FR310F - New therapeutic applications of epithio-2,3 steroids. - Google Patents

Description

310

The present addition relates to an improvement made to new therapeutic applications of 2,3-epithio sterol, which will be called here 2, 3-epithio-steroids, subject to the main French patent No. P "V" 919 "045 filed December 18, 1962 for" N ouve I therapeutic applications of 2,3-epithio sterol ",

The 2,3-epithiosferoids have the following formula:

OH .

(for example: vinyl or propenyl) or an alkynyl group having not more than 5 carbon atoms (for example: ethynyl or propinyl) and the broken line (|) 10 represents a configuration <x or |?> "La The present invention also relates to the production of these compounds.

The process of the present invention is represented by the following formulas:

OH

•at

(I)

310

2

in which R has the same meaning as above and R 1 is a cyano group or a carbon-containing group having no more than 6 carbon atoms (for example: acetyl, propionyl or butyryl), R "is a hydrogen atom an alkanoyl group having not more than 6 carbon atoms (for example: acetyl, propionyl or butyryl) or an alkylsulfonyl group having not more than 5 carbon atoms;

(For example: methanesulfonyl or ethanesulfonyl), a phenylsulfonyl group or a phenylsulfonyl group having no more than 11 carbon atoms (eg, toluenesulfonyl or xylenesulfonyl) and the broken line ( ) represents the configuration 0 (or the charge body (II or III) can be prepared from the corresponding 2,3-epoxystole by a large number of processes. methods are shown by way of illustration by the following diagram showing only the core A of the sclerol skeleton:

X iuH

Ove vV * SiH

HS.H

T, A

v! "

I iH

H

/ >> • »S« H V

■ 0 «

H

V4 / 'N "8" H

/ V- "

X. "¥

• * 0, »H

V

• S, H

H

"OH

S * H

H fa '. h s \ S '

Hs.a

B-

e

OLE

310

4

in which R 'has the same meaning as above, R "' is an alkonyl group having not more than 6 carbon atoms (for example: acetyl, propionyl or butyryl), an alkylsulfonyl group not having more than 5 carbon atoms (for example: methanesulfonyl or ethanesulfonyl), a phenylsulfonyl group or an alkyl phenylsulfonyl group having not more than 11 carbon atoms (for example: toluenesulfonyl or xylenesulfonyl) and X is an atom halogen (e.g., chlorine or bromine) or a hydroxyl group Examples of the starting body (II or III) include:

2'-Thiocyanato-3 'X.-methanesulfonyloxy-17alkyl-5 (X-androstan-17 (3-ol, 2α-thiocyanato-3-x-etbanesulfonyloxy) 7α-hynyl-5α-androstan-17β-ol, 2α-propionylthio-3α-propionyloxy-17β-vinyl-5α-anhydrostan-17α-ol,

2H-butyl-3-yloxy-1-yloxy-1-yl-5-yl (5-yl);

3α-t-1-yl-17-yl-1-yl-17α-yl-1-yl-diol,

3α-thiocyanato-17α-ethynyl-5 (X-androstane-2,1,7,7-diol,

2α-ethanesulfonyloxy-3oc-t-1-cyano-7-yl-5-yl-5-yl-1-yl-5-yl;

2β-toluenesulphonyloxy-3β-thiocyanato-17β-ethynyl-5α-androstan-17β-ol, 20-propionyloxy-3α-propionylthio-7α-vinyl-5α-androstan-17β-ene 2α-acetylthio-1,7α-vinyl-5β-i-drostane-3β, 17β-diol,

2α-X-propionylthio-3α-propionyloxy-17β-ethynyl-5H -androstan-17H-ol,

2oc-benzenesulfonyloxy-3-yl-cyano-17-yl-17-yl-3-yl-7-yl-3-yl-17-yl-yl-1-yl-17-yl-yl-1-yl-17-yl-3-yl-17-yl-yl-1-yl-yl-yl-yl-yl-yl-yl-yl-yl-yl (3-N-acetyloxy-3H-thiocyanato-17α-vinyl-5-yl) -androstan-2β, 3β, 17β-diol;

According to features of the process of the present invention, the starting material (II or III) is treated with a basic agent to give the corresponding 2,3-epifiosterol (I). As basic agent, it is possible to use a weak base such as alumina and a strong base such as potash and sodium hydroxide. Other basic agents such as sodium carbonate or potassium carbonate can also be used. The reaction temperature depends on the starting body and the basic agent. For the production of the recovered compound in good yield, it is generally preferred to carry out the reaction in an inert solvent (for example: methanol, ethanol, propanol, benzene, toluene, petroleum ether or diglyme, i.e. dimethyl dimethylethylene glycol) under relatively mild reaction conditions, i.e. at a temperature not higher than 100 ° C.

The configuration of the epithioic group in 2,3-epithiosterol thus produced having the partial structure of formula I corresponds to that of the sulfur-containing group in the starting sterol. Specifically, the 2, 3-hiosté rol'des include:

310

5

2β, 7H-1H-17H-N-vinyl-5α-β-androstan-17H-ol,

2α, 3H-epithio-17α-and hyny-5α-androstan-17β-ol,

2ck, 3a-epithio-1,7-methyl-5-yl-androstan-17β-ol,

2 ', 3' (X-epithio-17-vinyl-5-yl) -androstan-17ft-OI,

2c x, 3 (X-epityl-17α-ethynyl-5R) -androstan-17 (3-ol,

2α, 3α-epithio-17β-ethynyl-5 (3-androstan-17β-ol,

3 ', 3'-epiotho-17α-vinyl-5β-androstan-17β-ol,

2 (1,3,4-epithio-17-yl) -N-ethynyl-5H-androstan-17H3-ol, etc.

The following examples represent presently preferred embodiments of the present invention. The relationship between parts by weight and parts by volume is the same as that between grams and milliliters. Temperatures are expressed in degrees centigrade.

EXAMPLE 1

Preparation of 2cx, 3-x-epithio-17c-vin-I-5cx -an drostan -1 7-ol.

15

• * ch "CH2.

'H H

To a solution of 3α-thiocyanato-17α-vinyl-5α (-androstane-2 [α] β-diol (3.61 parts by weight) in dioxane (50 parts by volume) is added a solution of potassium carbonate (4.50 parts by weight) in water (20 parts by volume) and in methanol (50 parts by volume), the resulting mixture is left to stand

Room temperature (about 15 ° C.) The reaction mixture is concentrated under reduced pressure and water is added thereto. The precipitate is collected by filtration, crystallized from acetone solution and recrystallized from a mixture of acetone and hexane to give 2 <x, 3® <-epithio-17. 1-vinyl-5-butyran-17-ol (2, 26 parts by weight, in the form of crystals melting between 136 and 38 ° C.

[<*] + 17.5 + 2 ° (c = 1.043 in chloroform).

IR T Nujol 3348 3Q88 U42 1Q14 92 4 91Q cm-1 ^

V max

Analysis calculated for H ^ OS;

C. 75, 85; H. 9, 70; S. 9.64 Found: C. 75, 98; H. 9.80; S, 9, 86.

The starting material of this example, 3α-thiocyanato-17β-vinyl-5 (X-androstane)

[1, 17p] -diol, can be prepared by reducing with 3,13-epoxy-17α-ethynyl-5α-androstan-17-ol, catalyst, using the so-called Lindlar catalyst in acetate

310

6

of ethyl and reacting the resulting 2α, 3α-epoxy-17α-vinyl-5α-androstan-17β-ol with a solution of thiocyanic acid ether at room temperature,

EXAMPLE 2

Preparation of 2α, 3α-epithio-17α-ethynyl-5α-androstan-7-3-ol

C £ C3

To a solution of 1-ethyl-17α-ethynyl-5α-androstane-2α, 17β-diol (3.67 parts by weight) in dioxane (60 parts by volume) is added a solution of potassium carbonate (3.70 parts by weight) in water (27 parts by volume) and in methanol (85 parts by volume); the resulting mixture is allowed to stand at room temperature (about 15 ° C). The reaction mixture is concentrated under reduced pressure and water is added thereto. The precipitate is collected by filtration, washed with water, dried and crystallized from a mixture of dichloromethane and methanol to give the 2 ', 3'-x-epithel-17-hexyn-1-yl (-an ______________________________________ (1.7 parts by weight) in the form of crystals between 177 ° C. and 1 78 ° C. The starting liquid of the polymerization is chromatographed on alumina. with a mixture of benzene and benzene ether (2: 1) are crystallized from a mixture of acetone and hexane and recrystallized from a mixture of dichloromethane and methanol to give additional crystals. Is 2-x-epithiol-7α-ethynyl-5β-androstan-17β-ol (0.61 parts by weight).

20 [oc] 25-2

IR: ^)

Q -19.0 + 2 ° (c = 1.038 in chloroform).

Nuiol max

3405, 3294, 104 7 cm '21 H30C

Analysis calculated for C ", H ,, nOS:

9.70. 9, 79.

25

C. 76.31; H. 9.15;

Found: C, 76, 38; H. 9.00;

The starting material of this example 3α-thiocyanato-17α-ethynyl-5α-androsane-2β, 17β-diol can be prepared by reacting 2α, 3α-epoxy-17α-hynyl-5cx. -androstan-17 (3-ol with a solution in thiocyanato acid ether at room temperature.

The 2,3-epithiosterol (I) prepared by the present process are useful, for example, as control agents for menopausal diseases, as agents

Claims (12)

310 7 progesterone antagonists, as control agents for 11 hypergonadism or precocious puberty and as anabolic agents. The present invention is not limited to the embodiments which have just been described, it is instead capable of variations and modifications that will occur to those skilled in the art. RESUME The present addition to the main patent of December 18, 1966, relates to novel therapeutic applications of 2,3-epithiosteroids which are useful as control agents for menopausal diseases, as progesterone antagonists, such as control agents for 11-type regnotism or precocious puberty and as anabolic agents. Compounds useful for the present invention are as follows: 1) a 2,3-epithiosteroid having the following formula: Wherein R is an alkenyl group having not more than 5 carbon atoms (or an alkynyl group having not more than 5 carbon atoms) and the broken line (|) represents the configuration (x. 3> " 2 °) the following bodies: a) - 2oc, 3oc-t-hr-1 7 <X-viny I -5 (X-year drostan-1 7f - o I, B) - 2cx., 3 ".- Epithio-1,7o (-ethynyl-5oc-androstan-17-ol)" NEW DOCUMENTARY ADVICE Documents likely to affect the novelty of the drug: none. Documents illustrating the state of the art in this field: none.