DE1493163C3 - nalpha-ethynyl-ie-methyl-delta high 4-oestrene-3 beta-17 betadiols, processes for their preparation and agents containing them - Google Patents

Description

IO

R ² -O

wherein R ¹ denotes hydrogen, an acyl or a lower alkyl radical and R ² denotes hydrogen or an acyl radical.

2. 17 "- ethynyl - 18 - methyl - J ⁴ - oestrene - 3fi, 17 / i-diol-3-acetate.

3. 17a - ethynyl - 18 - methyl - zl ⁴ - oestrene 3 / 3,17j9-diol-3-acetate-17-methyl ether.

4. Process for the preparation of compounds of the general formula

R ² -O

wherein R ¹ denotes hydrogen, an acyl or a lower alkyl radical and R ² also denotes hydrogen or an acyl radical, characterized in that in 17a - ethynyl -18 - methyl -19 - nor testosterone according to methods known per se

a) first the 17 /? - hydroxyl group - if necessary with intermediate protection of the 3-keto group through known modification into less reactive functional Groups - esterified or etherified, then by splitting off the before or optionally the 3-keto group introduced with the reaction again in the usual way sets free, the latter preferably reduced to the 3-hydroxyl group by means of metal hydrides and if desired then esterified or

b) firstly reduces the 3-keto group and, if desired, then the one formed 3-hydroxyl group esterified.

5. The method according to claim 1, characterized in that the 3-keto group of the starting product is reduced by means of lithium tri-tert-butoxyaluminum hydride.

6. Medicament containing a compound according to the claims. 1 to 3 next to pharmaceutical usual additives.

- R, 0

wherein R ₁ denotes hydrogen, an acyl or a lower alkyl radical and R ₂ also denotes hydrogen or an acyl radical, and a process for their preparation, characterized in that in na-ethynyl-IS-methyl-lii-nor-testosterone after methods known per se

a) first the 17/3 hydroxyl group - if necessary with intermediate protection of the 3-keto group by known modification in

less reactive functional groups - esterified or etherified, then by splitting off those introduced before or, if appropriate, with the reaction The protective group sets the 3-keto group free again in the usual way, the latter preferably reduced to the 3-hydroxy group by means of metal hydrides and, if desired, subsequently these esterified or

b) first reducing the 3-keto group and, if desired, then reducing the 3-hydroxyl group formed esterified.

It has been found that the novel compounds which can be prepared according to the process are very therapeutic show valuable properties. They are noticeable both after oral and subcutaneous application due to its excellent progestative effect, especially when compared with 17a-ethynyltestosterone. In particular, the ester or ester / ether derivatives can be used advantageously because they are good Have solubility in common solvents for steroid hormones, e.g. B. in vegetable oils, such as sesame oil, castor oil and the like, as well as in other synthetic solvents such as glycols, Lactic acid esters, benzyl benzoate and the like, and it is thus possible, by injecting such solutions, the called derivatives to create hormone depots.

In addition, the new compounds have excellent central inhibitory effects and are, for. Stomach applicable as a strong orally effective ovulation inhibitor.

In addition, the higher esters still have good protracted effects.

The new compounds according to the invention are prepared according to those used in steroid chemistry common methods, the starting product being the well-known na-ethynyl-lS-methyl-lii-nortestosterone serves.

The necessary esterification reactions with the desired acid can be carried out in both acidic and alkaline reaction medium are carried out. However, acidic esterification is less suitable because aromatization takes place at the same time as the 17-monoesterification of the Α-ring to a considerable extent.

finds. The alkaline esterification, preferably with the desired anhydride, is therefore expedient Acid in the presence of an organic nitrogen base, such as pyridine or quinoline, because this is done simultaneously the 3-keto group is protected as an enol ester and thereby the disadvantageous A-ring aromatization is avoided.

The etherification in the 17-position takes place by means of the customary alkylating agents by methods also known per se, preferably in the cold with Alkyl iodide in an inert solvent, such as. B. tetrahydrofuran, in the presence of alkali amide, such as Sodium or potassium amide. Here it is necessary to first remove the 3-keto group, e.g. B. as a 3-ketal or 3-enol ethers, to be protected as intermediates in the usual way in order to avoid possible alkylations in the Α ring.

The 3-keto group is reduced by methods known per se with metal hydrides, the Use of lithium tri-tert-butoxyaluminum hydride is preferably suitable because this reducing agent does not attack already existing ester groups in the molecule and on the other hand the 3-keto group mainly reduced to the 3 /? - hydroxyl group.

The combination of the necessary process steps is essentially determined by the end product that is ultimately desired. Should z. B. compounds are prepared in which R ¹ = H and R ² = H or acyl, the reduction of the 3-keto group is inevitably the first stage of the reaction. However, if connections are made in which z. If, for example, the 17- and 3-hydroxy groups are functionally modified, it is advisable to carry out the conversion of the 17-OH group before reducing the 3-keto group. In this way, compounds in which R ₁ and R _{2 are} different acyl radicals can also easily be prepared.

For esterification - and thus as an acyl residue - come all those commonly used in steroid chemistry Acids in question. Aliphatic carboxylic acids with, in particular, 1 to 11 carbon atoms in the acid radical, such as acetic acid, are particularly suitable. Propionic acid, caproic acid, oenanthic acid, undecylic acid and the like also unsaturated, branched, polybasic or substituted in the usual way; named for example be trimethyl acetic acid, t-butyl acetic acid, phenylacetic acid, cyclopentylpropionic acid, haloacetic acid, Aminoacetic acid, oxypropionic acid, benzoic acid, succinic acid, adipic acid and others.

example 1

2 g of Na-ethynyl-IS-methyl-W-nor-testosterone are combined with 4 g of lithium tritertiary butoxyaluminum hydride in 50 ml of abs. Tetrahydrofuran reduced for 90 minutes at room temperature. The reaction mixture is then poured into 5% acetic acid and extracted with ether. The separated ether phase is washed neutral with aqueous bicarbonate and sodium chloride solution and concentrated to dryness in vacuo. 1.95 g of oily 17a-ethynyl-18-methyl-zl ⁴ -estren-3 | 5-17, S-diol are obtained in this way.

Example 2

800 mg of oily ^{17a-ethynyl-18-methyl-4} zl -estrene-3 / 3,17ß-diol are heated with 6 ml of pyridine and 3 ml of acetic anhydride 40 minutes for 100 ⁰ C. The cooled reaction mixture is then stirred into water, the precipitate formed is filtered off and washed neutral with water. The dried crude product (760 mg) is recrystallized from acetone / hexane. This gives 470 mg of 17a-ethynyl-18-methyl- <d ⁴ -estren-3 / ?, 17 | S-diol-3-acetate with a melting point of 175 to 176.5 ° C.

B e i s ρ i e 1 3

a) 4 g of 17a-ethynyl-18-methyl-19-nor-testosterone in 2 ml of ethanol and 8 ml of tetrahydrofuran in Presence of 40 mg p-toluenesulfonic acid with 8 ml Ethyl orthoformate reacted at room temperature. After 3 to 4 hours, the reaction mixture is poured into pyridine-containing water and mixed with Ether extracted. The separated, neutral washed and dried ether solution is finally in the Concentrated in vacuo to dryness. This gives 4.3 g of crude na-ethynyl-IS-methyl - ^ - nor-testosterone-3-enolethyl ether, which is processed further without further purification.

b) About 100 ml of liquid ammonia are used in - 80 to -60 ° C after adding a few ferric salt crystals 390 mg of sodium were added in small pieces. After the blue color has disappeared, stir 4.3 g of 17a - ethynyl -18- methyl -19 - nor - testosterone 3-ethylenol ether dissolved in 65 ml of tetrahydrofuran and after about 2 hours still dissolved 1.2 ml of methyl iodide added dropwise in 6.5 ml of tetrahydrofuran. This reaction mixture is stirred for a further 2½ hours and then poured onto ice and, after acidification with glacial acetic acid, extracted with ether. The detached, neutral washed and dried ethereal solution is up to

. Evaporated to dryness and the remaining 17a-ethynyl -18-methyl-19-nor-testosterone-3-ethyl-enol 17 / S-methyl diether for enol ether cleavage in about 90 to 95% aqueous methanol in the presence of 5 g of crystalline oxalic acid% hours heated to boiling. The reaction mixture is then stirred into ice water, and the precipitate formed is filtered off, washed neutral and dried. This gives 3.8 g of crude na-ethynyl-IS-methyl-ig-nor-testosterone-17-methyl ether, which after chromatography on 45 times the amount of silica gel (10% water) benzene / methylene chloride (7: 3) and recrystallization pentane melts according to the obtained crystalline form at 76 to 78 ° C or at 100-101 ⁰ C.

c) 0.9 g of na-ethynyl-IS-methyl - ^ - nor-testosterone-17-methyl ether were reduced with 1.8 g of lithium tritert-butoxyaluminum hydride analogously to Example 1 and worked up. 0.88 g of 17a-ethynyl-18-methyl-z) ^4- oestrene-3.17 _{l of} δ-diol-17-methyl ether are obtained as a viscous oil. The methoxyl determination corresponds to the calculated value.

B e i s ρ i e 1 4

a) 2.5 g of 17a-ethynyl-18-methyl-19-nor-testosterone in 100 ml of abs. Benzene with 15 ml of ethylene glycol (freshly distilled, bp 195 to 196 ° C) in the presence of Ig p-toluenesulfonic acid to about 100 ° C for 6 hours heated. The cooled reaction solution is diluted with about 100 ml of ether and neutralized with water washed. The dried and filtered solution is evaporated to dryness in vacuo. You get 2.75 g of crude na-ethynyl-lS-methyl - ^ - nor-testosterone-3-ethylene ketal, which is processed further without further purification.

b) 2.3 g of na-ethynyl-IS-methyl - ^ - nor-testosterone-3-ethylene ketal are etherified analogously to Example 3 b)

and worked up. For ketal cleavage, the isolated crude product with 20 ml of 90% acetic acid in the Heat treated. The reaction mixture is then stirred into ice water and the resulting Precipitate taken up in ether, the ether solution washed neutral, dried and dried to dryness evaporated. The residue is obtained after chromatography on silica gel and recrystallization from ether-hexane na-ethynyl-IS-methyl-W-nortestosterone-17-methyl ether from melting point 75.5 to 77.5 ° C; identical to that prepared according to Example 3b Methyl ether.

c) The crude na-ethynyl-IS-methyl-l ^ nor-testosterone-17-methyl ether is processed further to the 3-OH compound analogously to Example 3 c).

B e i s ρ i e 1 5

0.85 g of 17a-ethynyl-18-methyl-zl ^4- estren-3,17-diol-17-methyl ether (prepared according to Example 3) are heated to about 100 ° C. for 45 minutes with 6 ml of pyridine and 3 ml of acetic anhydride. The cooled reaction mixture is then stirred into ice water and the acetylation product which has separated out is taken up in ether-methylene chloride. The extracted extraction solution is washed successively with dilute sulfuric acid, bicarbonate solution and water, then dried and evaporated to dryness. Obtained 0.94 g of 17a-ethynyl-18-methyl-zl ^4- estren-3, l 7 ^ -diol-3-acetate-17-methyl ether, which melts at 163 to 164.0 ° C. after recrystallization from hexane.

Example 6

a) A solution of 2 g of 17a-ethynyl-18-methyl 19-nor-testosterone in 26 ml of pyridine is mixed with 13 ml of acetic anhydride and heated to 160 ° C. for 5 hours in a sealed tube. The cooled reaction mixture is then poured into ice water. The precipitate obtained is filtered off, washed neutral with water and, after drying, chromatographed on silica gel. This gives 1.2 g of crude 17a-ethynyl-18-methyl-zl ^{3> 5-} estradiene-3.17 / ϊ -diol diacetate which, after recrystallization from ether, melts at 156 to 159 ° C; Yield 840 mg.

b) 400 mg of 17a-ethynyl-18-methyl-zI ³ ' ⁵ -estradiene-3,17 / 3-diol diacetate are stirred with 400 mg of sodium bicarbonate in 40 ml of methanol and 4 ml of water for 6 hours at room temperature. The reaction mixture is then poured into ice water, neutralized with glacial acetic acid, and the precipitate formed is filtered off, washed with water and dried. 350 mg of crude Na-ethynyl-IS-methyl-W-nortestosterone acetate with a melting point of 156 to 157 ° C. are obtained. Ίο Recrystallized from ether, 260 mg of acetate with a melting point of 162 to 163 ° C. are obtained.

c) 0.2 g of na-ethynyl-IS-methyl-l ^ nor-testosterone acetate are reduced according to Example 1. 0.194 g of 17a-ethynyl-18-methyl-zl ⁴ -estren-3 ^ 17 ^ -diol- are obtained

! 5 17-acetate.

Example 7

0.6 g of the 17a-ethynyl obtained according to Example 6 c)

IS-methyl-J ^ oestren-S ^ n ^ -diol-n-acetate are acetylated analogously to Example 2. The isolated crude product (590 mg) is purified by chromatography on silica gel and recrystallized from hexane / pentane. This gives 320 mg of 17a - ethynyl -18 - methyl - J ⁴ - estrene 3ßl7 /? - diol diacetate of melting point 119 to 121 ⁰ C.

At s ρ iel 8

From 0.6 g of 17a-ethynyl-8-methyl- A ⁴ -estrene- " 3ß, 17/3-diol-17-acetate is obtained analogously to Example 7 with. Propionic anhydride / pyridine 290 mg of 17a-ethynyl-18-methyl - Α ^Λ - estrene - 3 / 3.17 / 9 - diol - 3 - propionate 17-acetate. Mp. 149 to 150 ° C.

Example 9

Of 400 mg of 17a-ethynyl-18-methyl -A ⁴ -estrene-3 / ?, 17/3-diol-17-acetate is obtained analogously to Example 7 with caproic anhydride / pyridine 320 mg of crude 17a-ethynyl -18 - methyl - A * - oestren -3 / 3.17 / 3-diol - 3 - capronate 17-acetate, which, after chromatographic purification on silica gel and recrystallization from hexane, melts at 83 to 85 ° C; Yield 255 mg.

Claims (1)

Patent claims: 1. 17a-ethynyl-1,8-methyl-z) ⁴ -estren-3 / 9,17 / 9-diols of the general formula The present invention relates to 17a-ethynyl-18-methyl- / ^{I 4} -estren-3/3 , 17/3-diols of the general formula