DE1643035B2 - 15BETA, 16BETA-METHYLEN-5ALPHA -ANDROST-L-ENE, PROCESS FOR THEIR MANUFACTURING AND THE PRODUCTS CONTAINED - Google Patents

Description

10

where R is a hydrogen atom, a lower alkyl or tetrahydropyranyl group or the acyl radical of one of the carboxylic acids customary in steroid chemistry means having 1 to 16 carbon atoms

2. 17 [ beta] -acetoxy- 15 [beta], 16 ^ -methylene-5 [deg.] -Androst-1-en-3-one.

3. Medicines based on active ingredients according to

Claims 1 and 2.

4. Process for the preparation of new 15j9,160-methylene-5 <x-androst-l-enes the general formula

30th

35

40

where R is a hydrogen atom, a lower alkyl or tetrahydropyranyl group or the acyl radical of one of the carboxylic acids customary in steroid chemistry with 1 to 16 carbon atoms, characterized in that one in corresponding, Steroids saturated in the Α ring introduces a l (2) double bond in a manner known per se and - depending on the ultimately desired meaning of R - the primary products obtained, if appropriate then etherified, esterified or saponified in the 17 position.

The invention relates to 15j3,16j3-methylene-5 <x-androst- -ene of the general formula

(i) 17-position etherified,

esterified or stranded.

The methyl and ethyl groups are preferably suitable as lower alkyl groups.

As physiologically acceptable acid residues, all should residues commonly used in steroid chemistry are understood. They are preferred Res e e of carboxylic acids with up to 16 carbon atoms The acids can also be unsaturated, branched, polybasic or in the usual way, for example Trch hydroxyl, amino groups or halogen atoms, may be substituted. The residues are also suitable cydoaliphatic, aromatic, mixed aromatic-static and heterocyclic acids, which can also be substituted. As preferred acids for The formation of the remainder R may be mentioned, for example: Acetic acid propionic acid. Caproic acid, oenanthic acid, undecylic acid, palmitic acid, trimethyl acid, Mono-, di- and trichloroacetic acid, phenyless.gic acid, phenoxyacetic acid, dialkylaminoacetic acid, pipend.noacetic acid, Nicotinic acid, cyclopentylpropionic acid. Lactic acid, succinic acid, benzoic acid and others

The introduction of the double bond in the 1,2-position of the steroid structure according to the invention takes place in an known way. .

To introduce the double bond by dehydration, for example, the saturated 5% - H-3-ketone in dissolved in an inert solvent and treated with a dehydrating agent such as 2,3-dichloro-5,6-d.cyano-benzoquinone, heated. Suitable solvents are those that are effective against the dehydrating agent used are inert, such as dioxane, benzene, toluene, tert-butanol and the like. .

However, the direct dehydration method has several disadvantages. For example, when working up larger batches, separating off the reduced or unconsumed dehydrogenating agent presents certain difficulties. In addition, in chemical and also in biological dehydration it can easily happen that the dehydrogenation does not stop at the level of the ^ «- connection, so that each time one obtains proportions of the corresponding 4> ⁴ -compound. For these reasons, in addition to direct dehydrogenation, halogenation of the 5 "-H-3-ketone in the 2-position and subsequent elimination of hydrogen halide has proven successful in introducing a ^« double bond. According to a preferred embodiment, the starting steroid saturated in the Α ring is dissolved in tetrahydrofuran and brominated with a solution of bromine in glacial acetic acid , with an alkali halide. such as lithium chloride or bromide, preferably in the presence of an alkali or alkaline earth carbonate, such as lithium or calcium carbonate, reacted at elevated temperature. The reaction time depends on the temperature at which

the elimination of hydrogen is carried out by you is ζ, B. at a reaction temperature of 115 ° C about 5 hours. The removal of hydrogen bromide is expedient with the exclusion of atmospheric oxygen, preferably in the presence of a protective gas, such as nitrogen or argon, carried out The bromination can be carried out with bromine as well as with bromine Compounds such as N-bromosuccinimide can be made. In addition, halogenation is also involved Chlorine possible.

The 15jJ, 16jS-methylene-5'-androst-1-enes which can be prepared according to the invention are strong anabolic steroids with a particularly favorable differentiation of the anabolic and androgenic effects. They can be subcutaneous, however can also be used per os.

The following table shows the values for the anabolic and androgenic effects of the new compounds using the example of 17ß-acetoxy-l5ß, i6ß-methylene -5a-androst-1-en-3-one, testosterone propionate, which is commonly used as a standard substance, and the unsubstituted njS -Acetoxy-Sa-androst-l-en-S-one compared. The values were determined in the usual levator ani seminal vesicle test on castrated male rats after the test animals had been administered the specified dose twelve times subcutaneously over the course of 14 days.

substance dose Levator ani Seminal
Ll- mg / animal / mg / 100 g Slide
mg / 100 g Day rat rat testosterone propionate 0.1 30th 146 17j3-acetoxy-5 <x-an- drost-l-en-3-cn 0.1 43 115 17 | 9-acetoxy-15j3, 16 /? - methylene-5 <x- androst-l-en-3-one 0.1 49 85

The table shows that the new 15jJ, 16/3 methylene compound compared to the comparison substances not only the benefit of a significantly increased anabolic effectiveness, but also the has a greatly reduced androgenic effect.

The new process products should be used in conjunction with those known in galenic pharmacy and customary carriers for the production of anabolically effective, subcutaneously or orally applicable drugs to serve. The esters among the steroids according to the invention in which the ester residue is from a higher Fatty acid derived, are due to their protracted effect particularly suitable for the production of corresponding Depot preparations.

The new active ingredients can be used for all indications in which protein cultivation is promoted is required by anabolic steroids. The following indications may be mentioned as examples: convalescence, reduced General condition, consuming diseases, cachectic conditions, poor appetite, underweight, Exhaustion, radiation therapy, anemia, long-term treatment with corticosteroids, osteoporosis, chronic Kidney disease, etc.

The 15,3,160-methylene-5% androstanolones used as starting materials for the process according to the invention can be prepared by methods known per se, for example as follows:

175 ml of dimethyl sulfoxide, 1.44 g of sodium hydride and 13.25 g of trimethyloxosulfonium iodide are at room temperature Stirred until the evolution of gas has ended (about 40 minutes). Then 16.5 g of 3,3-ethylenedioxy-5'-androst-15-en-17-one are added (M.p. 148.5 to 149.5 ° C; made from n.U-ethylenedioxy-SÄ-androst-lS-en-30-ol [Chem. Listy, 51, 1885, 1957 and J. Am. Chem. Soc

ίο 82, 3209, 1960] by oxidation of the 3-OH group, Ketalization of the 3-keto group formed and partial ketal cleavage with p-toluenesulfonic acid in aqueous acetone) entered. The mixture is stirred for 90 minutes at room temperature, and ice-water precipitation is carried out

• 5 and purifies the crude product by chromatography. 10.7 g of 33-ethylenedioxy-15j3,16jJ-methylen-5a-androstan-17-one are obtained from a melting point of 157.5 to 159 ° C (from diisopropyl ether).

To a solution of 10 g of 3,3-ethylenedioxy-15j9,160-

methylen-5a-androstan-17-one in 300 ml of tetrahydrofuran 1.5 g of lithium aluminum hydride are added and the mixture is stirred at room temperature for 1 hour. Then it becomes excess The reducing agent is decomposed with ethyl acetate, the reaction solution with ammonium chloride solution and diluted

Sulfuric acid is added and the organic phase is separated off. It is extracted three more times with ether, then dries with sodium sulphate and, after evaporation of the solvent, receives 10.5 g of crude 3,3-ethylenedioxy-15JJ, l ejJ-methylen-Sa-androstan-17jJ-ol, das

after recrystallization from diisopropyl ether at 193.5 to 195 ° C melts

10 g of crude 3,3-ethylenedioxy-150,16j3-methylene-5 «- androstane-170-o! are in 150 ml of methanol and 25 ml Dissolved water and after adding 12 g of oxalic acid 1

Heated to boiling hour after ice water precipitation, 9.5 g of crude 170-hydroxy-150,16j9-methylen-5a-androstan-3-one are isolated in the usual way, after recrystallization from diisopropyl ether at 173 to 175.5 ° C melts

9.5 g n / S-Hydroxy-lSftie / S-methylen-Sa-androstan-3-one (Crude product) are dissolved in 20 ml of pyridine and 10 ml of acetic anhydride and overnight at room temperature ditched. After precipitation with ice water, 10 g of crude product, which is obtained from diisopropyl-

ether is recrystallized. 7.95 g of 17j3-acetoxy-15j3,16j? -Methylene-5 "-androstan-3-one are obtained from the

Melting point 181.5 to 183 ° C obtained.

B e i s ρ i e 1 1

a) To a stirred solution of 5.75 g of 17β- acetoxy-150,16 /} - methylene-5'-androstan-3-one in 50 ml of tetrahydrofuran is added dropwise a solution of 0.855 ml of bromine in the course of 30 minutes 7 ml of glacial acetic acid and stir for 10 minutes. The crude product isolated after ice-water precipitation (6.8 g) is recrystallized from diisopropyl ether and 5.75 g of 2 "bromo-17j3-acetoxy-15 / 3,16j3-methylen-5" -androstan-3-one with a melting point of 200 are obtained to 202 ⁰ C (Z.).

b) 5.75 g of 2% - bromo-17/3-acetoxy-15jS, 16j3-methylen-5aandrostan-3-one are in 216 m! Dissolved dimethylformamide. Then 22.8 g of calcium carbonate and 12.1 g Lithium bromide entered, and the reaction mixture is stirred for 5 hours at 115 ° C. It is allowed to cool, sucks off the inorganic salts, concentrates the filtrate and then precipitates ice water. That Crude product (5.3 g) is chromato-

graphed (gradient chromatography, hexane / hexane / l 5% acetone). 3.22 g of 170-acetoxy-15j3,160-methylen-5a-androst-1-en-3-one are obtained from a melting point of 162 to 164 ° C (from diisopropyl ether).

UV: 6230 = 10,700.

Example 2

a) To a solution of 6.1 g of 17 /? - Hydroxy-15 / J, 160-methylen-5 (X-androstan-3-one a solution of 1.02 ml of bromine in 50 ml of tetrahydrofuran is added dropwise with stirring over the course of 30 minutes at room temperature 8 ml of glacial acetic acid and stir for 10 minutes. The crude product (7.5 g) isolated after ice water precipitation becomes from Diisopropyl ether recrystallized. 2 <x-bromo-17 / J-hydroxy-15 / M6j? -Methylene-5 "-androstan-3-one is obtained from a melting point of 170 to 172 ° Q

b) 7.5 g of 2 <x-bromo-17/3-hydroxy-150,160-methylen-5aandrostan-3-one (Crude product) will be dissolved in 270 ml of dimethylformamide. 28.2 g of calcium carbonate are then added and 15 g of lithium bromide are added, and the reaction mixture is stirred at 115 ° C. for 5 hours It is allowed to cool, the inorganic salts are filtered off with suction, the filtrate is concentrated and ice water is precipitated by. The crude product (5.5 g) is chromatographed on 300 g of silica gel. The unified parliamentary groups will be Recrystallized from diisopropyl ether. 3.5 g of njJ-hydroxy-methylene-carbonate are obtained 3-one from melting point 145.5 to 149 ° C.

Example 3

2.56 g of njS-acetoxy-IS & loji-methylen-Sa-androst-len-3-one are dissolved in 250 ml of distilled methanol. After adding 25 ml v / water and 2.3 g potassium carbonate is heated to boiling under nitrogen for 1 hour. Then it is concentrated to about 1/3 of the volume in vacuo Poured ice water, the precipitate is filtered off, washed out and dried. 2.4 g of 170-hydroxy-15j9,160-methylen-5a-androst-1-en-3-one are obtained from a melting point of 145.5 to 149 ° C.

Example 4

600 mg of UjS-Hydroxy-ISftloiS-methylen-Sa-androstl-en-3-one are left to stand in 2.4 ml of pyridine and 1.2 ml of propionic anhydride for 24 hours at room temperature. The reaction mixture is then poured into ice water, the precipitate is filtered off, washed out and dried. After recrystallization from diisopropyl ether, 300 mg of 170-propionylcxy-150,16j3-methylen-5a-androst-1-en-3-one with a melting point of 106 bis are obtained 108 ⁰ C.

Example 5

ίο 500 mg lJßHydroxylS / Mjy

l-en-3-one are in 2 ml of abs. Benzene and 0.5 ml abs. Dissolved pyridine and with ice cooling and stirring dropwise with 03 ml of phenylpropionic acid chloride in 1 ml abs. Benzene added. Then the ice bath is removed

and stirred for 24 hours at room temperature. After ice water precipitation, the precipitate is filtered off, washed out and dried. 410 mg are obtained after recrystallization from diisopropyl ether 17jS-phenylpropionyloxy-150.1 öjS-methylene-Soc-androst-

1-en-3-one from melting point 93 to 96 ° C.

Example 6

500 mg of 17iJ-Hydroxy-15jS, 16ß-methylen-5 "-androst-1-en-3-one are in 2 ml of abs. Pyridine with 1 ml of enanthic anhydride for 24 hours at room temperature stirred and worked up analogously to Example 5. One obtains WHeptanoyloxy-lSjS.ie/J-methylen-Sa-androst-l-en-

3-one from melting point 80 to 82 ° C (from diisopropyl ether).

Example 7

The solutions of 1 g of 17j9-hydroxy-15j3,16 £ -methylene-5 «-androst-l -en-3-one in 70 ml of benzene and 10 mg of p-toluenesulfonic acid in 20 ml of benzene are added evaporated half the volume in each case, cooled to room temperature, combined and with 1 ml of dihydropyran

offset. This mixture is stirred for 1 hour at room temperature, then with ice-cold sodium bicarbonate solution shaken and washed neutral with water. After drying with sodium sulfate and Evaporation of the solvent gives 17 /? - Tetra-

hydropyranyloxy-15j3,16 | 9-methylen-5 "-androsM-en-3-one.

UV: £ 230 = 10 500.

Claims (1)

Patent claims: 1. 15j3,16jS-methylene-5 <x-an <irost-l-ene of the general formula R a Wasserstoifatom, a lower alkyl or vranylgruppe, or is the acyl radical of one of the usual dchemie carboxylic acids having 1 to 16 Ko 4nÄtomen ^U, and a process for producing α ™ gekennze.cnnei by one AAU in / hende "m Α -ring saturated steroids in per se corresponding, .in A ^ gg ^^" ^ ^^^ "and - each ·· ■ '- - ¹ - ¹ -