DE1076127B - Process for the production of anabolic steroids with low androgenic side effects - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

kl. 12 ο 25/04

INTERNAT. KL. C 07 C

PATENT OFFICE

EXPLAINING PUBLICATION 1076127

Sch 24647 IVb / 12 ο

REGISTRATION DATE: AUGUST 30, 1958

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: FEB 25 RUARY 1960

OH

The production of preparations which have a strong anabolic effectiveness and are as low as possible androgenic Showing side effects is of great importance for therapeutic purposes. We already know a few Your testosterone-related steroids, which are a little increased anabolic compared to testosterone with at the same time noticeably reduced androgenic effectiveness. The diminution of androgenic effectiveness is not yet so pronounced in these steroids that it is in the for Do not interfere with the required dosage to produce sufficient anabolic efficacy would. The discovery of new compounds with a further shift in the ratio of effects in favor the anabolic effectiveness therefore represents an undoubted advance.

It has now been found that the introduction of a halogen atom in the 2-position of the anabolically active ^ l ¹ -androsten-17-ol-3-ones and their 17-esters surprisingly effects such a shift in this ratio of activity. For example, the 2-chloro / f ¹ -aridro ^l sten-17 /? - ol-3-one shows a reduction in androgenic activity to about a fifth compared to the chlorine-free compound with approximately the same anaibolic activity.

The previously not (described 2-halo-J ¹ -androsten-17-ol-3-ones can be prepared according to Me processes known to them)

anabolic. more effective steroids

with low androgenic side effects

Applicant:

Schering Aktiengesellschaft, Berlin N 65, Müllerstr. 170-172

Dr. Rudolf Wiechert, Berlin-Lichterfelde,

Dr. Emanuel Kaspar, Berlin-Wilmersdorf,

and Dr. Martin Schenck, Berlin-Frohnau,

have been named as inventors

methods of steroid chemistry are obtained. A preferred starting material is 1,2-oxido-androstan-17 /? - ol-3-one. If this compound is treated, for example, with hydrogen chloride in chloroform, instead of the chlorohydrin that is initially to be expected, its water release product, 2-Ciuor-A ¹ - androsten-17 /? - ol-3-one:

OH

OH

Further preferred starting materials are the alcohol treatment with methanol in the presence of perchloride products of the l ^ -oxido-androstan - ^ - ol-S-one, ins- is available. If this is treated with chlorine, the methanolysis product, which is, for example, hydrogen in chloroform, the 2-chloro- _i d ^{: t} -androsten-17 /?

OH

OH

OH

909 757/509

The reactions with the other hydrogen halides instead of hydrogen chloride proceed analogously. The 17-position hydroxyl groups of the new 2-halo-zi ^ androsten - ^ - ol-iS-ones can, if desired, by methods known per se with any physiologically acceptable acids are acylated.

example 1

200 mg of l, 2-oxido-androstane-17 β-όί-3-οη are dissolved in 25 ml of alcohol-free chloroform. Dry hydrochloric acid gas is passed into this solution at 0 ° C. for 2 hours. It is now diluted with water and extracted with methylene chloride. The methylene chloride phase is washed neutral with water and dried over sodium sulfate. After evaporation of the solvent, the residue is triturated with ether, filtered off with suction and recrystallized from ethyl acetate. 2-chloro-J ¹ -androsten-17 / S-ol-3-one melts at 221 Ms 222 ° C. UV: ε ₂₄₈ = 9500.

Example 2

3.2 g of 2a-oxido-androstan-17 /? - ol-3-one are left to stand for 16 hours at room temperature in 200 ml of methanol with 1.3 ml of 70% perchloric acid and then worked up as described in Example 1 . The residue obtained is triturated with methanol, filtered off with suction and dried. The dry crude product (9.4% OCH _?; UV inactive) melts at 77 to 81 ° C and is, as described in Example 1, treated with hydrochloric acid gas in chloroform, worked up and recrystallized. Yield 2.9. The recrystallized 2-chloro-J ¹ -androsten-17 _J S-ol-3-one melts at 221 to 222 ° C. UV: s _2i8 = 9500. The mixed melting point with the compound obtained in Example 1 does not result in any depression.

Example 3

50 mg of 2-chloro-J ¹ -androsten-17 _/ 5-ol-3-one, 0.2 ml of pyridine and 0.1 ml of acetic anhydride are heated on the steam bath for 2 hours. This solution is then stirred into ice water. The precipitated 2-chloro-zl ¹ -androsten-17 /? - ol-3-one-17-acetate is filtered off with suction and recrystallized from isopropyl ether. It melts at 156 ° C.

Example 4

576 mg / J ¹ -androsten-17yÖ-ol-3-one are dissolved in 8 ecm chloroform, 0.8 ecm acetic acid is added and 335 mg bromine in 9.4 ecm chloroform are then added dropwise over 30 minutes while cooling with ice and stirring. After stirring for a further 30 minutes, it is diluted with methylene chloride, washed neutral with water, and the solution is dried over sodium sulfate and concentrated in vacuo. The remaining solid residue is now, mixed with 5 ecm of dry pyridine, left to stand overnight at room temperature with exclusion of moisture, the reaction mixture is treated with methylene chloride, the solution is washed with water and dried with sodium sulfate. After concentration to dryness, the remaining solid residue is recrystallized from ethyl acetate, and 470 mg of 2-Bronwf ¹ -androsten-17 /? - ol-3-one with a melting point of 216 to 218.5 ° C. are obtained in this way. [Α ] ² ": + 29.9 ° (c = 0.92; CHCl ₃ ). UV: ε ₂₅₅ = 7450.

Example 5

1.15 g of ^I -Androsten-17y5-ol-3-one are dissolved in 70 ml of tetrahydrofuran and 6.1 ml of propionic acid containing 312 mg of chlorine are added at -60 ° C. This solution is kept in the dark at this temperature for 6 hours and then stirred into ice water. The aqueous solution is then extracted several times with methylene chloride. The methylene chloride phase is washed with sodium hydrogen carbonate solution and then with water. After drying over sodium sulfate, it is concentrated to dryness in vacuo and the residue that remains is taken up in 6 ml of pyridine. After standing for 19 hours, it is diluted with ether, washed with 2N hydrochloric acid and then with water. The residue remaining after drying over sodium sulfate and concentrating the ethereal solution is crystallized from ethyl acetate. 800 mg of 2-chloro-2 1 -androstane-17 /? - ol-3- ^{one with a temperature of 221 to 222 ° C. are obtained.}

ε ₂₄₈ = 9500.

Example 6

639 mg of l-methyl-J ¹ -anidrosten-17 / S-ol-3-one are dissolved in 38 ml of tetrahydrofuran and reduced to -60 ° C.

ao chilled. 165 mg of chlorine in 1.9 ml of propionic acid are added to this solution. The temperature is allowed to rise to -32 ° C. in the course of 6 hours and the solution is then stirred into ice water. It is extracted with methylene chloride, and the methylene chloride phase is washed with sodium hydrogen carbonate solution and then with water. After concentrating to dryness in vacuo, the remaining residue is stored in 4 ml of pyridine overnight at room temperature. It is then diluted with ether, washed with dilute hydrochloric acid and with water. After the ether phase has been dried over sodium sulfate, it is concentrated to dryness in vacuo and the residue that then remains is chromatographed over silica gel. By eluting with equal parts of carbon tetrachloride and methylene chloride, 2-chloro-methyl- ^ ¹ -androsten-17 _/ ö-ol-3-one, which melts at 156 to 157 ° C. after recrystallization from isopropyl ether, is obtained. UV: ε ₂₀₃ = 2180, ε ₂₅₇ = 10 360.

Example 7

302 mg of ^ ct-methyl - ^ - androsten-r ^ -ol-S-one in 15 ml of tetrahydrofuran, as described in Example 5, reacted with 78 mg of chlorine in 1 ml of propionic acid, worked up and then further with 1.5 ml Treated and worked up pyridine. 2-Chloro-17a-methylzl ¹ -androsten-17 _J ö-ol-3-one is recrystallized from isopropyl ether and melts at 167 to 168 ° C. UV: ε ₂₄₇ = 9100.

Example 8

350 mg of 2-chloro-zl ¹ -androstan-17 ^ -ol-3-one, 1.4 ml of pyridine and 0.7 ml of cyclopentylpropionic anhydride are heated to 125 ° C. for 3 hours and then steam distilled for IV2 hours. It is then extracted with methylene chloride. The methylene chloride phase is washed with water, dried over sodium sulfate and then concentrated to dryness in vacuo. The remaining residue is recrystallized from hexane. 2-chloro- _< il ⁱ -androsten-17 /? - ol-3-one-17-cyclopentylpropionate melts at m.s. = 95.5 to 96.5 ° C.

Example 9

200 mg of 2-chloro-zl ¹ -androsten-17β-ol-3-one are suspended in 0.6 ml of pyridine and 0.8 ml of dioxane. To this, 0.12 ml of benzoyl chloride are added while cooling with ice. This solution is stored for 48 hours at room temperature and then stirred into ice water. The precipitated 2-chloro-z ( ¹ -androsten-

17 /? - ol-3-one-17-benzoate is filtered off with suction and recrystallized from Bssigester. F. = 221.5 to 222.5 ° C. UV: S ₂₀₃ = 8730, S ₂₃₁ = 20140, ε ₂₄₈ = 11830, ε ₂₇₁ = 2000.

Example 10

1 gl, 2a-oxido-androstane-17jS-ol-3-one acetate is in 15 ecm abs. Tetrahydrofuran dissolved, cooled to - 60 ° C and treated with a solution of 10 ecm hydrogen fluoride in 25 ecm abs. Tetrahydrofuran added. After 30 ¹ minutes at - 60 ° C., the reaction mixture is left to stand for 48 hours at room temperature. For working up, the solution is poured into ice water, neutralized with potassium carbonate, extracted with methylene chloride and the organic phase is washed neutral. After the solvent has evaporated, the residue is _{chromatographed on silica gel (10% H 2} O). Eluting with methylene chloride-carbon tetrachloride (1: 1) ^{gives 2-fluoro- / l 1} -androstene-17 /? - ol-3-one acetate which, after recrystallization from isopropyl ether, melts at 172 to 173 ° C. U

₂₃₄

320 mg 2 - fluorine - A ¹ - androstene -17 /? - Oil - 3-on-acetate are dissolved in 25 ecm of methanol, an aqueous solution of 110 mg of potassium carbonate is added and the mixture is refluxed for 10 minutes. It is poured into ice water, the precipitated 2-fluoro-zf ¹ -an

25 drosten ~ ll /? - ol-3-one sucked off and made of isopropyl ether recrystallized. Melting point 167 to 168 ° C. UV: = 11,000

Claims (3)

Patent claims: 1. A process for the production of anabolically effective steroids with low androgenic side effects, characterized in that a halogen atom is introduced into the 2-position of the molecule of the z ^ -androstene - ^ - ol-3-ones according to known methods of steroid chemistry and the 17-hydroxyl group in the 2-position halogenated / l ¹ -androsten-17-ol-3-ones, if desired, acylated with any physiologically acceptable acids by methods known per se. 2. The method according to claim 1, characterized in that l, 2-oxido-androstane-17 /? - ol-3-one treated with hydrogen halide, especially hydrogen chloride, in chloroform. 3. The method according to claim 1, characterized in that that the alcoholysis products of the l ^ -oxido-androstan - ^ - ol-S-ones, especially that methanolysis product of des obtainable by treatment with methanol in the presence of perchloric acid l ^ -Oxido-androstane - ^ / J-ol-S-ons, with hydrogen halide treated in chloroform. © 809 757/509 2.60