NO172241B - NEW STEROID COMPOUNDS, FERTILIZATION PREVENTION CONTAINING ONE OR MORE OF THE COMPOUNDS AS ACTIVE INGREDIENT AND USE OF THE COMPOUNDS AS ACTIVE INGREDIENT IN A FERTILIZING PREVENTION AGENT - Google Patents

Description

The present invention relates to new steroid compounds which include a spiro ring in the 17-position, contraceptives containing one or more of the compounds as active ingredient and use of the compounds as active ingredient in a contraceptive.

The new steroid compounds have the general formula

— where

Rx denotes phenyl, benzyl, thienyl, isothienyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, each of these radicals being optionally substituted with one or more radicals chosen from: alkyl with 1-8 carbon atoms, alkoxy with 1-8 carbon atoms, halogen, hydroxyl, trifluoromethyl, alkanoyl of 1 to 6 carbon atoms, carboxy, C 1 -C 6 -alkoxycarbonyl; alkylthio with 1-8 carbon atoms which is optionally oxidized to the sulfoxide or sulfone form; amino which is optionally mono- or disubstituted with alkyl with 1-8 carbon atoms, and which is optionally oxidized to the N-oxide; bis-(chloroethyl)-amino, dimethylaminomethyl, dimethylaminoethyl, methyl-(dimethylaminoethyl)-amino, dimethylaminoethoxy and

methylthioethoxy,

or Rx denotes:

R2 in the alpha or beta position is hydrogen or methyl,

the wavy line in the spiroether indicates that the oxygen atom can be in the alpha or beta position,

the broken line in the 3'-, 4'-position indicates the possible presence of a second bond between the carbon atoms carrying it,

and rings A and B have one of the following structures:

a) A and B denote the group:

where R' and R" are the same or different and denote a hydrogen atom or an alkyl radical with 1-4 carbon atoms,

b) A and B denote the group:

where Re denotes a hydrogen atom, an alkyl radical with 1-6 carbon atoms, or alkanoyl with 1-6 carbon atoms,

c) A, B and C denote the group:

where Rx and R2 are as stated above, d) A and B denote the group: e) A and B denote the group:

and their acid addition salts.

Among the compounds of formula (I), the compounds are preferred where the oxygenator in the spiroether is in the 17-beta position and the rings A and B denote the group:

where R' and R" denote a hydrogen atom.

Among the compounds of formula (I), preferred compounds are those where denotes a phenyl or benzyl group which is either substituted with an amino group which in turn is disubstituted with alkyl of 1-8 carbon atoms, or which is substituted with a methylthio or ethylthio group.

The compounds of formula (I) where Rx is phenyl which has a substituent in the para position, as well as the salts thereof, are likewise considered particularly preferred. Particularly preferred meanings of Rx are 4-(dimethylamino)-phenyl and 4-(methylthio)-phenyl.

The R2 radical is preferably methyl, and it is preferred that it is in the beta position.

When R 2 includes a carboxy function, this may be salted. Among possible salts can be mentioned e.g. the sodium, potassium, lithium, calcium, magnesium or ammonium salts. Among the organic bases can be mentioned methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris-(hydroxymethyl)-aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methyl-glucamine.

When Rx includes a function that can be salted out with an acid, and in particular an amino function, addition salts with acids are obtained, e.g. the salts formed with the following acids: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acid, such as methane or ethanesulfonic acid, arylsulfonic acids , such as benzene or paratoluenesulfonic acid, and arylcarboxylic acids.

Particularly preferred are the following compounds, which are described in the following examples: (17 R)-4',5'-dihydro-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9- dien-17,2'-(3H)-furan)-3-one (Example 1),

(17 R )-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5 H )-furan)-3-one (Example 2),

(17 R )-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4, 9-dien-17,2'-(5 H )-furan)-3-one (Example 3) and

(17R)-4',5'-dihydro-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(3H)-furan)-3 -on (example 4)

and their salts.

The new steroid compounds of the formula (I) and their salts exhibit a remarkable anti-progestomimetic activity and, as a result of this activity, are useful as active ingredients in contraceptives.

INVESTIGATION OF THE EFFECT OF THE NEW COMPOUNDS

I. Investigation of the activity of the new compounds on the hormone receptors.

The proqestoqen receptor in the rabbit uterus.

Rabbits that are not fully grown and weigh approx.

1 kg, 25 mg estradiol is given subcutaneously. Five days after this treatment, the animals are killed and the uteri removed, weighed and homogenized at 0°C, using a Potter Teflon glass, in a buffered TS solution (10 mM Tris, 0.25 M sucrose, HCL to pH 7.4) (lg tissue per 50 ml TS). The homogenate is then ultracentrifuged (105,000 g x 90 min.) at 0°C.

Aliquots of the supernatant thus obtained are incubated at 0°C for a time t, with a constant concentration (T) of tritiated compound R (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione ) in the presence of increasing concentrations (0-2500.10"<9>M of either cold R or of cold progesterone or of cold compound to be tested. The concentration (B) of bound tritiated compound (R) is then measured in each incubate using the technique of adsorption on dextrancarbon.

Calculation of the relative binding affinity.

The calculation of the relative binding affinity (RBA) is the same for all receptors.

The following two curves are plotted: the percentage bound tritiated hormone B/T as a function of the concentration of the cold reference hormone, and B/T as a function of the logarithm of the concentration of the cold compound being tested. The straight line described by the equation I50= (B max + B min) /2

T T

is determined.

B/T max = the percentage amount of tritiated hormone that is bound by incubation of this tritiated hormone at the concentration (T). B/T min = the percentage amount of tritiated hormone bound by incubation of this tritiated hormone at the concentration (T) in the presence of a large excess of cold hormone (2500.10"<9>M).

The points where the straight line I50 intersects the curves enable the calculation of the concentrations of the cold reference hormone (CH) and of the cold compound being tested (CX) which give 50% inhibition of the binding of the tritiated hormone to the receptor.

The relative binding affinity (RBA) of the compound being tested is determined by the equation:

The following results are obtained:

Conclusion

The investigated compounds, especially the compound according to example 4, show a very marked affinity to the progestogen receptors.

From the results obtained, it can be concluded that the compounds can exhibit agonistic or antagonistic activity towards the progestogens.

II. Abortigenic activity in rats.

The day Jl for conception is determined through the presence of spermatozoa in mucous fluid from the vagina. On the ninth day (J9) of the gestation period, the compound is administered orally suspended in carboxymethylcellulose containing 0.5% Tween.

The animals are euthanized 72 hours after treatment, and the uterus is examined to determine the state of pregnancy.

A complete abortion was demonstrated in all of the animals in the group treated with the compounds of Examples 1-4, administered at a dose of 3 mg/kg.

The new steroid compounds are prepared as follows: a) For the preparation of the compounds of formula (IA): where R2 and R2 have the meanings given above and R' and R" each denote a hydrogen atom or an alkyl radical or one denotes a hydrogen atom and the other denotes an alkyl radical, becomes either a compound of formula (II):

where Rx and R2 have the meanings given above and K denotes

a group protecting the ketone radical,

or a compound of formula (III):

where R1 and R2 have the meanings given above, ring-closed by reaction with tosyl chloride or methylsulfonyl chloride in the presence of pyridine, whereby either one of the compounds of formula (IV) is obtained:

where Rlr R2 and K are as indicated above,

which compound of formula (IV) is dehydrated with a sulphonic resin in the acid form or with a mineral acid in a lower alkanol or with perchloric acid in acetic acid or with a sulphonic acid, whereby the keto function is released and a compound with the above formula (IA) is formed where R' and R" denote a hydrogen atom,

or a compound with the formula (Ia) is obtained,

and an obtained compound of formula (IA) wherein R1 includes a sulfur or nitrogen atom, if desired oxidized to form the corresponding compound wherein R1 includes a sulfur atom oxidized to sulfoxide or sulfone, or a nitrogen atom oxidized to N-oxide , and that the compound of formula (IR) is, if desired, transferred to a salt,

or the compound of formula (IR), if desired, is reacted with a strong base and then with an alkyl halide to form a compound of formula (Ia) where R' and/or R" denote an alkyl radical with 1-4 carbon atoms.

b) For the preparation of the compounds of formula (IB): where Rx and R2 and Re are as indicated above, a compound with the formula (I'A) becomes: where Rx and R2 have the meanings given above, reacted with an aromatizing agent consisting of an acid halide and/or an acid anhydride and the obtained compound if necessary reacted with a saponification agent, after which an obtained compound of formula (IB) where Re is a hydrogen atom, if desired, is reacted with an alkylating agent. c) For the preparation of the compounds of the formula (Ic):

where R-1 and R2 are as above, either becomes a compound

with the formula (V):

where Rx and R2 are, as indicated above, closed by being converted

with tosyl chloride or methylsulfonyl chloride in the presence of pyridine,

or a compound of the above formula (I'a) reacted with an acylating agent and the compound formed then saponified.

d) For the preparation of the compounds of formula (ID): where R1 and R2 are as indicated above, a compound of formula (I'a) is epoxidized with a peracid or hydrogen peroxide, alone or in the presence of hexachloro- or hexafluoroacetone; e) for the preparation of the compounds of formula (IE):

where R 2 and R 2 are as indicated above, a compound is reacted

with the above formula (I'a) with hydroxylamine.

f) For the preparation of the compounds of formula (I) where R1 denotes a phenyl or benzyl radical substituted with a carboxy radical which may be esterified or salted, a compound of formula (IF) becomes: where A, B, C and R2 are as indicated above, and X denotes a carbocyclic or heterocyclic aryl or aralkyl radical, subjected to acid hydrolysis in a manner known per se, preferably by reaction with a mineral acid in aqueous solution to form a compound with formula (IG): which, if desired, is reacted with a basic agent to form a compound of formula (IH): where X and R2 are as indicated above, and Alk denotes an alkyl radical with 1-6 carbon atoms, which compound, if desired, is saponified to form a compound of formula (Ia):

where X and R 2 are as above, which, if desired, are esterified. Finally, a compound obtained as indicated under one of points a)-f) above is optionally transferred to a pharmaceutically acceptable acid addition salt.

In a preferred embodiment of the methods described above, tosyl chloride in the presence of pyridine is the cyclization reagent which is preferably brought to act on the compounds of formulas (II), (III) or (V), but methylsulfonyl chloride can also be used.

The conversion of the compounds of formula (IV) by means of a dehydrating agent which is also capable of releasing the ketone function is preferably carried out with a sulfone resin (acid form), e.g. a commercially available sulfone resin with a polystyrene support or with a styrene/divinyl/benzene polymer support. However, a mineral acid, such as hydrochloric or sulfuric acid, in a lower alkanol or perchloric acid in acetic acid or a sulphonic acid, such as paratoluenesulphonic acid, can also be used.

The oxidizing agent which is caused to act on the compounds of formula (Ia) or the epoxidizing agent which is caused to react to form the compounds of formula (ID) is preferably a peracid, such as metachloroperbenzoic acid, peracetic acid or perphthalic acid. Hydrogen peroxide can also be used alone or in the presence of hexachloro- or hexafluoroacetone.

Depending on the number of functions that can be the target of an oxidation, one or more equivalents of the oxidizing agent can of course be used.

If, for example, If it is desired to oxidize the sulfur atom carried by Rx to sulfone, naturally at least two equivalents of the oxidizing agent must be used.

The strong base used on the compounds of formula (IA) can be an alkali metal amide, such as sodium or lithium amide, which can optionally be prepared in situ.

The alkyl halide used is preferably an iodide, such as methyl iodide.

The aromatizing agent used for the preparation of the compounds of formula (IB) is preferably an acyl halide, such as acetyl bromide or an acid anhydride, such as acetic anhydride or a mixture thereof.

The eventual acylation of the compounds of formula (Ib) and the acylation leading to the compounds of formula (Ic) are carried out according to usual methods. It is preferred to use an acyl halide.

The possible alkylation of the compounds of formula (IB) is carried out according to usual methods. For example, an alkyl halide is used.

The saponification agent used to obtain the compounds of formula (IB), (Ic) or (Ij) is preferably an alkali base, such as sodium or potassium hydroxide, and the reaction is carried out in a lower alcohol, such as methanol or ethanol.

The oximation of the compounds of formula (I'A) is carried out using hydroxylamine in the form of a salt, preferably the hydrochloride in an alcohol at the reflux temperature.

The acid hydrolysis to which the compounds of the formula (IF) are subjected is carried out according to the usual conditions. For example, a mineral acid, preferably hydrochloric acid, can be used in aqueous solution.

The basic agent used to form the compounds (IH) is preferably an alkaline alcoholate, such as sodium ethylate.

The salting out is carried out under normal conditions. For example, the treatment can be carried out in the presence of sodium hydroxide in ethanol. A sodium salt, such as the carbonate, or the acidic carbonate of sodium or potassium, can also be used.

In the same way, the salting out with an acid is also carried out under the usual conditions. Treatment with hydrochloric acid is preferred, e.g. in an ether solution.

The compounds with the formulas (II), (III) and (V) which are used as starting materials are known compounds or can be prepared by conventional methods, such as those described in European Patent Document No. 147 361.

The compounds with the formulas (II), (III) and (V) where the oxygen atom in the spiroether is in the alpha position can be prepared according to the method described in European patent document no. 129 499.

The following examples illustrate the preparation of the new steroid compounds.

EXAMPLE 1: (17R)-45'-dihydro-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-diene-17,21-(3H)-furan)- 3-Mon.

Step A: The gamma lactone of 5-alpha,17-beta-dihydroxy-11-beta-[4-(dimethylamino)-phenyl]-3,3-[(1,2-ethanediyl)-bisoxy]-1 9- nor-17-alpha-pregn-9-ene-21-carboxylic acid. 60 ml of tetrahydrofuran is introduced at -70°C into 60 ml of a 1.6M 15% solution of butyllithium in hexane. Then, at -60°C, a 9.2 ml<1>s solution of N, N,N',N'-tetramethylphosphoramidate of allyl in 30 ml of tetrahydrofuran. After stirring for 45 minutes at -10"C, 9.95 g of cyclic 3,3-(1,2-ethanediyl)-acetal of 11-beta- [4-(dimethylamino)-phenyl]-5-alpha-hydroxy-estr-9-ene-3,17-dione dissolved in 20 ml of tetrahydrofuran. A further 20 ml of tetrahydrofuran is then added, with stirring for one hour at 20°C.

The reaction mixture is poured into an aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with water, dried and concentrated to dryness by distillation under reduced pressure. The residue is chromatographed on silica gel with a mixture of cyclohexane and ethyl acetate (3:7) as eluent, whereby 3.9 g of the desired product is obtained in impure form. This is dissolved in methylene chloride, and it is filtered. Isopropyl ether is added to the filtrate, and methylene chloride is removed by distillation. After separation and washing, 3.45 g of the desired compound are obtained. Sm.p. 198°C.

aromatic bands at 1610cm~'1, 1560cm_<1>, 1516cm~<1>, 823cm"''. Analysis: C31H4-1<O>5N (507.67)

Step B: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(dimethylamino)-phenyl]-17-alpha-(3-

hydroxypropyl)-estr-9-en-3-one.

1.014 g of the compound obtained above is dissolved in 30 ml of tetrahydrofuran. 500 mg of lithium aluminum hydride are then added in portions under a stream of nitrogen and with stirring. The temperature is raised to 35°C and after stirring for one hour and 30 minutes at 20°C, ethyl acetate is added dropwise and then a saturated aqueous solution of ammonium chloride. The supernatant organic phase is decanted off, and the residue is extracted while stirring with a mixture of tetrahydrofuran and ethyl acetate. (1:1). The organic phases are washed with saline water, dried and concentrated to dryness by distillation under reduced pressure, thereby obtaining 993 mg of the desired compound in impure form (m.p. 210°C), which is used as it is in the following step.

The analytical sample obtained after purification by chromatography on silica, elution with a mixture of ethyl acetate and ethanol (95:5) and subsequent crystallization from ethanol, melts at 234°C.

IR spectrum (chloroform)

OH at 3620cm_<1> and bound OH

Aromatic bands at 161 Sem-1 , 1560cm-<1>, 1517cm_1, presence of ketal.

Analysis: C31<H>45<O>5N (511.7)

Step C: Mixture of cyclic (1,2-ethanediyl)-acetal of (17 R )-4',5'-dihydro-11-beta-[4-(dimethylamino)-phenyl1-5-alpha-hydroxy-spiro- (estr-9-ene-17,2'-(3H)-furan)-3-one (compound A) and (17R)-4',5'-dihydro-11-beta-[4-(dimethylamino) -phenyl]-spiro-(estra-4,9-dien-17,2<1->(3H)-furan)-3-one (compound B) 2 g of the above compound are dissolved in 30 ml of pyridine. At +3°C, 1.52 g of tosyl chloride is then added and the mixture is allowed to stand for 40 minutes at 20°C. The reaction medium is cooled to +3°C, water is added and then a solution of sodium bicarbonate followed by extraction with ethyl acetate, washing with water, drying and concentration to dryness by distillation under reduced pressure. The pyridine is removed by azeotropic distillation with toluene, and the residue is chromatographed on silica and eluted with a mixture of cyclohexane and ethyl acetate (7/3), whereby 395 mg of compound (B) and 500 mg of compound (A) are obtained.

Examination of compound A:

IR spectrum (chloroform)

absence of CO band, 50H 3512cm-<1>

Aromatic groups at 1613cm~'', 1557cm~'l/ 1517cm~<1>.

Step D: (17 R )-4',5'-dihydro-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-diene-17,2'-(3 H )- furan)-3-one (compound B) .

The 500 mg of compound A obtained in step C are dissolved in 15 ml of ethanol. 10 ml of a 2N aqueous solution of hydrochloric acid are added, and the mixture is allowed to stand for 45 minutes at 20°C. After addition of an aqueous solution of sodium bicarbonate, extraction is carried out with methylene chloride, washing, drying and concentration to dryness by distillation under reduced pressure. This gives 390 mg of compound B in impure form.

Purification of compound B.

The 395 mg of compound B obtained in step C and 390 mg of compound B obtained above are mixed together and chromatographed on silica with a mixture of cyclohexane and ethyl acetate as eluent (7:3). 645 mg of compound B are obtained.

After recrystallization from aqueous ethanol is obtained

367 mg of the expected compound with melting point 100°C.

(not very clean).

Compound B

IR spectrum (chloroform)

absence of OH; ketone in 3-position, 1653cm~<1>.

C = C, aromatic 1612cm_<1>, 1597cm_<1>, 1560cm-<1>, 1518cm_<1>. UV spectrum

in ethanol: max. 260 nm = 18,900

max. 302 nm = 22,100

in 0.1N HC1 in ethanol: max. 300 nm = 20,500

inflection points at 240, 249, 270 nm.

Analysis: C29H37<N>O2 431.62

NMR spectroscopy (deuterochloroform)

Peak at 0.59 ppm, hydrogen atoms in the 18-methyl group,

Peak at 2.30 ppm, hydrogen atoms in the dimethylamino group, Peak at 3.76 ppm", hydrogen atoms in CH2O,

Peak at -4.31 ppm, hydrogen atoms in the 11-position,

Peak at 5.70 ppm, hydrogen atoms in the 4-position,

Peaks at 6.64 and 7.03 ppm, aromatic hydrogen atoms.

EXAMPLE 2: (17Rj-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one. 1 , 425 g (Z)-11-beta-[4-(dimethylamino)-phenyl]-1 7-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-estra-4,9-dien-3 -one is dissolved in 30 ml of pyridine and 3 g of tosyl chloride is added at +3°C with stirring for 4 hours at +20°C. After cooling to +3°C, water is added and it is stirred for 15 minutes, followed by extraction with ethyl acetate, washing with water, drying and concentrating to dryness by distillation under reduced pressure. Azeotropic distillation is carried out with toluene to remove all pyridine. The residue is then dissolved in ethyl ether, after which it is filtered and concentrated to dryness to give 1.37 g of the desired compound in crystalline form.

Investigations

IR spectrum (chloroform)

3-keto, delta<4> C=0 1655™-"<!>

C=C 1612cm-<1>

aromatic 1597cm-'1, 1562cm_<1>, 1518cm-<1>.

UV spectrum

Ethanol max. at 260 nm = 19,600

max. at 302 nm = 23,300

Ethanol/HCl 0.1N

infl. 215 nm

infl. 238 nm

max. 300 nm = 21,600

NMR spectrum (deuterochloroform)

Peak at 0.62 ppm, hydrogen atoms in the 18-methyl group,

Peak at 2.92 ppm, hydrogen atoms in the dimethylamino group, Peak at 4.29 ppm", hydrogen atoms in the 11-position,

Peak at 4.60 ppm, hydrogen atoms in CH2O,

Peak at 5.78 ppm, hydrogen atoms in the 4-position,

Peak at 5.88 ppm, hydrogen atoms in the 3'- and 4<1->position, Peaks at 6.69 ppm, 7.00 ppm and 7.10 ppm, aromatic hydrogen atoms.

EXAMPLE 3: (17 R )-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-dien-17,2*-(5H)-furan)-3-one.

Step A: Cyclic 3,3-(1,2-ethanediyl)-acetal of 5-alpha,10-alpha-epoxy,17-beta-hydroxy-17-alpha-[3-(tetrahydro-2H-2-pyrannyloxy) -1-propynyl]-estr-9(11)-en-3-one.

5.06 ml of HC=C-CH 2 OTHP and 30 ml of tetrahydrofuran are mixed together under an inert atmosphere and cooled to -5°C. 20 ml of a 1.65M solution of butyllithium in hexane are then added dropwise, with stirring for 30 minutes at 0°C.

During 40 minutes at 0°C, 6.6 g of cyclic 3,3-(1,2-ethanediyl)-acetal of 5-alpha,10-alpha-epoxy-[estra-9(11)-en- 3,17-dione dissolved in 55 ml of tetrahydrofuran. After vigorous stirring for 16 hours at 20°C, the reaction mixture is poured into a 10% aqueous solution of ammonium chloride. The reaction mixture is extracted with ethyl acetate, washed with water, dried and concentrated to dryness by distillation under reduced pressure. The residue obtained is chromatographed on silica (1:1), whereby 8.3 g of the desired compound is obtained, which is used as it is in the next step.

IR spectrum (chloroform)

Free OH at 3601cm~^ + some absorption of bound OH,

C=C- at 1640cm-<1>,

presence of OTHP.

Step B: Cyclic 3,3-(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(methylthio)-phenyl]-17-alpha-[3-( tetrahydro-2H-2-pyranyloxy)-1-propynyl]-estra-9-en-3-one.

1 ) Preparation of the magnesium compound

3 g of magnesium shavings and 3 ml of tetrahydrofuran are mixed together under an inert atmosphere. The temperature is raised to 45°C, and a few drops of the following solution are added: 20.2

g of parabromothioanisole dissolved in 70 ml of tetrahydrofuran. After initiation of the reaction, the introduction of this solution is continued, so that the temperature is kept around 50°C. After the introduction is complete, the heating is continued for a further hour at 50°C.

2) Condensation

80 ml of the solution of the magnesium compound, 90 ml of tetrahydrofuran and 887 mg of copper (I) chloride are mixed together under an inert atmosphere and cooled to -15°C. During 15 minutes, a solution of 12.2 g of cyclic (1,2-ethanediyl)-acetal of 5-alpha,10-alpha-epoxy-17-beta-hydroxy-17-alpha-[3-(tetrahydro -2H-2-pyrannyloxy)-1-propynyl]-estr-9(11)-en-3-one in 25 ml of tetrahydrofuran, and stirring is carried out for one hour at 0°C. The reaction mixture is then poured into a 10% aqueous solution of ammonium chloride, and it is extracted with ethyl acetate, washed with water, dried and concentrated to dryness by distillation under reduced pressure. The residue obtained is chromatographed on silica with a 1:1 mixture of cyclohexane and ethyl acetate, which gives 15 g of the desired compound in impure form. 11 g of the product is crystallized from ethanol with 50% water, whereby 10.2 g of the desired compound is obtained. Melting point 160°C.

Surveys:

IR spectrum (chloroform):

OH in the 17-position at 3600cm-<1> (free) + bound in the 5-position at 3510cm~<1>

Aromatic groups at 1596cm-'', 1556cm~<1>, 1 492cm~1; presence of OTHP.

UV spectrum (ethanol):

Infl. 228 nm, max 255 nm (=15,000)

Infl. 288 nm,

Infl. 297 nm.

Step C: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(methylthio)-phenyl]-1 7-alpha-[3- (tetrahydro-2H-2-pyranyloxy)-1-propynyl]-estr-9-en-3-one.

594 mg of cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(methylthio)-phenyl]-17-alpha-[3-(tetrahydro-2H-2 -pyranyloxy)-1-propynyl]-estr-9-en-3-one obtained above is dissolved in 20 ml of ethyl acetate. 60 mg of palladium hydroxide on 10% activated charcoal is added with stirring under a hydrogen atmosphere for 14 hours. The catalyst is filtered off, and what remains is concentrated to dryness by distillation under reduced pressure. The residue obtained is chromatographed on silica and eluted with a 1 :1 mixture of cyclohexane and ethyl acetate, whereby 151 mg of the desired compound is obtained.

Surveys:

IR spectrum (chloroform)

Little free OH,

mainly bonded OH at 3500cm~'' ,

shoulder at 341Ocm-<1>

Aromatic groups at 1557cm~1 , 1,492cm~1, 831 cm-1; presence of OTHP.

NMR spectrum (deuterochloroform)

Peak at 0.53 ppm, hydrogen in the 18-methyl group,

Peak at 2.47 ppm, hydrogen in the -SCH3-methyl group,

Peak at 4.77 ppm, ketal hydrogen in the THP group,

Peaks at 5.6 to 5.84 ppm, ethylene hydrogen atoms,

Peaks from 3.44 to 4.5 ppm, hydrogen in the CH20 group and hydrogen in the 11-position,

Peak at 7.17 ppm, aromatic hydrogen atoms.

Step D: (Z)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-[4-(methylthio)-phenyl]-estra-4,9-dien-3 -on.

2.42 g of cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(methylthio)-phenyl]-17-alpha-[3- (tetrahydro-2H-2-pyranyloxy)-1-propynyl]-estr-9-en-3-one obtained above is dissolved in 44 ml of methanol, and 20 ml of 2N aqueous hydrochloric acid solution is added with stirring under an inert atmosphere for 1 hour and 30 minutes. After dilution

with water, extraction is carried out with ethyl acetate. The extracts are dried and concentrated to dryness by distillation under reduced pressure. The residue obtained is chromatographed on silica with a 1:1 mixture of cyclohexane and ethyl acetate, whereby the following is obtained:

- 904 mg of the desired compound,

- 567 mg (Z)-17-beta-hydroxy-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy)-1-propynyl]-11-beta-[4-(methylthio)-phenyl]-estra -4,9-dien-3-one, which is reintroduced to acid hydrolysis under the same conditions. After chromatographic purification, 188 mg of the desired compound are obtained.

Surveys:

IR spectrum (chloroform)

OH at 3609cm-<1> + bound,

dienone at 1653cm~^,

dienone at 1601 cm-1,

aromatic groups at ISSScm-<1> and 1493cm_<l>,

NMR spectrum (deuterochloroform):

Peak at 0.63 ppm, hydrogen in the 18-methyl group,

Peak at 2.47 ppm, hydrogen in the -SCH3-methyl group,

Peak at 4.33 ppm, hydrogen in the 11-position

Peak at 4.39 ppm, hydrogen atoms in the CH20 group

Peaks from 5.59 to 5.92 ppm, ethylene hydrogen atoms

Peaks from 7.04 to 7.24 ppm, aromatic hydrogen atoms.

Step E: (17 R )-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-dien-17,2 *-(5 H )-furan)-3-one.

11.04 g 1 7-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-[4-(methylthio)-phenyl]-estra-4,9-dien-3-

obtained above is dissolved in 20 ml of pyridine, and 2.1 g of tosyl chloride is added with stirring for 2 hours at 20°C. After dilution with water and ice, extraction is carried out with ethyl acetate. The extracts are washed with a dilute hydrochloric acid solution and with water, then dried and concentrated to dryness by distillation under reduced pressure. The residue obtained is chromatographed on silica with a mixture of cyclohexane and ethyl acetate in the ratio 6:4 as eluent.

820 mg of the desired compound are obtained in impure form.

The compound is crystallized from a mixture of methylene chloride and isopropyl ether, whereby 694 mg of the desired compound is obtained. '

Surveys:

IR spectrum (chloroform):

- absence of OH,

dienone, 1653cm~'' and 1601cm~'',

aromatic groups at 1555cm"'1 and 1492cm_<1>,

NMR spectrum (deuterochloroform):

Peak at 0.59 ppm, hydrogen atoms in the 18-methyl group,

Peak at 2.48 ppm, hydrogen atoms in the -SCH3-methyl group,

Peak at 4.30 ppm, hydrogen in the 11-position,

Peak at 4.6 ppm, hydrogen atoms in the CH20 group,

Peak at 5.81 ppm, hydrogen in the 4-position,

Peak at 5.89 ppm, hydrogen atoms in the 3' and 4' position, Peaks from 7.04 to 7.27 ppm, aromatic hydrogen atoms.

UV spectrum (impure formula)

Max at 260 nm 16,100

Max at 300 nm

Analysis: (m.v. 432.62)

EXAMPLE 4: (17 R )-4<1>,5'-dihydro-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(3H )-furan)-3-one.

Step A: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-14-(methylthio)-phenyl]-1 7-alpha-13-(tetra-hydro-2H -2-pyranyloxy)-propyl]-estra-9-en-3-one.

2.1 g of cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(methylthio)-phenyl]-17-alpha-[3-(tetrahydro-2H -2-pyranyloxy)-1-propynyl]-estra-9-en-3-one is dissolved in 21 ml of benzene and 21 ml of ethanol. 840 mg of Wilkinson's reagent (chloro-tris-(triphenylphosphine)-rhodium) are added, and the whole is subjected to hydrogenation for 16 hours. 420 mg of Wilkinson's reagent are added and the hydrogenation is continued

for another three hours. After concentration to dryness by distillation under reduced pressure, chromatography of the residue on silica and elution with a 6:4 mixture of cyclohexane and ethyl acetate, the following are obtained: - 336 mg of an ethylene compound, similar to the compound obtained in step C in example 3. - 185 mg of a mixture of the ethylene compound of the starting material and the desired compound. - 1.082 g of the desired compound, which is used as it is in the subsequent steps.

IR spectrum (chloroform):

-OH at 3600cm~<1>,

3504cm_1 , aromatic groups at 1600cm"'1, 1 492cm-1. NMR spectrum (deuterochloroform):

Peak at 0.50 ppm, hydrogen atoms in the 18-methyl group,

Peak at 2.46 ppm, hydrogen atoms in the -SCH3-methyl group, Peaks from 3.33 to 4.55 ppm, hydrogen atoms in the 11-position and hydrogen atoms in the CH20 group,

Peak at 4.63 ppm, ketal hydrogen in the THP group,

Peak at 7.17 ppm, aromatic hydrogen atoms.

Step B: 17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-11-beta-[4-(methylthio)-phenyl]-estra-4,9-dien-3-one.

1.51 g of cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(methylthio)-phenyl]-17-alpha-[3-(tetrahydro-2H -2-pyranyloxy)-propyl]-estr-9-en-3-one obtained in step A is dissolved in 25 ml of methanol, and 11.5 ml of a 50% diluted aqueous solution of hydrochloric acid is added, stirring under an inert atmosphere at 20°C for 30 minutes. After dilution with water, extraction is carried out with methylene chloride. The extracts are dried and concentrated to dryness by distillation under reduced pressure. The residue obtained is chromatographed on silica with a 1:1 mixture of ether and ethyl acetate as eluent, whereby the following is obtained:

- 768 mg of the desired compound.

IR spectrum (chloroform):

free OH at 3620cm_<1> + bound at 341Ocrn-1,

dienone at 1653cm~<1> and 1601 cm-1,

aromatic groups at 1555cm_i and I492cm-1.

Step C: (17R)-4',5'-dihydro-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,21-(3H)-furan )-3-one.

1.04 g of 17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-11-beta-[4-(methylthio)-phenyl]-estra-4,9-dien-3-one obtained in step B is dissolved in 20 ml of pyridine, and 2.1 g of tosyl chloride are added with stirring for one hour at 20°C. After dilution with water and ice, extraction is carried out with ethyl acetate. The extracts are washed with a dilute aqueous hydrochloric acid solution, then with water" and with aqueous bicarbonate solution. The mixture is dried and concentrated to dryness by distillation under reduced pressure. The residue obtained is crystallized from a mixture of methylene chloride and ethanol, whereby 818 mg of the desired compound, m.p. 105°C (not very sharp).

IR spectrum (chloroform):

-C - O - C - at 1078cm-<1>, 1055cm-<1>,

dienone at 1653cm~<1>, 1602cm~^,

aromatic groups at 1555cm~1 , 1 493cm~''.

NMR spectrum (deuterochloroform):

Peak at 0.57 ppm, hydrogen atoms in the 18-methyl group,

Peak at 2.46 ppm, hydrogen atoms in the -SCH3-methyl group,

Peak at 3.78 ppm, hydrogen atoms in the CH2-0 group,

Peaks from 4.35 to 4.42 ppm, hydrogen atoms in the 11-position, Peak at 5.81 ppm, hydrogen in the 4-position,

Peak at 7.17 ppm, aromatic hydrogen atoms.

Analysis: C28H34<O>2S (434.64)

EXAMPLE 5: (17R)-11-beta-12-(methoxyphenyl)-spiro-(estra-4,9-dien-17,21-(5H)-furan-3-one.

Step A: The (Z)-dimethyl ketal of 5-alpha,10-alpha-epoxy-17-beta-hydroxy-17-alpha-[3-(tetrahydro-(2H)-2-pyranyloxy)-1-propynyl1-estra- 9(11)-en-3-one.

400 ml of a 1.6M solution of butyllithium in hexane is cooled to 0°C, and at this temperature 98 g are added

of HC=C-CH2OTHP reagent in 180 ml of tetrahydrofuran with stirring for 30 minutes at 0°C.

66.4 g of dimethoxyketal of 5-alpha,10-alpha-epoxy-estra-9(11)-en-3,17-dione dissolved in 200 ml of tetrahydrofuran is added dropwise with stirring for 2 hours while the temperature is allowed to return to the ambient temperature. The reaction mixture is then poured into an aqueous solution of ammonium chloride, and it is extracted with ethyl acetate and then with methylene chloride. The organic phases are combined, washed with water and dried. The solvents are then removed under reduced pressure. The residue is chromatographed on silica (eluent: cyclohexane:ethyl acetate in the ratio 7:3 with 1% triethylamine). 53 g of the compound are obtained in impure form, which is purified by chromatography on silica (eluent: methylene chloride:acetone in the ratio 95:5, with 1% triethylamine).

Step B: The (Z)-dimethyl ketal of 5-alpha,10-alpha-epoxy-17-beta-hydroxy-17-alpha-13-(tetrahydro-(2H)-2-pyranyloxy)-1-propenyl-estra-9 (11)-en-3-one.

2.5 g of the impure compound obtained in step A in 400 ml of ethyl acetate are hydrogenated for 30 minutes under a pressure of 1100 mb in the presence of 25 mg of palladium on 10% barium sulfate and 1 ml of pyridine. After filtering off the catalyst, washing and extraction with ethyl acetate, the organic phases were combined and the solvents removed under reduced pressure. 2.5 g of the compound are recovered in impure form, which is purified by chromatography on silica with methylene chloride: acetone in the ratio 95:5 as eluent. 728 mg of the desired compound are obtained.

IR spectrum, (CHCl3):

OH 3600cm-<1>, 3400cm~<1> (F)

Presence of alpha-epoxy.

Step C: The (Z)-dimethyl ketal of 5-alpha,17-beta-dihydroxy-11-beta-(2-methoxyphenyl)-17-alpha-t3-(tetrahydro-(2H)-2-pyranyloxy )-1-propenyl ]-estr-9-en-3-one.

Preparation of the magnesium compound:

The operation is carried out as in step B in example 3, starting from magnesium and orthobromoanisole. A solution with a titer of 0.72 M/l is obtained.

Condensation:

3 g of the compound obtained in the previous step are dissolved in 60 ml of tetrahydrofuran under an inert atmosphere. 187 mg of cuprous (I) chloride are added with heating to 34°C 1°C. In the course of 20 minutes, 26.2 ml of the magnesium compound prepared above are introduced, with stirring for 16 hours. The temperature is allowed to return to ambient temperature. The reaction mixture is poured into a solution of ammonium chloride with stirring for 15 minutes, after which extraction is carried out with ethyl acetate. The extracts are washed with an aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure. There is obtained 6, 58 g of the impure compound, which is purified by chromatography on silica (eluent: methylene chloride:acetone in the ratio 92:8, with 1% triethylamine).

IR spectrum (CHCl3):

free OH 3600cirr1 , bound 3450cm.-1 ,

aromatic groups 1597cm-1 , 1584cm_<1>, 1 490cm-'1.

Step D: (Z)-11-beta-(2-methoxyphenyl)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-estr-4,9-dien-3-one.

1.08 g of the compound obtained in step B is dissolved

in 10 ml of ethanol at ambient temperature. A solution of 1.08 g of potassium hydrogen sulphate in 6.5 ml of water is added while stirring for five hours at ambient temperature. After removal of the ethanol, extraction is carried out with methylene chloride. The organic phase is washed with water, dried and evaporated to dryness under reduced pressure. After chromatography on silica (eluent: cyclohexane: ethyl acetate in the ratio 1:1) 0.703 g of the desired compound is obtained.

IR spectrum (CHCl3):

free OH 3612cm_<1> and bound 3415cm_<1>,

dienone I654cm-<1>, 1597cm-<1>

aromatic groups at 1488cm~^.

Step E: (17 R )-11-beta-(2-methoxyphenyl)-spiro-(estra-4,9-dien-17,2'-(5 H )-furan-3-one).

0.661 g of the product obtained in the previous step is dissolved in 13.2 ml of pyridine at ambient temperature. The solution is cooled to 0°C, and within five minutes 1.32 g of tosyl chloride is added. The temperature is allowed to return to ambient and stirred for one hour. The temperature is lowered again to 0°C, and 14 ml of 6N hydrochloric acid is added. After decantation, the aqueous phase is extracted with ethyl acetate, washed with water and dried and the solvents are removed under reduced pressure. After chromatography on silica with cyclohexane: ethyl acetate in the ratio 8:2 as eluent, 0.459 g of the desired compound is obtained.

IR spectrum (CHCl3):

dienone 1655cm~<1>, 159.7cm~'<1>,

aromatic groups at 1488cm~'1 ,

1080cm-<1>, 1040cm-<1>.

EXAMPLE 6: (17R)-11-beta-(4-chlorophenyl)-4',5'-dihydro-spiro-(estra-4,9-dien-17,2'-(3H)-furan-3-one .

Step A: The dimethyl ketal of 5-alpha,10-alpha-epoxy-17-beta-hydroxy-17-alpha-[3-tetrahydro-2H-2-pyranyloxy)-propyl]-ester-9(11)-ene-3 -on. 6 g of the dimethyl ketal of 5-alpha,10-alpha-epoxy-17-beta-hydroxy-17-alpha-[3-tetrahydro-2H-2-pyranyloxy)-1-propynyl]-estra-9(11)-ene -3-one prepared as in step A in Example 5 is dissolved in 60 ml of benzene and subjected to hydrogenation at 1860 mbar in the presence of 1.5 g of Wilkinson's reagent for seven hours. The mixture is diluted with ether and filtered. The filtrate is concentrated to dryness under reduced pressure, and 7.7 g of the impure compound is collected and chromatographed on silica with petroleum ether (b.p. 40-70°C) and ethyl acetate in the ratio 4:6 as eluent. 4.95 g of the expected compound are obtained.

IR spectrum (CHCl3)

Free OH 3620cm_<1>, 3600cm~<1>,

-C=C- 1640cm-<1>.

Step B: The dimethyl ketal of 11-beta-(4-chlorophenyl)-5-alpha,17-beta-dihydroxy-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy)-propyl]-ester-9(11 )-en-3-one.

Preparation of the macfnesium compound:

The operation is carried out as in step B in example 3, starting from 1.22 g of magnesium and 3 ml of the prepared solution and starting with 7.65 g of parabromochlorobenzene in 50 ml of tetrahydrofuran.

Condensation:

The operation is carried out as in step B in example 3, using 23 ml of the solution of the magnesium compound, 165 mg of copper (I) chloride and 2.46 g of the compound obtained in the preceding step A dissolved in 12 ml of tetrahydrofuran. After chromatography on silica (eluent: petroleum ether (b.p. 40-70°C) and ethyl acetate in the ratio 1:1) 2 g of the expected compound are obtained in impure form, which is used as it is in the following step.

IR spectrum (CHCl3):

OH in the 5 position 3478cm"<1>,

OH in the 17 position max 3620cm_<1>, shoulder 3600cm_<1>,

aromatic

1599cm-1 , 1489cm-1 , -OCH 3 , 2835cm-1 .

Step C: 11-beta-(4-chlorophenyl)-1 7-beta-hydroxy-17-alpha-(3-hydroxypropyl)-estra-4,9-dien-3-one. 15 ml of 2N hydrochloric acid is added to 1.99 g of the compound obtained in the previous step, in 20 ml of methanol.

The mixture is heated to 50°C for 45 minutes, poured into an aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic phases are dried and concentrated to dryness under reduced pressure. After recrystallization from a mixture of methylene chloride and isopropyl ether, 1.42 g of the expected compound is obtained. Melting point 262PC.

IR spectrum (CHCl3)

OH, free + bound, 3620cm"<1>,

dienone 1655cm-<1>, 1602cm-<1>. aromatic bands at I570cm-1, 1490cm-<1>.

Step D: (17R)-11-beta-(4-chlorophenyl-4<1>,5'-dihydro-spiro-(estra-4,9-diene-17,2'-(3H)-furan)-3 -on.

1 g of the compound obtained in step C is dissolved in

20 ml of pyridine under an inert atmosphere, and the solution is cooled to 0-5°C. 2.2 g of tosyl chloride are added with stirring for one hour and 30 minutes at ambient temperature. The reaction mixture is poured into ice water and stirred for 15 minutes, and then extracted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The skimming is separated and dried, whereby 694 mg of the desired compound is obtained.

The filtrate is dried and the solvent is removed under reduced pressure. The residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate in the ratio 6:4), and the desired compound is obtained, which is recrystallized from a mixture of ethanol and chloroform (2:1). Sm.p. 308°C.

IR spectrum (CHCl3)

dienone 1654cm_<1>, leOScm-<1>.

aromatic groups at 1572cm~'', 1 490cm 1 .

1078cm"<1>, 1055cm-<1>.

Analysis: C27<H>31C102 (422.99)

EXAMPLE 7: (17R)-4<1>5'-dihydro-11-beta-(4-methoxyphenyl)-spiro-(ester-4,9-diene-17,21-(3H)-furan)-3- Wed.

Step A: The dimethyl ketal of 5-alpha,17-beta-dihydroxy-11-beta-(4-methoxyphenyl)-17-alpha-13-(tetrahydro-3H-2-pyranyloxy)-propyl]-estr-9-ene- 3-Mon.

Preparation of the magnesium compound:

The operation is carried out as in step B in example 2, starting with 45 g of magnesium and 9.15 g of parabromoanisole in 45 ml of tetrahydrofuran. A magnesium compound with a titer of 0.9 M/l is obtained.

Condensation:

The operation is carried out as in example 3, using 15 ml of the magnesium compound prepared as described above, 15 ml of tetrafuran, 165 mg of copper (I) chloride and 2.4 g of the compound prepared in example 6, step A. After chromatography on silica (eluent: petroleum ether (b.p. 40-70°C) and ethyl acetate in the ratio 1:1) 6 g of the desired compound are obtained, which is used as it is in the subsequent step.

Step B: 17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-11-beta-(4-methoxyphenyl)-estra-4,9-dien-3-one.

The operation is carried out as in example 6, step C, starting from 6 g of the compound obtained in step A. 5 g of the expected compound is obtained in impure form, and chromatography is carried out on silica eluting with a mixture of methylene chloride and acetone in the ratio 7:3.

IR spectrum (CHCl3)

OH, free + bound, 3620cm-<1>,

C=0 1656cm-<1>,

aromatic C=C 1608cm_<1>, 1509cm.-1,

Step C: (17R)-4<1>5'-dihydro-11-beta-(4-methoxyphenyl)-spiro-(ester-4,9-diene-17,2'-(3H)-furan)-3 -on.

The operation is carried out as in example 6, step D, starting from 655 mg of the compound obtained in step B and 1.4 g of tosyl chloride. After chromatography, 650 mg of the compound are obtained in impure form. The compound is recrystallized from a mixture of methylene chloride and isopropyl ether, whereby 500 mg of the expected compound is obtained. Sm.p. 192°C.

IR spectrum (CHCl3)

C=0 1655CIII-1,

aromatic C=C 1608cm-<1>, (max) 1582cm-<1> (shoulder) 1509cm_<1>, C-O-C 1078cm-<1>, 1055cm-<1>

Analysis: C28H34<O>3<-> (418.58) "

[α]D = +133.5° 2.5° (c = 1% CHCl 3 ).

EXAMPLE 8: (17R)-11-beta-(3-thienyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha,10-alpha-epoxy-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy)-1-propenyl]- estr-9(11)-en-3-one.

940 mg of the compound prepared in Example 3, step A is dissolved in 20 ml of ethyl acetate in the presence of 5 ml of pyridine. 9 mg of 10% palladium on barium sulphate is added, and the mixture is hydrogenated for 24 minutes at atmospheric pressure. The catalyst is filtered off, the filtrate is washed with ethyl acetate and concentrated to dryness. 965 mg of compound are obtained in impure form,

which is chromatographed on silica (eluent: methylene chloride:ethyl acetate in the ratio 8:2).

795 mg of the expected compound are obtained.

IR spectrum (CHCl3)

Free OH 3600cm_<1>, bound <*> 3400cm_<1>

delta 9-11 1640cm-"1 ,

epoxy 971cm~^.

Step B: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha-17-beta-dihydroxy-17-alpha-13-(tetrahydro-2H-2-pyranyloxy)-1-propenyl]-11 -beta-(3-thienyl)-estr-9-en-3-one.

Preparation of the magnesium compound:

The operation is carried out as in step B in example 3, starting from magnesium and with 13-bromothiophene. A solution with a titre of 0.6 M/l is obtained.

Condensation:

A suspension consisting of 335.2 ml of the magnesium compound prepared above in 14 ml of tetrahydrofuran is cooled to -20°C. 0.210 g of copper (I) chloride is added with stirring for 10 minutes. A solution of 2.5 g of the compound obtained in step A, 25 ml of tetrahydrofuran is added dropwise with stirring for one hour while the temperature is maintained at

-20°C. After the temperature has been allowed to return to ambient temperature, 10 ml of saturated ammonium chloride solution is added dropwise. The reaction medium is then poured into 90

ml of saturated ammonium chloride solution, and the mixture is stirred for 15 minutes. After decantation, the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and dried, and the solvents are removed under reduced pressure.

4.68 g of compound are obtained in impure form, which compound is chromatographed on silica (eluent: cyclohexane: ethyl acetate in the ratio 6:4 with 1% triethylamine). 2.107 g of the expected compound are obtained. Sm.p. 158°C.

IR spectrum (CHCl3)

OH in the 5-position, 3501 cm-1

Step C: (Z)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-(3-thienyl)-estra-4,9-dien-3-one.

2.1 g of the compound obtained in the previous step is dissolved in 42 ml of ethanol under an inert atmosphere. 6.3 ml of a 2N aqueous hydrochloric acid solution are added with stirring for three hours at ambient temperature. After cooling to approx. 5°C, 52 ml of water is gradually added while stirring for 30 minutes. The skimming is separated, washed with water until neutrality is achieved, then dissolved in methylene chloride and dried. The solvents are removed under reduced pressure, whereby 1.15 g of the expected compound is obtained. Sm.p. 240-C.

IR spectrum (CHCl3)

OH, free and bound, 3611 cm-1,

dienone, 1657cm~<1>, 1603cm-<1>.

Step Dr (17R)-11-beta-(3-thienyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 5, step D, using 1.15 g of the compound prepared in the previous step, 23 ml of pyridine, 2.3 g of tosyl chloride and 23 ml of 6N hydrochloric acid.

1.03 g of the impure compound is obtained, which is purified by chromatography on silica eluting with ethylene chloride and acetone in the ratio 98:2. 0.755 g of the expected compound is obtained, which is recrystallized from isopropanol. M.p. 242 °C.

IR spectrum (CHCl3)

EXAMPLE 9: (17R)-11-beta-(4-acetylphenyl)-spiro-(estra-4,9-dien-17,2<1->(5H)-furan)-3-one.

Step A Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(2-methyl-1 ,3-dioxolan-2-yl)- phenyl]-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy)-propenyl]-estra-9-en-3-one.

Preparation of the magnesium compound

The operation is performed as in example 3, step B,

starting from 1.45 g of magnesium and 12.15 g of ethylene ketal of parabromoacetophenone. A suspension with a titer of 0.8 M is obtained. Condensation

21 mg of copper (I) chloride is added to 8 ml of suspension of the magnesium compound under an inert atmosphere. Cooling is carried out to 0-5°C with stirring for 15 minutes. 1 g of the compound prepared in example 8, step A dissolved in 15 ml of tetrahydrofuran is then added dropwise with stirring for one hour at ambient temperature. The reaction medium is poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness. 3.5 g of the compound are obtained in impure form, which compound is purified by chromatography on silica with cyclohexane-ethyl acetate in the ratio 1:1 as eluent.

IR spectrum (CHCl3)

OH in 5-position: SSOOcm-<1>,

OH, free + bound : 3600cm"<1>

aromatic C=C: 1605cm-<1>, 1502cm-'1.

Step B: (Z)-11-beta-(4-acetylphenyl)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-estra-4,9-dien-3-one.

2.07 g of the compound prepared in the previous step are dissolved in 40 ml of methanol. 16 ml of an aqueous 2N hydrochloric acid solution are added while stirring for one hour and 30 minutes at 50°C. The reaction medium is poured into an aqueous sodium bicarbonate solution, and it is extracted with ethyl acetate, washed with water, dried and concentrated to dryness under reduced pressure. 1.63 g of the compound is obtained in impure form, which is chromatographed on silica (eluent: methylene chloride:acetone in the ratio 7:3), and then recrystallized from ethanol, whereby 1.48 g of the expected compound is obtained. Sm.p. about. 130°C.

IR spectrum (CHCl3)

C = 0 : 1678cm-<1>

-CH3 <:> 1359cm"1

C = C + aromatic : 1604cm"<1>, 1565cm~<1>

dienone : 1657cm~<1>

free OH : 3609cm"<1>

bound OH : 341 Ocm"1.

Analysis: C 29 H 34 <O> 4 <:> 444.57

C%H%

Calculated : 77.99 7.67

Found : 78 7.7

Step C: (17R)-11-beta-(4-acetylphenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan-3-one.

0.704 g of the compound prepared in the previous step is dissolved in 16 ml of pyridine under an inert atmosphere and then cooled to 0°C. 1.49 g of tosyl chloride is added with stirring for two hours, and the temperature is allowed to return to ambient temperature". The reaction medium is poured into ice water, stirred for 15 minutes, and extracted with ethyl acetate, washed with sodium bicarbonate solution, dried and evaporated to dryness. 0.775 g of the compound is obtained in impure form, which is chromatographed on silica (eluent: cyclohexane-ethyl acetate in the ratio 1:1), and then recrystallized from a mixture of ethanol and methylene chloride. 0.555 g of the expected compound is obtained. M.p. .about 125-130°C.

IR spectrum (CHCl3)

C = 0 : 1678cm-<1>

CH3 : 1359cm_<1>

C = 0 + aromatic : 1604cm"^, 1565cm_<l>

dienone : 1657cm"<1>

[α]D = +231.5° ± 3° (c = 1% CHCl 3 ).

Analysis: C 29 H 32 <O> 3 <:> 428.57

C%H%

Calculated : 81.27 7.52

Found : 81 .1 7.8

EXAMPLE 10: (1 7 R )-11 -beta-[4-(methylthio)-phenyl]-spiro-(estra-5(10),9(11)-diene-1 7,2'-(5'H) -furan)-3-one and (17R)-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3 -on.

1.5 g of the compound prepared in example 3, step C is dissolved in 30 ml of methanol, and 15 ml of 1N hydrochloric acid is added. A further 30 ml of methanol and 30 ml of dioxane are added with stirring for two hours at ambient temperature. The reaction medium is poured into water, and it is extracted with

methylene chloride and concentrated to dryness, whereby 1.23 g of residue is obtained, which is again dissolved in 25 ml of pyridine. 1.91 g of tosyl chloride is added with stirring for one hour and 30 minutes at ambient temperature, after which the mixture is poured into ice water and extracted with ethyl acetate. The organic phase is washed with aqueous hydrochloric acid solution and then with aqueous sodium chloride solution, separated and evaporated to dryness. 1.12 g of the compound is obtained in impure form, which is chromatographed on silica with methylene chloride: ethyl acetate in the ratio 9:1 as eluent, whereby 98 mg of the expected compound and 863 mg of the corresponding 4,9-diene are obtained. (Identical to the compound obtained in Example 3, step E.)

IR spectrum (CHCl3) for the estra-5(10),9(11)-diene.

C = 0 : 1712cm"<1> ..

C = C + aromatic : 1590cm-<1>, 1492cm_<l>

C = C in the spiro ring : 1626cm~<1>

IR spectrum (CHCl3) for the estra-4,9-diene

C = 0 : 1653cm-<1>

C = 0 conjugated with C = 0 : leOOcm"<1>

aromatic : 1492cm~<1>.

EXAMPLE 11: The N-oxide of (17R)-4',5<1->dihydro-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-diene-17,2' -(3H)-furan)-3-one.

1.43 g of (17R)-4',5'-dihydro-11-beta-[4-(dimethyl-amino)-phenyl-1-spiro-(estra-4,9-diene-1 7,21-(3H )-furan)-3-one prepared in example 1 (compound B) is dissolved in 30 ml of methylene chloride and cooled to 0-5°C. In the course of 15 minutes, 0.666 g of an 85% solution of metachloroperbenzoic acid in methylene chloride is added.

After stirring for one and a half hours at 0-5°C, the reaction medium is poured into 100 ml of 0.2N sodium thiosulphate solution and extracted with methylene chloride. It is washed with aqueous sodium bicarbonate solution and then with water. After drying and removal of the solvents, 11.8 g of compound are obtained in impure form, which is chromatographed on silica with methylene chloride:methanol in the ratio 7:3 as eluent. 1.34 g of the expected compound (solvate containing methylene chloride) is obtained, which is lyophilized.

IR spectrum (CHCl3)

- C = 0 : 1655cm-<1>

C = C and aromatic : 1 602cm-1 , 1498cm~'1

[cc]D + 128° ±2° (c = 1% ethanol).

EXAMPLE 12: (17R)-4'5"-dihydro-11-beta-[4-(1-methylethyl)-phenyl]-spiro-(estra-4,9-diene-17,21-(3H)-furan )-3-one.

Step A: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,10-alpha-epoxy-17-beta-hydroxy-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy)-propyl ester -9(11)-en-3-one.

The operation is performed as in example 6, step A,

using 1 g of the compound cyclic (1,2-ethanediyl)-acetal of 17-beta-hydroxy-5-alpha,10-alpha-epoxy-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy) -1-propynyl]-estr-9(11)-en-3-one prepared in Example 3, step A, and 0.25 g of Wilkinson catalyst, whereby 1.28 g of the expected compound is obtained.

IR spectrum (CHCl3)

Free OH : 3620cm.-1 , 3605cirr<1>

Strongly bound OH : 3485cm.-1

C = C : 1643cm-1.

Step B: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(1-methylethyl)-phenyl-17-alpha-[3-(tetra-hydro -2H-2-pyranyloxy)-propyl]-estr-9-en-3-one.

2.45 g of the compound prepared as in step A, dissolved in 10 ml of tetrahydrofuran is cooled to 0°C and 110 mg of copper (I) chloride is added while stirring for 10 minutes.

During 15 minutes, 32 ml of a 0.66 M/l solution of 4-isopropylphenylmagnesium bromide in tetrahydrofuran are then added. After stirring for two hours at +3 ±1"C, the mixture is poured into an ice-cooled aqueous ammonium chloride solution, and it is extracted with ether and then with methylene chloride. The extracts are dried, and the solvents are removed under reduced pressure. 4.65 g of the crude compound are obtained form, which is chromatographed on silica with cyclohexane:ethyl acetate as eluent.The compound is used as is in the following step.

Step C: 17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-11-beta-[4-(1-methylethyl)-phenyl)-estra-4,9-dien-3-one.

2.58 g of the compound obtained in the previous step is stirred for two hours at ambient temperature in 20 ml of ethanol with 5 ml of 2N hydrochloric acid. After concentration to a small volume under reduced pressure, extraction is carried out with methylene chloride, washing and drying, and the solvent is removed under reduced pressure, whereby 2.2 g of the expected compound is obtained. This is purified by chromatography on silica with n-hexane:ethyl acetate in the ratio 3:7 as eluent.

IR spectrum (CHCl3)

Free OH : 3620cm_<1> + bound

dienone : 1655cm~<1> to 1601 cm-'',

aromatic : 1590cm~<1>.

Step D: (17R)-4'5<1->dihydro-11-beta-[4-(1-methylethyl)-phenyl]-spiro-(estra-4,9-diene-17,2<1-> (3H)-furan)-3-one.

1.15 g of the previously obtained compound, 20

ml of pyridine and 2.1 g of tosyl chloride are stirred for one and a half hours at ambient temperature. After dilution with 50 ml of water and ice, 20 ml of concentrated hydrochloric acid is added slowly. The aqueous phase is then extracted with methylene chloride and dried, and the solvents are removed under reduced pressure, thereby obtaining 1.686 g of compound in impure form. Chromatography is carried out on silica with methylene chloride:acetone in the ratio 95:5 as eluent and then recrystallization from ethanol, whereby 659 mg of the expected compound is obtained. Sm.p. 114°C.

IR spectrum (CHCl3)

aromatic )

c = c J 1601 cm"1, 1510 cm"1

Analysis: C30H38<O>2 <:> 430.635

EXAMPLE 13: (17R)-11-beta-[3-(methylthio)-phenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Stage A: Cyclic. (1,2--ethanediyl)-acetal of 5-alpha-1 7-beta-dihydroxy-11-beta-[3-(methylthio)-phenyl1-17-alpha-[3-(1-tetra-hydro-2H -2-pyranyloxy)-1-propenyl]-estr-9-en-3-one.

The operation is carried out as in example 8, step B, using 2.5 g of the compound prepared in example 8, step A, and 110 mg of copper (I) chloride and 18 ml of the magnesium compound prepared as in example 3. 3-bromothioanisole with a titre of 1.17 M/l, whereby 3 g of the expected compound are obtained.

IR spectrum (CHCl3)

Free OH approx. 3600cm-<1> + bound 3498cm-<1> (max)

3440cm-<1> (shoulder)

aromatic 1587cm~'', 1586cm"<1>.

Step B: (Z)-17-beta-hydroxy-1 7-alpha-(3-hydroxy-1-propenyl)-11-beta-[3-(methylthio)-phenyl]-estra-4,9-diene- 3-Mon. 3 g of the compound obtained earlier, 30 ml of ethanol and 5 ml of 2N hydrochloric acid are mixed together for two hours at ambient temperature and then concentrated to a small volume under reduced pressure. Extraction is carried out with methylene chloride, washing and drying, and the solvents are removed under reduced pressure. The residue is chromatographed on silica with cyclohexane: ethyl acetate in the ratio 5:3 as eluent, whereby 1.083 g of the expected compound is obtained.

Sm.p. 168°C.

IR spectrum (CHCl3)

OH : 3613cm-<1> + tied 3440cm-<1>

dienone : 1656cm~'' to 1601cm~<1>

aromatic : 1587cm-<1>, 1569cm_<1>, 1474cm-<1>.

Step C: (17R)-11-beta-13-(methylthio)-phenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 12, step D, starting from 1.050 g of the compound obtained in the previous step B, whereby 592 mg of the expected compound is obtained in pure form. Sm.p. 150'C.

IR spectrum (CHCl3)

dienone : 1657cm_<1> to 1601 cm-1

aromatic : 1587cm-1 ,- 1569cm-1 , 1473cm~1

-C-O-C- : 1080cm-<1> to 1041 cm"1.

Analysis: C28<H>32 SO2 : 532.62

EXAMPLE 14: (17R)-11-beta-(4-chlorophenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: Cyclic (Z)-(1,2-ethanediyl)-acetal of 11-beta-(4-chlorophenyl)-5-alpha,17-beta-dihydroxy-17-alpha-C3-(tetrahydro-2H-2 -pyranyloxy)-1-propenyl]-estr-9-en-3-one.

The operation is carried out as in example 8, step B,

starting from 2.5 g of the compound prepared in Example 8, step A, 160 mg of copper (I) chloride and 18 ml of a solution of the magnesium compound prepared in Example 3 by starting with 4-chlorobromobenzene with a titer of 0.87 M/l. 3,082 is obtained

g of the expected compound in pure form.

IR spectrum

OH : 3500cm_<1> + bound, against 3405cm_<1>

aromatic : 1600cm_<1>, 1490cm"<1>.

Step B: (Z)-11-beta-(4-chlorophenyl)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-estr-4,9-dien-3-one.

3.05 g of the compound obtained in the previous step is stirred for three hours at ambient temperature for 30

ml of ethanol and 30 ml of water in the presence of 3 g of potassium hydrogen sulphate.

The mixture is concentrated to a small volume under reduced pressure, diluted with water and extracted with methylene chloride. The extracts are dried, and the solvents are removed under reduced pressure, thereby obtaining 2.54 g of the compound in impure form. Chromatography is carried out on silica with cyclohexane:ethyl acetate in the ratio 5:5 as eluent and then recrystallization from ethyl acetate. Sm.p. 214°C.

IR spectrum (CHCl3)

OH: approx. 361 limb-1 + bound

dienone : 1654cm_<1> to 1602cm_<l>

aromatic : 1013cm_<1>~

Step C: (17R)-11-beta-(4-chlorophenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 12, step D, starting with 1.03 g of the compound obtained in the previous step B, 20 ml of pyridine, 3 g of tosyl chloride and 25 ml of concentrated hydrochloric acid, thereby obtaining 726 mg of the expected compound in crystalline form. Sm.p. >260°C.

IR spectrum (CHCl3)

dienone : 1654cm-'! to 1602cm~<1>

aromatic : 1572cm_'1, (shoulder) 1490cm"<1>

1081 cm-1 to 1039 cm-<1>. Analysis: C27<H>29 C102 : 420.98

EXAMPLE 15: (17R)-11-beta-[4-(1-methylethoxy)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-14-(1-methylethoxy)-phenyl]-17-alpha-[3- (tetrahydro-2H-2-pyranyloxy)-1-propenyl]-estr-9-en-3-one.

The operation is carried out as in Example 8, Step B, using 2.5 g of the compound prepared as described in Example 8, Step A, 110 mg of copper (I) chloride and 35 ml of the magnesium compound prepared as in Example 3, starting with 1-bromo-4-(1-methylethoxy)-benzene. 6.764 g of the compound are obtained in impure form, which is chromatographed on silica (eluent: cyclohexane: ethyl acetate in the ratio 7:3 with 1% triethylamine), whereby 3.173 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step B: (Z)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-[4-(1-methylethoxy)-phenyl]-estra-4,9-diene -3-on.

The operation is carried out as in example 13, step B, starting from 3.14 g of the compound obtained in the preceding step A, 20 ml of ethanol and 2 ml of 2N hydrochloric acid, thereby obtaining 1.257 g of the expected compound in impure form.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-[4-(1-methylethoxy)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 12, step D, starting from 1.22 g of the compound obtained in the

previous step B, 20 ml of pyridine, 2.1 g of tosyl chloride and 25 ml of concentrated hydrochloric acid, thereby obtaining 849 mg of the compound in impure form, which is recrystallized from ethanol. Sm.p. 155-C.

IR spectrum (CHCl3)

cm-<1> cm-<1>

dienone: 1656 to 1608

aromatic : 1506

1086 to 1040

Analysis: C30H36<O>3 <:> 444.619

EXAMPLE 16: (17R)-11-beta-[4-(1-pyrrolidinyl)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Stage A: Cyclic. (Z )^(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(1-pyrrolidinyl)-phenyl]-17-alpha-[3-(tetrahydro- 2H-2-pyrranyloxy)-1-propenyl]-estr-9-en-3-one.

The operation is carried out as in example 8, step B, starting from 1.71 g of the compound obtained in example 8, step A, 180 mg of copper (I) chloride and 20 ml of 4-(1-pyrrolidinyl)-f eny Imagnesium bromide, with a titer of 1 M/l.

After extraction with ether, washing with water and concentration under reduced pressure, 4.39 g of the compound are obtained in impure form. This is chromatographed on silica with cyclohexane:ethyl acetate in the ratio 7:3 as eluent, whereby 2.3 g of the expected compound is obtained, which is used as it is in the subsequent step.

Step B: (Z)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-1 4-(1-pyrrolidinyl)-phenyl]-ester-4,9-diene -3-on.

2.3 g of the compound prepared in step A in 25 ml of methanol is mixed with 10 ml of 2N hydrochloric acid for two and a half hours at ambient temperature and then for 30 minutes at 50°C. The mixture is cooled, diluted with water and made alkaline by adding of 20 ml of an aqueous N sodium hydroxide solution and then with an acidic sodium carbonate solution.After extraction with ethyl acetate, washing with water and drying, the solvents are removed under reduced pressure to give 1.825 g of the expected compound.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-[1-pyrrolidinyl)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 2, starting from 1.4 g of the compound obtained in the previous step B, 30 ml of pyridine and 3 g of tosyl chloride and extracting with ether, thereby obtaining 1", 25 g of the compound in impure form This is chromatographed on silica (eluent: cyclohexane:ethyl acetate in the ratio 7:3, then with benzene-ethyl acetate in the ratio 85:15), whereby 0.9 g of the expected compound is obtained.

IR spectrum (CHCl3)

Analysis: C31<H>37N7O2

EXAMPLE 17: (17R)-11-beta-(2-thienyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-17-alpha-[3-(tetrahydro-2H-2-pyrranyloxy)-1-propenyl]- 11-beta-(2-thienyl)-estr-9-en-3-one.

The operation is carried out as in example 8, step B, starting from 2.5 g of the compound obtained in example 8, step A, 110 mg of copper (I) chloride and 22.2 ml of the magnesium compound prepared as in example 3 by start with 2-bromothiophene, with a titer of 1.05 M/l.

3.6 g of compound are obtained in impure form, which is chromatographed on silica with cyclohexane:ethyl acetate in the ratio 5:5 as eluent, whereby 2.196 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step B: (Z)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-(2-thienyl)-estra-4,9-dien-3-one.

The operation is carried out as in example 13, step B, starting from 2.1 g of the previously obtained compound, 20 ml of ethanol and 2 ml of 2N hydrochloric acid, whereby 1.1 g of the expected compound is obtained in pure form.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-(2-thienyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 12, step D, starting from 1.03 g of the compound obtained in the previous step, 20 ml of pyridine, 2.1 g of tosyl chloride and 25 ml of concentrated hydrochloric acid. 984 mg of the compound are obtained in pure form, which is recrystallized from ethanol. Sm.p. 182°C.

IR spectrum (CHCl3)

Analysis: C25<H>28SO2

EXAMPLE 18: (17R)-11-beta-[4-(ethylthio)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: Cyclic (1,2-ethanediyl acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(ethylthio)-phenyl]-17-alpha-[3-(tetrahydro-2H-2 - pyranyloxy)-1-propenyl]-estr-9-en-3-one.

Preparation of the magnesium compound

The operation is carried out as in example 3, starting from 1.125 g of magnesium and 9.3 g of 1-bromo-4-ethylthiobenzene, whereby a solution of the magnesium compound with a titer of 0.87 M/l is obtained.

Condensation

The operation is carried out as in example 8, step B

using 3 g of the compound obtained in Example 8, step A, 110 mg of copper (I) chloride and 30 ml of the magnesium compound prepared above. It is extracted with methylene chloride, washed and dried, and the solvents are removed under reduced pressure. 10 g of the compound are obtained in impure form, which is chromatographed on silica with cyclohexaneethyl acetate in the ratio 5:5 as eluent, whereby 3.159 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step B: (Z)-beta-[4-(ethylthio)-phenyl1-17-beta-hydroxy-1 7-alpha-(3-hydroxy-1-propenyl)-estra-4,9-dien-3-one .

3.474 g of the compound obtained in the previous step is stirred for 30 minutes in 60 ml of methanol with 2 ml of methylene chloride and 5 ml of 2N hydrochloric acid, and concentrated to a small volume. 10 ml of aqueous N sodium hydroxide solution is added, followed by extraction with methylene chloride. The extracts are washed with water and dried, and the solvents are removed under reduced pressure, thereby obtaining 2.574 g of compound in impure form. Chromatography is carried out on silica with cyclohexane:ethyl acetate in the ratio 3:7 as eluent, and the residue obtained is crystallized from ethanol, whereby

one obtains 1.052 g of the expected compound in pure form. Sm.p. 100°C.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-[4-(ethylthio)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 12, step D, starting with 600 mg of the compound obtained in the previous step, 15 ml of pyridine and 1.5 tosyl chloride.

872 mg of compound are obtained in impure form, which is chromatographed on silica with cyclohexane:ethyl acetate in the ratio 5:5 as eluent, and crystallized from ethanol. Sm.p. 100°C.

IR spectrum (CHCl-j)

Analysis: C 30<H>34 O 2 S 446.657

EXAMPLE 19: (17R)-11-beta-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-phenyl]-spiro-(estra-4,9-diene-17,2' -(5H)-furan)-3-one

Step A: Cyclic (1,2-ethanediyl)-acetal of 11-beta-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-phenyl]-5-alpha, 17-beta- di-hydroxy-17-alpha-[3-tetrahydro-2H-2-pyranyloxy)-1-propenyl]-estr-9-en-3-one.

Preparation of the magnesium compound

The operation is carried out as in example 3, starting from 3.5 g of magnesium and 25 g of 2-(4-bromophenyl-4,5-dihydro-4,4-dimethyloxazole), whereby a solution with a titer of 0.74 M is obtained /l.

Condensation

The operation is carried out as in example 3, starting from 80 ml of the solution of the magnesium compound above, 800 mg of copper (I) chloride and 10 g of the compound prepared as in example 8, step A. After chromatography on silica

(eluent: cyclohexane:ethyl acetate in the ratio 3:7)

14.3 g of the expected compound is obtained, which is used as is in the next step.

IR spectrum (CHCl3)

Step B: (Z)-11-beta-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-phenyl]-17-beta-hydroxy-1 7-alpha-(3-hydroxy -1-propenyl)-estra-4,9-dien-3-one.

Under an inert atmosphere, 13.1 g of the preceding compound are dissolved in 130 ml of dioxane and 130 ml of 2N hydrochloric acid with stirring for one hour. The solution is then poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extracts are washed with water and dried, and the solvents are removed under reduced pressure, whereby 10.3 g of compound are obtained in impure form, which is recrystallized from ether. Sm.p. 269°C.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-[4-(4,5-dihydr~4,4-dimethyl-2-oxazolyl)-phenyl]-spiro-(estra-4,9-diene-17,2' -(5H)-furan)-3-one.

0.49 g of the compound obtained earlier is added

in suspension to 10 ml of pyridine and 1 g of tosyl chloride is added. The whole thing is stirred for two and a half hours. After dilution with ice-cooled water, the skimming is separated and dissolved in methylene chloride. The organic phase is separated and dried, and the solvents are removed under reduced pressure. The residue is chromatographed on silica with methylene chloride:ethyl acetate in the ratio 1:1 as eluent, whereby 0.41 g of the expected compound is obtained. Sm.p. 250°C.

IR spectrum (CHCl3)

Analysis: C32<H>37NO3 483.65

EXAMPLE 20: (17R)-11-beta-C4-[2-(dimethylamine)-ethoxy]-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H))-furan)- 3-Mon.

Step A: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-14-t2-(dimethylamino)-ethoxy]-phenyl]-17-alpha-[3- (tetrahydro-2H-2-pyranyloxy)-1-propenyl]-estra-9-en-3-one.

The operation is carried out as in example 8, step B,

starting with 75.5 ml of a solution of magnesium compound prepared from 4-(N,N-dimethylaminoethoxy)-bromobenzene with a titer of 0.7 M/l, 0.25 g of copper (I) chloride and 5 g of the compound prepared in example 8, step A. After chromatography on silica (eluent: ethyl acetate:triethylamine in the ratio 93:2) 2.620 g of the expected compound are obtained.

IR spectrum (CHCl3)

Step B: (Z)-11-beta-[4-[2-(dimethylamino)-ethoxy]-phenyl]-1 7-beta-hydroxy-17-alpha-[3-hydroxy-1-propenyl]-estra- 4,9-dien-3-one.

A solution containing 2.62 g of the compound obtained above in 13 ml of ethanol is cooled to 0°C, and 7.9 ml of 2N hydrochloric acid is added with stirring for 30 minutes. 6 ml of ammonium hydroxide and 25 ml of water are added with further stirring for 30 minutes. The resulting slurry is separated and dissolved in methylene chloride, after which the solution is dried and evaporated to dryness under reduced pressure. 1.948 g of compound are obtained in impure form, which is chromatographed on silica with ethyl acetate:triethylamine in the ratio 8:2 as eluent. The residue is then recrystallized from isopropanol. Sm.p. 136°C.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-[4-[2-(dimethylamino)-ethoxy]-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)-furan)- 3-Mon.

The operation is carried out as in example 12, step D, starting from 2.268 g of the compound prepared in the previous step B, 45 ml of tosyl chloride and 45 ml of 6N hydrochloric acid. Chromatography is carried out with ethyl acetate:triethylamine in the ratio 95:5 as eluent and crystallization from isopropanol, whereby 0.815 g of the expected compound is obtained. Sm.p. 136°C.

[cc]D = +156.5° ± 3°. (c = 0.6% CHCl 3 ).

IR spectrum (CHCl3)

EXAMPLE 21: (17R)-11-beta-[4-[2-(methylthio)-ethoxy]-phenylJ-spiro-(estra-4,9-dien-1 7,2'-(5H)-furan)- 3-Mon.

Step A: Cyclic 1,2-ethanediyl acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-{ 2-(methylthio)-ethoxy]-phenyl]-17-alpha-[3-( 1-tetrahydro-(2H)-2-pyranyloxy)-1-propenyl]-estra-9-en-3-one.

Preparation of the magnesium compound

The operation is carried out as in Example 3, using 0.8 g of magnesium and 6.1 g of 4-bromo-2-[(methylthio)-ethoxy]-benzene. A solution with a titer of 0.59 M/l is obtained.

Condensation

The operation is carried out as in example 8, step B. The starting point is 0.472 g of the compound prepared in example 8, step A, 22 mg of copper (I) chloride and 8.3 ml of the solution of the solution of the magnesium compound prepared above, thereby obtaining 0.46 g of the expected compound.

IR spectrum (CHCl3)

The 4-bromo-2-[(methylthio)-ethoxy]-benzene used in step A was prepared as follows.

Under an inert atmosphere, 73.9 g of parabromophenol are dissolved in 430 ml of 1N aqueous sodium hydroxide solution. In the course of five minutes, 47.3 g of 2-chloroethylmethylsulfide are added, and the mixture is boiled for 18 hours with reflux cooling. It is cooled, and the sodium chloride formed is separated, washed with ethanol and dried, and the solvents are removed under reduced pressure. The residue is taken up with water and extracted with ether. The organic phase is washed with 1N aqueous sodium hydroxide solution, and then with water, dried and evaporated to dryness. The residue is chromatographed on silica with hexane-ethyl acetate in the ratio 95:5 as eluent, whereby the expected compound is obtained, which is used as it is for the preparation of the magnesium compound.

Step B: 1 7-beta-hydroxy-17-alpha-(3-hydroxypropenyl)-11-beta-[4-[2-(methylthio)-ethoxy]-phenyl]-estra-4,9-dien-3- Wed.

The operation is carried out as in example 18, step B, using 2.75 g of the compound prepared in the preceding step A, 60 ml of methanol, 10 ml of methylene chloride and 6 ml of 2N hydrochloric acid. After chromatography on silica with methylene chloride:acetone in the ratio 85:15 as eluent, 3 g of compound are obtained, which is used as is in the following step.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-[4-[2-(methylthio)-ethoxy]-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)-furan)- 3-Mon.

The operation is carried out as in example 12, step D, starting with 1.4 g of the compound prepared above, 28 ml of pyridine, 2.26 g of tosyl chloride and 28 ml of 6N hydrochloric acid. 1.82 g of the expected compound in crystalline form is obtained.

[<x]D = +184.5° ± 2°. (c = 1% CHCl 3 ).

IR spectrum (CHCl3)

Analysis: C30H36<O>3S 476.68 with solvation in 5% EtOH

EXAMPLE 22: (17R)-11-beta-(3-methoxyphenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: The dimethyl ketal of {Z)-5-alpha,17-beta-dihydroxy-11-beta-(3-methoxyphenyl)-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy)-1-propenyl] -estra-9-en-3-one.

The operation is carried out as in example 5 C, starting with 3 g of the compound prepared as in example 5

B, 100 mg of copper (I) chloride and 19 ml of the solution of magnesium compound prepared from 3-bromoanisole with a titer of 1 M/l. After chromatography on silica (eluent: cyclohexane:ethyl acetate in the ratio 7:3 with 1% triethylamine) 1.522 is obtained

g of the expected compound.

Step B: (Z)-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-(3-methoxyphenyl)-estra-4,9-dien-3-one.

The operation is carried out as in example 5 D, with 1.5 g

of the compound obtained in the previous step and 1.5 g of potassium hydrogen sulfate. After chromatography on silica with n-hexane:ethyl acetate in the ratio 7:3 as eluent, 0.8 g of the expected compound is obtained. Sm.p. 167-168°C.

IR spectrum (CHCl3)

Step C: (17R)-11-beta-(3-methoxyphenyl)-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one.

The operation is carried out as in example 5, step E, using 0.77 g of the compound prepared in the preceding step B, 20 ml of pyridine, 2.7 g of tosyl chloride and 25 ml of concentrated hydrochloric acid. After chromatography on silica (eluent: cyclohexane:ethyl acetate in the ratio 5:5), 0.624 g of the expected compound is obtained, which is crystallized from ethanol. Sm.p. 170°C.

IR spectrum (CHCl3)

Analysis: C28H32<O>3

EXAMPLE 23: (17R)-11-beta-(4-methoxyphenyl)-spiro-(estr-4,9-dien-17,2'-(5H)-furan)-3-one.

Step A: The dimethyl ketal of (Z)-5-alpha,17-beta-dihydroxy-11-beta-(4-methoxyphenyl)-17-alpha-[3-(tetrahydro-2H-2-pyranyloxy )-i-propenyl] -estr-9-en-3-one.

The operation is performed as in example 5, step C,

using 3 g of the compound prepared as in example 5, step B, 190 mg of copper (I) chloride and 19 ml of the solution of magnesium compound prepared from 4-bromoanisole with a titer of 1 M/l. After chromatography on silica (eluent: petroleum ether (b.p. 40-60°C): ethyl acetate in the ratio 7:3

with 1% triethylamine) 1.078 g of the expected compound and 0.625 g of the corresponding 5-beta-hydroxy-11-alpha-(4-methoxyphenyl)-i isomer are obtained.

Step B: (Z)-1 7-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-(4-methoxyphenyl)-estra-4,9-dien-3-one.

The operation is performed as in example 5, step D,

starting with 1 g of the compound obtained in the preceding step A and 1 g of potassium hydrogen sulphate, whereby 736 mg of the compound in impure form are obtained, which is used as it is in the following step.

Step C: (17R)-11-beta-(4-methoxyphenyl)-spiro-(estr-4,9-dien-17,2<1-(5H)-furan)-3-one.

The operation is performed as in example 5, step E,

starting with 736 mg of the compound prepared in the previous step, 20 ml of pyridine, 2.1 g of tosyl chloride and 25 ml of concentrated hydrochloric acid. After chromatography on silica (eluent: cyclohexane:ethyl acetate in the ratio 7:3), 383 mg of the expected compound is obtained, which is crystallized from ethanol. Sm.p. 170°C.

IR spectrum (CHCl3)

EXAMPLE 24: (17R)-4',5'-dihydro-11-beta-[2,3-dihydro-1-methyl-(1H)-indol-5-yl]-spiro-(estra-4,9- dien-17,2'-(3H)-furan)-3-one.

Step A: Cyclic (1,2-ethanediyl)-acetal of 11-beta-12,3-dihydro-1-methyl-(1H)-indol-5-yl]-5-alpha, 1 7-beta-dihydroxy- 17-alpha-[3-(tetrahydro-2H-2-P<yra>n<y>loxypropyl)-estra-9-en-3-one.

The operation is carried out as in example 12, step B, starting from 2.45 g of the compound prepared in example 12, step A, 110 mg of copper (I) chloride and 35 ml of the solution of the magnesium compound prepared as in example 3 by starting with 5-bromo-2-methylindoline, with titer 0.6 M/l. 1.218 g of the expected compound are obtained.

Step B: 11-beta-12,3-dihydro-1-methyl-(1H)-indol-5-yl]-17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-estra-4,9- diene-3-one.

The operation is carried out as in example 12, step C, starting with 3.025 g of the compound prepared as in the previous step, 30 ml of ethanol and 5 ml of 2N hydrochloric acid, whereby 1.658 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step C: (17R)-4<1>,5'-dihydro-11-beta-[2,3-dihydro-1-methyl-(1H)-indol-5-yl]-spiro-(estra-4, 9-dien-1 7,2'-(3H)-furan)-3-one.

The operation is carried out as in Example 12, step D, starting with 1.658 g of the compound prepared in step B, 20 ml of pyridine, 2.1 g of tosyl chloride and 20 ml of concentrated hydrochloric acid. After chromatography on silica (eluent: cyclohexane:ethyl acetate in the ratio 7:3), 0.729 g of the expected compound is obtained.

IR spectrum (CHCl3)

Analysis: C30<H>37NO2 443.634

EXAMPLE 25: (17R)-4',5*-dihydro-11-beta-14-[(3-methylbutyl)-thio]-phenyl]-spiro-(estra-4,9-diene-17,2*- (3H)-furan)-3-one.

Step A: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-[(3-methylbutyl)-thio]-phenyl1-17-alpha-[3- (tetrahydro-2H-2-pyranyloxy)-propyl]-estr-9-en-3-one. The operation is performed as in example 12, step B,

starting with 3.5 g of the compound prepared in the example

12, step A, 1.24 g of copper (I) chloride and 22 ml of a solution of magnesium compound prepared as in example 3 from 4-[(3-methyl)-butylthio]-bromobenzene, with titer 0.7 M /l.

After chromatography on silica (eluent: methylene chloride:acetone in the ratio 95:5 with 1% triethylamine) 4.08 g of the expected compound are obtained.

IR spectrum (CHCl3)

Step B: 17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-11-beta-[4-[(3-methylbutyl)-thioJ-phenyl]-estra-4,9-dien-3-one.

The operation is carried out as in example 16, step B, starting with 4.05 g of the compound prepared above, 30 ml of methanol and 12 ml of 2N hydrochloric acid, whereby 3.34 g of the compound is obtained in impure form. Chromatography is carried out on silica with methylene chloride:acetyl acetate in the ratio 3:7 as eluent, whereby 2.3 g of the expected compound is obtained in pure form.

IR spectrum (CHCl3)

Step C: (17R)-4',5'-dihydro-11-beta-14-[(3-methylbutyl)-thio]-phenyl]-spiro-(estra-4,9-diene-17,2'- (3H)-furan)-3-one.

The operation is carried out as in example 2, starting from 2.3 g of the compound obtained above, 45 ml of pyridine and 4.3 g of tosyl chloride.

2.14 g of compound are obtained in impure form, which is purified by recrystallization from ethanol. Sm.p. 200°C. IR spectrum (CHCl3)

EXAMPLE 26: (17R)-4',5'-dihydro-11-beta-[4-(1-pyrrolidinyl)-phenyl]-spiro-(estra-4,9-diene-17,2'-(3H) -furan)-3-one.

Step A: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(1-pyrrolidinyl)-phenyl]-1 7-alpha-[3-[ ( tetrahydro-2H-2-pyranyloxy]-1-propynyl]-estr-9-en-3-one.

The operation is performed as in example 3, step B,

starting from 3.5 g of the compound prepared as in example 3, step A, 73 mg of copper (I) chloride and 23 ml of the solution of the magnesium compound prepared as indicated in example 3 by starting with N-( 4-bromophenyl)-pyrrolidine and with a titre of 1.3 M/l.

After chromatography on silica (eluent: methylene chloride:acetone in the ratio 92:8 with 1% triethylamine and then ethyl acetate:n-hexane in the ratio 5:5 with 2% triethylamine) 3.52 g of the expected compound are obtained in pure form.

IR spectrum (CHCl3)

Step B: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,17-beta-dihydroxy-11-beta-[4-(1-pyrrolidinyl)-phenyl]-17-alpha-[3-(tetrahydro- 2H-2-pyranyloxy)-propyl]-estr-9-en-3-one.

The operation is performed as in example 4, step A,

starting from 2.62 g of the compound prepared above dissolved in 172 ml of a 1:1 solution of benzene and ethanol and with 1.048 g of Wilkinson's reagent, and carrying out hydrogenation for four hours and 45 minutes. Thereby 2.1 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step C: 17-beta-hydroxy-17-alpha-(3-hydroxypropyl)-11-beta-[4-(1-pyrrolidinyl)-phenyl]-estra-4,9-dien-5-one.

The operation is carried out as in example 4, step B, starting from 2.09 g of the compound obtained above, 32 ml of methanol bg 10^45 ml of 2N hydrochloric acid.

After chromatography on silica (eluent: methylene chloride:methanol in the ratio 95:5 with 2% triethylamine) 1.31 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step D: (17R)-4',5'-dihydro-11-beta-[4-(1-pyrrolidinyl)-phenyl]-spiro-(estra-4,9-diene-17,21-(3H)- furan)-3-one.

The operation is carried out as in example 4, step C, starting from 1.28 g of the compound obtained in the previous step, 20 ml of pyridine and 2.6 g of tosyl chloride.

After chromatography on silica (eluent: cyclohexane:ethyl acetate in the ratio 75:25 with 2% triethylamine) 0.73 g of the expected compound is obtained.

IR spectrum (CHCl3)

Analysis: C31<H>39NO2 457.66

EXAMPLE 27: (17R)-11-beta-[4-methylthio)-phenyl]-spiro-(estra-1,3,5(10)-trien-17,2'-(5H)-furan)-3- beer.

1• Formation of phenol acetate

0.5 g of the compound prepared as in example 3E dissolved in 10 ml of methylene chloride is cooled to 3°C. 0.5 ml of acetic anhydride is then added dropwise followed by 0.25 ml of acetyl bromide while stirring for 50 minutes. The reaction medium is diluted with 20 ml of ice-cooled water, and 5 ml of an N aqueous sodium hydroxide solution is added with stirring for 30 minutes. After extraction with methylene chloride, the organic phase is washed and dried, and the solvents are removed under reduced pressure. 0.584 g of compound is obtained in impure form, which is chromatographed on silica with n-hexane:ethyl acetate in the ratio 7:3 as eluent, whereby 0.241 g of the expected acetate is obtained.

2. Saponification

The compound obtained above is taken up in 3 ml of ethanol, and 4 drops of an N aqueous sodium hydroxide solution are added. After stirring and diluting with 10 ml of water, the precipitate is filtered off and washed, and then dried under reduced pressure. The residue is purified by chromatography on silica with n-hexane:ethyl acetate in the ratio 8:2 as eluent, whereby 0.205 g of the expected compound is obtained.

IR spectrum (CHCl3)

EXAMPLE 28: (17R)-11-beta-14-[2-(methylthio)-ethoxy]-phenyl]-spiro-(estra-1,3,5(10)-triene-17,2'-(5H) -furan)-3-ol and its acetate and (17R)-11-beta-[4-[2-(methylthio)-ethoxy]-phenyl]-spiro-(estra-5(10)-9(11)- diene-1 7,2 * -(5H)-furan)-3-one.

1. Formation of phenol acetate

A solution consisting of 1 g of the compound obtained in example 21 in 20 ml of methylene chloride is cooled to approx. 5°C. 1 ml of acetic anhydride and 0.5 ml of acetyl bromide are added, after which the temperature is allowed to return to the ambient temperature. After stirring for 50 minutes, the reaction medium is poured into an ice-cooled sodium bicarbonate solution and stirred for 10 minutes, after which extraction is carried out with methylene chloride. The organic phases are separated, washed with water and dried, and the solvents are removed under reduced pressure. The residue is chromatographed on silica with hexane:ethyl acetate in the ratio 80:20, and then in the ratio 85:15, whereby 0.509 g of the acetate of (17R)-11-beta-[4-[2-(methylthio)-ethoxy] is obtained -phenyl]-spiro-(estra-1,3,5(10)-trien-17,2'-(5H)-furan)-3-ol.

IR spectrum (CHCl3)

In addition, 90 mg of (17R)-11-beta-[4-12-(methylthio)-ethoxy]-phenyl]-spiro-(estra-5 (10)-9 (11)-dien- 17.21 -

(5H)-furan)-3-one.

IR spectrum (CHCl3)

2. Saponification

0.5 g of the above phenol acetate is taken up in 7.5 ml of methanol and 1 ml of methylene chloride. 0.5 ml sodium hydroxide is then added dropwise and with stirring for 20 minutes at ambient temperature. The reaction mixture is diluted with hydrochloric acid and extracted with methylene chloride. The extracts are washed with water and dried, and the solvents are removed under reduced pressure. The residue is chromatographed on silica (eluent: hexane:ethyl acetate in the ratio 8:2, and then methylene chloride), whereby 354 mg of the

expected (17R)-11-beta-(4-[2-(methylthio)-ethoxy]-phenyl]-spiro-(estra-1,3,5(10)-trien-17,2'-(5H)- furan)-3-ol, which is recrystallized from isopropanol, mp 198°C.

IR spectrum (CHCl3)

EXAMPLE 29: (17R)-2-beta-methyl-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)-furan)- 3-one and the corresponding 2-alpha isomer, and (17R)-2,2-dimethyl-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17, 2'-(5H)-furan)-3-one.

2.45 ml of n-butyllithium dissolved in 1.6M hexane and

5 ml of tetrahydrofuran is cooled to -65/-70°C under an inert atmosphere. In the course of 20 minutes, 0.66 ml of cyclohexylisopropylamine in 5 ml of tetrahydrofuran is added. After stirring for 15 minutes, 1.4 g of the (17R)-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-dien- 17,2'-(5H)-furan)-3-one dissolved in 15 ml of tetrahydrofuran, and the mixture is stirred for 15 minutes. 0.4 ml of methyl iodide is then added. The temperature is allowed to return to ambient temperature with stirring for one hour, after which 20 ml of an aqueous ammonium chloride solution is added. After decantation, the organic phase is washed with saline water. Extraction is carried out again with ethyl acetate, and the extracts are dried and evaporated to dryness, thereby obtaining 1.5 g of the compound in an impure form. Chromatography is carried out on silica with a mixture of petroleum ether (boiling point 40-70°C) and ethyl acetate in a ratio of 9:1 as eluent, which gives: 290 mg of (17R)-2-beta-methyl-11-beta-[ 4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)-furan)-3-one- isomer, which is recrystallized from isopropyl ether. Sm.p. 176°C. 355 mg of the 2-alpha-methyl isomer, which is recrystallized from isopropyl ether, m.p. 164°C, and

65 mg (17R)-2,2-dimethyl-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)-furan)-3 -on.

IR spectrum (CHCl3)

EXAMPLE 30: (E)-(17R)-oxime of 11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)-furan)- 3-one and the corresponding (Z)-isomer

1.36 g of (17R)-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-dien-17,2'-(5H)-furan)-3-one obtained in Example 3 is heated under reflux for 75 minutes under an inert atmosphere in 14 ml of ethanol with 3.6 ml of pyridine and 0.44 g of hydroxylamine hydrochloride. The temperature is allowed to return to ambient temperature, and the reaction medium is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed, dried and evaporated to dryness under reduced pressure, whereby 1.47 g of the compound are obtained in impure form. Chromatography is carried out on silica, eluting with a mixture of petroleum ether (boiling point 40-70°C) and ethyl acetate in the ratio 8:2.

805 mg of the (E) isomer is obtained, which is dissolved hot in methylene chloride and recrystallized from isopropyl ether, m.p. 250°C, together with 390 mg of the (Z)-isomer, which is recrystallized in the same way, m.p. 266"C.

The (E) isomer:

IR spectrum (CHCI3) Analysis: C28H33<N>O2S 447.64 IR spectrum (CHCI3)

Analysis:

EXAMPLE 31: (17R)-4'5'-dihydro-9-alpha,10-alpha-epoxy-11-beta-[4-[3-methylbutyl)-sulfonyl]-phenyl]-spiro-(estra-4- en-17,2'-(3H)-furan)-3-one. 0.8 g of the compound obtained in example 25 is dissolved in 20 ml of methylene chloride, the solution is cooled to 0°C, and 1.64 g of metachloroperbenzoic acid is added in small portions with stirring for one hour. A 0.2N sodium thiosulfate solution is added with stirring for five minutes, after which the reaction medium is poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic phase is washed with water and dried, and the solvents are removed under reduced pressure, whereby 0.980 g of the expected compound is obtained, which is recrystallized from a mixture of methylene chloride and isopropyl ether. Sm.p. 203°C. IR spectrum (CHCl3) Analysis: C32<H>42<O>5S 538.75

EXAMPLE 32: (17R)-4-[3-oxo-spiro-(estra-4,9-diene-17,21-

2-amino-2-methylpropyl (5H)-furan)-11-beta-yl]-benzoate.

4.32 g (17R)-11-beta-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-phenyl]-spiro-(estra-4,9-diene-17,2 The ((5H))-furan)-3-one prepared as in example 19 is dissolved in 40 ml of dioxane and 40 ml of 2N hydrochloric acid. The solution is heated for three and a half hours at 60°C and cooled. The reaction medium is poured into an ice-cooled aqueous sodium bicarbonate solution and extracted with methylene chloride. The extracts are washed with water and dried, and the solvents are removed under reduced pressure.

4.5 g of compound are obtained in impure form. Chromatography is carried out on silica (eluent: ethyl acetate, then ethyl acetate with triethylamine, in a ratio of 9:1). After crystallization from ether, and then from ethyl acetate, 2.54 g of the expected compound are obtained. Sm.p. 178°C.

IR spectrum (CHCl3)

Analysis: C32<H>39NO4 501.67

EXAMPLE 33: Ethyl-(17R)-4-[3-oxo-spiro-(estra-4,9-dien-1 7,21-(5H)-furan)-11-beta-yl]-benzoate and (17R )-4-[3-oxo-spiro-(estra-4,9-diene-17,21-(5H)-furan)-II -beta-yl]-N-2-hydroxy-(1,1-dimethylethyl )-benzamide.

2.06 g of the compound prepared in example 32 suspended in 50 ml of ethanol and 8 ml of a 0.7 M solution in ethanol and sodium ethylate are stirred for two hours under an inert atmosphere and at ambient temperature.

The suspension is poured into an ice-cooled aqueous hydrochloric acid solution and extracted with methylene chloride. The organic phase is washed and dried, and the solvents are removed under reduced pressure. The residue is chromatographed on silica (eluent: cyclohexane:ethyl acetate in the ratio 7:3, then ethyl acetate:triethylamine in the ratios 9:1 and 6:4), which gives: 1.375 g of the expected compound in the form of ethyl benzoate (compound A), which is recrystallized from ether, and then from ethanol. Sm.p. 140°C, and 182°C, and

0.385 g of the expected compound, N-2-hydroxy-{1,1-dimethylethyl)-benzamide (compound B), which is recrystallized from ether, then from isopropanol. Sm.p. 147 to 157"C.

IR spectrum of compound A (CHCl3)

IR spectrum of compound B (CHCl3)

EXAMPLE 34: (17R)-4-[spiro-(3-oxo-estra-4,9-dien-17,2'-(5H)-furan)-11-beta-yl]-benzoic acid.

0.3 g of compound A obtained in example 3 suspended in 3 ml of ethanol is swept over with nitrogen for 20 minutes, after which 1 ml of an N aqueous sodium hydroxide solution is added. The suspension is heated for one and a half hours at 60°C, cooled, and then poured into dilute hydrochloric acid solution. After extraction with ethyl acetate, the organic phase is washed with water and dried. The solvents are removed under reduced pressure, thereby obtaining 0.250 g of compound in impure form, which is purified by chromatography on silica with ethyl acetate as eluent. Sm.p. about. 170°C.

EXAMPLE 35: (17R)-13-beta-ethyl-11-beta-[4-(methylthio)-phenyl]-spiro-(gona-4,9-diene-17,2'-(5H)-furan)- 3-Mon.

Step A: Cyclic (1,2-ethanediyl)-acetal of 5-alpha,10-alpha-epoxy-13-beta-ethyl-gona-9(11)-ene-3,17-dione.

21.3 g of hexafluoroacetone sesquihydrate is added to a solution consisting of 21.36 g of cyclic (1,2-ethanediyl)-acetal of 13-beta-ethyl-gona-5(10),9(11)-ene-17- on in 213 ml of methylene chloride, and the mixture is cooled to 0-5" C. In the course of five minutes, 42.7 ml of hydrogen peroxide are added with stirring for two hours and 15 minutes under an inert atmosphere. Sodium thiosulphate is added, and extraction is carried out with methylene chloride The extracts are washed and the solvents removed under reduced pressure to give 26.41 g of the expected compound.

IR spectrum (CHCl3)

Step B: Cyclic (Z)-3,3-(ethanediyl)-acetal of 5,10-epoxy-13-beta-ethyl-17-beta-hydroxy-17-alpha-[3-(1-tetrahydro-2H- 2-pyranyloxy)]-1-propynyl-gona-9(11)-ene-3,17-dione.

The operation is carried out as in Example 5, step A, starting from 19.9 g of the compound obtained above and 14.6 ml of the HC=C-CH2OTHP reagent and allowing the reaction to continue for 15 minutes at ambient temperature. 33.533 g of compound in impure form, which is chromatographed on silica with methylene chloride: ethyl acetate in the ratio 9:1 as eluent, whereby 15.498 g of the expected compound is obtained.

IR spectrum (CHCl3)

Step C: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha-10-alpha-epoxy-13-beta-ethyl-17-beta-hydroxy-17-alpha-[3-(tetra- hydro-2H-2-pyranyloxy)-1-propenyl]-gona-9(11)-en-3-one.

15.45 g of the compound obtained in step B in 320 ml of ethyl acetate and 3.2 ml of pyridine are hydrogenated for four hours under a pressure of 1.2 bar in the presence of 154 mg of barium sulfate with 10% palladium. The catalyst is filtered off and washed with ethyl acetate, and the filtrate and washing liquid are evaporated to dryness. 14.705 g of compound are obtained in impure form, which is chromatographed on silica with methylene chloride:ethyl acetate in the ratio 9:1 as eluent, whereby 9.819 g of the expected compound is obtained.

Step D: Cyclic (Z)-(1,2-ethanediyl)-acetal of 5-alpha-17-beta-dihydroxy-13-beta-ethyl-11-beta-[4-(methylthio)-phenyl]-17- alpha-13-(tetrahydro-2H-2-pyranyloxy)-1-propenyl]-gona-9(11)-en-3-one.

The operation is carried out as in example 3, step B, starting from 3.5 g of the compound obtained in the previous step, 178 mg of copper (I) chloride and 16.3 ml of a solution of parabromothioanisolemagnesium compound, with

titer 1.1 M/l.

After chromatography on silica with cyclohexane: ethyl acetate in the ratio 7:3 as eluent, 3.46 g of the expected compound are obtained.

IR spectrum (CHCl3)

Step E: (Z)-13-beta-ethyl-17-beta-hydroxy-17-alpha-(3-hydroxy-1-propenyl)-11-beta-[4-(methylthio)-phenyl]-gona-4 ,9-dien-3-one.

17 ml of 2N hydrochloric acid is added to a suspension consisting of 3.4 g of the compound obtained in the previous step in 68 ml of ethanol, and it is stirred for one hour and 30 minutes at ambient temperature. The reaction medium is poured over

ice, and 5 ml of concentrated ammonia is added. It is washed with water, dried and evaporated to dryness under reduced pressure, thereby obtaining 2.961 g of the compound in impure form, which is chromatographed on silica with cyclohexane:ethyl acetate in the ratio 5:5 as eluent. After crystallization from isopropyl ether, 1.816 g of the expected compound are obtained. Sm.p. 186°C.

IR spectrum (CHCl3)

Step F: (17R)-13-beta-ethyl-11-beta-[4-(methylthio)-phenyl]-spiro-(gona-4,9-diene-17,2'-(5H)-furan)- 3-Mon.

The operation is carried out as in example 3, step E, starting from 5 g of the preceding compound, 30 ml of pyridine, 3 g of tosyl chloride and 180 ml of 2N hydrochloric acid. 1.981 g of compound are obtained in impure form, which is chromatographed on silica (eluent: cyclohexane: ethyl acetate in the ratio 7:3, and then in the ratio 8:2).

IR spectrum (CHCl3)

EXAMPLE 36: (17R)-11-beta-[4-[2-(dimethylamino)-ethoxy]-phenyl]-spiro-(estra-1,3,5(10)-trien-1 7,2'- (5H)-furan)-3-ol and its acetate.

1. Formation of the phenol acetate

The operation is carried out as in example 28, starting with 0.250 g of the compound obtained in example 20, 0.25 ml of acetic anhydride and 0.2 ml of acetyl bromide.

After purification by chromatography, 0.150 g of the desired acetate is obtained.

2. Saponification

The operation is carried out as in example 28, starting from 70 mg of the acetate obtained above in 1.5 ml of methanol with 0.1 ml of sodium hydroxide, whereby 60 mg of the expected compound is obtained.

IR spectrum (CHCl3)

Claims (7)

1. Steroid compounds, characterized in that they are compounds with the general formula (I): where Rx denotes phenyl, benzyl, thienyl, isothienyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, each of these radicals being optionally substituted with one or more radicals selected from: alkyl with 1-8 carbon atoms, alkoxy with 1-8 carbon atoms, halogen, hydroxyl, trifluoromethyl, alkanoyl of 1-6 carbon atoms, carboxy, C 1-6 -alkyloxycarbonyl; alkylthio with 1-8 carbon atoms which is optionally oxidized to the sulfoxide or sulfone form; amino which is optionally mono- or disubstituted with alkyl with 1-8 carbon atoms, and which is optionally oxidized to the N-oxide; bis-(chloroethyl)-amino, dimethylaminomethyl, dimethylaminoethyl, methyl-(dimethylaminoethyl)-amino, dimethylaminoethoxy and methylthioethoxy, or Rx denotes: R2 in the alpha or beta position is hydrogen or methyl, the wavy line in the spiroether indicates that the oxygen atom can be in the alpha or beta position, the broken line in the 3'-, 4'-position indicates the possible presence of a second bond between the carbon atoms carrying it, and the rings A and B have one of the following structures: a) A and B denote the group: where R' and R" are the same or different and denote a hydrogen atom or an alkyl radical with 1-4 carbon atoms, b) A and B denote the group: where Re denotes a hydrogen atom, an alkyl radical with 1-6 carbon atoms, or alkanoyl with 1-6 carbon atoms, c) A, B and C denote the group: where Rx and R2 are as stated above, d) A and B denote the group: e) A and B denote the group: and their acid addition salts. 2. Compound according to claim 1, characterized in that it is (17R)-4',5'-dihydro-1 1-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-diene- 17, 2'-(3H)-furan)-3-one or an acid addition salt thereof. 3. Compound according to claim 1, characterized in that it is (17R)-11-beta-[4-(dimethylamino)-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H)- furan)-3-one or an acid addition salt thereof. 4. Compound according to claim 1, characterized in that it is (17R)-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17,2'-(5H) - furan)-3-one or an acid addition salt thereof. 5. Compound according to claim 1, characterized in that it is (17R)-4',5'-dihydro-11-beta-[4-(methylthio)-phenyl]-spiro-(estra-4,9-diene-17 ,2'-(3H)-furan)-3-one or an acid addition salt thereof. 6. Antifertility agent, characterized in that it contains as active ingredient one or more steroid compounds according to claims 1-5. 7. Use of a steroid compound according to claims 1-5 as an active ingredient in a contraceptive.