DE1249267B - Process for the production of la 7a dimethyl steroids of the androstane series - Google Patents

Description

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ο -25/04

Number: I 249 267

File number: Sch 34998IV b / 12 ο

Filing date ^ April 18, 1964

Opened on: September 7, 1967

The invention relates to a method of manufacture of 1,7-dimethyl steroids of the general formula

CH ₃

in which Ri is a hydrogen atom or a lower alkyl, vinyl or ethynyl radical and R> a hydrogen atom or the remainder of a physiologically acceptable inorganic or organic acid means.

The compounds which can be prepared according to the invention are strong androgens. This is surprising in that as z. B. in 17a-methyl-testosterone the introduction of a la- or 7a-methyl group sex-specific effectiveness significantly reduced.

The androgenic effect of, for example, the l, 7n-dimethyl and IaJaATa - trimethyl - 5a - androstane - 17 / versus testosterone is observed. The new substances can be used not only subcutaneously, but also z. B. also apply peroal, for which the 17u-methyl compounds are particularly suitable. The esters of the steroids which can be prepared according to the invention with higher fatty acids show protracted effectiveness.

The table below shows the values for the androgenic and anabolic effects of the invention Connections and testosterone juxtaposed. The values listed are in the usual Androgen anabolic test on castrated billy rats after twelve subcutaneous applications of 1 mg of the substance to be tested per animal has been determined daily.

substance

Seminal Lcvator bladder I nni
(mg 100 g rat)

l «.7u-dimethyl-5« -andtOstan- j |

17 /> '- ol-3-one "627 I 55

l'i, 7a, 17 "-trimethyl-5a-an- |

drosian-17 / i-ol-3-on j 505 55

Testosterone j 99 31

Method of manufacture

of 1, 7 * -dimethyl steroids of the androstane series

Applicant;

Schering Aktiengesellschaft,
Berlin 65, Mullerstr. 170/172

Named as inventor:

Dr. Josef Hader,

Dr. Rudolf Wiechert,

Dr. Friedmund Neumann, Berlin

The substances which can be prepared according to the invention are androgenic because of their surprisingly high levels Efficacy can be used advantageously in all diseases that are known to be androgen therapy make necessary such. B. for the treatment of climacteric virile and its sequelae, for the treatment of peripheral circulatory disorders, heart failure. protein depletion in infectious diseases, Liver cirrhosis or for preparation and follow-up treatment, etc.

However, new strongly androgenic substances are also of great clinical interest in Treatment of breast cancer and genital cancer, for which the new lf /, 7 (/ - dimethyl steroids according to the invention are therefore preferably suitable appear because, in addition to the already mentioned high androgenic effect, they also have a sufficient have high anabolic effects.

The new l, 7u-dimethylsteiOids are used for therapeutic purposes with those in the pharmaceuticals Usual pharmaceutical additives. Carriers and taste corrections according to known Methods processed into the commercially available drug forms. Come for oral application especially in question tablets. Coated tablets. Capsules, pills, suspensions or solutions and for parenteral administration, especially oily solutions, such as. B. Scsem oil or castor oil solutions, optionally also a diluent, such as. B. benzyl benzoate or benzyl alcohol,

709 640/579

may contain. The concentration of the active ingredient in the drugs formulated in this way is natural also depending on the form of administration: the orally administrable medicaments preferably contain 1 to 20 mg per 1 to 1.5 g of finished drug and the oily solutions per 1 ml, preferably 5 to mg of active ingredient.

The compounds that can be prepared according to the invention are synthesized by methods known per se, which are characterized in that, if Ri in the end product is a hydrogen atom,

a) the C - C double bond of la, 7a-dimethyltestosterone, optionally after ketalization of the 3-keto group, reduced or

b) the 17-keto group of a la, 7a-dimethyl-5a-androstane-3,17-dione-3-ketal reduced to the hydroxyl group or, if Ri is a lower alkyl, vinyl or ethynyl radical in the end product means,

c) a laJ

tal in 17-position grignardieit or for introduction of the 17a-ethynyl radical reacts with an acetylide and optionally the introduced 17ü-ethynyl group partially or completely hydrogenated or

d) the J ⁴ - or the. ^ - double bond of a 17a-alkyl-, 17a-vinyl- or 17a-ethynyl-la, 7a-dimethyl- / l ⁴ -androstene-17 / tf-, if appropriate ketalised in the 3-position ol-3-one is reduced and, if appropriate, a 3-OH group formed during the reduction is oxidized back to the 3-keto group

and then the ketal group present after a) to d) and optionally the according to a) to d) any free 17/7 hydroxyl group present esterified. The 17a-vinyl and 17a-ethyl steroids which can be prepared according to the invention are expedient obtained by partial or complete hydrogenation of the corresponding 17a-Älhinylverbindungen to the synthesis of which, instead of the Grignard compounds, the corresponding acetylides can also be used. The ketals of l «, 7a-dimethyl-5a-androstane-3,17-dione used as starting material] can, for example by Birch reduction of IaJa-Dimethyltestosterone, Chromic acid oxidation of the 1 a, 7a-dimethyl-5a-androstan-17jS-ol-3-one thus obtained to the corresponding 3,17-diketone and ketalization of the 3-keto group. For this procedure no protection is sought within the scope of the present invention. The following formula scheme provides an overview of the synthetic route.

OH

Formula scheme
OH

H ₃ C

OH

Reduction, possibly reoxidation of a 3-OH group formed as an intermediate

-CH ₃

example 1

25 ml of condensed ammonia and 100 mg of metallic lithium, added in small portions, are left to react for ^{2 1 Za hours.} Then Ig la, 7a-dimethyl- ^{I 4} -androsten-l7 ^ -ol-3-one, dissolved in 20 ml of absolute ether and 20 ml of absolute dioxane, is added dropwise within 30 minutes. After a further 30 minutes, 5 g of ammonium chloride are added and the ammonia is allowed to evaporate. Ether extraction, washing, drying and evaporation in vacuo give a crude product which is _{chromatographed on 50 g of SiO 2} (10% H ₂ O content) with methylene chloride and a CHaClj - CHCk mixture. After the UV-inactive fractions have been combined and recrystallized from isopropyl ether, I «, 7a - dimethyl - 5» - androstane · 17 / i - oil - 3 - one with a melting point of 157 to 158 ° C. Yield 55% of theory.

Example 2

a) The crude reduction product shown in Example 1 is dissolved in 15 ml of methylene chloride and 50 ml of acetone, then 1.2 ml of 8N chromic acid solution is added dropwise while cooling with ice water. The mixture is stirred for a further 15 minutes at room temperature, poured into ice water and extracted with methylene chloride. After drying over Na ^ SO-i, concentration and recrystallization from isopropyl ether, 1α, 7α-dimethyl-5α-androstane-3,17-dione with a melting point of 161.5 to 162 ° C. is obtained ml of absolute CH2Cl2 dissolved, 1 ml of freshly distilled ethylene glycol was added to the solution and stored for 22 hours at room temperature with exclusion of moisture and stirring. Then the mixture is stirred into ice water and NaHCO-solution, and extracted with CHoCl * and chromatographed on neutral Al2O3 4- I ⁰ ZoHaO. Elution with benzene, 36% of theory is obtained IaJa-dimethyl-5a-androstan-3,17-dione-3-äthylenketal a melting point of 147.5 to 149 C. ^A yield.

b) 610 mg of 1 "I" -dimelhyl-5 "-andio>> Uin-.3.17-dione-3-ethyl ketal is dissolved in 35 ml of methanol, 0.85 ml of 1N NaOH is added and the mixture is stirred at 0 ° ⁰ C with 120 mg NaBHj. The mixture is then stirred for a further 1 hour at room temperature, poured into ice water and extracted with CH 2 Cl 3. Washing, drying over NagSOi and concentration in vacuo gives laJu-dimethyl-5a-androstane-17 /: i-ol-3-one-3-ethylenketai. The crude ketal is dissolved in 40 ml of methanol, 1.2 ml of 8volumpro2entige sulfuric acid are added and the mixture is heated on the steam bath for 35 minutes. After cooling, the mixture is stirred into ice water, neutralized with NaHCO ₃ and extracted with CHjCl. After washing, drying and concentrating in vacuo, it is recrystallized from isopropyl ether. 1, 7a-dimethyl-5-i-androstane-17 /? - o1-3-one with a melting point of 157 to 158 ° C., identical to the product obtained according to Example 1, is obtained. Yield 65% ₍ of theory.

35

Example 3

1.5 g of the IaJa-dimethyl-5'-androstane-3,17-dione-3-äthyIenketal which can be prepared according to Example 2, a) are dissolved in 100 ml of absolute benzene and, with ice-cooling and stirring, to an ethereal methylmagnesium iodide solution, prepared from 2 , 7 g of Mg turnings, 6 ml of methyl iodide and 35 ml of absolute ether, added dropwise. This reaction mixture is stored for 4 hours with stirring at room temperature. 400 ml of a 10% strength aqueous ammonium chloride solution are then added while cooling with ice. The aqueous phase is separated off and extracted with ether. Ether phase and benzene phase are combined, washed neutral with water, dried over Na> SOi and concentrated in vacuo. After recrystallization from isopropyl ether, 1 ", 7", 17 "-trimethyl-5a-androstane-17 / i-ol-3-one-3-ethylcnketal is obtained. This is dissolved in 60 ml of methanol, treated with 1.7 ml of 8 percent strength by volume sulfuric acid, refluxed for 35 minutes and, after cooling, stirred _{into 180 ml of water containing 0.6 g of Na 2 CO 2.} It is extracted with CHsCk, washed neutral, dried over Na2SOj and concentrated in vacuo. The residue is recrystallized from isopropyl ether. 1,7a, 17a-trimethyl-5a-androstane-17 / i-ol-3-one with a melting point of 173.5 to 174.5 ° C. are obtained. Yield 58% of theory.

Example 4

Analogously to Example 3, 1d, 7a-dimethyl-5a-androstane-3, l7-dione-3-ethylene ketal is obtained by reacting with ethyl magnesium iodide IuJa-dimethyl-lJu-ethyl-Sa-androstan-n / I-ol ^ -one; F. 138.5

up to 139.5 ⁰ C.

Example 5

1 g of the IaJu-dimethyl-5a-androstane-3,17-dione-3-ethylcnketal prepared according to Example 2, a). dissolved in 40 ml of absolute tetrahydrofuran, is added dropwise to a Grignard solution, which is prepared as follows has prepared:

6.5 g of ethyl bromide, dissolved in 30 ml of tetrahydrofuran, are added dropwise with stirring to 2.9 g of Mg turnings in absolute tetrahydrofuran. After 45 minutes of refluxing, the solution is decanted off from the residue and, while stirring and passing in acetylene, 35 ml of absolute tetrahydrofuran, through which acetylene had previously been passed for 15 minutes, are slowly added. After 30 minutes of further introduction of acetylene, the steroid solution is then added dropwise. After a reaction time of 21 hours at 70 ° C., the mixture is cooled to O ¹ C. and 400 ml of 10% strength aqueous NHCl solution are added. After extraction with ether, washing and drying of the ether phase, it is concentrated to dryness in a vacuum. The residue is triturated with isopropyl ether and filtered off with suction. The ta, 7a-dimethyl-17 "- ethinyl - 5a - androstane -1 Iß - oil - 3 - one - 3 - ethylene ketal is obtained. This is dissolved in 40 ml of methanol, 1.5 ml of 8 percent strength by volume sulfuric acid are added and the mixture is refluxed for 35 minutes. After cooling, the solution is stirred into ice water and extracted with methylene chloride. The CH ^ Ck phase is washed neutral with water, dried over Na ^ SOj, evaporated in vacuo and the residue is recrystallized from ethyl acetate. Obtained Iaj ₁ X- dimethyl na-ethynyl-Sa-androstan-17 / y-ol-3-one: F. 161 to 162.5 ⁰ C.

Example 6

770 mg of the 1 ", 7" -dimethyl-17 "-äthinyl-5a-androstane-17, ⁱ -ol-3-one-3-ethylcnketal prepared according to Example 5 are dissolved in 80 ml of pyridine and added with 120 mg 5% Pd-Kohlc catalyst hydrogenated until 1 mol of hydrogen is absorbed. The catalyst is then filtered off and evaporated to dryness in vacuo. The residue is dissolved nu: n in 20 ml of methanol, 0.7 ml of 8% by volume sulfuric acid is added and the mixture is refluxed for 30 minutes. It is then poured into an aqueous ice-cold solution of 0.3 g of sodium carbonate and extracted with .Methylene chloride. After washing. Drying and concentration in vacuo, the residue is recrystallized from isopropyl ether. One obtains lii _> 7a-dimethyl-17a-vinyl-5a-andiOstan-17p'-ol-3-one; F. 140.5 to 141.5 ⁰ C.

Example 7

10 ml of ammonia are condensed and 35 mg of lithium are added in small portions. After one hour, a solution of 302 mg of la.7u, 17 </ - trimethyll.i-androsten-17 / i-ol-3-one, dissolved in 6 ml of absolute tetrahydrofuran, is added dropwise and the mixture is stirred for a further 30 minutes. 1.5 g of ammonium chloride are then added and the ammonia is allowed to evaporate. It is extracted with ether, washed with water, dried over NaoSOi and concentrated in vacuo. The residue is dissolved in 4 ml of CHiCl. » and 12 ml of acetone and oxidized with 0.4 ml of standard chromic acid solution at ⁰ ° C. After pouring into ice water, extraction is carried out with CI-LCl. ;, washed out, dried, concentrated in vacuo and the residue is chromatographed on 35 g of SiO ₂ (10% H ₂ O content). Eluting with CCl4-CHCl> -enuschen and pooling the UV-inactive fractions gives laJa.na-trimethyl-Sa-androstan-n / J-ol-3-one with a melting point of 173.5 to 174 ° C, identical to the product prepared according to Example 3. Yield 42% of theory.

Example 8

to 2g 1a, 7 "-Dimethyl-.l ⁴ -andiOsten-17 /? - ol-3-one are dissolved in 100 ml of absolute benzene, 50 mg of p-toluenesulfonic acid and 5 ml of ethylene glycol are added and stirred for 48 hours in a nitrogen atmosphere Heated to reflux. The water formed during the reaction is suitably bound by attaching an extraction _{thimble, filled with neutral Al 2} Os, between the reaction flask and the reflux condenser. The benzene solution is washed with 1N NaOH and with water and, after drying and concentration, chromatographed in vacuo over 150 neutral Λ1 ·> 03 I 1% water. Elution with benzene obtained lu, 7a-Dimethyk.l -androsten47p' ^{5-ol-3-one-3-äthylenketal,} mp 150.5 to 153.5 ⁰ C. 695 mg of the thus obtained 1 ', 7a- Dimethyl-l ⁵ -androstan-17 | i-ol-3-one-3-ethylene ketals are dissolved in 40 ml of absolute ethanol and, after the addition of 77 mg of 5% Pd on BaSOj, which had been pre-hydrogenated in 30 ml of ethanol, hydrogenated under normal conditions. After the uptake of hydrogen has come to a standstill, the catalyst is filtered off, concentrated in vacuo and the residue is recrystallized from pentane. Lo, 7u-dimethyl-5rt-androstane-17ß-ol-3-one-3-ethylene ketal is obtained from

F. 160 to 161 ⁰ C.

The 3-ethylene ketal thus obtained is dissolved in 40 ml of methanol and refluxed for 30 minutes with the addition of 1.5 ml of 8% by volume sulfuric acid. After cooling, it is poured into ice water, neutralized with sodium carbonate, extracted with methylene chloride, washed, dried, concentrated in vacuo and the residue recrystallized from isopropyl ether. Is obtained la, 7u-dimethyl-5 "androstan-17 / i-ol-3-one, melting at 156-158 ⁰ C, identical to that prepared according to Example 1 product. Yield 26% of theory.

Example 9

414 mg of! U, 7u-dimethyl-5'-androstan-17p'-ol-3-one are dissolved in 1.66 ml of absolute pyridine, 0.83 ml of acetic anhydride are added, and the reaction mixture is left to stand for 16 hours at room temperature. It is then stirred into ice water, acidified with dilute hydrochloric acid, extracted with CH ₂ Cl ?, washed neutral, dried over Na> SO 4, concentrated in vacuo and the residue recrystallized from isopropyl ether. 7a-dimethyl-5'-androstane-17 / ^ - ol-3-one-17-acetate with a melting point of 159.5 to 161 ° C. is obtained. Yield 86% of theory.
60

Example 10

318 mg of 1 «Ju-dimethyl-sci-androstan-17p'-ol-3-one are dissolved in 1 ml of dry pyridine, 0.70 ml of propionic anhydride are added and the mixture is left to stand for 15 hours at room temperature. After stirring into ice water and acidification with dilute hydrochloric acid, the _{mixture is extracted with CH 2} Cb, washed neutral, dried over Na — SO — O, concentrated in vacuo and

recrystallizes from isopropyl ether. 1ct, 7a-dimethyl-5a-androstane-17 / io] -3-one-17-propionate is obtained; F. 125 to 126 ⁰ C.

B e i s ρ i e 1 11

318 mg of la, 7a-dimethyl-5o-androstan-17-ol-3-one are dissolved in 2 ml of dry pyridine and 0.3 ml of dichloroacetyl chloride is added dropwise ^{at 0 ° C.} It is left to stand in the refrigerator overnight, then poured into ice water, acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride phase is washed neutral with water, dried over Na2SOi and evaporated in vacuo. After recrystallization of the residue from isopropyl ether, 1, 7 "-Dimethyl-Sa-androstane-IV / i-ol-S-one - ^ - dichloroacetate is obtained; F. 144 to 145 ⁰ C.

Claims (1)

Claim: 20th Process for the production of la, 7a-dimethyl steroids the androstane series of the general formula OR ₂ CH ₃ Γ-Ri -CH ₃ in which Ri is a hydrogen atom, a lower one 10 Alkyl, a vinyl or ethynyl radical and R ₂ denotes a hydrogen atom or the residue of a physiologically acceptable inorganic or organic acid, characterized in that, according to methods known per se, if Ri in the end product denotes a hydrogen atom, a) the C - C double bond of la, 7a-dimethyltestosterone, optionally after ketalization of the 3-keto group, reduced or b) the 17-keto group of a 1,7α-dimethyl-5α-androstane-3,17-dione-3-ketal reduced to the hydroxyl group or, if Ri is a lower alkyl, vinyl or ethynyl radical means, c) a 1, 7a-dimethyl-5'-androstane-3,17-dione-3-ketal Grignarded in 17-Stellun ^ or to introduce the 17 "-ethynyl radical with a Acetylid converts and optionally the introduced 17a-Äthmylgruppe partially or fully hydrogenated or d) the J ⁴ - or the / ^ - double bond of a 17a-alkyl-, 17a-vinyl- or 17a-ethynyl-1 a, 7a-dimethyl- / |, which is optionally coalized in the 3-position ⁴ -androsten-17 /? - ol-3-one is reduced and, if appropriate, a 3-OH group formed during the reduction is oxidized back to the 3-keto group and then the Kctalgruppe present after a) to d) is split off again and optionally the free 17β-hydroxyl group present according to a) to d) is esterified. 709 640/579 8.67 O Bundesdruckerei Berlin