DE1768700C - Unsaturated 2,2-dimethyl steroids of the estran or gonan series and process for their preparation - Google Patents

Description

The invention relates to Λ ⁴ · ⁹ · ¹¹ -unsaturated 2,2-dimethyl steroids of the estran or gonan series. The invention relates in particular to steroid derivatives of the general formula I

45

(D

in which R denotes an alkyl radical having 1 to 4 carbon atoms.

The new compounds according to the invention have interesting hormonal properties and in particular have anti-androgenic activity.

The process according to the invention for the preparation of these new compounds, which is a geminal dimethylation delivers, basically consists in the fact that it creates working conditions in which immediately after the introduction of the first methyl group Carbanion of the monomethylated derivative forms to ensure the introduction of the second methyl group. As a result, one does not isolate the monomethylated derivative and the action of the same Meth'ylation agent allows direct production of the desired dimethylated product.

The process according to the invention for production of the compounds of general formula I is now characterized in that a 3-oxo-17a-methyl - 17 / 9- hydroxy - 13/3 - R - gona - 4,9,11 - trien with a lower alkyl formylated in the presence of an alkali metal hydride or amide and the alkali metal salt des S-formyl-S-oxo-na-methyl-n / S-hydroxy-13 /} - R-gona-4,9, ll-triene methylated with methyl iodide.

The modification of this process is characterized in that a 3-oxo-17a-methyl-17 / J-hydroxy-13 / J-R-gona-4,9, ll-triene with methyl iodide in the presence of potassium tert-butoxide at low temperature in hexamethylphosphoric triamide as Reacts solvent.

For this purpose, one can first prepare the derivative formylated in the 2-position, which, if it is with a methylating agent and in particular with methyl iodide in the presence of an alkaline agent is treated in excess, the monomethylated derivative provides, the formyl radical in situ by the alkaline agent is eliminated by forming the carbanion of the monomethylated derivative, which in turn under the action of the methyl iodide present in the reaction medium, the geminaldimethylated Derivative supplies.

An alkali metal carbonate or a tertiary alkali metal alcoholate is preferably used as the alkaline agent, such as potassium tert-butoxide or potassium tert-amylate. An alkali metal hydride such as sodium hydride is also suitable.

The one used as the starting product, in two positions formylated derivative can be obtained by. a formylating agent such as ethyl formate in Presence of sodium hydride on a triene steroid of general formula II

R OH

(H)

can act. This leads to the sodium salt of the corresponding derivative formylated in the 2-position, which is subjected to the geminal dimethylation, as described above.
The carbanion of the 2-position monomethylated derivative of the triene steroid can also be obtained directly by starting from the steroid of the formula II. For this purpose, it is subjected to the action of a methylating agent and, in particular, of methyl iodide in the presence of an alkaline agent such as potassium tert-butoxide, working at a low temperature in a strongly enolizing medium and in particular in hexamethylphosphoric triamide. The second methyl group in the 2-position is then introduced in situ into the resulting carbanion of the derivative monomethylated in the 2-position, in such a way that this process ultimately has only a single step to move from structure II to structure I from the standpoint of the operating conditions reach.

3 4

This variant of the UV spectrum according to the invention (ethanol) is used:

Method preferably as follows: _M. - " ₇ - p 840

First introduction of the starting steroid and the τ η · w ^ '™' _m ? 98Π

Methyl iodide in a suitable solvent, such as ¹ Jf * ¹ "? £ ^e f * ^{a 27} ° ^mfl ' ⁼ ₃ n OM

z. B. an ether, and especially TeU & ydrofiiran, 5 max. At 341 ηΐμ e = 30,000

then addition of the alkali metal alcoholate in enoli- circular dichroism (ethanol):

sizing solvent, e.g. B. hexamethylphosphorus-. _=? ,

triamid, to the solution of the steroid. _f ³⁶ * _ _ ~ i

This addition must be carried out under strong cooling in the ^ f ³²⁵ In ₀

The order of magnitude of -35 ° C takes place around the second, f ²⁵⁷ ^ _ »" 2

dark reactions between methyl iodide and the ^, .. 235 »

Alkali metal alcoholate, which is used to lower the output As far as is known, this compound is

prey lead to diminish. The temperature is then not described.

the reaction mixture is based on ambient tem- The 2a, 2ß, 17a-triciethyl-3-oxo- 17 /? - hydroxy-

heat up the temperature, isolates the product formed 15 östra-4,9, ll-triene can still through its conversion

according to the usual procedures. ment in the 2o ^ / i, 17a-trimethyl-3-oxo-l7 ^ -methoxy-

Under these conditions the methylation can be characterized oestr-4,9, ll-triene: so obtained

lead to the corresponding methyl ether. by methylating the 2a, 2 / J, 17a-trimethyl-

It has been found that a particularly advantageous 3-oxo-17 / i-hydroxy-oestra-4,9, l 1-triene with methyl

Blucking egg halls are kaiin by putting the 20 iodide and sodium hydride in a polar solution

17-alcohol is converted into tetrahydropyranyl ether by means of 2o, 2 / U7a-trimethyl-17 /? - methoxy-3-oxo-estra-

The ether is obtained by the action of di-4,9,11-triene, m.p. = 152 ° C.

hydropyran by standing in the presence of an acidic The product is in the form of a yellow, completely

Catalyst works, for example p-toluenesulfone-crystallized solid before, is soluble in ethanol

acid. The splitting off of this ether after methyl 25 and chloroform. Its ability to rotate is

lation takes place easily by acid hydrolysis by a _B = -57 ± 2 ° (c = 0.5%, chloroform),
one in an aqueous mixture of acetic acid and

Perchloric acid works. Infrared spectrum:

The following examples are intended to illustrate the invention in more detail. C = O complex at 1656 to 1640 cm ' ¹ ,

explain without, however, limiting them to them. 30 C = C complex at 1578 cm " ¹ .

Example 1 UV spectrum (ethanol):

Preparation of 2a, 2 / S, 17a-trimethyl-3-oxo- A _mox , 236 πΐμ t = 5,800

17 / miydroxy-estra-4,9, l 1-triene from previous inflection, 270 πΐμ f = 3 200

Formylation ³⁵ ^ _x , 340 πΐμ _f = 30100

10 g of 3-oxo-17a-me are introduced into 500 cm ^{3 of} benzene. As far as is known, this compound is in the lit-

ethyl-17 / J-hydroxy-estra-4,9, l 1-triene and 16 cm ³ ethyl rature not described,

formate, gives 3 g of sodium hydride in a 50% strength Example 2
Suspension in vaseline oil and allows the reaction 40

mixture for 5 hours while stirring and producing the 2a ^ / ?, 17a-trimethyl-3-oxo-17ß-hy-

stand in an inert gas at ambient temperature. droxy-estra-4,9, ll-triene by direct methylation

Filter and dry under vacuum; the product with its alcohol in the 17-position is obtained in the form

17 g of the sodium salt of the tetrahydropyranyl ether formylated in the 2-position is protected

Derivative that one in 65 cm ^{3 of} dimethylformamide under 45 _{ preparation of the tetrahydropyranyl ether
Stirring and maintaining the temperature of

25 ° C dissolves. 3.9 potassium carbonate and 25 cm ³ are added. 21.7 g are introduced into 870 cm ^{3 of anhydrous ether}

Add methyl iodide, stir for 1 hour at ambient 3-oxo-17 / i-hydroxy-17a-methyl-estran-4,9, l1 -tnen

temperature, pour the reaction mixture into water, give 30 cm ^{3 of} dihydropyran and 540 mg of p-toluene

and extracted with isopropyl ether. The sulfonic acid (monohydrated) is washed in. That under one

organic phases with water, dried and concentrated in a nitrogen atmosphere

to dryness and obtain 11.245 g of crude product, which is stirred for 23 hours at ambient temperature,

one on silica chromatographies. ^{2.2 cm 3 of} triethylamine are then obtained and washed

1.815 g of the 2,2-dimethylated derivative, which one with a dilute sodium bicarbonate solution and

by pasting in isopropyl ether, then re-55 with water. Extract with ether, dry and

crystallization in ethyl acetate in the warm and in concentrated under vacuum to dryness.

the cold cleanses. 0.839 g of 2a, 2 / ?, 17 "-Tri- is obtained. The residue consists of 3-oxo-17" -methyI-

methyl - 3 - oxo -1 Iß - hydroxy - oestra - 4,9,11 - triene, the 17 / metrahydropyranyloxy-oestra-4,9,11 -tnen, the one

melts at 139 ° C. so used for methylation.

60 As far as is known, this connection is

Analysis: C ₂₁ H ₂₈ O ₂ = 312.42. rature not described.

Calculated ... C 80.72, H 9.03%; 2. methylation "

found .... C 80.85, H 9.1%. _{Man, Ö3t the} product obtained _{in the step objgen}

Tr, c 1 "^ Ui r \ ⁶ 5 duct in 560 cm ^{3 of} anhydrous tetrahydrofuran, the

IR spectrum (chloroform): is _{placed under a nitrogen atmosphere} , gives 113 cm ³

Trienone C = O complex at 1667 - 1640 cm " ¹ methyl iodide, stirs and gives within a time

C = C at 1589cm " ¹ OH at 3600 cm" ¹ . ,. IV space of ₂ hours with cooling to -35 ⁰ C

(± 5 ° C) a solution prepared at ambient temperature from:

Potassium tert-butoxide 57 g

anhydrous tetrahydrofuran 570 cm ³

Hexamethylphosphoric triamide 140 cm ³

and then allowed to stand at ambient temperature for about 1 hour, then pour into water and extracted with petroleum ether. The extracts are washed with water, dried and under vacuum concentrated to dryness.

The residue consists of 2a, 2 / f, 17a-trimethyl-3 - oxo -17 / i - tetrahydropy ranyloxy - östra - 4,9,11 -triene, which is subjected to hydrolysis without further purification.

As far as is known, this compound is not described in the literature.

3. Splitting off of the ether in position 17

The residue from the above stage is dissolved in 140 cm ^{3 of} tetrahydrofuran, operating under a nitrogen atmosphere, 56 cm ^{3 of} acetic acid and 11.2 cm ^{3 of} concentrated perchloric acid are added and the reaction mixture is left to stand at 25 to 30 ° C. for 2 hours. It is then poured into water, extracted with methylene chloride, the extracts washed with water, then with 1 η sodium hydroxide solution and again with water, dried and concentrated to dryness in vacuo.

The residue is crystallized from isopropyl ether and then recrystallized from ethyl ether. I2.4g 2ü, 2 / i, 17a-trimethyl-3-oxo-17 / i-bydroxy-estra-4,9,11-triene are obtained, F. = 139 ° C (corresponding to a yield of 52%), which with the product of des Example 1 is identical.

Starting from the crystallization mother eyes, a further amount of product is obtained by chromatography over magnesium sulfate and elation with methylene chloride with 0.5% methanol. The total yield reaches 62%.

Test report

Study of anti-androgenic activity against testosterone propionate

Experiment description

Male castrated rats 4 weeks of age are exposed for 7 days starting with the day following the castration. On the eighth day the animals are killed, and the The seminal vesicles, prostate glands, and levator ani are removed and weighed.

The products to be examined are dissolved in olive oil, which contains 5% benzyl alcohol, on a subcutaneous basis Routes administered.

The comparison animals were only treated with the solvent.

The results obtained are summarized in the following table:

treatment

Daily dose of Levator ani
mg

Seminal vesicles mg

Prostate glands mg

Comparison animals

Testosterone propionate

2α-2 /? - 17r ^ -trimethyl-3-oxo-17 / J-hydrΌxyöstra-4,9,11-triene

2a, 2ß, 17a-trimethyl-3-oxo-17 /? - hydroxyöstra-4,9,11-triene

Testosterone propionate,

Comparison animal,

Testosterone propionate

2a, 2 / U7a-trimethyl-3-oxo-17 /? -Hydroxyostra-4,9,11-triene

2a, 2 / ?, 17a-trimethyl-3-oxo-17/3-hydroxyöstra-4,9,11-triene

Testosterone propionate

Comparison animals,

Testosterone propionate

Ha-methyl-B-nortestosterone,

Πα-methyl-B-nortestosterone

Testosterone propionate

Comparison animals

Testosterone propionate

na-methyl-B-nortestosterone

Ha-methyl-B-nortestosterone,

Testosterone propionate

5Oy

0.4 mg 0.4 mg

5Oy

5Oy

1 mg

1 mg + 50y

0 50y

1 mg

1 mg

50y 0

25 y 1 mg 1 mg +

25 ν 16.8
25.0

15.1
25.6

14.8
29.9

13.8

24.5

18.5
26.2
24.0

33.2

17.7
33.9
23.6

30th

6.7
56.7

10.3

34.9
(-38%)

5.5
62.2

7.7

13.1 90.1

22.4

71.9 (-20%)

8.0 86.8

14.5

31.1 54.5 (-50%) (-37%) 7.4 11.3 47.9 80.1 7.1 14.0 41.4 72.6 (-14%). (-9%) 6.0 11.2 26.4 63.5 ' 5.7 8.9 19.7 42.1 (-27%) (-33%)

Claims (4)

Patent claims: 1. Unsaturated 2,2-dimethyl-steroids of the estran or gonan series of the general formula IO in which R denotes an alkyl radical having 1 to 4 carbon atoms. 2. 2α, 2 / ϊ, 17α - trimethyl - 3 - oxo -17/3 hydroxyöstra-4,9, n-triene. 3. Process for the preparation of the compounds according to claim 1, characterized in that one S-OxO- ^ a-methyl-W / J-hydroxy-IS / J-R-gona-4,9,11-triene with a lower alkyl formate formylated in the presence of an alkali metal hydride or amide and the alkali metal salt des 2-formyl-3-oxo-17a-methyl-17 /? - hydroxy-13/3-R-gona-4,9, ll-triene methylated with methyl iodide. 4. Modification of the method according to claim 3, characterized in that a 3-oxo-17n-methyl-17/3-hydroxy-13 / S-R-gona-4,9, l 1 -triene with methyl iodide in the presence of potassium tert-butoxide at low temperature in hexamethylphosphoric triamide implemented as a solvent. 35