DE1468632C - öalpha Acetylthio 4 en 3 on steroids and process for their production - Google Patents

Description

The present invention relates to new 6u-acetylthio-4-en-3-one steroids the general formula

SCOCH ₃

in which R _{1 is} a hydrogen atom or the methyl group and R _{2 is} a hydrogen atom or an HC ξξ C group. The invention also relates to a process for the preparation of these compounds. This process is characterized in that a corresponding 5a-hydroxy-6 /? -AcetyIthio-3-one compound of the general formula is used in a manner known per se

HO

SCOCH ₃

in which Rj has the above meaning, R _{2 stands} for OCOCH ₃ or OH and R _{3 stands} for a hydrogen atom or a HC == C group, optionally under intermediate protection of further hydroxyl or oxo groups present in the molecule, with an acid or successively with the halide of an inorganic oxygen acid in the presence of a base and then treated with an acid and optionally then acetylated with an acetylating agent.

Sa-hydroxy-o / i-acetylthio-S-one compounds serve as the starting material for the process according to the invention of the following general formula:

HO

SCOCH,

in which R _{1 is} hydrogen or the methyl group, R _{2 is} the group OCOH ₃ or OH and R _{3 is} a hydrogen atom or the ethynyl group. As specific examples of the starting materials are mentioned as follows: 5 'hydroxy-6 / i-acetylthio-17 / i-acetoxy-5 "androstan-3-one, 5' l7ß-dihydroxy- 6ß - acetylthio - 5" - androstan - 3 - one, 5 "- hydroxy- 6ß- acetylthio-17 / i-acetoxy- 5" -estran - 3 -one, 5a- hydroxy - 6ß - acetylthio - 1 7β - acetoxy - 17a - äthinyl-5a - estran - 3 - one, 5a, l 7β - dihydroxy - 6ß - acetylthiona-äthinyl-Sa-oestranO-one. These 5a-oxy-6 / i-acetylthio-3-one steroids used as starting materials are made from the corresponding 4-en-3-one steroids, through the intermediates 5-en-3-ketal steroids and 5 ", 6" -epoxy-3- on-steroids by successive treatments with an alcohol such as ethylene glycol in the presence of an acid, a peroxide such as monoperphthalic acid and a lower alkanethiolic acid.

The dehydration is carried out with the aid of an acid or a halide of an inorganic oxy acid in the presence of a base. If an acid is used as the reactant in this reaction, the product consists of the 6'-acetylthio-4-en-3-one steroid. If a halide of an inorganic oxygen acid in the presence of a base is used as the reactant, the 6β-acetylthio _: 4-one steroid is obtained as the product. It has been found that the latter product, ie the 6 / i-epimer, can easily be converted into the former product, the 6a-epimer, by means of an acid. Therefore, the former product can also be synthesized by sequentially treating with a halide of an inorganic oxyacid in the presence of a base and then with an acid. Both organic and inorganic acids can be used as acids for the preparation of the 6a product from the starting materials or from the 6 / f epimer. There are z. B. hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, tartaric acid or acetic acid. Halides of sulfuric and phosphoric acid, such as thionyl halides, phosphoryl halides, in which the halides are chloride, bromide or iodide, can be used as halides of an inorganic oxygen acid. Organic tertiary amines, such as pyridine, trialkylamine (for example trimethylamine, triethylamine) or dimethylaniline, can be used as the base together with the halides of the inorganic oxygen acids.

The reaction using the acid is carried out in one solvent or a mixture of several Solvent, advantageously carried out with a higher dielectric constant. For example become an organic acid such as acetic acid, an alkylated amide such as dimethylformamide, or others polar solvents such as acetone, dioxane or tetrahydrofuran are preferred. The reaction can be great fast, d. H. within minutes or hours, using severe conditions such as dry Hydrogen chloride in acetic acid, or slowly, especially within 1 or 2 days, using weak acids. The reaction with the halide of the inorganic Oxygen acid occurs much faster in the presence of the base listed above, within several Minutes at a low temperature; d. H. at about 0 "C. When reacting with the halide of the Inorganic oxyacid can also contain hydroxyl groups as the 5'-hydroxyl group, e.g. B. the 17-hydroxy group, becoming dehydrated. In such cases it is advantageous to have additional ones present in the molecule To protect hydroxyl or oxo groups intermediately.

The compounds of the invention show characteristic physiological activities, e.g. Legs striking inhibition of gonadotropic hypersecretion, about 1 to 10 times the inhibitory effect of Testosterone or the 10- to 100-fold inhibitory effect of progesterone, with slight side effects the hormonal activities due to the basic structure, i.e. the antigonadotropic activity dominates

about the other hormonal activities. For example, the compound Ι, οα-acetylthio-l 7 / J-acetoxy-4-androsten-3-one, a gonadotropic hypersecretion in the same degree as the compound T, testosterone, which has the same basic structure as the Compound I, as can be seen from Table I below.

Table I.

Comparison of antigonadotropic activity and androgenic / myotropic effectiveness

in parabiotic mice ¹ )

Total dose (mg) ² )

Castrated males S. Β.ψ) V. R ³ J *)

Untouched female ovaries *)

Inhibition

Compound I

Connection T

Untouched males — females castrated males — females.

1.0 1.0

95.3

245.2 '

61.1

30.9

17.6

44.4

15.2

8.3

41.9 (C)

42.0 (C)

48.0 (Fi)

95.0 (V)

113.0 112.8

') See "Inhibitory effect of various steroids on gonadotropic hypersecretion in parabiotic mice", T. Miyake et al., Endocrinology, 69 (3), pp. 534-546 (1961).

² ) Subcutaneously for ten consecutive days in a castrated male in symbiosis.

³ ) Seminal vesicles and ventral prostates, each of which exhibits androgenic / myotropic activity. ) All weights of the organs are given in milligrams per 100 g of body weight.

⁵ ) Calculated according to the formula: 100 X (V-QI (V-Vi), where V, C and Vi mean the average weight of the ovaries of the untouched female (column 4), namely V of castrated males-females (line 4 ), C from compound I or T (line 1 or 2) and Vi from untouched males-females (line 3), according to the literature cited above.

From the information given above, it can be seen that the compound I has a low androgenic / myotropic Efficacy in comparison with Compound T shows as can be seen from the S.B. and V.P. values

is. The weak androgenic effect was determined by comparative tests, as can be seen from Table II it is confirmed.

Table II
Comparison of the androgenic / myotropic effects in rats ¹ )

Total dose (mg) ² )

Castrated males

S. B.Y)

VP ³ ) *)

.1 (SB) ⁵ )

1 (VP) ⁵ )

comparison

Compound I
comparison
Connection T
Effect I / T

2.0 2.0

6.3

12.4

7.1

131.0

6.4

21.5

6.8

116.5

6.1

123.9 20.3

15.1

109.7 7.3

') See "Myotrophic activity of 19-nortestosterone and other steroids determined by modified levator and muscle, ethod",

LG H ershberger and coworkers, Proc. Soc. Exper. Biol. Med., 83 (1), pp. 175-180 (1953). ² ) Subcutaneously for ten consecutive days in a castrated male in symbiosis. ^J ) Seminal and ventral prostate, each of which exhibits androgenic / myotropic activity.

⁴ ) All weights of the organs are given in milligrams per 100 g of body weight.

⁵ ) Difference between comparison and connection (f or T) in each of the SB and VP who

-Values.

In addition, the compound H, 6'-acetylthio-65 with a lower androgenic / myotropic activity (j-ethinyl-17 / i-acetoxy-4-estren-3-one, shows a higher one than Compound I, as shown in Table III llemin effect on gonadotropic hypersecretion, about can be seen. ten times the inhibitory effect of testosterone,

Table III

Comparison of the antigonadotropic effectiveness and androgenic / myotropic effectiveness

on mice (parabiosis) ¹ )

Total dose (mg) ² )

Castrated male S.B? F) V. RY) 35.7 7.7 147.2 50.1 37.2 11.6 27.6 7.0

Untouched

female

Ovaries ⁴ )

Inhibition

Compound II

Connection T

Untouched male-female
Castrated male — female.

0.1 1.0

48.9 (C)

42.2 (C)

38.7 (K /)

125.5 (V)

88.2 96.0

') See "Inhibitory effect of various steroids on gonadotropic hypersecretion in parabiotic mice", T. Miyak e and coworkers, Endocrinology, 69 (3), pp. 534 to 546 (1961).

² ) Subcutaneously for ten consecutive days in a castrated male in symbiosis.

³ ) Seminal vesicles and ventral prostates, each of which demonstrated androgenic / myotropic activity. *) All weights of the organs are given in milligrams per 100 g of body weight.

³ ) Calculated according to the formula: 100 X (VC) I (V- Vi), where V, C and Vi mean the average weight of the ovaries of the untouched female (column 4) , namely V of castrated males-females (line 4 ), C from compound I or T (line 1 or 2) and Vi from untouched males-females (line 3), according to the literature cited above.

From the experiments cited above it is clear that the compounds produced according to the invention as a control agent for menopausal diseases and for hypergonadism or earlier Puberty, as ovulation inhibitors and contraceptives particularly suitable.

The compounds according to the invention are also of essential importance as intermediates in the production of thieno-fJ4 ', 3', 2'-4,5,6] -steroids, which are characterized by their hormonal effectiveness. You have z. B. specific antiprogesteronal, especially antidecidomatogenic activity and are suitable as anti-fertilizers.

25 A with a melting point of 225 to 226 ° C; [a] S * = -83.1 ± 2 ° (c = 1.030, chloroform). UV spectrum: 4 ^hI k SaO ¹

4'a ^h * ^ai1oI 233.5n ^ ( _f 5140). IR spectrum: y

example 1

6a-Acetylthio-17 /? - acetoxy-4-androsten-3-one
a)

35

40

Sa-hydroxy-oß-acetylthio-nß-acetoxy-5a-androsten-3-one

To prepare the starting product, a solution of 7.557 g of S ^ -äthylenedioxy-Sa.oa-epoxy-17 /? -Acetoxy-5a-androstene. (Ringold and coworkers, Tetrahedron, 7, p. 138 [1959]) in 30 ml Thiolacetic acid left to stand at room temperature for 3 days. After evaporating to dryness under reduced pressure, the reaction mixture was added with 80 ml of acetic acid and 15 ml of water and then heated on a water bath for 1 hour. Water was then added to the mixture and the mixture was extracted with ether. The extract solution was then washed successively with sodium hydroxide solution and with water, dried and evaporated. To the obtained residue, 10 ml of acetic acid and 30 ml of pyridine was added and heated on a water bath for I ¹ T ₂ hours. The acetylated mixture was worked up in the usual way and the crude acetate obtained was recrystallized from an ether-petroleum ether mixture, 6.103 g of crystals being obtained.

After chromatography on synthetic magnesium silicate (known under the trade name “Florisil”) turned an eluate of the recrystallized mother liquor into 428 mg of crystals of the same substance receive. The combined crystals gave, after recrystallization from acetone-hexane, pure 5a-hydroxy-o / f-acetylthio-n / I-acetoxy-Sa-androstan-S-one 3454 (OH); 1724, 1277, 1252, 1046, 1034 (O-acetyl); 688, 1136, 1120 (S-Acetyl and 3-On).

Analysis for C ₂₃ H ₃₄ O ₅ S:

Calculated ... C 65.37, H 8.11, S 7.59; Found ... C 65.37, H 8.18, S 7.61.

b) 6a-acetylthio-l 7/9-acetoxy-4-androsten-3-one

Dry hydrogen chloride was allowed to flow through a solution of 1.00 g of the Sii-hydroxy-o / f-acetylthio ^ / J-acetyloxy-sa-androstan-3-one obtained above in 30 ml of glacial acetic acid for 1 hour. After that, water was added to the reaction mixture and then extracted with ether. The ethereal solution was washed neutral with water and evaporated to dryness, yielding 934 mg of the crude product. After chromatography over 30 g of "Florisil", eluates with benzene and benzene-ether mixtures (9: 1-8: 2) gave 638 mg of a crystalline substance, which after recrystallization from methanol 498 mg of 6a-acetylthio-17 /? - acetoxy-4-androsten-3-one in the form of prisms with a melting point of 192 to 194 ° C; Ia] I " = + 40.3 ± 2 ° (c = 1.016, chloroform). UV spectrum: A * 2? ^Bo1 235 m ₍ x (f 16 820). IR spectrum: y £>cm" ¹ : 1741, 1244, 1044, 1016 (O-acetyl); 1687, 1618, 1134 (S-acetyl and # -3-On).

Analysis for C ₂₃ H ₃₂ O ₄ S:

Calculated ... C68.28, H7.97, S7.93; Found ... C 68.39, H 8.10, S 7.89.

Example 2

6a-acetylthio-l 7 /? - acetoxy-4-androsten-3-one a) 6 / J-AcetyIthio-l 7 /? - acetoxy-4-androsten-3-one

To a solution of 6.531 g of 5-hydroxy-6 ^ -acetylthio-17/5-acetoxy-5a-androstan-3-one in 65 ml of pyridine was added dropwise 4 ml of thionyl chloride with stirring and at 0 ⁰ C. After allowing to react for 5 minutes, the reaction mixture was poured into ice water and then extracted with chloroform. The extract solution was diluted with

aqueous hydrochloric acid solution and then washed with water, then dried and evaporated to dryness. 4.75 g of a solid crude product were obtained. After recrystallizing it from an acetone-hexane mixture, 2.55 g of crystals were obtained. From the mother liquor from this recrystallization, an additional 205 mg of the same crystals were obtained by chromatography on “Florisil”. After further recrystallization from ether-petroleum ether, the combined amounts of crystals yielded pure 6 ^ -acetylthio-17 ^ -acetoxy-4-androsten-3-one in the form of small crystals with a melting point of 144 to 145 ° C; [α] ?, '= +186.5 ± 2 ° (c = 1.026, chloroform). UV spectrum: A ** f ^no1 237 πΐμ (ε 15960). IR spectrum: y ™ ⁴ 4cm " ¹ : 1740, 1243, 1046, 1040 (O-acetyl); 1698.1132 (S-acetyl); 1683.1614 (zf-3-On). Analysis for C ₂₃ H ₃₂ O ₄ S:

Calculated ... C 68.28, H 7.97, S 7.93;
found .... C 68.54, H 8.04, S 7.82.

b) 6 <z-Acetylthio-l 7 /? - acetoxy-4-androsten-3-one

2.755 g of the o / S-acetylthio-n / S-acetoxy-4-androsten-3-one obtained above are in a mixture of 600 mg of p-toluenesulfonic acid monohydrate and 30 ml Glacial acetic acid dissolved and the mixture was subjected to reaction at room temperature for 2 days. To After adding water, the reaction mixture was extracted with ether. The extract solution was with Water and then washed with dilute sodium carbonate solution, then dried and evaporated. The residue was chromatographed on 60 g of “Florisil”. From eluates with benzene and with benzene-ether mixtures in a ratio of 9: 1 to 4: 1, 1.972 g of solid product were obtained, which according to Recrystallization from methanol 1.241 g of 6a-acetylthio-17/3-acetoxy-4-androsten-3-one in the form of prismatic crystals with a melting point of 184 to 18 6 ° C. Another recrystallization from The same solvent gave a pure substance with a melting point of 192 to 194 ° C.

Example 3

6a-acetylthio-l 7a-ethyinyl-l 7jS-hydroxy-4-estren-3-one and its acetate

a) Sa.nß-Dihydroxy-ojS-acetylthio-na-äthinyl-5a-oestran-3-one

To prepare the starting compound, 322 mg of 5a, 6a-epoxy-17a-ethinyl-5a-estran-3 (3.17jS-diol (R i η g ο 1 d and coworkers, J. Am. Chem. Soc, 81, 436, p. 3120 [1959]) dissolved in 6 ml of thiolacetic acid and the solution was allowed to stand at room temperature for 9 days. Thereafter, the reaction mixture was to Dry evaporated under reduced pressure. Glacial acetic acid was added to the resulting residue and evaporated again under reduced pressure. The residue obtained was initially washed with water added and then extracted with ether. The ether solution was made with dilute aqueous sodium hydroxide solution and then washed with water, dried over sodium sulfate and then, to remove the solvent, distilled, whereby 384 mg of an oily product was obtained. This product was identified as the amorphous 6 / S-acetylthio-17a-ethinyl-5a-estran-3ß, 5a, 17 / S-triol by means of the IR spectrum:

_y chloroform _cm -l. 3 ^ 345 ^ 335g

(S-acetyl) recognized.

The amorphous 6 / I-acetylthio-17a-ethinyl-5a-estran-3jS, 5a, 17yS-triol obtained above was oxidized with 77 mg of chromium trioxide in a dilute sulfuric acid-acetone mixture according to the Jones method for about 1 minute. Water was then added to the mixture and extracted with dichloromethane. The extract was washed with dilute aqueous sodium carbonate solution and then with water and treated further as mentioned above. The crude product obtained, weighing 376 mg, was chromatographed over "Florisil", whereby 328 mg of a pure substance consisting of 5a, 17 /? - dihydroxy-6 / 5- from eluates of benzene-ether (9: 1) to ether acetylthio-17a-äthinyl-5a-estran-3-one, were obtained. IR spectrum: y ^ f ¹ cm " ¹ : 3365 (OH); 3275 (ethynyl); 1705, 1130 (S-acetyl and 3-one).

b) 6a-acetylthio-l7a-äthinyl-l7 /? - hydroxy-4-estren-3-one and its acetate

328 mg of the amorphous 5α, Πβ - dihydroxyo / S-acetylthio-na-äthinyl-Sa-estran-S-ons obtained according to the above procedure were dissolved in 10 ml of glacial acetic acid, and dry hydrogen chloride was passed through the solution for 2 hours. After reacting for 10 minutes, water was added and extracted with ether. The ethereal solution was then washed with water, with sodium carbonate solution and finally with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 312 mg of an oily product. This product was found to be oa-acetylthio-na-äthinyl-nß-hydroxy-4-estren-3-one by its IR spectra: yiJai ⁰¹ cm " ¹ : 3400 (OH), 3275 (ethynyl); 1715, 1130 ( S-acetyl);

1683, 1628 (^ -3-On); yS cm " ¹ : 3626 (OH); 3286 (ethynyl); 1700, 1130 (S-acetyl); 1687, 1622 (/ l ⁴ -3-On) and by the constitution and structure of the acetate.

Acetone-hexane gives prisms of the acetate of 6a-acetylthio-17a-ethinyl-17/3-acetoxy-4-estren-3-one with a mp = 216 to 219 ° C; [α] Τ = -34.4 ± 2 ° (c = 0.999, chloroform). UV spectrum: /.^ _x ³ "" ¹ 235.5 ηΐμ (f 17343). IR spectrum: y _x ^oroform cm ^-1 : 3300 (ethynyl); 1742,1260,1022 (O-acetyl); 1690 (shoulder),

1134, 1120 (S-acetyl); 1674, 1623 (zl ⁴ -3-On).

Analysis for C ₂₄ H ₃₀ O ₄ S:

Calculated ... C 69.53, H 7.29, S 7.74;
found .... C 69.54, H 7.35, S 7.86.

Claims (2)

Patent claims: 1. 6a-Acetylthio-4-en-3-one steroids of the general formula O —COCH, r R, SCOCH ₃ in which R _{1 is} a hydrogen atom or the methyl group and R _{2 is} a hydrogen atom or an HC = C group. 009 535/296 2. Process for the preparation of 6 <z-acetylthio-4-en-3-one steroids the general formula SCOCH, in which R _{1 is} a hydrogen atom or the methyl group and R _{2 is} a hydrogen atom or an HC =C group, characterized in that a corresponding 5a-hydroxy-6 (S-acetylthio-3-one compound is obtained in a manner known per se the general formula HO SCOCH ₃ in which R _{1 has} the above meaning, R _{2 represents} OCOCH ₃ or OH and R _{3 represents} a hydrogen atom or a HC ^ C group, optionally with intermediate protection of further hydroxyl or oxo groups present in the molecule, with an acid or successively with the halide of an inorganic oxygen acid in the presence of a base and then treated with an acid and optionally then acetylated with an acetylating agent.