DD218624A5 - PROCESS FOR THE PREPARATION OF 13 ALPHA ALKYLGONANES - Google Patents

Abstract

The invention relates to a process for the preparation of 13a-alkylgonanes for use in postcoital fertility control. The aim of the invention is the provision of new compounds with strong antigestagen effect. According to the invention, 3a-alkylgonanes of general formula I are prepared in which, for example: -N RIR 1 -N RII with RI and RII in the meaning of water - N RIIstoff or alkyl having 1 to 4 carbon atoms u. R2 is a hydrogen atom, a methyl or ethyl group, R3 / R4 are various meanings, R5 is a hydrogen atom or an a- or b-positional alkyl group having 1-4 C atoms. Formula I DD # AP

Description

-1-264102 4

Process for the preparation of 13a-Alkyigonanen

Field of application of the invention

The invention relates to novel 13a-alkylgonanes of the general formula I, and to a process for their preparation.

The compounds of the general formula I have a strong affinity for the gestagen receptor, without possessing self-gestagenic activity. They are competitive antagonists of progesterone (anti-progagens) and are used to trigger abortions

suitable because they displace the required to maintain pregnancy progesterone from the receptor. The

Compounds are therefore valuable and interesting in terms of their use for postcoital (p.c.)

Fertilitätskontrölle.

Characteristic of known technical solutions

Corresponding compounds in the estran series are already described as antigestagen compounds in Fertility and Sterility 40 (1982), page 253 described.

Object of the invention

The aim of the invention is to provide novel compounds with improved efficacy for use as competitive progesterone antagonists. ,

Explanation of the essence of the invention

The invention has for its object to provide novel compounds with the desired properties and methods for their

To find production.

According to the invention, 13a-alkylgonanes of the general formula I '

produced, in which

(D

R ¹ -N ^ ii with R 'and R "in the meaning of R

Is hydrogen or alkyl having 1 to 4 carbon atoms or R ¹ and R "including N in the meaning of a saturated 5- or 6-membered ring, wherein in the ring except N, another heteroatom such as O, N, S may be included, as well as

the corresponding tertiary N-oxides and the acid addition salts,

OR ¹ "with R ¹ " in the meaning of methyl, ethyl, propyl, methoxyphenyl, allyl or / 3-dimethylaminoethyl, R ^{2 is} a hydrogen atom, a methyl or ethyl group, R ³ - (CH ₂ J _n -CH ₃ with η = 0-4,

- (CH ₂ ) _n -CH ₂ -O (S) R ^lv with η = 0-4 and R ^lv in the meaning of hydrogen or alkyl having 1 to 4 carbon atoms,

-CH = CH- (CH ₂ ) _n -OR ^v mitn = 1- ^ and '

R ^{v is} hydrogen, alkyl or alkanoyl having in each case 1 to 4 carbon atoms,

-C ^ C-X with X in the meaning of hydrogen, alkyl having 1 to 4 carbon atoms or halogen,

- (CH ₂ ) _n -CH ₂ CN with η = 0-3 or

Ii '. 'ν' '. · ·

-C-CH ₂ Y with Y in the meaning of hydrogen or 0R ^v , '

R ^{4 is} hydroxy, alkyloxy or alkanoyloxy each having ibis 4 carbon atoms or

R ³ / R ⁴

where R ^{3 is} in (»position and R ⁴ in / 3-position or R ³ in / 3-position and R ⁴ in α-position to the steroid skeleton,

R ^{6 represents} a hydrogen atom or a «- or / 3-membered alkyl group having 1 to 4 carbon atoms

 The previously known structure-activity relationships for competitive progesterone antagonists indicated that a 1,3-diacial arrangement of 11/3 aryl radical and 13/8 alkyl group was absolutely necessary for the unfolding of antigestagenic activity. All the more surprising is the strong and selective antagonistic effect of the type I 13C * -alkylgonanes, which is a completely. has different molecular topography compared to the Estran series.

In order to characterize the antigestagenic activity of the compounds according to the invention, the abortive effect was evaluated in the early post-nidationem phase (Experiment I) and in the advanced post-nidation phase (Experiment II).

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

The treatment of the animals with the substance or solvent to be tested was carried out after the nidation of the blastocysts of d5 p.c. to d7 p.c. (Experiment I) or d13 p.c. to d15 p.c. (Experiment II). To d9 p.c. or d17 p.c. the animals were killed and the uteri examined for implants and resorption sites. Photos were taken of all the uteri.

The absence of implants was considered an abortion.

As antigestagens were investigated: ''

A: 1iVi (4-dimethylaminophenyl) -17j8-hydroxy-17ff-propynyl-4,9-estradiene-3-ori (reference substance).

B: 11 / 3- (4-dimethylaminophenyl) -17 / 3-hydroxy-17α- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one (according to the invention).

C: 11/8- (4-dimethylaminophenyl) -17a-hydroxy-17 / 3- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one (according to the invention).

The test substances were dissolved in a benzyl benzoate-castor oil mixture (ratio 1: 4). The vehicle volume per single dose was 0.2 ml. Treatment was subcutaneous (s.c.).

Table 1 (Experiment I)

Abortive effect in early pregnancy of rats Treatment of d5 p.c. to d7 p.c., autopsy d9 p.c.

connection dose abortion rate (%) mg / animal / day s.c. η abort / n total (100) 30.0 4.4 - 10.0   - (100) A 3.0 4/4 · (50) 1.0 2.4 (0) 0.3 0/4 (0) 0.1 0/4 (100) 10.0 4.4 (100) 3.0 4.4 (100) B 1.0 4.4 (0) 0.3 0/4 (0) 0.1 0/4 (100) 10.0 4.4 (100) , 3.0 4.4 (100) C 1.0 4.4 (0) 0.3 0/4 (0) 0.1 0/4 Solvent as - (0) Control: - 0/4 ' 0.2 ml benzyl benzoate + Castor oil (1: 4)

η = 4 rats / group

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Table 2 (Experiment II)

Abortive effect in an advanced stage of pregnancy of rats treatment with 3,0mg / d. s.c. Antigestagen (AG) of d 13 p.c. to d 15 p.c .. Autopsy d 17 p.c. % Complete Aborte = empty Nidationsstellen

90. * , ο % '(10) D AG of the rats 52.3 35, <t% (6) 80 () number 70. control 60 50 _ Ίο (6) C 30 20 10 3.5 (6 % ) , 0 J- H B A

Compounds B and C according to the invention have a fully abortive effect in the early-gravid rat in doses of> 1.0 mg / d (Abort rate: 4/4). In contrast, the reference substance A shows maximum abort-causing (antigestagenic) effect only at doses of> 3.0 mg / d (Table 1).

At an advanced stage of pregnancy (d 13-15 p.c.), the percentage of complete miscarriages at 3-day s.c.

Of 3.0 mg / d for B 35.4%, for C 52.3% and for the comparison substance A 3.5% (Table 2).

The 13a-Alkylgonane of the general.formula I can be used in the form of pharmaceutical preparations. The preparation of the preparations is carried out according to known methods of galenics by mixing with organic or inorganic inert carrier material which is suitable for enteral, percutaneous or parenteral administration.

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

Alkyl groups in R 'and R "of the general formula 1 should contain 1 to 4 carbon atoms, the methyl and

Ethyl group are preferred. The group ,

N _S pll is also a saturated 5- or 6-membered

Ring, which except C-atoms and N may contain another heteroatom such as O, N or S, for example, pyrrolidino, piperidino, piperazino, morpholino, oxa and Thiazolidino- and Thiadiazolidinoring.

, ., · '. ,. .. ..

Under | \ |

-r "

should also be the corresponding tertiary

N-oxides, such as dimethylamino-N-oxide, pyrrolidino, piperidino, piperazino, etc. N-oxide. The alkyl and alkanoyl groups contained in R ^IV and R ^v should each have 1 to 4 carbon atoms, with methyl, ethyl and acetyl, propionyl being preferred. ,

4-264102

The new 13a-alkylgonanes of the general formula I are prepared according to the invention by irradiation of the 1 3ß- : alkyl steroids of the general formula II

(II)

OH

wherein R ¹ , R ² and R ^{5 have} the meaning given in formula I and Z is an ethylene or 2,2-dimethylpropylene group

represents,;, '..

with ultraviolet light and in good yield in the 13-episteroids (T3a-alkyl steroids) of the general formula III

(III)

OH

in which R ¹ , R ² , R ⁵ and Z have the meaning given in formula II.

The good yield of conversion product is surprising. Although it has long been known that 17-oxosteroids of the normal series (can be converted into the 13-episteroids by UV irradiation (A. Butenandt et al., Ber. Deutsch. Chem. Ges. 74, 1308 [1941]), pan was always obtained Mixtures of starting material and epimerized compound, which had irradiation times of several hours, and the yields were extremely low, so the search for an alternative {chemical access to the 13-epi series is still relevant, as a recent work by Barton et al., JCS Perkin 1,2163, (1977), but this alternative is not suitable for the preparation of Type I compounds It has been found that the irradiation of Type II compounds under certain conditions is much more favorable than 11-unsubstituted 17-oxo steroids in the series, the average irradiation times are only 10 to 30 minutes, and the yields of 13-epitheroid are between 60-80% Optionally, products may be further reacted without chromatographic purification. An essential prerequisite for a good result is the correct choice of solvent, the concentration of the substrate to be irradiated and the exact observance of the irradiation time. These parameters must be determined separately for each new substrate.

The irradiation is carried out with the full light of a Hg high-pressure lamp in the quartz glass apparatus. The temperature of the reaction solutions is adjusted to about 25 ⁰ C, the concentration of the solutions is 0.1-1.0 weight percent. As a solution center! Tetrahydrofuran and dioxane are preferably used, but also non-polar aprotic solvents such as hexane, cyclohexane, benzene, toluene and mixtures thereof can be used. The irradiation time is about 10 to 50 minutes.

The thus obtained 13-epistidides III are converted by the usual methods by nucleophilic addition to the 17-ketone and subsequent reactions in the final compound of general formula I. The nucleophilic addition to III generally proceeds to form both possible, isomeric forms at C-17, which, however, are readily separable by chromatography or fractional crystallization. In many cases, both isomers are pharmacologically active, although differences in potency may exist.

The nucleophilic addition of acetylene (ethyne) or propyne is carried out by means of the remainder -C = CH or -C = C-CH ³ donating agent. Such agents include, for example, alkali metal acetylides such as potassium and lithium acetylide and methyl acetylide, respectively.

The organometallic compound can also be formed in situ and reacted with the 17-ketone of the formula II. Thus, for example, the 17-ketone can be allowed to act in a suitable solvent on acetylene and an alkali metal, in particular potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia. The alkali metal may also be used in the form of, for example, methyl or butyllithium. Djalkyl ethers, tetrahydrofuran, dioxane, benzene and toluene are particularly suitable as solvents.

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The 17-ethynyl-17-hydroxy compounds can be hydrated in alcoholic solution under mercury salt catalysis to form the 17-acetyl-7-hydroxy compounds (Chem. Ber. 111 [1978] 3086-3093). The introduction of 3-hydroxypropane or 3-hydroxypropene in the 17-position is carried out by reacting the 17-ketone with metal-containing derivatives of propargyl alcohol, for example with 1-lith'ium-3-tetrahydropyran-2'-yloxy-pVopin-1 to the 17- (3-hydroxy-1-propynyl) -17-hydroxy compounds, which are subsequently hydrogenated to the 17- (3-hydroxypropyl- or 3-hydroxypropenyl) -17-hydroxy-compounds, respectively. The hydrogenation must be carried out under conditions which ensure exclusive attack on the C-C triple bond without abzusättivjon the tetrasubstituierte 9 (10) double bond. The oil for example in the hydrogenation at room temperature and atmospheric pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of noble metal catalysts such as platinum or palladium. The compound having the Z-configured double bond in the hydroxypropenyl group is formed by hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, JA Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, page 134, and HOHouse: Modem Synthetic Reactions 1972, page 19). As deactivated noble metal catalysts are, for example, 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate in question. The hydrogenation is stopped after the uptake of one equivalent of hydrogen.

The compound with the E-configured double bond in the hydroxypropenyl group is formed by reduction of the acetylenic triple bond in a manner known per se. A number of methods for the conversion of alkynes to trans-olefins are described in the literature, for example reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 [1941] 216), with sodium amide in liquid ammonia (J. Chem. Soc., 1955, 3558), with lithium in low molecular weight amines (J. Am. Chem. Soc., 77 [1955], 3378) with boranes (J. Am. Chem. Soc. 93 [1971] 3395 and 94 [1971 ] 6560), with diisobutylaluminum hydride and methyl-lithium (J-Am. Chem. Soc., 89 [1967] 5085), and in particular with lithium aluminum hydride / alcoholate (J. Am. Chem. Soc., 89 [1967J4245]. Another possibility is the reduction of the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide in a weakly acidic medium (J. Am. Chem. Soc., 86 [1964] 4358) and in general the reduction by the action of transition metal compounds with change the oxidation stage

Are end products of the formula I desired with R ³ / R ⁴ in the meaning

Thus, the 17- (3-hydroxypropyl) 17-hydroxy compounds become known in the art

oxidized. The conditions for the oxidation depend on the nature of the substituent R ¹ in formula I. If R ^{1 is,} for example, a dialkylamino group, chromic acid reagents are unsuitable for oxidation, since they primarily attack the di-alkylamino group. In these cases, oxidizing agents, such as silver carbonate / Celite (Fetizon reagent, M. Fetiz'on and M. Golfier, Comp. Rend. 267 [1968] 900) or platinum / oxygen (H. Muxfeldt et al .. Angewandte Chemie, International Ed. 1 [1962] 157). On the other hand, if R ^{1 is} an alkoxy group, oxidizing agents such as Jones reagent, chromic acid-pyridine, pyridinium dichromate or pyridinium chlorochromate can also be used. <

The structure of the 17-cyanomethyl side chain is carried out in a conventional manner from the 17-ketone of the general formula III, for example via the 17-spiroepoxide and cleavage of the spiro epoxy with HCN according to Z. Chem. 18 (1978) 259-260. The introduction of the 17-hydroxyacetyl side chain is also carried out by methods known per se, for example by the method described in J. Org. Chem. 47 (1982), 2993-2995.

Free hydroxy groups in the 17-position can be esterified or etherified in a manner known per se. After reaction (nucleophilic addition) of the 17-ketone, the compounds of formula III are treated with dehydration to form the 4 (5) double bond and for simultaneous ketal cleavage and removal of any further acid-cleavable protecting groups with acid or an acidic ion exchanger.

The acid treatment is carried out in a manner known per se by reacting the compound of the formula III which contains a 3-ketal group and a 5a-hydroxy group and an optionally 0-protected 17- (3-hydroxypropyl) group in a water-miscible Dissolves solvents such as aqueous methanol, ethanol or acetone, and on the solution catalytic amounts of mineral or SulfonsäUre, such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid or an organic acid such as acetic acid, allowed to act until water is eliminated is and protective groups are removed. The reaction, which proceeds at temperatures of 0 to 100 ⁰ C, can also be carried out with an acidic ion exchanger. The course of the reaction can be followed by analytical methods, for example by thin-layer chromatography samples taken. ,,

embodiment

The invention is explained in more detail below with reference to some examples.

example 1

a) A solution of 2.0 g of 11j3- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-9 (10) -estren-17-one (F. 143 to 145 ⁰ C) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25 ° C with a high-pressure mercury lamp (Philips HPK 125, immersion lamp, quartz glass reactor). The solvent is then distilled off in vacuo and the residue is chromatographed on alumina (Merck, neutral, stage III) with hexane / ethyl acetate. 1.46 g of 11) 3- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-13a-methyl-9 (10) -gone 17-on as a colorless oil.

b) absolute THF (248ml) at 5 ⁰ C for 30 minutes saturated by introducing with acetylene. 51 ml of a 15% solution of n-butyllithium in hexane are then slowly added dropwise, and the mixture is stirred for a further 15 minutes while cooling with ice-water. A solution of 2.7 g of 11j3- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-13a-methyl-9-gonen-17-one

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in 40 ml of absolute THF is then added dropwise within 15 minutes to the suspension of the lithium acetylide and stirred for a further 2 hours at room temperature. For working up, it is poured into ice-water and extracted with ethyl acetate. The resulting crude product (2.85 g) is used without further purification in the next stage.

c) 2.8 g of the crude product obtained under b) are suspended in 28 ml of 70% aqueous acetic acid and 3 hours at

'50 ⁰ C stirred. After cooling, the mixture is diluted with about 100 ml of water and adjusted by adding kpnzentrierter aqueous NH ₃ -LoSUng a pH of 10.5. After extraction with ethyl acetate, an oily mixture of isomers, which is separated by column chromatography on silica gel with hexane / ethyl acetate; Mari gets in the elution order:

1. 530 mg of 11/3 - (, 4-dimethylaminophenyl) -17a-ethynyl-T7β-hydroxy-13a-methyl-4,9-gonadien-3-one of melting point 120 to 123 ° C (ethyl acetate / diisopropyl ether) and

2. 1.33 g ii / SI ^ DimethylaminophenylKiy / J-ethynyl-iya-hydroxy-ISa-methylAS-gonadiene-S-on of melting point 201 to 204 ⁰ C (ethyl acetate).

Analogous b) and c) are obtained with methylacetylene instead of acetylene:

1. 11 / 3- (4-Ominethylaminophenyl) -17: 8-hydroxy-13 "-methyl-17a-propynyl-4,9-gonadien-3-one, oil.

2. 11 / 3- (4-dimethylaminophenyl) -17a; -hydroxy-13a-methyl-17ii-propynyl-4,9-gonadien-3-one as an oil.

d) A suspension of 1.02 g of mercury oxide (HgO, red) in 20 ml of water is stirred after the addition of 0.87 ml of concentrated sulfuric acid at 60 ⁰ C for 30 minutes. 9 ml of this mercuric salt solution are added to a solution of 3.25 g of 11 / M4-dimethylaminophenyl) -17 / 3-ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one in 32 ml of glacial acetic acid. Mixture is then stirred for 2 hours at 6O ⁰ C. For working up, the mixture is poured into ice water, the cooled reaction solution, is by addition of concentrated aqueous NH ₃ solution to pH 10.5 and extracted with ethyl acetate. The oily crude product thus obtained is crystallized from methylene chloride / diisopropyl ether. This gives 2.37 g of 11ß- (4-dimethylaminophenyl) -Uft-hydroxy-ISa-methyl-IS.ig-dinorAS-pregnadiene-S ^ O-dione of melting point 224 to 225 ⁰ C.

e) A suspension of 2.3 g of 11/3 (4-dimethylamino-phenyl) -17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione in 58 ml of toluene is added Addition of 11.6 ml of acetic anhydride and 5.8 g of 4-dimethylaminopyridine for 20 hours at 25 ⁰ C stirred. It is then poured into saturated NaHCO ₃ solution and extracted with ethyl acetate. The crude product is chromatographed on 200g silica gel with hexane / ethyl acetate. After crystallization of the main fraction from hexane / ethyl acetate, 1.71 g of 17 "- acetoxy-11 / M4-dimethylamino-phenyl) -13a-methyl-i8,19-dinoro-4,9-pregnadiene-3,20-dione are obtained Melting point 194 to 195 ° C,

Example 2

a) A solution of 1.8 g of 11j3- (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-9-estrene-17-one (F. 2 ° -326 ° C) in 300 ml of THF is irradiated under the conditions of Example 1 a) for 26 minutes. Chromatography of the crude product gives 1.58 g of 11/3 (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-13a-methyl-9- gonen-17-one as a colorless oil.

b) From 3.94 g of 3-tetrahydropyran-2'-ylxy-1-propyne in 85 ml abs. THF and 23.1 ml of a 15% solution of n-butyllithium in hexane are prepared at ^{0 0} C, the organolithium compound forth. Then, a solution of 3.53 g of the product described under 2a) is added dropwise in 71 ml abs. THF and stirred for 4 hours at room temperature. The reaction solution is

\ Then poured into ice water and extracted with Essigester. The crude product (3.85 g) 11/3 (4-diethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13a-methyl-17a [3-tetrahydropyran-2-yloxy ) -1-propynyl] -9-gonen-5a, 17/3-diol and 11 / S- (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -13 « -methyl-17 / 3- [3- (tetrahydropyran-2-yloxy) -1-propynyl] -9- _/ gonen-5 ", 17a-diol is used without further purification for hydrogenation, ι

c) 3.85 g of the crude product obtained under 2b) are hydrogenated in 95 ml of ethanol after addition of 400 mg of 10% palladium carbon at room temperature and normal pressure. After taking up 191 ml of hydrogen, the catalyst is filtered off and concentrated.

d) The hydrogenation crude product obtained under 2c) (3.85 g) is stirred in 30 ml of 70% acetic acid for 2 hours at 60 ⁰ C. After cooling, the procedure is as under 1 c) and chromatographies the isomer mixture obtained. In the elution order you get:

1. 410mg of 11β- (4-diethylaminophenyl) -17α- (3-hydroxypropyl) -17 / 3-hydroxy-13a-methyl-4,9-gonadien-3-one as a yellowish oil.

UV (Methanoi): E ₂₆₆ = 19080.8309 = 19110. '

2. 1.39 g of 11/8- (4-diethylaminophenyl) -17 / 3- (3-hydroxypropyl) -17a-hydroxy-13a-methyl-4,9-gonadien-3-one as a solid * foam.

Analogous b) to d) are obtained using 11/3 (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5 (rhydroxy-13a ^: methyl -9-gonen-17-one as starting material:

1.) 110- (4-Dimethylaminophenyl) -17 / 3-hydroxy-17a (3-hydroxy-propyl) -13a-methyl-4,9-gonadien-3-one as an oil.

2.) 11jS- (4-dimethylaminophenyl) -17a-hydroxy-17 / 3- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one as an oil.

Example 3

a) A solution of 1.75 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-11 / 3- (4-methoxyphenyl) -9-estrene-17-one in 290 ml of dioxane are irradiated for 19 minutes under the conditions of Example 1 a). After chromatography, 1.45 g of 3,3-

- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-11 / 3- (4-methoxyphenyl) -13a-methyl-9-gonen-17-one as a colorless oil.

b) To a suspension of lithium acetylide, prepared from a saturated solution of acetylene in 450 ml of THF and 130 ml of a 15% solution of n-butyllithium in hexane, is added dropwise a solution of 8.2 g of 3,3- (2,2-dimethyl -propane-1,3-dioxy) -5e * - hydroxy-11j8- (4-methoxyphenyl) -13a-methyl-9-gonen-17-one in 130mL THF.

Then it is carried out at room temperature for 3 hours, then the reaction solution is poured into about 31% of ice water and extracted with ethyl acetate. The crude product is chromatographed on alumina with hexane / ethyl acetate. The elution sequence gives: 1. 1.8 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -17a-ethynyl-11 / 1- (4-methoxyphenyl) -13-methyl- 9-gene-5 (i, 17 / i-diol as

colorless oil

^f 2. 5,1 g 3,3- (2,2-dimethyl-propane-1,3-dioxy) -17 / 3-ethynyl-11 / 3- (4-methoxyphenyl) -13-t-methyl-9-gono- 5, 170 diol as solid foam.

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c) A solution of 3.28 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -170-ethynyl-11 / 3- (4-methoxyphenyl) -13d-methyl-9-gonehyde 5a, 17a-diol in 33 ml of 70% aqueous acetic acid is stirred at 60 ° C for 30 minutes. After cooling, pour into ice water,. extracted with methylene chloride, the MeCl ₂ extracts are washed with saturated NaHCO ₃ solution and concentrated. Crystallization of the crude product from ethyl acetate gives 2.0 g of 17/3 -ethynyl-17a-hydroxy-11β- (4-methoxyphenyl) -13a-methyl-4,9-gonadien-3-one, m.p. 186-187 ° C. '

Example 4,

Zmin-minute irradiation of 1.84 g of 11-j8- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propari-1,3-dioxy) -5-hydroxy-18-methyl-9-estrene-17- on in 280 THF under the conditions of Example 1 a) leads to 1.36 g} of 1j8- (4-dimethylamino-phenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -13a ethyl 5a-hydroxy-9-gonen-17-one as a foam.

6.1 g of 11/3 (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -13a-ethyl-5a-hydroxy-9-gonen-17-one reacted under the conditions of Example 1 b) with lithium acetylide and the resulting crude product under the conditions of Example 1 c) cleaved with acetic acid. Chromatography and crystallization from ethyl acetate / diisopropyl ether gives 3.2 g of 11β- (4-dimethylaminophenyl) -17β-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one of melting point 197 to

[a] |> ⁵ + 450.4 ° (CHCl ₃ , c = 0.505). -

By mercury salt-catalyzed hydration analogous to Example 1 d) and subsequent acetylation analogously to Example 1 e) is obtained from 1.3 g of 11/3 (4-dimethylaminophenyl) -17j3-ethynyl-13a-ethyl-17a-hydroxy-4,9- gonadien-3-one after chromatographic purification 720 mg of 17a-acetoxy-1-10- (4-dimethylaminophenyl) -13a-ethyl-18,19-dinoro-4,9-pregnadiene-3,20-dione as a solid foam.

Hg ⁶ + 290.8 ° (CHCl ₃ , c = 0.515).

Example 5

a) By reacting 7.3 g of 11j8- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dipoxy) 5a-hydroxy-13a-methyl-9-gonen-17-one with 10.7 g of 3-tetrahydropyran-2'-yloxy-1-propyne under the conditions of Example 2b), after chromatography of the crude product on aluminum oxide with hexane / ethyl acetate, 4.83 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -13a-methyl-17i3- [3- (tetrahydropyran-2-yloxy) -1-propyl] -9-gonen-5-yl, 17-thiol as yellowish Foam. .

b) A solution of 2.2 g of the adduct obtained under a) in 67 ml of ethanol and 0.56 ml of triethylamine is hydrogenated after addition of 210 mg of palladium on barium sulfate (10%) at room temperature and normal pressure. After uptake of 83.5 ml of hydrogen, the catalyst is filtered off and concentrated. The hydrogenation crude product thus obtained is cleaved with 14 ml of 70% acetic acid under the conditions of Example 1c). After crystallization from ethyl acetate / diisopropyl ether, 1.1 g of 11j3- (4-dimethylaminophenyl) 17a-hydroxy-17j3- (3-hydroxy-1 ([Z]) -propenyl) -13a-methyl-4,9-gonadiene are obtained. 3-one of melting point 133 to 135 ° C.

Examples

Preparation of 11 (3- (4-dimethylaminophenyl) -17-3-ethynyl-16) 3-ethyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one

a) A suspension of 29.3 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one and 28.6 g of bis-dimethyl -aminotert. ^: Is stirred under argon for 60 minutes at 16O ⁰ C butoxymethane. After cooling, the crude product is triturated with about 50 ml of ethyl acetate, filtered and crystallized from the filtrate residue from ethyl acetate. This gives 27.6 g of 16-dimethylaminomethylene-3,3- (2,2-dimethyl-propane-1,3-dioxy) -5- (10), 9 {11) -estradien-17-one of the melting point 208 to 211 ° C.

b) A solution of 14.4 g of 16-dimethylaminomethylene-3,3- (2,2-dimethyl-propane-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one in 220 ml of toluene is added dropwise with ice-cold water 85 ml of a 5% solution of methyl lithium in diethyl ether. After addition, it is stirred for 15 minutes at +5 to + 1O ⁰ C, decomposes excess reagent by careful addition of about 20ml of water, the reaction solution is then poured into about 31 iced water and extracted with methylene chloride. The crude product is chromatographed on neutral alumina with hexane / ethyl acetate. After crystallization of the main fraction from ethyl acetate, 13.0 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradiGn are obtained. 17-one of melting point 121 to 123 ° C.

c) To a solution of 9.4 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradiene-17- one in 43ml of methylene chloride, 0,34ml hexachloroacetone and 0.01 ml of pyridine is added dropwise with ice water cooling, 4.3 mL of 30% hydrogen peroxide, and then stirred for 16 hours at 25 ⁰ C. for working up, the reaction solution diluted with

, 100 ml of methylene chloride, washed successively with 5% Na ₂ S ₂ O ₃ solution and water, the methylene chloride phase is dried over Na ₂ SO ₄ and concentrated. The resulting 5,10-epoxide mixture is on Al ₂ O ₃ , neutral. Step III, chromatographed with hexane / ethyl acetate. This gives 4.7 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a, 10 <* - epoxy-16 (E) -ethylidene-9 (11) -estren-17-one of melting point 139 to 141 ⁰ C (ethyl acetate / diisopropyl ether).

d) A solution of 8.2 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a, 10a-epoxy-16 (E) -ethylidene-9 (11) -styrene-17- On in 400 ml of ethanol is hydrogenated after addition of 930m palladium carbon (10%) at room temperature and atmospheric pressure. After uptake of 510 ml of hydrogen, the catalyst is filtered off and concentrated in vacuo. This gives 7.7 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a, 10a-epoxy-16/3-ethyl-9 (11) -estren-17-one as a colorless Oil.

e) From 1.4 g of magnesium, 0.05 ml of methyl iodide and 17.9 g of 4-bromo-N, N-dimethylaniline in 150 ml abs. THF, the organomagnesium compound is prepared. After addition of 344 g of CuCI is stirred for 15 minutes at 0 ° C and then added dropwise a solution of 7.7 g of the product obtained under d) in 70ml abs. THF added. Thereafter, it is stirred at room temperature for 3.5 hours. For workup, the reaction solution is poured into a mixture of ice-water and NH ₃ -L ösimy and extracted with ethyl acetate. After chromatography of the crude product on aluminum oxide with hexane / ethyl acetate and crystallization of the main fraction from diisopropyl ether / ethyl acetate, 6.5 g of 11/3 (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3- dioxy) -16 / 3-ethyl-5a-hydroxy-9 (10) -estren-17-one, mp 180-181 ° C.

f) A solution of 4.0 g of the product obtained under e) in 600 ml of dioxane is irradiated under the conditions of Example 1 a). Crystallization of the irradiation crude product from diisopropyl ether gives 1.74 g of 11 / tf- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -16 / 1-ethyl-5α-hydroxy -13a: -methyl-9 (10) -gonen-17-one of melting point 192-194 ° C.

-8-264102

g) Under the conditions of Example 1b), 1.4 g of the product obtained under f) are reacted with lithium acetylide.

Crystallization of the crude product from ethyl acetate / diisopropyl ether gives 960 mg of 11/3 (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -17 / 3-ethynyl-16/3 -ethyl-13a-methyl-9 (10) -gone-5a, 17 <* -diol to mp 132 to

' _v ': 134 ⁰ C, '.' , · · · · ·:

h) Under the conditions of Example 1c), 760 mg of the product obtained under g) are reacted with 8 ml of 70% if | 6r Essiosiiiuo. Crystallization of the crude product from hexane / diethyl ether gives 460mg of 11 / i (4-dimethylammophonyl) 17 / t''-methyl / ethylethyl-17 (v-hydroxy-13 "-methyl-4,9-gonadien-3-one of melting point 195 to 197 "C.

Example 7

Preparation of 17- 3-cyanomethyl-11β- (4-dimethylaminophenyl) -17a-hydroxy-13a-methyl-4,9-gonadien-3-one

a) A suspension of 5.0 g of 11/3 (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-13a-methyl-9 (10) - g'onen-17-one and 4.74 g Trimethylsulfoniumiodid in 60ml dimethylformamide is added in portions with 2.63 g of potassium tert-butoxide while cooling with ice water. The mixture is stirred for 4 hours at 25 ° C, then poured into ice water and extracted with ethyl acetate. After removal of the solvent, the initially oily crude product is crystallized from ethyl acetate / diisopropyl ether and thus obtained 4.2 g of 11/3 (4-dimethylaminophenyl) -3,3- {2,2-dimethyl-propane-1,3-dioxy) -5ahydroxy-13a-methyl-9 (10) -gone-17a-spiro-1 ', 2'-oxirane of melting point 234 to 236 ⁰ C.

b) 2.0 g of the spiro-oxirane obtained under a) are dissolved in 84 ml of ethanol and heated to reflux for 4 hours after the addition of 4.6 g of potassium cyanide. The cooled solution is poured into saturated NaHCO ₃ solution and extracted with ethyl acetate. The crude product obtained after concentration is taken stirred for 60 minutes at 6O ⁰ C without further purification in 26 ml 70% acetic acid and. After cooling, it is poured into ice-water, adjusted by the addition of NH ₃ solution has a pH of 10.5 and extracted with methylene chloride. After chromatography of the crude product on silica gel with hexane / acetone and crystallization of the main fraction from ethanol, 1.4 g of 17J8-cyanomethyl-11J3- (4-dimethylaminophenyl) -17-hydroxy-13a-methyl-4,9-gonadiene-3 are obtained. on from the melting point 135 to 137 ° C.

Claims (10)

1. A process for the preparation of 13a-alkylgonanes of the general formula I. (D, with R 'and R "in the meaning of , Hydrogen or alkyl having 1 to 4 carbon atoms or R ¹ and R "including N in the meaning of a saturated 5- or 6-membered ring, wherein in the ring except N, another heteroatom such as O, N, S may be included, and the corresponding tertiary N-oxides and the acid addition salts, OR ¹ "with R ¹ " in the meaning of methyl, ethyl, propyl, methoxyphenyl, allyl or / 3-dimethylaminoethyl, R ^{2 is} a hydrogen atom, a methyl or ethyl group,
R ³ - (CH ₂ I _n -CH ₃ with η = 0-4, - (CH ₂ ) _n -CH ₂ -O (S) R ^lv with η = 0-4 and R ^IV in the meaning of hydrogen or alkyl having 1 to 4 carbon atoms, -CH = CH- (CH ₂ ) "- OR ^V with η = 1-4 and R ^v in the meaning of hydrogen, alkyl or alkanoyl having in each case 1 to 4 carbon atoms, -C ^S CX with X in the meaning of hydrogen, alkyl having 1 to 4 carbon atoms or halogen, - (CH ₂ J _n -CH ₂ CN with η = 0-3 or -C-CH ₂ Y with Y in the meaning of hydrogen or OR ^V , R ^{4 is} hydroxy, alkyloxy or alkanoyloxy having in each case 1 to 4 carbon atoms or R ³ / R ⁴ η 17 where R ^{3 is} in the α position and R ^{4 is} in the β position or R ^{3 is} in the α position and R ^{4 is} α to the steroid skeleton, and ' ; ·. R ^{5 represents} a hydrogen atom or a -or 3-membered alkyl group having 1 to 4 carbon atoms, characterized in that a compound of the general formula II (ID, OH ίο- 264 102 wherein R ¹ , R ² and R ^{5 have} the meaning given in formula I and Z represents an ethylene or 2,2-Dimethylpropyiengruppe, irradiated with ultraviolet light and the obtained by UV irradiation 13-epistoxy of the general formula III (III) OH wherein R ¹ , R ² , R ⁶ and Z have the meaning given in the formula II, according to methods known per se by nucleophilic addition to the 17-ketone, cleavage of the 3-ketal protection and dehydration of 4,5-position in the Compounds of general formula I transferred. 2. The method according to item 1, characterized in that HjS-l ^ -DimethylaminophenyD-IVa-ethynyl-iy / a-hydroxy-ia 4,9-gonadien-3-one and 11 / M4-dimethylaminophenyl) -17 / 3- ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one. 3. The method according to item 1, characterized in that 11/3 _r (4-dimethylarninophenyl) -17 / 3-hydroxy-13a-methyl-17'-propynyl-4,9-gonadien-3-one and 11i <- ( 4-oimethylaminophenyl) -17a-hydroxy-13a-methyl-17/3-propynyl-4,9-gonadien-3-one. 4. The method according to item 1, characterized in that 11 / 3- (dimethylaminophenyl) -17a-hydroxy-13-a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione and 17a-acetoxy -110- (4-dimethylaminophenyl) -13a-methyl-18,19-dinoro-4,9-pregnadiene-3,2-dione. Process according to item 1, characterized in that 11/3 (4-ethylaminophenyl) -17a (3-hydroxypropyl) -11 / 3-hydroxy-13'-methyl-4,9-gonadien-3-one and 11 / 8- (4-diethylaminophenyl) -17j8- (3-hydroxypropyl) -17a-hydroxy-13 "-methyl-4,9-gonadien-3-one. 6. The method according to item 1, characterized in that 11/3 (4-dimethylaminophenyl) -17 / 3-hydroxy-17a (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one and 11 / 3- (4-diethylaminophenyl) -17a-hydroxy-17 / 3- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one. 7. The method according to item 1, characterized in that 17 ^ -Ethinyl-17a-hydroxy-11 / 3- (4-methoxyphenyl) -13 "-methyl-4,9-gonadien-3-one is prepared. 8. The method according to item 1, characterized in that 110- (4-dimethylaminophenyl) -17 / 3-ethynyl-13a-ethyl-17'-hydroxy-4,9-gonadien-3-one and 17α-acetoxy-11J3- (4-dimethylaminophenyl) -13α-ethyl · 18,19-dinor-4,9-pregnadiene-3,20-dione. 9. The method according to item 1, characterized in that 11 / 3- (4-dimethylaminophenyl-17 "-hydroxy-170- (3-hydroxy-1 (Z) -propenyl) -13a-methyl-4,9-gonadiene- 3-on is produced. 9-264102 Invention claims: ' 10. A process according to item 1, characterized in that 11/3 (4-dimethylaminophenyl) -17 / 3-ethynyl-16j3-ethyl-17a-hydroxy i3a-methyl-4,9-gonadien-3-one is produced.
11. The method according to item 1, characterized in that 17/3 cyanomethyl-11 / 3- (4-dimethylaminophenyl) -17 "-hydroxy-13" - methyl-4,9-gonadien-3-one is produced.