DE3306121A1 - 11 beta -Arylspirolactones in the steroid series, process for the preparation thereof and pharmaceutical products containing these compounds - Google Patents

Abstract

11 beta -Arylspirolactones in the steroid series of the general formula I <IMAGE> in which R1 is <IMAGE> with R<I> and R<II> meaning in each case alkyl with 1 to 4 carbon atoms or R<I> and R<II>, with the inclusion of N, meaning a 5- or 6-membered saturated heterocyclic ring, it being possible for the ring to contain, besides N, also another hetero atom N, O or S, and the corresponding N-oxides, -SR<III> with R<III> meaning methyl, ethyl or phenyl and -OR<IV> with R<IV> meaning methyl, ethyl, propyl, methoxymethyl, allyl or beta -dimethylaminoethyl, R2 is a hydrogen atom, a methyl or ethyl group and <IMAGE> or <IMAGE> where the wavy lines &tilde& &tilde& &tilde& indicate that the substituent is in the alpha or beta position and <IMAGE> is <IMAGE> or <IMAGE>, with M = K, Na or Li and R<V> and R<VI> are each alkyl with 1 to 4 carbon atoms Original abstract incomplete.

Description

The invention relates to new 11ß-aryl spirolactones in the Series of steroids, processes for their production and pharmaceutical preparations containing these compounds according to of the claims.

11ß-aryl steroids are already known. For example 11β-Aryl-17a-propynyl- and -ethynyl-4,9 (10) -estradienes in European patent application 82400025.1 (publication no. 0057115) as compounds with antigestagens and antiglucocorticoid effects.

It has now been found that the new compounds of the general formula I are antigestagens and antimineralcorticoids Have effects. The simultaneous occurrence of antigestagenic and antimineralcortxcoid effects one substance has not yet been described. Surprisingly, the two effects occur in the case of the new compounds, even when administered orally, in comparison with the compounds of the prior art Technique comparable strength of action, with some compounds according to the invention the antigestagens and in others the antimineralcorticoid effect predominates. The new compounds of general formula I. are thus in principle both for fertility control as well as for the treatment of primary hyperaldosteronism.

The antimineralcorticoid effect was determined in the antialdosterone test. In this test, adrenalectomized Wistar rats substituted with fluocortolone and fluocortolone caproate were treated with 1.0 - 2.0 - 4.0 mg of test substance per animal. The test substance was administered orally as a crystal suspension in NaCl / Myrj 53. One hour after application, the animals received a
Continuous intravenous infusion of physiological saline solution with an addition of 0.15 μg of aldosterone per animal per hour. From the third to the tenth hour, Na and K salt excretion were measured every hour, and es
the Na / K quotient and the log Na (100) / K quotient were determined.

The test substances according to the invention were used
11β- (4-Dimethylaminophenyl) -17β-hydroxy-17a- (3-hydroxypropyl) -4,9 (10) -estradien-3-one (A) and the known
Spironolactone (B).

In the following table 1 the Na / K and
log Na (100) / K quotient as well as the relative antialdosterone effects (RW) of A based on B = 1
compiled.

-y-

η ν β φ 0 H H η 0 Φ Ό H (Q • Η (B. ■ Ρ 5

(mg) ο vO jf cn CM CM tv. CA O 03 _ ■ * [ν. O CM * ~ CM CM CM VO O cn ο CA τ— tv. Jf cn 01 Jf CM cn cn cn cn CM CM CM cn CM CM cm CM CM O O VO co CO VO CA O ΙΛ CM O O co co CO bO CM CM CM CM <" - O
O S. CA Jf tv. ΙΛ VO O ΙΛ O Jf O cn tv. ΙΛ ΙΛ Jf < Jf Al CM (P
bO CO O O cn CM CA tv. tv. O (M I ^s - ΙΛ CM cn cn cn cn cn CM CM CM CM CM CM CM c? O CM CM 30th vO jf cn VO O Jf co r— «- O\ CA ON -. CM CM CM CM , _ _r _ , _ CM O O O cn CA IV. __ ON CA τ— Γν- CO tv. CO co • ^
fen CM tv. S. O ΙΛ cn VO ΙΛ tv. tv. VO η Jf CA ON cn CA CA O O «- O O CA O O τ— τ— O cn cn vo T— Jf tv. cn en . CM CM ΙΛ cn VO cn cn vO VO Jf ON cn cn cn cn (M O CA ON ON ΙΛ tv. _T _ fv. CO * - cn O VO ΙΛ T— ON O M. B. ΙΛ CM »- ^ r- O T- O O cn CM Jf Jf __ ΙΛ O (Q Jf cn tv. cn CA CO in VO Jf cn <- O O O O O O Jf ON Jf O tv. Jf Ό CM ΙΛ τ— CM cn ΙΛ = 0 -μ VO ■ * CM cn cn cn cn CM O VO VD CO CA ΙΛ CM VD CA τ— vO CO O ΙΛ O ON O ΙΛ CM T— τ—. <- O cn ΙΛ VO CA Jf CM vO cn ON tv. CO CO CO ON CM O O O O O O cn Jf VO tv. co CA O

The table shows that compound A according to the invention has about the same effectiveness as spironolactone.

To characterize the antigestagens effect, the abortive effect was determined.

The experiments were carried out on female rats weighing approx. 200 g. After mating was successful the onset of pregnancy is confirmed by the detection of sperm in vaginal smears. The day of the sperm detection counts as day 1 of pregnancy (= d1 p.c.).

The treatment of the animals with the respective to be tested The substance or the solvent took place after the nidation of the blastocysts from d5 p.c. up to d7 p.c. At d9 p.c. the animals were sacrificed and the uteri examined for implants and resorption sites. Photographs were taken of all uteri. The absence of implants was counted as an abortion.

The test substances were in a benzyl benzoate-castor oil mixture (Ratio 1 + 9) solved. The vehicle volume per single dose was 0.2 ml. The treatment took place subcutaneously.

Test substances were compound A according to the invention and 11β- (4-dimethylaminophenyl) -17β-hydroxy-17a- (propyn-1-yl) -4,9 (10) -estradien-3-one described in European patent application 82 400 025.1 (C).

Table 2

Abortion test in the pregnant rat

dose

Substance mg / animal / day η abortion-positive / η total

s. c.

10.0 k / k

3.0 k / k

1.0 0 / k

3.0 k / k

1.0 2 / k

0.3 0 / k

From Table 2 it can be seen that both the compound A according to the invention and the known compound C in a dose of 3.0 mg is fully effective in abortion.

In contrast, the compounds according to the invention have to the known compound C not antiglucocortxcoxde, but antitnineralcorticoid side effect. In the Use of the compounds according to the invention as antigestagens for the termination of pregnancies or for the early induction of menstruation is an antimineralcorticoide Effect not harmful and even desirable in cases of primary hyperaldosteronism.

Treatment of certain forms of primary aldosteronism, hypertension, edema and others Aldosterone related disorders may also be the main area of application the connections of the general

Formula I be.

The invention also relates to pharmaceutical preparations which contain compounds of the general formula I.

The pharmacologically active compounds according to the invention of the general formula I can be pharmaceutical according to known methods of galenics Preparations for oral or parenteral administration are processed.

The dosage of the compounds according to the invention is 10 to 1000 mg per day in humans.

In the compounds of general formula I, the aryl radical in the 11β-position of the steroid structure is a _{phenyl radical substituted by R 1} in the para-position

I I II

R is ■ R, R and R are alkyl groups

having 1 to k carbon atoms, the methyl and ethyl groups being preferred. The group R also stands

for a saturated heterocyclic five- or six-membered ring, which in addition to N and C atoms also has one May contain O or S atom; Examples include the pyrrolidino, piperidino, piperazino, Morpholino, oxa and thiazolidino and thiadiazolidino rings. The corresponding

N-oxides are understood, such as dimethylamino-N-oxide, Pyrrolidino, piperidino, piperazino, etc. N-oxide.

V VI
The radical represented by R or R in formula I is an alkyl radical having 1 to 4 carbon atoms, preferably the methyl or ethyl radical.

The new compounds of the general formula I are according to the invention by the process according to claim 12 manufactured.

The process is characterized in that compounds of the general formula II are used to split off water with formation of the 4 (5) double bond and at the same time Ketal cleavage and removal of any existing ones further protective groups which can be split off with acid are treated with acid or an acidic ion exchanger.

-X-

The acidic treatment is carried out in a manner known per se, by adding the compound of the formula II which has a 3-ketal group and one 5 <x -hydroxy group and one optionally O-protected 17ct- (3-b.ydroxypropyl) group contains, in a water-miscible solvent, such as aqueous methanol, ethanol or acetone, dissolves and the solution catalytic amounts of mineral or sulfonic acid, such as hydrochloric acid, Sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid or an organic acid such as Acetic acid, left to act until water has split off and protective groups have been removed. The implementation, which takes place at temperatures from 0 to 100 C, can also be carried out with an acidic ion exchanger. The course of the reaction can be taken with analytical methods, for example by thin layer chromatography Samples to be tracked.

If end products of the formula I are desired in which Y is for

stands, the 17ct- (3-hydroxypropyl)

OH J (CH) -CH OH) s., · ZZ 2

Connections (Y => r 'in per se

known to be oxidized. The conditions for the oxidation depend on the nature of the substituent R ₁ in formula I. The person skilled in the art will decide on a case-by-case basis which of the known methods is suitable and which is out of the question. If R _{1 is,} for example, a dialkylamino or alkylthio radical, then chromic acid reagents are unsuitable for the oxidation, since they primarily attack the dialkylamino or alkylthio group. In these cases, oxidizing agents such as silver carbonate / Celite (Fetizon reagent; M. Fetizon and M. Golfier, Compt. Rend. 267 (1968) 900) or platinum / oxygen (H. Muxfeldt et al., Angewandte

Chemistry, Int. Ed. 1 (1962) 157) can be used. If, _{on the other hand, R 1 is} an alkoxy group, then oxidizing agents such as Jones ¹ reagent, chromic acid pyridine, pyridinium dichromate or pyridinium chlorochromate can also be used.

If end products of the formula I are desired in which Y is .XCH ₂ ) ₂ -C00M

with M = alkali metal, so will

the 17-spirolactones (Y = / ~~~~ \ ) also in

implemented in a known manner. For this purpose, the lactone is treated with dilute alkali lye, whereby the alkali salt is which forms 17a-propionic acid. Alkali salts are potassium, Sodium or lithium salts, the potassium salt being preferred.

The starting compounds of the general formula II required for carrying out the process according to the invention contain the grouping OH / (CH ₀ J ₀ -CH ₀ OR,

Y =

where R is a hydrogen atom or in an acidic medium represents an easily split off group. Alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, or ring-closed ethers such as tetrahydropyran.

The preparation of the starting compounds of the general formula II should be based on the following reaction scheme explained:

X "= X with Y =

- fl

OH

.CH ₂ -CH ₂ -CH ₂ OR

(II)

OH CH ₂ -CH ₂ -CH ₃ OR

- x

CHC-CH ₀ OR

HO, CSC-CHgOR

CSC-CH ₂ OR

Oxiranes (1) according to European Patent Application No. 82 ^ 00025.1 (Publication No. 0057115) are converted to 17cc- / 3 with metalated derivatives of propargyl alcohol, for example with 1-lithium-3-tetrahydropyran-2'-yloxypropyne-1 -oxygenated-1-propynyl7-1? ßhydroxy compounds (2) implemented. The 11β-aryl radical to (3) is introduced either by a Cu (I) -catalyzed Grignard reaction with the corresponding aryl magnesium halides (Tetrahedron Letters 1979, 2051) or by reaction with mixed organocuprates of the type R ₃ Cu (CN) Li ₂ ( J. Am. Chem. Soc. 103 (1981) 7672). The hydrogenation of (3) to the starting compounds (II) must be carried out under conditions which ensure attack only on the CC triple bond without saturating the tetrasubstituted 9 (10) double bond. This succeeds, for example, when hydrogenation is carried out at room temperature and normal pressure in solvents, methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate, with the addition of noble metal catalysts such as platinum or palladium.

-X-

The preparation of some starting compounds of the general formula II is explained in more detail below:

a) To a solution of 35 »7 g of 3-tetrahydropyran-2 ■ yloxy-1-propyne 208 ml of a 15% strength are added dropwise to 760 ml of absolute tetrahydrofuran while cooling with ice water Solution of n-butyllithium in hexane. After the addition, the mixture is stirred at +5 to +10 ° C. for a further 15 minutes and then add dropwise a solution of 23.7 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a, 10a-oxido-9 (11) -estren-17-one in 470 ml of absolute THF added. The mixture is then stirred for 20 minutes at 25 C, then the reaction solution is poured into about 5 liters Ice water and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate / activated charcoal and concentrated in vacuo. After, filtration over aluminum oxide with hexane / ethyl acetate as eluent 29 »3 g of 3i3- (2,2-dimethyl-propane-1 , 3-dioxy) -5a, IOoc-oxido-1 7a- / 3- (tetrahydropyran2-yloxy) -1-propynyl7-9 (11) -estren-17β-ol as a colorless oil.

b) A suspension of 5 »28 g of magnesium (shavings) in 275 ml of absolute THF is successively mixed with 0.05 ml of methyl iodide and a solution of 50.27 g of 4-bromodimethylaniline in 245 ml of absolute THF. The mixture is stirred in an argon atmosphere until the magnesium has completely dissolved, the internal temperature not exceeding 50.degree. It is then cooled to +5 C, the Grignard solution are added 1.12 g of CuCl and stirred for 15 minutes at +5 - +10 C. Thereafter, a solution of 29.3 S d is ^there under a) the product obtained in 275 ml of absolute THF were added dropwise and the mixture was stirred at room temperature for 5 hours. The reaction solution is then poured into approx. 4 l of ice water and extracted with ethyl acetate. The chroma

tography of the crude product thus obtained over aluminum oxide with hexane / ethyl acetate gives 32.6 g 11ß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -17a- / 3- (tetrahydropyran-2-yloxy) -1-propynyl7-9 (iO) -estrene- 5a »17β-diol as a yellowish oil.

c) A solution of 2.0 g of the product obtained under b) in 20 ml of ethanol is hydrogenated after addition of 120 mg of palladium carbon (10%) at room temperature and normal pressure. After 2 hours and an H ₂ uptake of 141 ml, the catalyst is filtered off and the filtrate is concentrated. The crude product obtained in this way is used in Example 1 without further purification.

a) According to 1 a), 22.6 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -18-methyl-5a, 10a-oxido-9 (11) -estren-17-one are used (Melting point 156-158 C) with 1-lithio-3- (tetrahydropyran-2-yloxy) -propine-1 µm and receives 25.4 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) 1 8-methyl-5a, IOoc-oxido-1 7a- / 3- (tetrahydropyran-2-yloxy) -1-propynyl-7-9 (11) -estren-17β-ol as a colorless oil.

b) At 25 ° C., it is first added dropwise to a suspension of 4.3 g of magnesium (shavings) in 40 ml of absolute THF 0.1 ml of methyl iodide, then a solution of 40 g of p-dimethylaminoethoxy-phenylbroraid (prepared according to D. Lednicer et al., J. Med. Chem. JS, 52 (1964)) in 200 ml of absolute THF. The mixture is stirred at a bath temperature until the magnesium has completely dissolved of a maximum of 70 ° C. After cooling to 0 ° C., 820 mg of CuCl are added and the mixture is stirred 20 minutes at 0 C. A solution of 15.9 g of the product obtained under a) in 120 ml

absolute THF was added dropwise. The mixture is stirred for 16 hours 25 C, poured into ice water and extracted with ethyl acetate. Chromatography on alumina (neutral, III) with hexane / ethyl acetate results in 17.1 g of yellowish 01.

c) The hydrogenation of 3Λ S of the product obtained under b) according to 1 c) gives 3, ^ g 11ß- / 5- (2-dimethylaminoethoxy) -phenyl7-3,3- (2,2-dimethyl-propane-1, J- dioxy) -18-methyl-17a- / 3- (tetrahydropyran-2-yloxy) -propyl7-9 (10) -estrene-5a, 17β-diol.

a) From 2.4 g of magnesium in 120 ml of absolute THF and 11.6 ml of 4-bromanisole is described as under 1 b) a Grignard reagent prepared and mixed with 260 mg CuCl. A solution of 6.4 g of the under 1 a) The adducts produced in 80 ml of absolute THF are added dropwise at 0.degree. The reaction solution becomes Stirred for 4 hours at 25 ° C. and worked up as under 1 b). 7/15 g of oily product are obtained.

b) 7.15 g of the product obtained under a) are hydrogenated as under 1 c). 7 »05 g of crude product are obtained, which is used in Example 3 without further purification.

a) From 6.7 g of propargyl tetrahydropyranyl ether in 100 ml of THF and 40 ml of n-butyllithium (15 % in hexane) the organolithium compound is prepared under the conditions of 1 a) and with 4.63 g of 3,3- (2 , 2-dimethyl-propane-1,3-dioxy) -16ß-methyl-5a, 10a-oxido-9 (11) -estren-17-one implemented. After chromatography, 4.22 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -i6β-methyl-50, 10a-oxido-17a / 3- (tetrahydropyran-2-yloxy) are obtained ) -prop-1-ynyl7 ~ 9 (11) -estren-17ß-ol as a crystalline mixture of isomers with a melting point of 156 - 166 ° C.

- lh -

b) From 1.23 g of magnesium turnings in 100 ml of absolute THF, 11.48 g of 4-dimethylaminophenyl bromide in 50 ml of absolute THF, 0.03 ml methyl iodide and 23O mg CuCl a Grignard reagent prepared under the conditions of 1 b) and with 3.55 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -16ß-methyl-5a, IOa-oxido-1 7a- (3-tetrahydropyran-2-yloxy-prop-1-ynyl) -9 (11) -estren-17β-ol implemented. After chromatography, 3 »56 g are obtained 11β- (4-Dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1 , 3-dioxy-16β-methyl-17ct- / 3- (tetrahydropyran-2-yloxy) prop-1-ynyl7-9 (10) -estrene-5α, 17β-diol as an oily mixture of isomers.

c) hydrogenation of 3 »56 g of the product of the Grignard reaction under the conditions of 1 c) gives 3, ^ 2 oily 11β - (^ - dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1 , 3-dioxy) -i6ß-methyl-1 7a- / 3- (tetrahydropyrane-2-yl oxy) -propyl7-9 (10) -estren-5a, 17β-diol

example 1

3- / Tiß- (4-dimethylaminophenyl) -17ß-hydroxy-3-oxo-4, 9 (10) -estradien-1 7oc-yl7-propionic acid lactone

1.96 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-diraethylpropane-1 , 3-dioxy) -1 7oc- / 3- (tetrahydropyran-2-yloxy) propyl7-9 ( iO) -estren-5ct, 17β-diol are in 19 ml 70% aqueous acetic acid added and 3 hours stirred at 60.degree. It is then poured into ice water, and concentrated aqueous NH solution is added a pH of about 10 and extracted with methylene chloride. After filtering the crude product over Silica gel (hexane / ethyl acetate) gives 1.15 g of 1 1β- (4-dimethylaminophenyl) -1 7β-hydroxy-17cc- (3-hydroxypropyl) -4,9 (10) -estradien-3-one as solid foam.

¹ H-NMR (CDCl3): 6 = 0.60 ppm (δ, 3H, H-18), 2.92 (δ, 6H ₁ N (CH ₃ J ₂ ; 3.71 (m, 2H ₁ CH ₂ OH ); 4.34 (m, 1H.H-11);

5.77 (m, 1H, H-4); 6.66 and 7.00 (AA ¹ BB ¹ system, each 2H, arom. H). UV (MeOH): X 260 nm (ε = 16,990); 304 (19 720).

A solution of 1.0 g of the above product in 150 ml of toluene is refluxed for 6 hours after the addition of 7.45 g of silver carbonate on Celite (prepared according to M. Fetizon and M. Golfier, Compt. Rend., 1968, 267, 900) heated. After cooling, it is filtered, the filter residue is washed thoroughly with methylene chloride and the filtrate is concentrated. 730 mg of the lactone are obtained as an amorphous solid. NMR (CDCl3): δ = 0.68 ppm (S, 3H, H-18); 2.96 (s, 6H, N (CH ₃ J ₂ ); 4.42 (m, 1H, H-11);

5.81 (m, IH ₁ H-4); 6.69 and 7.02 (AA ¹ BB'-, 2H each, arom. H).

Example 2

3- {i1β- / 5- (2-dimethylaminoethoxy) -phenyl7-17β-hydroxy-1,8-methyl-3-oxo-4,9 (10) -estradien-1,7oc-ylJ-propionic acid lactone

A solution of 3.4 g of 11ß- / 4 "- (2-dimethylaminoethoxy) -phenyl7-3,3- (2,2-dimethyl-propane-1,3-dioxy) -18-methyl-17a- / 3- tetrahydropyran-2-yloxy) -propyl7-9 (1O) -estren-5a, 17ß-diol in 120 ml of 90% strength aqueous ethanol is refluxed for 15 minutes after the addition of 1.75 g of p-toluenesulphonic acid the pH is adjusted to 10.5 by adding NH 3 solution and the mixture is extracted with methylene chloride.Chromatography over silica gel with hexane / ethyl acetate gives 1.86 g of 11β / 5- (2-dimethylaminoethoxy) -phenyl7-17β-hydroxy -17 <x- (3-hydroxypropyl) -1 8-methyl-4, 9 (10) -estradien-3-one as a solid foam ¹ H-NMR (CDCl). δ = 0.32 ppm (t, 3H , CH ₃ -CH ₃ ); 2.32 (s, 6H, N (CH ₃ ) ₂ ); 2.70 (t, 2H ₁ CH ₂ -CH ₂ -N); 4.01 (t, 2H ₁ CH ₂ -CH ₂ -O); 4.36 (m, 1H, H-1i); 5.74 (m, 1H, H-4). UV (methanol): λ. 282 (10,400);

Max

289 (13,600); 3Ο6 nm (ε = 18 720).

Oxidation of 1.6 g of the above product under the conditions of Example 1 (paragraph 2) gives 1.3 g of the lactone as a yellowish, amorphous glass. IR (CHCl): 173Ο cm " ¹ (lactone carbonyl); 1685 (C = 0).

--2T-

-2k-

Example 3

3- / T7β-Hydroxy-11β- (4-methoxyphenyl) -3-oxo-4,9 (1O) -estradiene-1 7oc-yl7-propionic acid lactone

A solution of 7.05 S 3 ι3- (2,2-dimethyl-propane-1,3- dioxy) -11ß- (4-methoxyphenyl) -17a- / 3-tetrahydropyran-2-yloxy) -propyl7-9 ( 10) -estren-5oc, 17a-diol is stirred in 50 ml of 70% aqueous acetic acid at 60 ° C. for 2 hours. After cooling, it is poured into water and the acidic, aqueous solution is extracted with methylene chloride. Chromatography of the crude product obtained in this way over silica gel with hexane / ethyl acetate gives 3 »8 g of 17 [beta] -hydroxy-17 <x- (3-hydroxypropyl) -11 [beta ]- (4-methoxyphenyl) -4.9 (10) estradiene -3-on as a yellowish foam.
¹ H-NMR (CDCl3): δ = 0.56 ppm (s, 3H, H-18);

3.76 (8.3H ₅ OCH ₃ )? 4.33 (m, iH, H-1i); 5.71 (m, 1H, H-4); 6.74 and 7.03 (AA ¹ BB ¹ , 2H each, aromatic H).

A solution of 2.5 g of the product obtained above in 150 ml of methylene chloride is mixed in portions with 3 »3 g of pyridinium chlorochromate at room temperature and then stirred at 25 ° C. for 2 hours. It is then filtered through Celite, the piltrate is washed first with NaHCO 3 solution, then with saturated NH.Cl solution, dried over sodium sulfate / activated charcoal and concentrated. Column chromatography over silica gel with hexane / ethyl acetate gives 1.45 g of the lactone. ¹ H-NMR (CDCl3): δ = 0.62 ppm (s, 3H, H-18);

3.77 (s, 3H ₁ OCH ₃ ); 4.40 (m, iH, H-ii); 5.77 (s, iH, H-4); 6.91 (AA ¹ BB ¹ , 4H, aromat. H).

Example 4

11β- (4-dimethylaminophenyl) -17β-hydroxy-17a- (3-hydroxy propyl) -16β-methyl-4,9 (10) -estradien-3-οπ

The cleavage of 3 »42 g of 11ß- (4-dimethylaminophenyl) -3, 3- (2, 2- dimethyl-propan-1, 3-dioxy) -i 6β-methyl-17a - / 3- (tetrahydropyran-2-yloxy) -propyl7-9 (iO) -estrene-5a, 17β - diol with 60 ml of 70% aqueous acetic acid under the The conditions of Example 1 yield 1.97 g of 11β- (4-dimethylatninophenyl) -1 7β-hydroxy-1 7a- (3-hydroxypropyl) -1 6β-methyl-4,9 (iO) -estradien-3-one as a yellowish oil.

¹ H-NMR (CDCl3): δ = 0.51 ppm (s, 3H, H-18); 0.96 / d (J = 7Hz), 3H, 16 [beta] -CH7; 2.88 / i, 6H, N (CH _{3) 2} 7;

3.63 (m, 2H ₁ CH ₂ OH); 4.32 (m, 1H, H-1i);

5.73 (s, 1H, H-4); 6.60 and 6.98 (AA ¹ BB ¹ , each 2 H, aromatic H),

Example 5

11β (4-Dimethylaminophenyl) -17ass-hydroxy-17aa- (3-hydroxy propyl) -D-homo-4,9 (10) -estradien-3 ~ one

From 1.43 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a, 10aoxido-D-homo-9 (11) -estren-17a-one, 1a is obtained after carrying out the reaction sequence -d (ld = example 1) without purification of the intermediate stages 63Ο mg of 11ß- (4-dimethylaminophenyl-17ass-hydroxy-17aa- (3-hydroxy-propyl) -D-homo-4,9 (10) estradien-3-one . as a yellowish foam ¹ H-NMR (CDCl): δ = 0.58 ppm (s, 3H, H-i8);

2.97 / 5,6H, N (CH _{3) 2} 7; 4.36 (m, 1H, H-1i); 5.74 (s, 1H, H-4); 6.63 and 6.69 (AA ¹ BB ', 2H each, aromatic H).

Example 6

11β- (4-Dimethylaminophenyl) -17β-hydroxy-17a- (3-hydroxy propyl) -i8-methyl-4,9 (10) -estradien-3-one

From 4.32 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -18-methyl-5a, iOa-oxido-17a- / 3- (tetra- hydropyran-2-yloxy) prop-1-ynyl7-9 (11) -estren-17β-ol obtained after reaction under the conditions of 1 b) - d) (Id = Example 1) 2.25 g of 11ß- (4-dimethylaminophenyl) -17ß-hydroxy-17a- (3-hydroxypropyl) -18-methyl- 4,9 (10) estradien-3-one as a light yellow oil.

¹ H-NMR (CDCl): δ = 0.32 ppm / t (J = 7Hz), 3H, 13-CH "-CH J \ 2.90 / i, 6H, N (CH _{3) 3} 7; 3.68 (m, 2H, CH ₂ OH); 4.31 (m, 1H, H-1i);

5.72 (s, IH ₁ H- (I); 6.63 and 7.03 (AA ¹ BB ¹ , 2H each, aromatic H).

UV (methanol): X 260 nm (ε = 17 090); 307. (ε = 19500).

St. 3 DC

Claims (12)

Claims wherein with R and R meaning in each case alkyl with 1 to k carbon atoms or R and R including N in the meaning of a 5- or 6-membered saturated heterocyclic ring, where the ring _{can contain, in addition to N, a further heteroatom N 1} O or S and the corresponding N-oxides , -SR with R meaning methyl, ethyl or phenyl and IV IV
-OR with R meaning methyl, ethyl, propyl, methoxymethyl, allyl or ß-dimethylaminoethyl, R _{0 represents} a hydrogen atom, a methyl or ethyl group and X = ^! X or -, VI whereby the wavy lines ^^^ indicate that the substituent is in α- or ß-position and for OH 0; ^ CH_) _Q -CH_OH or 2'2-2 OH with M = K, Na or Li stands, and V VI ■ R and R are each alkyl of 1 to 4 carbon atoms mean. 2.) 3- / Tiß- (4-Dimethy laminophienyl) -17ß-hydroxy-3-oxo-4,9 (1O) -estradien-17a-yl7-propionic acid-lactone and propionic acid potassium salt. 3.) 11β- (4-Dimethylaminophenyl) -17β-hydroxy-17α- (3-hydroxypropyl) -4,9 (10) -estradien-3-one. 4.) 3-13- / 4 * - (2-dimethylaminoethoxy) -phenyl7-17ß-hydroxyi8-methyl-3-oxo-4,9 (iO) -estradien-1 7cc-yl} propionic acid lactone and propionic acid potassium salt. ·) 11 ß- / 4 "- (2-dimethylaminoethoxy) -phenyl7-1 7ß-hydroxy-17a- (3-hydroxypropyl) -i8-methyl-4,9 (10) -estradien-3-one. 6.) 3 - /? 7ß-Hydroxy-11ß- (4-methoxyphenyl) -3-oxo-4,9 (1O) -estradien-1 7cc-yl7-propionic acid lactone and propionic acid sodium salt. 7.) 17ß-Hydroxy-17a- (3-hydroxypropyl) -11ß- (4-methoxyphenyl) 4, 9 (10) -estradien-3-one. 8.) 11β- (4-Dimethylaminophenyl) -17β-hydroxy-17a- (3-hydroxypropyl ) -i6ß-methyl -4, 9 (10) -estradien-3-one. 9.) 11ß- (4-dimethylaminophenyl) -17ß-hydroxy-17a- (3-hydroxypropyl) -1 8-methyl-4,9 (10) -estradien-3-one. 10.) 11β- (4-Dimethylaminophenyl) -17β-hydroxy-17 "- (3-hydroxypropyl ) -D-homo-4,9 (10) -estradien-3-one. 11.) Pharmaceutical preparations, characterized by the content of compounds according to claims 1-10. 12.) Process for the preparation of 1Iß-Aryl-Spirolaktonen of the general formula I. (D, wherein with R and R meaning in each case alkyl with 1 to k carbon atoms or R and R including N in the meaning of a 5- or 6-membered saturated heterocyclic ring, where the ring can contain a further heteroatom N, O or S and the corresponding N-oxides in addition to N , -SR with R meaning methyl, ethyl or phenyl and IV IV
-OR with R meaning methyl, ethyl, propyl, methoxymethyl, allyl or ß-dimethylaminoethyl, R is a hydrogen atom, a methyl or ethyl group and X = «2 V ^Β 2 _χ or the wavy lines ^^^^ indicate that the substituent is in α- or ß-position and for OH , - (CH_) _O -CH ₀ OH or 2'2 2 OH with M = K, Na or Li stands, and V VI
R and R each denote alkyl having 1 to k carbon atoms, characterized in that a compound of the general formula II (ID, R _n and R _{0 have} the meaning given in formula I, Z represents an ethylene or 2,2-dimethylpropylene group X ¹ like X in formula I with Y meaning "*" ^N "" ^ΛΤ \ where R is a hydrogen atom or a represents an easily split off group, with a dilute acid or an acidic ion exchanger at temperatures of 0-100 C and optionally the 17oc- (3-hydroxypropyl) compound thus obtained of the general formula I oxidized in a manner known per se to form 17a-propionic acid lactone and optionally opens the lactone ring with alkali to the corresponding 17a-propionic acid alkali salt.