further dilution with 40 ml of 2N HCl. The product was extracted with ethyl acetate. After drying and concentrating, the residue was triturated with diisopropyl ether, to provide 460 mg of crystalline 1_3; p.f. 166- 168 ° C; R, 0.36 (hept./etilac 7/3).

EXAMPLE II r7-alpha.16-a [fa] -16r4-rhymethyl (1,1-dimethylethinylsulipoxy-1-buty-3-methoxy-7-propylestra-1, 3, 5 (10) -trien-17-on-dimethyl-hucid reasons (14) To a solution of 3.9 g of the hydrazone 6 in 45 ml of dry THF was added, at -60 ° C, 8.5 ml of a solution of 1.5 N BuLi in hexane. After stirring for 0.5 hours, a solution of 4.2 g of 4-iodobutanol-TBDMS ether in 5 ml of THF was added dropwise. The mixture was subsequently stirred at -20 ° C for 1 hour and then was emptied into 200 ml of water and extracted with ethyl acetate. Chromatographic purification on silica gel provided 6.2 g of 14. as an oil; Rf 0.52 (hept./etilac 7/3). 7-alpha.16-alpha) -16 (4-hydroxybutyl) -3-methoxy-7-propylestra-1.3.5 (101-trien-17-on-dimetihydrazone (15) A solution of 6 g of 14 in 5 ml of THF was treated with 20 ml of 1 M of tetrabutylammonium fluoride in THF for 2 hours. The reaction was poured into water and extracted with ethyl acetate. After chromatography, 4.1 g of 15 remained as an oil; Rf 0. 17 (hept./etilac 7/3).

I7-alpha.16-alfal-16- (4-hydroxybutyn-3-methoxy-7-propylestra-1.3.5 (101-trien-17-one (16) A mixture consisting of 4 g 15., 40 ml of acetone, 4 ml of water and 4 g of acidic resin Amberlyst-15, was stirred for 2 hours at 50 [deg.] C. The mixture was filtered, concentrated, taken in 40 ml of toluene, dried and concentrated, to provide 3.7 g of essentially pure I ß, Rf 0.61 (hept./ acetone 1/1), Rf of the starting material 0.65. (7-alpha.1 ß-alpha) -16-r4-rr (4-methylpheninesulfonylnoxpbutyn-7-pro ilestra-1.3.5 (10) -trien-7-one (17) A mixture of 3.7 g of 16 and 3.2 g of tosyl chloride in 10 ml of dry pyridine was dried at 0-5 ° C for 3 hours.After dilution with water, the product was extracted with ethyl acetate.Chromatographic purification provided 4.6 g of tosylate 1 £; Rf 0.45 (hept./etilac 7/3) 0.45. f7-alpha.17-alpha) -16 (4-vodobutyl) -3-7-methoxy-7-propylestra-1.3.5 (10) -trien-17-one (18) A mixture of 4.6 g of 17 and 20 g of sodium iodide in 50 ml of acetone was heated at 60 ° C for 1.5 hours. The reaction mixture was concentrated, diluted with water and extracted with toluene. After drying and reaching a concentration of 4.4 g of iodide 1_8 it remained as an essentially pure material; Rf 0.50 (hept./etilac 7/3). (7-alpha.16-alpha.17-alpha) -3-methoxy-7-propyl-16, 24-cyclo-19-21 -dinorcola-1.3.5 (10) -trin-17-ol (19 ) A solution of 3.8 g of the iodide 18_ in 20 ml of dry THF was treated at -60 ° C with 9 ml of a solution of 1.7m of tert-butyllithium in heptane. After stirring for an additional 15 minutes at -60 ° C, the mixture was poured into water and extracted with ethyl acetate. The crude product obtained after the removal of the volatiles was titrated with heptane, to provide 1.9 g of essentially pure 1.9; p.f. 161 -162 ° C; R, 0.40 (hept./etilac 7/3). (7-alpha.16-alpha.17-alpha) -17-hydroxy-7-propyl-16.24-cyclo-19.21 -dinorcol-4-en-3-one (21) To a solution of 1 g of lithium in 90 ml of liquid ammonia a solution of 1.3 g of 19 in 30 ml of dry THF was added at -33 ° C. After refluxing the ammonia for a further 4 hours, the reaction was treated with 20 ml of ethanol followed by evaporation of the ammonia under a stable stream of nitrogen. The residue was diluted with 50 ml of water and extracted with ethyl acetate. Concentration of the organic phase, followed by titration of the residue with heptane, provided 1.1 g of the dienolic ether intermediate; p.f. 190-192 ° C. This material was dissolved in 25 ml of THF and treated with 5 ml of 6 N of H2SO4. After stirring for 6 hours, the mixture was neutralized with Na2CO3 and the product was extracted with ethyl acetate. Chromatographic purification of the crude material thus obtained gave 610 mg of 21 as a foam; Rf 0.25 (hept./etilac 7/3). (7-alpha.16-alpha.17-alpha) -7-propyl-16.24-cyclo-19-21 -dinorcola-1.3.5 (10) -trien-3, 17-diol (20) To a solution of 600 mg of 1_9 in 5 ml of dry toluene was added 12 ml of 1 M DIBAH (diisobutylaluminum hydride) in toluene. After 2 hours at reflux, the demethylation was complete; the excess reagent was destroyed through the careful addition of water and subsequently the mixture was poured into 50 ml of 4N hydrochloric acid, and the product was extracted into ethyl acetate. The organic layer was dried, concentrated, and the residue was treated with diisopropyl ether, to provide 310 mg of 2; p.f. 240 ° C, Rf 0.20 (hept./etilac 7/3).

EXAMPLE III (1,2-ethanediin-acetal 3-cyclic of (1 1 -beta.16-alpha) -1 1 -methyl-16f2-r (trimethylsilynmetillprop-2-eninestr-5-en-3.17-dione (23) To a solution of 12.7 ml of hexamethyldisilazane in 50 ml of THF were added, at -50 ° C, 40 ml of a 1.5M solution of BuLi in heptane. After stirring for 20 minutes, the solution of 16.5 g of 22 in 100 ml of RH F was slowly operated at -50 ° C. After stirring for an additional 0.5 hours, a solution of 25 g of 3-iodo-2-trimethylsilylmethylpropane in 25 ml of THF was introduced. The reaction mixture was stirred at -20 ° C for a further 3 hours, and then it was poured into 400 ml of water. The product was extracted with ethyl acetate and chromatographed on silica gel. After titration with heptane, 12.5 g of the product 23 were obtained; p.f. 184-185 ° C; Rf 0.55 (hept./etilac 7/3). (1,2-ethanediyl-acetal) 3-cyclic of (11-beta-1 β-beta-17-beta) -4,5 .5M-6,17-tetrahydro-17-hydroxy-1-methyl-4, -methylene-3, HCl-pentari ß.171estra-5.16-dien-1 -one (24) A solution of 8.8 g of 23 in 200 ml of dry THF was treated with 4 ml of 1 M tetrabutylammonium fluoride (TBAF). The mixture was refluxed for 15 minutes to complete the ring closure reaction. Then, an additional 15 ml of a 1 M solution of TBAF was added and the reflux was prolonged for 1 hour in order to separate the 17-O-silyl ether formed during the reaction. The mixture was subsequently concentrated to a small volume and diluted with water, followed by extraction with ethyl acetate. Chromatographic purification provided 4.0 g of 24; p.f. 141-142 ° C, Rf 0.28 (hept./etilac 7/3). (1,2-ethanediyl-acetan 3-cyclic of (4'S.11-beta.16-beta.17-beta) -4'.5'.1ß.17-tetrahydro-17-hydroxy-4 '- (hydroxymethyl) 11-methyl-3'Hc¡clopentapß.171estra-5,16-dien-3-one (25) v its analog 4'R (26) A solution of borobiciclononane (9-BBN) was prepared from 3 ml of a 10M complex of borane-dimethyl sulfide and 4 ml of 1, 5-cyclo-octadiene in 30 ml of dry THF. To this was added a solution of 3.8 g of 24. in 10 ml of THF. The mixture was stirred for 2 hours and then the excess reagent was destroyed through a careful addition of 1 ml of ethanol, followed by 20 ml of a 2N solution of NaOH and 10 ml of 30% H2O2. This mixture was stirred for another 3 hours and then further diluted with water and extracted with ethyl acetate. The crude product was chromatographed on silica gel (toluene / acetone as eluent) to provide 2.1 g of 25 (mp 178 ° C, Rf 0.47 (tol./acet./1) and 1.2 g of 26 (Rf 0.55 (tol. ./ acet. 1/1)). (3-cyclic 1,2-ethanediyl-acetah of (4'R.11-beta.16-beta.17-betal-4,, 5'.1ß, 17-tetrahydro-17-hydroxy-11-ethyl-4-rrr (4-methylfenylsulfonylloxylmethyl-3'H-cyclopentari6.17lestra-5,16-dien-3-one (31) A solution of 1.2 g of 26 and 0.8 g of tosyl chloride in 5 ml of pyridine was stirred at 0-5 ° C for 2 hours, then the mixture was diluted with ice water, stirred for 15 minutes and extracted with ethyl acetate.Drying and concentration of the organic phase provided 1.6 g of 3 _ essentially pure; Rf 0.52 (tol./etilac 7/3). (4'R.11 -beta.16-beta.17-beta) -4"-butyl-.4, .5, .1ß, 17-tetrahydro-17-hydroxy-11-methyl-3'Hc'clopentari 6.171estra-5.16-dien-3-one (32) A cuprate reagent was prepared by adding 12 ml of a 2M solution of propylmagnesium bromide / ether to 2.3 g of Cul in 20 ml of TH F at -20 ° C. C. After stirring for 15 minutes, a solution of 600 mg of 31 in 3 ml of THF was added.The stirring was continued for a further 2 hours at -20 ° C. The reaction was processed through the addition of 60 ml. NH4CI saturated and 10 ml of 10% ammonia, followed by extraction with ethyl acetate The crude product was chromatographed, to provide 420 mg of 3_2, mp 97-98 ° C, Rf 0.45 (hex / ethyl 7 /3) . 4, R.11 -beta.1 ß-beta.17-beta) -4'-butyl-.4, .5M ß, 17-tetrahydro-17-hydroxy-1-methyl-3'H-cyclopentari 6.17lestra -4.16-dien-3-one (33) A solution of 400 mg of 32 in 5 ml of acetone was treated with 2 ml of 4N of H2SO4. After 2 hours at room temperature, the mixture was diluted with water and extracted with ethyl acetate. The chromatographic purification provided 360 mg of 33 essentially pure as an amorphous material; Rf 0.27 (hept./etilac 7/3). (1,2-ethanediyl-acetal) 3-cyclic of (4'S.11 -beta.16-beta.17-beta) -4'.5'.16.17-tetrahydro-4 '- (hydroxymethyl) -1 1 -methyl-17 -r (trimethylsilyn-oxi1-3'H-cyclopentap ß.171estra-5.1 ß-dien-3-one (27) The protection of the 17-OH function was carried out in a multistep procedure. The primary solution was acetylated. Thus, to a solution of 750 mg of 25 in 2 ml of pyridine was added 5 mg of 4-dimethylaminopyridine (DMPA), followed by 0.5 ml of acetic anhydride. g of ice water, followed by extraction of the product with ethyl acetate.The concentration of the organic material, and the treatment of the residue with heptane-diisopropyl ether provided 730 mg of monoacetate, mp 1 12 ° C. This material was dissolved in 3 ml of DMF containing 200 mg of imidazole, then 240 μl of TMS chloride was added, and the mixture was stirred for 0.5 hour at room temperature After the addition of 15 ml of water, the product was extracted with ether. After drying and concentrating, 900 mg of the essentially pure silyl ether derivative were obtained; Rf 0.54 (hept./etilac 7/3). This product was dissolved in 3 ml of dry THF and 70 mg of LiAIH4 was added. After stirring for 10 minutes, the mixture was subsequently treated with 0.3 ml of water and 0.1 ml of 2N NaOH and 1 g of NaSO4. Then, it was filtered through Celite and concentrated to provide 700 mg of 27 as an amorphous material; Rf 0.29 (hept./etilac 7/3). (4'S.11 -beta.16-beta.17-beta) -3.3-p.2-ethanediylbis (oxm-4'.5'.16,17-tetrahydro-11-methyl-17-r (trimethylsilyl ( oxi) -3, -Hc¡clopentap 6.171-estra-5, 1 ß-dien-4'-carboxyaldehyde (28) To a solution of 600 mg of 27. in 15 ml of methylene chloride was added 1.5 g. of anhydrous sodium acetate, 2.5 g of silica gel followed by 2 g of pyridinium chlorochromate, the mixture was stirred for 1 hour at room temperature, then 50 ml of ether was added and after stirring for an additional 15 minutes, the The reaction was filtered through Celite, followed by evaporation of the volatiles, to provide 420 mg of the carboxyaldehyde 28. essentially pure, a compound of slow solidification at rest, Rf 0.48 (hept./etilac 7/3). (1,2-ethanediyl-acetal) 3-cyclic of (4'S.11 -beta.16-beta.17-beta) -4'-ethenyl-4a.5'.16,17-tetrahydro-1-methyl-17- r (trimethylsilyl (oxm-3'H-cyclopentari β, 171-tetra-5.16-dien-one (29) To 1.3 g of methyltriphenylphosphonium chloride in 25 ml of THF was added 1.7 ml of a solution of 1 -5 M BuLi in hexane at -40 ° C. After stirring for 30 minutes, 400 mg of 28 were added in 2 ml of TH F. The mixture was allowed to warm to room temperature in about 0.5 hours and then quenched by emptying it in 100 ml of water. The product was extracted with diethyl ether, and subsequently chromatographed to provide 280 mg of 29. as an oil; Rf 0.53 (hept./etilac 7/3); starting material Rf 0.23. (4, S.11 -beta.16-beta.17-beta) -4'-ethenyl-4, .5, .16.17-tetrahydro-1 1 -methyl-17-hydroxy-3'H-cyclopentam 6 71estra-4.16-dien-3-opa (30) A solution of 260 ml of 29. in a mixture of 3 ml of THF and 3 ml of 4N of H SO 4 was stirred for 2 hours at 45 ° C. The reaction was then neutralized with a 5% solution of NaHCO3 and the product was extracted into ethyl acetate. Short path silica gel chromatography provided 150 mg of 30; Rf 0.25 (hept./etilac 7/3).

EXAMPLE IV 3-rr (1,1-dimethylethyl) dimethylsilylnoxMestra-1, 3.5 (10) -trien-17-n-di-methylhydrazone (35) To a solution of 15.5 g of 3-hydroxyestra-1, 3.5 (10) -trien-17-on-dimethylhydrazone (34) in 200 ml of DMF, 13 g of imidazole were added, followed by the dropwise addition of 15 g of TBDMSCI in 20 ml of ether. After stirring for a further 16 hours, the reaction mixture was poured into 2 liters of water and the resulting mixture was stirred for a further 10 minutes. The precipitate was filtered and dried in vacuo to provide 20 g of 35; p.f. 100-103 ° C. (16alpha) -3-rr (1,1-dimethylethyl) dimethylsilylnoxy-16- (4-butynestra-1.3.5 (10) -trien-17-on-dimethylhydrazone (36) The alkylation of the steroid was carried out with the anion generated first of 4-bromo-1-butyne The procedure was as follows: A solution of 1 1.9 g of 35 in 100 ml of TH F was treated at -20 ° C with 20 ml of a solution of 1.5 M BuLi in hexane After stirring for 1 hour at -20 ° C, the reaction mixture was cooled to -70 ° C. A cold solution of the 4-bromo-1-butyne anion (prepared by the addition of 36 ml of BuLi to 7.7 g of 4-bromo-1-butine in 50 ml of THF at -78 ° C) was added dropwise, and the reaction mixture was allowed to warm to room temperature.The mixture was then stirred for an additional 1 hour and then The product was extracted with ethyl acetate, after chromatography, 9.5 g of 36 were obtained as an oil, Rf 0.85 (toluene / ethyl acetate 6/4). (16alpha) -3-rr (1,1-dimethyl) dimethylsilynoxy116- (4-butynyl) estra-1.3.5 (10 rien-17-on (37) To a solution of 9 g of 36 in 100 ml of TH F and 70 ml of 1 M acetate pH buffer (pH 4.5) was added to 15 g of periodic acid in 40 ml of ethanol, the mixture was stirred for 24 hours, then 500 ml of water was added and the product was added. extracted with ethyl acetate The chromatography of the crude material thus obtained yie 4.2 g of 37. (16alpha.17beta) -3-rr (1,1-dimethyl) dimethylsilinoxH16.23-cyclo-19.24-dinorcola-1, 3,5 (10), 20-tetraen-17-ol (38) A solution of lithium naphthalenide is prepared from 3.4 g of naphthalene and 150 mg of lithium wafers in 30 ml of dry THF. This solution was added dropwise to a solution of 560 mg of 37 in 5 ml of TH F until a dark green color of the reaction persisted. After stirring for a further 10 minutes, the reaction mixture was emptied into 30 ml of N H 4 Cl and the product was extracted with ethyl acetate. Chromatographic purification provided 150 mg of 38 crystalline. (16alpha.17alpha) -16.23-cyclo-19.24-dinorcola-1.3.5 (10) .20-tetraen-17-diol (39) A solution of 130 mg of 35 in 5 ml of 5% HCl in methanol, stirred for 2 hours at room temperature. The reaction mixture was then treated with 3 ml of pyridine and concentrated and diluted with 10 ml of water. The product was extracted into ethyl acetate and finally through chromatography, to provide 65 mg of 39; p.f. 203-205 ° C.

EXAMPLE V 3,3-dimethylacetal of (7a, 16a) -7-methyl-16- (prop-2-enyl) -estr-5 (10) -en-3,17-dione (41) A solution of diisopropylamide was prepared from lithium from 16. 6 ml of 1.5 M butyllithium in hexane and 3.85 ml diisopropylamine in 35 ml of THF at -20 ° C. After stirring for 20 minutes, a solution of 8.3 g of steroid 40 was added in 30 ml of THF, and the mixture was stirred for 20 minutes. After cooling to -40 ° C, 2.2 ml of allyl bromide was added and then stirring was continued for a further 4 hours at -20 ° C, after which tic verification showed the end of the reaction. The mixture was quenched through the addition of 200 ml of a 5% solution of NaHCO3, followed by extraction with ethyl acetate. Chromatography on silica gel (hexane-5% ethyl acetate as eluent) provided 7.2 g of 41 as a white solid; p.f. 85-86 ° C. 3. 3-dimethylacetal of (7a.16a.17B) -7-methyl-16.17-bis (prop-2-enin-17-hydroxy-estr-5 (10) -en-3-one (42) To a solution of 15 ml of 1 M allylmagnesium bromide in 30 ml of THF was added, at -40 ° C, to a solution of 4.5 g of 4J_, in 30 ml of TH F. After stirring for 30 minutes, at this temperature, the The mixture was poured into 250 ml of a 10% solution of N H4CI and extracted with ethyl acetate.The product thus obtained was chromatographed to provide 3.2 g of the 16a, 17a diallyl derivative 42 as a white amorphous material. 3. 3-dimethylacetal of (7a.16a.17a) -7-methyl-17-hydroxy-16.24-cyclo-19,21 -dinorcola-5 (10) .22.dien-3-one (43) To a solution of 1 .3 g of 42 in 30 ml of methylene chloride, was added 200 mg of bis (tricyclohexylphosphine) -benzylidene-ruthenium chloride. The reaction was stirred until complete. The solvent was partially removed through concentration and the residual material was chromatographed on a column of silica gel to provide 1.1 g of 43 as a white amorphous material. Rf = 0.38 (heptane / ethyl acetate 7/3 v / v). (7a.16a.17a) -7-methyl-17-hydroxy-16.24-cyclo-19.21 -dinorcola-4.22.dien-3-one (44) A solution of 1 g of 43 in 30 ml of acetone was treated with 5% of the solution. ml of 2N HCl. After stirring for 2 hours at room temperature, the reaction was complete. After neutralization with a 5% NaHCO3 solution, the mixture was extracted with ethyl acetate and the product was passed through a short silica gel column. The product thus obtained was treated with diisopropyl ether to provide 0.65 g of 44; p.f. 130-131; Rf (heptane / ethyl acetate 7/3) 0.14.

EXAMPLE VI 3. 3-dimethylacetal of (7a.16a.17a) -7-methyl-16- (prop-2-enyl) -17-hydroxy-pregna-5 (10) .20-dien-3-one (45) A solution of vinyl lithium was prepared by adding 0.8 ml of a solution of 1.6M of butyllithium in hexane to 0.32 of vinyltributyltin in 3 ml of THF at -50 ° C. After stirring for 20 minutes, a solution of 300 mg of 41 in 2 ml of THF was added dropwise. After stirring for an additional 15 minutes, the mixture was quenched by the addition of 20 ml of a 10% solution. of N H4CI, followed by extraction of the product in ethyl acetate. Subsequent chromatographic purification provided 120 mg of 45. as an amorphous material; Rf 0.56 (heptane / ethyl acetate 7/3 v / v). 3. 3-dimethylacetal of (7a.16B.17B 1-16.17-dihydro-17-hydroxy-5'H-cyclopentaM β.171estra-5 (10) .16-dien-3-one (46) To a solution of 120 mg from 45. in 4 ml of methylene dichloride were added 30 mg of bis (tricyclohexylphosphine) benzylidene ruthenium dichloride.After stirring for 2 hours, the mixture was concentrated and filtered through a column of silica gel provide 80 mg of 46., Rf (heptane / ethyl acetate 7/3 v / v). (7a.16B.17ß) -7-methyl-16.17-dihydro-17-hydroxy-5? -cyclopentari 6.17l estra-4.16-dien-3-one (47) A solution of 80 mg of 46. in 2 ml of Acetone was treated with 0.2 ml of 2N HCl. After stirring for 2 hours at room temperature, the reaction mixture was neutralized by the addition of NaHCO3, and diluted with water. The product was extracted with ethyl acetate and passed through a short silica column to provide 45 mg of 47; p.f. 175-176 ° C, Rf 0.49 (heptane / ethyl acetate 1/1 v / v).

SCHEME I SCHEME II 21 20 SCHEME lll SCHEME IV 39 SCHEME V 44 SCHEME VI EXAMPLE VII Test for the Prevention of Bone Loss Induced by Rat Ovariectomy (Anti-Osteoporosis Test) Introduction Ovariectomy induced bone loss in rats, which is due to an estrogen deficiency. The administration of estrogenic compounds avoids this effect. The test is used to evaluate a compound for anti-osteoporotic activity in ovariectomized rats. The effect on bone mass can be evaluated through the measurement of peripheral quantitative computed tomography (pQCT) of the mineral density of trabecular bone.

Test Animal Preferentially, female Wistar rats, mature virgins, weighing 225-250 g. Strain: Hsd / C? D: Wu, race SPF by Harían, CPB, Zeist, Holland.

Experiment On day 1 of the experiment, the rats were weighed and distributed in cages in order of body weight. The rat with the lowest body weight in the first cage and the heaviest rat in the last cage. The treatments were randomized in rats per block. One block (group of 3 + n treatments) consisted of placebo rat Intacto 1, placebo rat 1 OVX, reference rat 1 OVX and rat 1 of each n treatments. An alleged operation and oophorectomy were performed under ether anesthesia. After recovering from anesthesia, in 24 hours, a vehicle, reference compound or test compound was administered once or twice a day for 4 weeks.

Measurement of Bone Mineral Density through pQCT The trabecular bone mineral density (mg / cm3) of the metaphyseal part of the femur was measured with a pQCT (peripheral Quantitative Computed Tomography machine, XCT 960A, Stratec, Birkenfeld, Germany) directly after autopsy of fresh tissue. Two 360 ° scans were taken, which have, due to the X-ray beam, a normal thickness of 1 mm. The scans have a resolution of 0.148 x 0.148 mm. A scan was taken at 5.5 mm from the far end of the femur, where the mineral density of the trabecular bone of the metaphyseal part was measured. The other scan was taken at the diaphysis at 13.5 mm from the far end, which does not contain trabecular bone. In the last exploration, the mineral density of the cortical bone and the geometrical parameters were determined, such as the cortical thickness, the total bone area, the external and internal diameter. The intra- and inter-assay variation for the measurement of the mineral density of the trabecular bone in the distant femur was approximately 2-3%. The XCT-960A was calibrated with a hydroxyapatite standard embedded in the acrylic plastic.

Interpretation of Results Ovariectomy caused a statistically significant reduction in the mineral density of the trabecular bone (P <_ 0.05, 2 ANOVA forms). The test compounds were considered active when the average bone mineral density values of the distant femur increase significantly as compared to the ovariectomized control group. The active dose (ED5o) is the dose where a mean proportional difference in the mineral density of the trabecular bone is reached, between 40 and 60%, as compared with the imitation and ovariectomized group.

References Wronski T. J. and Jen C. F.: The ovariectomised rat as an animal model for postmenopausal bone loss. Cells and Material, Supp. 1 (1991): 69-76. Yamazaki I. and Yamaguchi H. : Characteristics of an ovariectomised osteopenic rat model. J. Bone. Min. Res. 4 (1989): 12-22. Ederveen A.G. H., Spanjers C. P.M., Quajitaal J. H. M. and Kloosterboer H. J. : Effect of treatment with tibolone (Org OD 14) or 17a-ethiny estradiol on bone mass, bone turnover and biomechanical quality of cortical and trabercular bone in mature ovariectomised rats. Osteoporosis Int. In press, 1998.

EXAMPLE VIII Test for In Vitro Receptor Binding Relative progesterone receptor binding affinity of the compounds of the invention was measured for cytoplasmic progesterone receptors present in human breast tumor cells (MCF-7 cells, incubation time 16 hours , temperature 4 ° C) and compared with the affinity of (16a) -16-ethyl-21-hydroxy-19-norpregn-4-en-3,20-dione (according to the procedure described by EW Bergink et al. ., J. Steroid Biochem., Vol. 19, 1563-1570 (1983)). The binding affinity of the relative estradiol receptor was measured in the same manner as described above, but using 17β-estradiol as a reference.

Test for in vivo Estrogenic Activity Estrogenic activity was determined in vivo through the well-known Alien Doisy test, described by F. Alien, L.A. Daisy, J. Amer. Med. Assoc. 8_1, 819-821 (1923) Test for in vivo Progestagenic Activity Progestagenic activity was measured in vivo through the well-known McPhail test, described by McPhail, M.K.: The assay of progestin, Journal of Physiology, 1934, 83: 145-156. Several of the compounds according to Examples I-VI, as well as other compounds according to the invention synthesized in an analogous manner, were subjected to the tests described in Examples VII and VI I. The results are described in the Table, where the type of ring A and the substitution in the carbon atoms are indicated. 7, 11 and 17. In the columns with the letters E and P, the relative binding affinities for the estrogen and progesterone receptors are given; The EDS0 results of the Alien Daisy and McPhail tests have been reported in μg / kg. In the column entitled "Osteoporosis", the ED50 results of the anti-osteoporosis test are given (dose in μg / kg, day, as described above).

TABLE Representation of Union Affinities Relating to Estradiol (E) or Progesterone Receptor (P) v In Vivo Activities (EDso) after Oral Administration NC Non-Competitive; ND Not Determined

Claims (10)

1. - A steroidal compound that has the formula: where, ,.. . R3 is = O; -OH; = NOR; -OR or -OOCR, wherein R is an alkyl group having from 1 to 6 carbon atoms; R6 is H; = CH2 or - (CH2) mH, m is 1 or 2; R7 is H; C1 alkyl-; C2-5 alkenyl or C2-5 alkynyl, wherein the alkyl, alkenyl or alkynyl group can be substituted with 1 to 3 halogen atoms independently selected from the group consisting of fluorine or chlorine atoms; Rn is H; C? .4 alkyl; C2 alkenyl.; C2-4 alkynyl or C1.4 alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene group can be substituted with 1 to 3 halogen atoms independently selected from the group of fluorine or chlorine atoms; E represents, together with the 16 and 17 carbon atoms of the D ring, a ring of four to seven members, said ring being a with respect to ring D, substituted with RE and optionally comprising one or two endocyclic double bonds; RE is H; C? .6 alkyl; C2-6 alkenyl; C2.6 alkynyl; alkylidene of d.6; C2-6 cycloalkyl-spiro bent; -OR; -MR; -OOCR; -N H R; -NRR; -N HCOR, wherein R (and in the case of ER being -N RR, each R independently of the other) is an alkyl of 1 to 6 carbon atoms; -NCO; - (CH2) n-N3 or - (CH2) n-CN, with n from 0 to 5, wherein the alkyl, alkenyl, alkynyl, alkylidene or cycloalkyl group can be substituted with 1 to 3 substituents independently selected from the group consisting from -OR; -MR; -OOCR; -NHR; -N RR; and -NHCOR, R being defined above, fluorine atoms and chlorine atoms; R17 is -OH; -OCH2OR; -OR or -OOCR, wherein R is an alkyl with 1 to 6 carbon atoms; wherein the steroidal compound optionally may have one or more double bonds selected from the group consisting of D9 (10); D5 (10); D4 (5); D1 1 (12); 14 (15); or any of fos ring A or B can be aromatic.

2 - A steroidal compound according to claim 1, wherein ring E is a six-membered ring.

3 - A steroidal compound according to claim 1 or 2, wherein ring A is aromatic, and the remaining rings are saturated.

4. A steroidal compound according to claim 3, wherein R7 is a-propyl, ring E is a six-membered ring, R3 and R17 are OH, R6, Rn and RE are H.

5.- A na pharmaceutical composition comprising the steroidal compound according to any of the preceding claims, and a pharmaceutically acceptable auxiliary.

6. The use of a steroidal compound according to any of claims 1-5 for the manufacture of a medicament for the prevention or treatment of peri-menopausal or post-menopausal complaints.

7. A use according to claim 7, wherein the complaint is osteoporosis.

8. The use of a steroidal compound according to any of claims 1-5 for the manufacture of a medicament having a contraceptive activity.

9. A procedure for the preparation of a ringed steroid 16, 17 according to any of claims 1-5, which comprises taking the steroid 17-keto having the formula, wherein the substituent groups have the meaning as described in the preceding claims, and join, at the carbon atom 16, ie, adjacent to the 17-keto portion, an alkyl chain, substituted or not, suitably functionalized for the purpose to obtain a portion? -iodoalkyl, and achieve the ring closure of the? -alkyl portion through the treatment with an organometallic reagent.

10. - A method for the preparation of a ringed steroid 16, 17 according to any of claims 1-5, which comprises taking a 17-keto steroid having the formula: wherein the substituent groups have the meaning described in the preceding claims, and join, at each of carbon atoms 16 and 17, a substituted or unsubstituted alkyl chain, and achieve ring closure via olefin metathesis, using a catalyst derived from a transition metal.