HU188995B - Process for production of new steroid-spiro-lactons - Google Patents

Abstract

Novel steroidal-spiro-lactones of general formula (I) and their salts obtd. by opening the lactone ring, are prepd. by reacting a cpd. of general formula (IV) in the presence of a base with a malonic-acid-dialkyl-ester with 1-3 carbons. In the formulae R1 is hydrogen or methyl, R2 is alkyl with 1-3 carbons, R3 is hydrogen or 1-3C alkyl-thio gp. or 2-4C alkanoyl-thio gp. Z is a gp. of formula (II) or (III), X is H or 2-4C alkoxy-carbonyl with 2-4 carbons. M is metal. The dotted line between carbons 6 and 7 can mean an additional valency bond, with the proviso, that if the dotted line does stand for an additional bond, R3 can only be hydrogen. - If in the prod. of formula (I) resulting from the reaction X is an alkoxy-carbonyl gp. and Z is a gp. of formula (II), the cpd. of formula (I) is opt. heated in the presence of water. If in the resulting cpd. of formula (I) R3 is hydrogen, the dotted line between carbons 6 and 7 does not mean an additional bond, Z stands for a gp. of formula (II) with X meaning hydrogen, a further valency bond can opt. be produced in the 6(7) position of the stern structure using a benzo-quinone deriv. Alternatively an alkyl-mercaptan with 1-3 carbons or a thiol-carboxylic-acid with 2-4 carbons can be opt. additioned to the double bond in position 6(7), and/or salt can opt. be formed with the equiv. amt. of alkali from cpds. of formula (I) when Z means a gp. of formula (II) and X stands for hydrogen.

Description

The present invention relates to novel steroid spirolactones of formula I wherein:

R ¹ is hydrogen or methyl,

R ² is C 1-3 alkyl,

R ³ is hydrogen or C 2-4 alkanoylthio

Z is a group of formula II wherein.

X is hydrogen or C 2-4 alkoxycarbonyl, the dotted line between 6 and 7 carbon atoms may represent an additional 10 valence linkages, provided that when the dotted line of 6 to 7 carbon atoms represents an additional divalent bond, R ³ represents hydrogen only - 1O preparing

The novel steroid derivatives of the formula I according to the invention have a significant biological effect, in particular an antialdosterone effect.

The novel steroid spiro-lactones of formula I may be prepared according to the invention by reacting a compound of formula IV wherein R ¹ , R ^2, and C 6 -C 7 are as defined above in the presence of a base. malonic a 1-3 carbon reacted jg atomic number dialkyl ester, if desired, a resulting compound is of formula I wherein Z is II, a group of formula whereby X is from 2 to 4 carbon atoms alkoxilkarbonil group, R ^1, R ^2, and and the dotted line is as defined above and R ³ is hydrogen, heated in the presence of water, optionally on a compound of formula I wherein R *, R ² are as defined above and R ³ is hydrogen, wherein the carbon atoms of 6-7 dotted line does not represent a further bi bond and Z represents a group of formula II wherein X is a hydrogen atom, an additional valence bond is formed with the benzoquinone derivatives at the 6 (7) position of the sterane backbone and / or, if desired, a 2-4 carbon thiolcarboxylic acid is added to the double bond at the 6 (7) position.

In a preferred embodiment, the steroid 17S-spiro-lactone derivatives of Formula I are prepared by reacting the steroid-17S-spiro-oxirane derivatives of Formula IV with diethyl malonate in the presence of a base. The base is preferably a lower alkali metal alcoholate, preferably sodium ethylate, but also an alkali metal amide such as sodium amide or an alkali metal hybrid such as sodium hydride may be used. ..

The new spirolactone derivatives thus prepared contain an alkoxycarbonyl group on the carbon atom 21. Hydrolysis and decarboxylation of this group according to the invention by heating in an organic solvent, preferably toluene, in the presence of gg of water, preferably 80-130 ° C.

C, under pressure.

Also included in the process of the invention are transformations to form an additional conjugated double bond on the spirolactone molecule. A preferred embodiment is the oxidation of 2,2-dimethyl-3-oxo-4-ene-type spiro-lactone derivatives with chloranil to form a 6 (7) double bond.

Also included in the process of the invention are modifications to introduce a sulfur-containing substituent on the carbon atom of the sterane backbone. These derivatives are preferably prepared from 2,2-dimethyl-3-oxo-steroid-4,6-diene-17S-spiro-lactones by addition of thiolcarboxylic acid. Addition is done by heating excess reagent.

The starting compounds of the process of the invention, the 2,2-dimethylsteroid-17S-spirooxiranes of formula IV, are novel compounds. Preferably, these compounds can be prepared from the corresponding 17S-spirooxiranes by known methods of sterol chemistry (see, e.g., Fried, J., Edwards, I.A., Organic Reactions in Steroid Chemistry,

Volume 2, page 92; V.N. Reinhold Comp., New York, 1972) wherein methyl iodide is methylated at low temperature, preferably below -30 °, in the presence of potassium tert-butylate.

The antimineralocorticoid (aldosterone inhibitor) activity of the novel steroid 17S-spirolactone derivatives of the present invention was tested in rats according to Kagawa (C.M. Kagawa et al., J. Pharmacol. Exp. Ther. 126, 123 (1959)). The results for the compounds of Examples 2, 3, 4, 6 and 15 are summarized in Table 1.

Rats were sacrificed 18 hours prior to treatment. At the same time as the test substance, deoxycorticosterone acetate (DOCA) supplemented with an aldosterone effect was added and the Na ⁺ - and K ⁺ content of the rats' urine was determined by flame photometry. Spironolactone (17-alpha-carboxyethyl-17-betahydroxy-7-alpha-acetylthio-androst-4-en-3-one-lactone) was used as a reference substance at 0.5 mg / animal po.

Evaluation was based on log values (λ 2 ≤ 12). K ⁺

The results are shown in the table.

The mineralocorticoid effect of DOCA was suspended by each compound. Particularly preferred was the compound of Example 2, which achieved the efficacy of Spironolactone.

Table 1

Investigation of antimineralocorticoid activity in rats according to Kagawa

The example Dose N Urine number mg / animal p. 0th 1 (Na-XH ', K ⁺ .

Second 0.5 8 1.21 Third 0.5 8 0.99 4th 0.5 8 1.06 6 0.5 6 0.94 15th 0.5 6 0.94 DOCA 28 0.78 Spirono- lactone 0.5 21 1.21 •Comment.· each experimental animal was 12.5 pg / animal s.c. DOCA given,

N = number of animals

The following examples illustrate the method of the present invention.

Example 1

2.2-Dinethyl-3-oxo-21 H -ethoxycarbonyl-17α-pregn-4-ene 21,17-carbolactone

3.8 g of 2,2-dimethyl-3-oxo-4-androstene-17S-spirooxirane are dissolved in a solution of 0.54 g of sodium in 35 ml of dry ethanol and 4.7 g of diethyl malonate are added. The reaction mixture was refluxed for 4 hours and then added to a solution of 17.5 gammonium chloride in 88 ml of water with stirring at room temperature. After stirring for one hour, the product was isolated by filtration. The crude air dry product was recrystallized from methanol to give 3 g of the title compound.

M.p .: 157-160 ° C; α] _D : + 14.56 ° (c = 0.5, chloroform)

EtOH 240 nm (ε = 180) max ^k

The starting material of this example, 2,2-dimethyl-3-oxo-4-androstene-17S-spirooxirane, can be prepared as follows:

2,2-Dimethyl-3-oxo-4-androstene-17S-spirooxiran g 3-oxo-4-androstene-17S-spirooxiran [Z. Chem. 18, 259 (1978)] was dissolved in a mixture of 30 ml of tetrahydrofuran and 17.4 ml of methyl iodide. The solution was cooled to -70 ° C and a cooled suspension of 8.3 g of potassium tert-butylate in 46 ml of tetrahydrofuran under nitrogen was added with stirring, so that the temperature did not rise above -60 ° C. The reaction mixture was stirred for half an hour at -60 ° C and then poured into 800 ml of water. The product was extracted with dichloromethane and the solution was washed with water, dried over magnesium sulfate and evaporated. The residue was recrystallized from isopropyl ether to give 2.91 g of the title compound.

140-141 ° C; [α] D: + 34.4 °, (c = 0.5, chloroform) δ: 239 nm (e = 14 700)

Example 2

2.2-Dimethyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone 3 g of 2,2-dimethyl-3-oxo-21β-ethoxycarbonyl-17α-pregn-4- obtained in Example 1 were obtained. To a solution of en-21,17-carbolactone in 57 ml of toluene was added 3 ml of water and heated in a steel bomb at 120-130 ° C for 24 hours. The solvent was evaporated in vacuo and the residue was evaporated twice with 10 ml of ethanol. The crude product obtained is recrystallized from a 2: 1 mixture of isopropyl ether-acetone. Recrystallization gave 1.5 g of the title compound.

95-100 ° C; [a] D: + 40.2 ° (c = 0.5, chloroform) ^x m x ^{L? 239 nni (£ = 14 7θθ)}

Example 3

2.2-Dimethyl-3-oxo-21β-ethoxycarbonyl-17α-pregna-4,6-diene-21,17-carbolactone

3.8 g of 2,2-dimethyl-3-oxo-4,6-androstadiene-17S-spirooxirane, 0.54 g of sodium and 35 ml of dry ethanol, and

4.7 g of diethyl malonate were used as in Example 1. The crude product obtained is recrystallized from ethanol. Yield: 3.1 g.

193-195 ° C; [α] β: -37.10 ° (c = 0.5, chloroform) ^λ Εί ^"Η °: 281 nm (e = 25,330) max

The 2,2-dimethyl-3-oxo-4,6-androstadiene-17S-spirooxirane starting material of this example may conveniently be prepared as follows:

2,2-dimethyl-3-oxo-4,6-andorsztadién-17S-spiro-oxirane

From a solution of 4.32 g of 3-oxo-4,6-androstadiene-17S-spirooxirane (German Patent No. 2,404,947) dissolved in 36 ml of tetrahydrofuran using a suspension of 18 ml of methyl iodide and 9 g of potassium tert-butylate in 50 ml of tetrahydrofuran. All procedures were carried out in the same manner as in the starting material of Example 1. The crude product (4.48 g) obtained by evaporation was chromatographed on a column of 450 g of silica gel with benzene-ethyl acetate (7: 3). Concentrate on a -G thin layer benzene-ethyl acetate (7: 3) to give a mixture of Rf: 0.68] and combine to give 3.58 g of a residue which is recrystallized from methanol.

Mp 200-202 ° C; [α] _D : + 11.40 ° (c = 0.5, chloroform)

X ^EtOH : 281nm (e = 25,400) max ^{v J}

Example 4

2,2-Dimethyl-3-oxo-17a-pregna-4,6-diene-21,17-carbolactone

1.5 g of 2,2-dimethyl-3-oxo-21E-ethoxycarbonyl-17α-pregna-4,6-diene-21,17-carbolactone prepared in Example 3

To a solution of 28.5 ml of toluene is added 1.5 ml of water and the procedure of Example 2 is followed. The received

The crude product (1.32 g) is chromatographed on a column of 130 g of silica gel with c-hexane-ethyl acetate (1: 1). The fractions containing the main product (0.05 mm layer on Kieselgel-G thin layer in c-hexane-ethyl acetate (1: 1) developing mixture Rf: 0.55) were evaporated to give 1.02 g of crude product which was purified by filtration with isopropyl ether.

M.p. 165-168 ° C; [α [ρ: 0 ° (c = 0.5, chloroform)

X ^EtOH : 282nm (e = 25,300) ma *

Example 5

19-Nor-2,2-Dimethyl-3-oxo-21H-ethoxycarboml-17a-pregna-4-ene-21,17-carbolactone

2.2 g of 19-nor-2,2-dimethyl-3-oxo-4-androstene-17S-spirooxirine, 0.33 g of sodium and 25 ml of dry ethanol, and

Using 2.86 g of diethyl malonate, the procedure of Example 1 was followed. The crude product was recrystallized from ethanol

1.43 g of the expected product are obtained.

Mp 164-167 ° C; [α] β: -15.3 ° (c = 0.5 in chloroform) λ ^Εί θ ^Η : 238nm (e = 16900) '- IIIA

The starting material of this example, 19-nor-2,2-dimethyl-3-oxo-4-androstene-17S-spirooxirane, is conveniently prepared as follows:

19-Ncr-2,2-dimethyl-3-oxo4-an, drostene-17S-spirooxiran

2.86 g of 19-nor-3-oxo-4-androstene-17S-spirooxirane.

188 995 (Pharmazie 33, 792 (1978)), a suspension of 24 ml of dry tetrahydrofuran, 12 ml of methyl iodide and 5.44 g of potassium tert-butylate in 27 ml of tetrahydrofuran are prepared according to the starting material of Example 3, except that the crude product is chromatographed by pooling the pure fractions eluted second from the column (Rp0.63 in 0.05 mm Kieselgel-G thin layer benzene-ethyl acetate (7: 3)).

The crude product obtained by evaporation of the combined fractions was recrystallized from ethanol to give 0.96 g of the title compound.

160-161 ° C; [α] D: + 27.6 ° (c = 0.5, chloroform) ^λ ma ° ^{H; 237 nm} (e = ¹⁰⁰ ° O) _{1 g}

Example 6

19-Nor-2,2-Dimethyl-3-oxo-17a-pregn-4-ene-21,17-carbolactone

2.8 g of a solution of 19-nor-2,2-dimethyl-20 -3-α-21β-ethoxycarbonyl-17α-pregn4-ene-21,17-carbolactone prepared in Example 5 in 53 ml of toluene, Water (8 ml) was added and the procedure of Example 2 was followed.

The crude product (2.09 g) was recrystallized from methanol. Yield: 1.35 g of the title compound. 25

M.p. 167-170 ° C; [α] D: + 14.7 ° (c = 0.5, chloroform) ^λ max ^{H: 238 nm} ( ^{e = 1600} °)

Example 7 3Q

19-Nor-2,2-Dimethyl-3-oxo-21% -ethoxycarbonyl-17α-pregna-4,6-diene-21,17-carbolactone

Using 2.5 g of 19-nor-2,2-dimethyl-3-oxo-4,6-androstadiene-17S-spirooxirane, 0.36 g of metal sodium in 25 ml of dry ethanol and 3.16 g of diethyl malonate, We follow 35 steps. The crude product was dissolved in ethanol (200 mL), warmed with charcoal and concentrated in vacuo to one third of its volume.

Recrystallization of 1.6 g of crude product from the solution yielded 1.35 g of pure title compound, m.p.

Mp 203-204 ° C; [α] D: -98.7 ^δ (c = 0.5, chloroform) ^λ maT ^{: 281nm} (ε = ²⁴⁹⁰ °)

The starting material of this example, 19-nor-2,2-dimethyl-3-oxo-4,6-andorstadiene-17S-spirooxirane, is conveniently prepared as follows:

19-Nor-2,2-Dimethyl-3-oxo-4,6-androstadiene-17S-spirooxirane 50

1.65 g of 19-nor-3-oxo-4,6-androstadiene-17S-spirooxirane (German Patent No. 2,440,947), 14 ml of dry tetrahydrofuran, 6.5 ml of methyl iodide and 3.2 Using a suspension of potassium tert-butylate (28 g) in tetrahydrofuran (28 mL), the starting material of Example 3 was prepared. The crude product obtained is recrystallized from Rf: 0.70] θθ in ethyl acetate in a 0.05 mm layer of Kieselgel-G thin layer benzene ethyl acetate (7: 3). Yield: 1.35 g of the expected product.

M.p .: 165-168 ° C; [?] D: -45.7 ° (e = 0.5, chloroform) λ ^ ^θ Η: 281 nm (6 = 25 500) ₆₅

Example 8

19-Nor-2,2-dimethyl-3-oxo-17a-pregna-4,6-diene-21,17-carbolactone

To a solution of 1.79 g of 19-nor-2,2-dimethyl-3-oxo-21β-ethoxycarbonyl-17α-pregna-4,6-diene-21,17-carbolactone prepared in Example 7 in 24 ml of toluene was added 1.7 ml of water. and then proceed as in Example 2 above. The crude product was recrystallized from ethyl acetate to give the title compound (1.02 g).

Mp 226-227 ° C; [?] _D: -66.3 ° (c = 0.5, ^chloroform)? max ^{= h; 280 nm (ε = 2S 700)}

Example 9

18-Homo-19,9-nor-2,2-dimethyl-3-oxo-21β-oxoxycarbonyl-17α-pregn-4-ene-21,17-carbolactone

Using 1.5 g of 13 N-ethyl-2,2-dimethyl-3-oxo-4-gonene-17S-spirooxirane using 0.2 g of metal sodium and 20 ml of dry ethanol and 1.87 g of diethyl malonate as in Example 1. except that the reaction mixture is refluxed for 36 hours. The crude product was extracted with dichloromethane and the water-washed extract was dried over magnesium sulfate and evaporated. The evaporation residue was purified by column chromatography on silica gel (200 g) with c-hexane-ethyl acetate (1: 1). 0.88 g of the title compound is obtained (Rf: 0.6) in a silica gel developing layer (0.05 mm silica gel, c-hexane-ethyl acetate (1: 1)), which is recrystallized from isopropyl ether.

M.p. 163-166 ° C; [α] D: -74.2 ° (c = 0.5, chloroform) λ ^Ε ι ^ί θ ^Η : 238ηιη (ε = 17,500)

ΠιαΧ

The starting material of this example, 130-ethyl-2,2-dimethyl-3-oxo-4-gonene-17S-spirooxirane, is conveniently prepared as follows:

13 / i-ethyl-2,2-dimethyl-3-oxo-4-ene-17S-spiro-oxirane

The step

13β-ethyl-3-oxo-4-gonene-17S-spiro-oxirane

14.8 g of 13β-Cetyl-17α-chloroethyl-17β-hydroxy-4-gonene-3-ore (Pharmazie 33, 792, 1978) are dissolved in 440 ml of methanol and 4.41 g of sodium hydroxide in 79 ml of methanol and 9 ml of water are stirred. After stirring for 10 minutes, the reaction mixture is poured into 900 ml of ice-water and stirred until the precipitate is filtered off. The crude product is filtered, washed with water to neutral and recrystallized from 80% aqueous methanol. 10.02 g of the title compound are obtained, m.p. 145-146 ° C, [α] _D : 48.1 ° (c = 0.5, chloroform).

The L239 ^EtOH nm (e = 15,400) ^v max

Step B.

13β-ethyl-2-2, dimethyl-3-oxo-4gonene-17S-spiro-oxiran 5.25 g of 13β-ethyl-3-oxo-4-gonene-17S-spiro-oxiran from Step A, 42 using a slurry of dry tetrahydrofuran (19.5 mL), methyl iodide (19.5 mL) and potassium tert-butylate (952) in tetrahydrofuran (47 mL), the title compound of Example 5 was used, except that the resulting product was subjected to a silica gel column.

-4188995

Chromatography is carried out with a mixture of cyclohexane-ethyl acetate (8: 2). Pure fractions of the second eluted material (Rf: 0.45 in 0.02 mm Kieselgel-G thin film developing c-hexane-ethyl acetate (8: 2)) were combined. The crude product obtained by evaporation of the combined fractions was crystallized from methanol. 1.52 g of the title compound are obtained.

170-172 ° C; [α] _D : + 46.2 ° (c = 0.5, chloroform)

X ^{Et 0H} : 238nm (e = 15,600) max ^v '

Example 10

18-Homo-19-nor-2,2-dimethyl-3-oxo-17a-pregn-4-ene, 21,17-carbolactone

1.18 g of 18-homo-19-nor-2,2-dimethyl-3-oxo-21E-ethoxycarbonyl-17α-pregn-4-ene-21,17-carbolactone prepared in Example 9 are 22 ml. in toluene

Water (2.2 ml) was added and all proceeded as in Example 4 except that the reaction mixture was heated for 40 hours. The crude product obtained by chromatography [Kieselgel-G (0.05 mm thin layer, cyclohexane-ethyl acetate (1: 1)) Rf 0.6] is purified by filtration with isopropyl ether. Yield: 0.7 g

Mp 212-214 ° C; [α] _D : + 31.6 ° (c = 0.5, chloroform) ^{Et Et} : ^H : 238 nm (δ = 15,500)

IlldA.

Example 11

18-Homo-19-nor-2,2-dimethyl-3-oxo-211-ethoxycarbonyl-17-ol-pregna-4,6-diene-21,17-carbolactone

2 using 2 g of 13β-ethyl-2,2-dimethyl-3-oxo-4,6-gonadiene-17S-spirooxinan, 0.31 g · of sodium metal and 20 ml of dry ethanol and 2.72 g of diethyl malonate The crude oily product was extracted with dichloromethane and the water-washed extract was dried over magnesium sulfate and evaporated to give 1.04 g of the title compound.

Mp 168-172 ° C; [α] D 20 -110.7 ° (c = 0.5, chloroform) ^λ max ^{H: 281nm (e = 23 50} °)

The starting material of this example, 13 (3-ethyl-2,2-dimethyl-3-oxo-4,6-gonadiene-17S-spirooxirane) is conveniently prepared as follows:

130-Ethyl-2,2-dimethyl-3-oxo-4,6-gonadiene-17S-spirooxirane

13β-Ethyl-3-ethoxy-3,5-gonadiene-17S-spirooxiran 7 µg of 130-ethyl-3-ethoxy-3,5-gonadiene-17-one (U.S. Patent 3,471,531) 90 suspended in ml of dried dimethylformamide and

18.2 g of trimethylsulfonium iodide are added. 28.75 g of potassium tert-butylate are added with stirring at 20-22 ° C. Stir at room temperature overnight and then pour into 900 ml of 10% aqueous saline. After stirring for one hour, the precipitate was filtered off and washed with water. After drying, 6.9 g of crude product are obtained, m.p. 139-142 ° C, which is used without further purification for Step B.

Step B.

13β-β-Benzo-3-oxo-4,6-gonadiene-17S-spirooxirane g, 130-Ethyl-3-ethoxy-3,5-gonadiene-17S-spirooxirane from Step A, 71 mL of acetone and 4 mL. of water (3.75 g). The suspension was stirred under light exclusion for 3 hours and then poured into water (240 mL, 5 mL of 30% aqueous sodium hydroxide). After stirring for one hour, it is filtered, washed with water to neutral and dried. The crude product (4.3 g) was recrystallized from ethyl acetate. Yield: 2.4 g.

145-148 ° C; [.alpha.] D @ 25: -35.6 DEG (c = 0.5, chloroform)

282 nm (δ = 27,240)

Step C.

13-ethyl-2,2-dimethyl-3-oxo-4,6-gonadiene-17S-spirooxirane 3.44 g of 13 (3-ethyl-3-oxo-4,6- Using a suspension of gonadiene-17S-spiro-oxirane, 28 ml of dry tetrahydrofuran, 13 ml of methyl iodide and 6.3 g of potassium tert-butylate in 32 ml of tetralohydrofuran, all proceed according to the procedure for the starting material of Example 3. The product was recrystallized from ethyl acetate in a 0.05 mm thin layer of Kieselgel-G thin layer benzene / ethyl acetate 7: 3 Rf: 0.65 to yield 2.57 g, mp 164-167 ° C; ρ: -49.7 ° (c = 0.5, chloroform) λ ^Εί θ ^Η : 282 nm (ε = ^25,900 )

ΓΙ SdX

Example 12

18-Homo-19-nor-2,2-dimethyl-3-oxo-17a-pregna-4,6-diene-21,17-carbolactone

5.8 g of 18-homo-19-nor-2,2-dimethyl-3-oxo-21E-ethoxycarbonyl-17a-pregna-4,6, diene-21,17-carbolactone prepared in Example 11 are 110 ml. 5.8 ml of water was added to a solution of toluene and all of the procedure of Example 4 was repeated except that the reaction mixture was heated for 32 hours. The product obtained by chromatography (Rf 0.58 Rf 0.58 in a developing solvent of c.hexane-ethyl acetate (1: 1) on a thin layer of Kieselgel-G, 0.05 mm) was recrystallized from ethyl acetate to give 3 g of crystalline title compound.

. Mp 204-205 ° C; [α] β: -50.0 ° (c = 0.5, chloroform) λ ^Εΐ θ ^Η : 281ηητ (6 = 25 300) π »ax

Example 13

2,2-Dimethyl-oxo-7a-acetylthio-17a-pregn-4-ene-21,17-carbolactone g 2,2-Dimethyl-3-oxo-17? (-Pregna-4,6- The diene-21,17-carbolactone was suspended in a mixture of methanol (3.6 ml), thioacetic acid (4.3 ml) and water (0.4 ml), heated in a water bath for 1 hour, diluted with methanol (10 ml) and poured into ice-water (10 ml). After extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate and evaporated to give the crude product which was crystallized from methanol (1.26 g).

Op .: 270-271 «

Mp 270-271 ° C; [α] β: -85.9 ° (c = 0.5, chloroform) λ ^ ^θ Η: 236 nm (? = 18140)

Example 14] 9-Nor-2,2-Dimethyl-3-oxo-7a-acetylthio-17a-pregn-4-ene-21,17-carbolactone

1.5 g of 19-nor-2,2-dimethyl-5 prepared according to Example 8

188,995

The oxo-17α-prggna-4,6-diene-21,17-carbolactone was suspended in a mixture of 2.8 ml of methanol, 3.35 g of thioacetic acid and 0.3 ml of water and heated on a water bath for 1 hour.

The solvent was evaporated under reduced pressure and. the residue was evaporated 3 x 10 ml of ethanol. The crystalline crude product is recrystallized from methanol by charcoal clarification. Yield: 0.82 g.

Mp 222-224 ° C; [α] ρ: -85.5 ° (c = 0.5, chloroform) λ · ^Εί ° ^Η : 236nm (6 = 19,700) in max ^{7, υ}

Example 15

18-Homo-19-nor-2,2-dimethyl-3-oxo-7a-acetylthio-17a-pregn-4-ene-21,17-carbolactione

1.56 g of 18-hoino-19-nor-2,2-dimethyl-3-oxo-17a-pregna-4,6-diene-21,17-carbolactone prepared in Example 12,

Using the procedure of Example 14 using 3.5 ml of thioacetic acid, 2.8 ml of methanol and 0.3 ml of water. The residue was triturated with diisopropyl ether, filtered and recrystallized from acetonitrile. 0.86 g of 2θ pure title compound is obtained, containing one mole of acetonitrile as a crystalline solvent.

Mp 128-130 ° C; [.alpha.] D @ 20: -70.0 DEG (c = 0.5, chloroform)

FtOH 25 ^A max ^{: 2} 36 nm (6 = 20,900)

Claims (2)

A process for the preparation of new steroid spirolactones of the formula I wherein: R ¹ is hydrogen or methyl, R ² is C 1-3 alkyl, R ³ is hydrogen or C 2 -C 4 alkanoylthio, Z is a group of Formula II, wherein X is hydrogen or C3 -C4 alkoxycarbonyl, the dotted line between 6 and 7 carbon atoms may represent an additional valence bond, provided that when the dotted line between 6 to 7 carbon atoms is is an additional bond, then R ³ is a hydrogen atom only, wherein a dotted line between R ', R ² and C 6-7 is as defined above, with a base being present as a base. with a C 1-3 dialkyl ester and optionally forming a compound of formula I wherein Z is a group of formula II wherein X is a C 2 -C 4 alkoxycarbonyl group, R ¹ , R ² and a the dotted line is as defined above and R ² is hydrogen, heated in the presence of water and then optionally en on a compound of formula I wherein R ¹ , R ² are as defined above and R ³ is hydrogen, wherein the dotted line between 6 and 7 carbon atoms does not represent an additional valence bond and Z 'represents a group of formula II wherein X is hydrogen, an additional valence bond is formed with a benzoquinone derivative at the 5 (7) position of the sterane backbone and / or, if desired, a C 2-4 thiolcarboxylic acid is added to the 6 (7) position double bond. A process for the preparation of a dhircicidal pharmaceutical composition comprising the compound of the formula I as claimed in claim 1, alone or in combination with other compounds having no similar synergistic effect with the compounds of the general formula I, optionally as a carrier. in combination with a surfactant, flavoring agents, to form a medicament in the form of tablets, capsules, pills, suppositories, emulsions, suspensions, solutions for injection.