DE1814304B2 - 3-OXO-12-METHYL-OESTRA-4,9,11-TRIENE, PROCESS FOR THEIR MANUFACTURING, THESE THERAPEUTIC COMPOSITIONS AND THE APPROPRIATE INTERMEDIATES - Google Patents

Description

The products of general formula I have interesting pharmacological properties. In particular, they have a significant antiandrogenic level Effect.

So they differ more clearly in their pharmacological properties from those already 3-oxo-estra-4,9,1 1 -trienes described. One knows in particular through the publication Th. Feyel C ab a η η e s, Annales d'Endocrinologie, 26, 95 (1965) and through the publication Velluz et Coll., C.R.Ac. Sci., 265, (1967) 1396, the highly androgenic and anabolic Activity of this connection type. In particular, the 17 »-methyl derivative turned out to be the most active androgenic and anabolic compound that is known. In addition, the connections turned out with an unsaturated side chain, like the 17 * -ethynyl compound or the na-chloroethinyl compound as Proizestomimetics or pituitary inhibitors that exhibit no estrogenic effects, while the 17-vinyl derivative is androgenic and anabolic Has activity (see U.S. Patent 32 57 2781. The 3-oxo-estra-4,9,11-trienes therefore form a class of compounds with strong androgenic or procestomimetic properties. With conventional In doses, their estrogenic effect is absent. The introduction of a methyl radical in position 12 in such a molecule therefore has a profound change in pharmacological properties of the molecule.

This substituent, on the one hand, causes the androenic or progestomimetic properties of the molecule disappear and, on the other hand, that remarkable estrogenic properties appear. either by testing for estrogenic effects or by demonstrating anti-androgenic properties shown on the male animal.

This appearance of estrogenic properties by simply adding a methyl group in position 12 was also not to be expected, because the insertion of a methyl group in other positions (1 or 6 or 7 z. B.) brings with it either an increase or a relative decrease in androgenic properties. The compounds according to claim 1 also have what is known as "post-coitum activity". they are at a fertility rate of 0 door with 10 ug per day of the compound 3 -oxo-12-methyl-17 \ -äthinyl- ^ /, ■ -hydroxy-estra- ^ ll-triene treated rats substantially more effective than the comparison compounds ethynyl estradiol and ethynyl norestosterone.

Among the products of general formula I, the following compounds have a special one Interest:

3-O \ c) -12-methyl-l7 / i-acetoxy-oestra-4.9,11 -triene,
3-oxo-12-methyl-17 * -methyl-17 / (- hydroxyösira-4.9.11-triene,

3-Oxo-12 methyl-17, * -äthinyl-17 / f-hydroxyöstra-4,9.1 l-lricn.

The process for the preparation of the compounds of the general formula I is characterized. dal :, one 3-oxo-12-methyl-17 / <- hydroxy-estra-4.9.1 I-trien by reaction of a methylmagnesium halide with 3-oxo-17 / miydroxy-oestra-4.9.1 I-triene (this is described in French patent 13X0 414) in the presence of a copper-1-halogcnidcs produces, the 3-oxo-12 "-methyl-17, (- hydroxyöstra-5 (IO) .9 (ll | -diene is formed, which one with the help of a dihalodicyanobenzoquinone in one inert solvent dehydrated, the resulting 3-oxo-12-methyl-17 / f-hydroxy-estra-4,9, l 1-trien either the action of an esterification or a decomposition

submits and isolates the corresponding esterified or etherified derivative in / - / - position, or subjected to the action of an agent to block the keto function located in the 3-position, the resulting n-methyl-H / miydroxy-

östra-4,9,11-triene derivative with an oxidizing agent converts the 12-methyl-n-oxo-estra-4,9,11-triene derivative formed, whose keto function is blocked in the 3-position, the action of an organometallic Subjects derivative, in which the organic

Rest of R _{3 is} represented, which leads to the corresponding 12-methyl-Ha-R ₃ -17 / i-hydroxy-estra-4,9, lltriene, the keto group of which in the 3-position is liberated by acid hydrolysis, the desired 3- Oxo-12-methyl-17 \ -R ₃ -17 // - hydroxy-oestra-4,9.11 -triene isolated.

that one may be exposed to the effects of an or etherifying agent and thereby esterifying the corresponding in the 17 / i-position or etherified derivative receives.

According to a preferred embodiment, can

the procedure of the present invention can still be characterized by the following points:

The blocking agent is hydroxylamine or a lower alkyl derivative of hydroxylamine.

of the formula R ₄ ONH ₂ , in which R _{4 represents} a lower alkyl radical, these compounds in the form of addition salts containing strong mineral acids such as hydrochloric acid. can be used.

the blocking agent is an alkylene glycol

of the formula HO- (CH ₂ J _n -OH, where η is the number 2. 3 or 4,

the oxidizing agent is a ketone, which according to the "Oppenaucr" Melhode by double ex

exchange of functions in the presence of an AI

Miniumalkoholates reacts like cyclohexanone in the presence of aluminum isopropylate. the organometallic derivative is an alkyl magnesium halide or alkyl zinc halide.

4s an alkenyl magnesium halide or alkenyl

zinc halide, an alkynyl magnesium halide or alkynyl zinc halide, an alkyllithium or an alkynyl alkali metal compound. the acid hydrolysis is carried out with the help of a mineral

acid or organic acid.

The invention relates to the following products'

.VOximino - ^ - methyl-H / i'-hydroxyöstra-4.9.11-triene,

3-oximino-l 2-methyl-l7-oxo-estra-4.9.11-triene.

3-oximino-l2, l7 \ -dimethyl-l7 /) '- hydro \\ - (> o östra-4.9.1 I-trien,

3-oximino-12-methyl-l 7 \ -äthinyl-17,; - hydroxy-estra-4,9.11-triene

as well as the two connections below:

(15 3 - () xo-l2 \ -methyl-17 // - hydroxy-estra-

5 (IO |. ^L ) lll) -dien and
l-Oxo - ^ - methyl-W / i-hydroxy-oestra-4.9.1 I-triene

Example!
3- Oxo-12-methyl-17 ^ acetoxy-oestra-4.9.11-triene

0.82 g of 3-oxo-! 2-methyl-] 7 ^ -hydroxyestra-4,9, II-triene are carried in 4 ecm of pyridine. add 2 ecm acetic anhydride and stir for 15 hours Room temperature; ice water is poured into the mixture, extracted with methylene chloride. washes the organic phases with water, dry them over sodium sulfate and evaporate to dryness: man ge ίο winnt 0.993 g of crude 3-oxo-12-methyl-17, - / - aceloxyöstra-4,9,11-irien, which is purified by chromatography on silica eluting with a benzene / ethyl acetate (7/3) mixture; you get that 3-oxo-12-methyl-17 / i-acetoxy-oestra-4.9, l 1-triene.

This compound is a solid colorless product, soluble in alcohol, ether, acetone, benzene and chloroform: insoluble in water.

UV spectrum (ethanol).

Max. At 242 ΐημ. EjX = 206.
Max. At 269 270 m *. Ej ". =
Infl. around 285 ma, EjX = 118.

107.

Max. At 350 351 m *. EjX = 861st, ^ 2X100.

-s

IR spectrum (chloroform):
Acetate at 1727 cm '.
Conjugated ketone:

Complex band at 1662 cm 'and ifr-1 " ¹ cm' band at 1606 cm" ¹ .

Complex band at 1574 cm '.

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

The starting product, the 3-O>; o-l 2-methyl-I 7 /> '- hydroxy-estra-4.9, l 1-triene. can be made as follows will:

Level a

3-Oxo-12 \ -methyl-17 / Mydro \} - oestra-5 (IO), 9 (II) -diene

0.94 g of copper (l) chloride is carried in 300 ecm an O.Xn solution of methylmagnesium bromide in tetrahydrofuran and 300 ecm tetrahydrofuran, bring the temperature to - 2 C. under a nitrogen atmosphere. Add 15 g of 3-oxo-170-hydroxv-oestra-4.9.11-triene added (described in French patent 13 80 414); the mixture is stirred for 2 hours at un-so danger 0 C and adds 1 1 1 n-hydrochloric acid: it is extracted with methylene chloride, the washes organic phases with water until the wash water is neutral, dried over sodium sulfate and evaporates to dryness; 18 g of crude product are obtained, which can be obtained by chromatography on silica gel. Elute with a benzene / ethyl acetate (1 l) gel • gel. Evaporation of the eluate to dryness and purifies crystals in ether; 8.28 g are obtained 3 - oxo -12 χ - methyl -17 / (- hydroxy - estra - 5 (1 ()), 9 (11) -diene.

The product is in the form of colorless needles. soluble in most organic solvents And insoluble in water. Mp = 155 ° C.

UV spectrum (ethanol):

Max. At 240 241 ηΐμ. EjX - 710.
Infl. by 250 him. Ej "'= 471.

fts

= 203 (K).

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

Level B.

3-Oxo-12-methyl-l 7 /> - hydroxyöstra-4,9,11-triene

7.8 g of 3-oxo-12 \ -methyI-17p'-hydroxy-oestra-5 (10), 9 (l l) -diene in 390 ecm benzene, add 10 g dichlorodicyanobenzoquinone and stir at room temperature under nitrogen for 3 hours and 30 minutes; it is filtered and the filtrate is washed with a 0.1 N aqueous thiosulfate solution. then with water, dried over sodium sulfate and evaporated im Vacuum to dryness; 3.721 g of the crude 12-methyl-triene compound are obtained.

By treating the precipitate with a mixture of 0.51 5N sodium hydroxide and 0.5 J an O.fn sodium thiosulphate solution and extraction a second fraction is also obtained with benzene of 0.407 g of the 12-methyl derivative.

You clean the product with chroma! .graphic at Kieseleel. Elute with a benzene and / or acetate mixture (1 1). Evaporate to dryness and then paste the dry residue in Isopropyl ether: 3-oxo-12-methyl-17p'-hydroxy-estra-4.9.11-triene is obtained, which melts at 145 C.

This compound is in the form of a colorless product. soluble in acetone, benzene and chloroform: slightly soluble in alcohol and ether: insoluble in water.

UV spectrum (ethanol):

Max. At 244 ma.EJX = 232.
Max. At 269 270 ηΐμ, EjX = 127.
Max. At 283 284 ΐτίμ. EjX = 130.
Infl. around 299-300 πΐμ, EjX = 171.
Max. At 357 πΐμ, EjX = 1030., = 29 300.

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

Example 2

3-Oxo-12,17. * - dimethyl-17 / <- hydroxyöstra-4,9,11-triene

Level a

3-oximino-12-methyl-l 7 / f-hydroxyestra-4,9,11-triene

8.3 g of 3-oxo-12-methyl-17 / i-hydroxyöstra-4.9.11-triene (described in Example 11 in 220 ecm of ethanol, add a solution of 24.5 g of sodium acetate and 11.4 g of hydroxylamine hydrochloride in 115 ecm of water and reflux with stirring and nitrogen for 2 hours; after cooling, the reaction mixture is poured into ice water, stirred for 30 minutes, filtered, the precipitate is washed with water and dried at 60 ° C.; 8.6 g are obtained 3- Oximino -12 - methyl -17 β- hydroxy-estra -4.9.1I-triene. In the form of light yellow crystals, soluble in ethanol and chloroform and insoluble in water, which melt at 120 to 130 C.

The compound obtained is a mixture of syn- and antioximes.

UV spectrum (ethanol):

Max. At 237-238 mu. EJl = 117.

Max. At 328 mu .. EU = 1160. , = 34700.

Infl. around 335 ηΐμ. E ^ _n , = 1125.

IR spectrum (chloroform):
Absence of conjugated C = O.
Presence of free OH (oxime)
at 3580 cm " ¹ .

Presence of conjugated C = C
at 1601 and 1578 cm " ¹ .

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

Level B.
3-oximino-12-methyl-17-oxo-estra-4.9.11-triene

20th

6.8 g of 3-oximino-12-methyl-17, - hydroxyöstra-4.9.11-triene are dissolved in 1 1 toluene and 130 ecm cyclohexanone, at reflux, with stirring and under nitrogen, expelled 20 ecm of the solvent and adds a solution of 30 g of aluminum isopropoxide in 2 Γ toluene, adding 2 l of the solvent distilled; 200 ecm of water is added, then the excess cyclohexanone is drawn off by evaporation in the course of 1 hour and 30 minutes from: after the mixture has cooled, 200 ecm of methylene chloride are added and the aluminum hydroxide is filtered off and wash the filtrate with methylene chloride; the organic phase is washed with water and the aqueous phase is extracted with methylene chloride and evaporate the combined organic masses to dryness: one chromatographed the Residue on silica gel, eluted with chloroform, which contains 20% acetone, and receives 4 g of 3-oxirnino-12-methyl-17-oxo-oestra-4.9.11 -triene in the form of orange crystals, soluble in alcohol and chloroform. insoluble in water, which melts at 210 to 220 C.

IR spectrum (chloroform):
Presence of cyclopentanone at 1725 cm " ^1. Presence of oxime.

Presence of conjugated C = C at 1570 and 1598 cm " ¹ .

chloride solution added, decanted and extracted the aqueous phase with ethyl acetate; the organic phases are washed with water, dried and evaporated to dryness; the residue is chromatographed on silica gel and eluted with chloroform which contains 20% acetone; 3.3 g of 3-oximino-12 are obtained. i 7 «-dimethyl-17 ^ -hydroxy-oestra-4.9,11 -triene, in the form of yellow crystals, soluble in alcohol, insoluble in water, which melt ^{at about 230: C.}

Analysis for C ₂₀ H ₂₇ O ₂ N = 313.44: Calculated ... N 4.67%:
found .... N 4.0%.

, ·, UV spectrum (ethanol):

Max. At 338-339 with, EJ *, = 107. Infl. around 312 ηΐμ. EJ * '= 873. Max. At 327 mu. EJ * _m = 1180, t - 37000. Infl. around 335 ηημ, EJ * "= 1130.

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

-4?

UV spectrum (ethanol):
Max. At 237 Γη _μ , EJ * = 115.
Infl. at 310 with, EJ *. = 838. so

Max. At 325 τπμ, EJ * = 1145. f = 34000 ..
Infl. around 334 πΐμ, EJ * = 1055.

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

Level C

3-oximino-12,17 a-dimethyl-17 / J-hydroxy-estra-4,9,11-triene

In 650 ecm of a 2m solution of methyl magnesium bromide in ether, a solution of 3.7 g of 3-oximino-12-methyl-17-oxo-oestra-4,9, l is added with stirring and under nitrogen 1-triene in 225 ecm benzene and reflux for 2 hours; after cooling, 1! saturated, aqueous ammonium

60 Level D

3-Oxo-l 2.17 -c-dimethyl-17 /i-hydroxyöstra-4.9.11-triene

It carries with stirring and under nitrogen, 3.1 g of 3- oximino-12,17-dimethyl-17 * β- hydroxy - estr-4.9.11-trien in a mixture of 120 cc of acetic acid. 120 ecm of water and 12 ecm of pyruvic acid and reflux for 1 hour; after cooling, the reaction mixture is poured into a mixture of 1.5 l of water. 200 g of sodium carbonate and 200 ecm of ether: the organic phase is decanted and washed with water until the washing water is neutral: the aqueous phase is extracted with ethyl acetate and the combined organic phases are evaporated to dryness: the residue is dissolved in methylene chloride, the Contains 20% ether, send the solution through a column of silica gel to elute with methylene chloride, the 15% ether contains 1.9 g of 3-oxo-12,17a-dimethyl-! 7fi-hydroxy oestra-4.9.11-triene. that melts at 156 C. [\] \ = -140 ^; ± 2 (c = 1%. Chloroform).

The product is soluble in alcohol and chloroform and insoluble in water.

Analysis for C ₂₀ H ₂₆ O ₂ = 298.42: Calculated ... C 80.49, H 8.75%; found .... C 80.3, H 8.8%.

IR spectrum (chloroform):
Presence of OH at 3610 cm " ^1. Presence of conjugated C = O + C = 'at 1661, 1651, 1649, 1635, 1600 and 1568 cm"

UV spectrum (ethanol):

Max. At 245 mu, EJ * = 224. Max. At 270 mu, EJ * = 119. Max. At 285 mu. EJ * = 122. Max. At 355 mu, EJ * = 1035, _f = 30900.

As far as is known, this connection is not described in the liter door.

Example 3

3-O \ o-l2-methy] -l 7 x-ethinyl-

17, i-hydroxy-estra-4,9, l 1-triene

Level a

3-oximino-12-methyl-17 \ -äthinyl-17 / (- hydroxy-estra-4,9, l 1-trien

In a solution, cooled to +5, +10 C, of 30 g of potassium tert-butoxide in 600 ecm of tetrahydrofuran a stream of acetylene is passed in for 1 hour and 15 minutes; 5.4 g of 3-oximino-12-methyl-17-oxo-estra-4,9, l 1-triene (described in Example 2), in solution in 120 ecm of tetrahydrofuran, is added and let the acetylene bubble through for an additional hour and 30 minutes; one adds 6 (X) ecm Aqueous, saturated sodium chloride solution is added, the organic phase is decanted and the aqueous phase is extracted Phase, the combined organic phases are washed with water, dried and evaporated to dryness; 5.7 g of crude product are obtained, which is eluted with silica gel chromatography a chloroform / acetone mixture (8/2) purifies; 2.2 g of 3-oximino-12-methyl-17 * -äthinyl-17f) -hydroxy-oestra-4,9, l are obtained 1-trien. that is used as it is in the next stage.

IR spectrum (chloroform):
Presence of OH at 3520 cm '.
Presence of C = C at 3290 cm " ¹ .

UV spectrum (ethanol):
Max. At 238 πΐμ, Ei * = 98.
Max. At 327 mu. E \\ = 1065,
Infl. by 334 mu. E ^ = 1035.

= 34450.

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

Level B.

3-oxo-12-methyl-l 7. \ - ethinyl-17 p'-hydroxy-östra-4.9.11 -trien

2.2 g of 3-oximino-12-methyl-17 \ -äthinyl-17 / * -hydro.xy-oestra-4,9.11-triene are introduced into a mixture of 90 ecm water, 90 ecm acetic acid and 9 ecm pyruvic acid Reflux for 1 hour; the reaction mixture is brought back to room temperature, neutralized with sodium bicarbonate and extracted with ethyl acetate; the organic phase is washed with an aqueous, saturated sodium bicarbonate solution. then extracted with water, the aqueous phase with ethyl acetate, dry the combined organic phases and evaporate to dryness; 1.74 g of crude product are obtained because: one is obtained by chromatography on silica gel. Purify fluidized egg with methylene chloride and recrystallization from ethanol; 702 mg of 3-oxo-12-methyl-17 \ -äthinyi-17 / i-hydroxy-estra-4,9.11-triene are obtained. the ers melts at 188 C and then above 215 C [v] ^ -39 (c = 0.47%, chloroform).

The product is soluble in alcohol and insoluble ii Water.

Analysis for C ₂₁ H ₂₄ O ₂ = 308.42:
Calculated
found .

C 81.78, H 7.84%;
C 81.7, H 7.5%.

IR spectrum;

Presence of OH at 3590 cm '.

Presence of CsCH at 3293 cm '■

Presence of C = O. Complex, at 1659.1651

and 1643 cm " ¹ .

Presence of C = C at 1602 and 1568 cm ' ¹ UV spectrum (ethanol):

Max. At 355 ηΐμ. , = 30400.

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

As already mentioned above, the new 3-oxo · 12-methyl-oestra-4,9, ll-trienes have the general formula I have interesting pharmacological properties. In particular, they have considerable antiandrogenic properties Effect.

They can be used to treat prostate adenomas Prostate cancers, from hyperandrogenia. used by acne and hirsutism.

They become oral, perlingual, transcutaneous. Applied rectally and topically.

They can be in the form of injectable solutions or suspensions, packaged in ampoules, in vials for multiple withdrawal, in the form of tablets, coated tablets, sublingual tablets. Suppositons, creams and ointments are present.
_Jp ^le suitable dosage is between 10 mg and XR) mg per day in adults depending on the route of administration.

The pharmaceutical forms like injectable Solutions or suspensions, tablets, coated tablets, sublingual tablets, suppositories, creams and ointments are made by conventional methods.

Claims (2)

• i patent claims: 1. 3-Oxo-12-niethyl-oestra-4,9, ll-trienes of the general type formula in the R ₁ OR, OR; OH R ₃ represents wherein R _{2 represents} the radical of an organic carboxylic acid having 1 to 18 carbon atoms or an alkyl radical having 1 to 5 carbon atoms, R _{3 represents} an alkyl radical having 1 to 4 carbon atoms or an unsaturated hydrocarbon radical having 2 to 4 carbon atoms. 2. Process for the preparation of 3-oxo-12-methyl-estra-4.9,11-trienes the general formula 3 ° 35 40 in the R, 5 ° denotes an alkyl group with 1 to 5 carbon atoms and R denotes an alkyl group with 1 to 4 carbon atoms or an unsaturated hydrocarbon group with 2 to 4 carbon atoms, characterized in that 3-oxo-17 / mydroxyestra-4,9, ll-triene allows a methyl magnesium halide to act in the presence of a copper (I) halide in order to produce the 3-Üxo-12λ-methyl-17 / N hydroxy-oestra-5 (10), 9 (II) -diene by 1,8 addition, which is dehydrated with the aid of a dihaloene-dicyanobenzoquinone in an inert solvent; the 3-oxo-12-methyl-170-hydroxy-estra-4,9,11-triene obtained is either subjected to the action of an esterifying or etherifying agent and the corresponding derivative esterified or etherified in the 17 ^ position is isolated, or to the action of a By means of blocking the keto function located in the 3-position, the resulting 12-methyl-17 / i-hydroxy-estra-4,9, l 1-triene derivative reacts with an oxidizing agent, the 12-methyl-17- oxo-estra-4.9, l 1-triene derivative. whose keto function is blocked in position 3. subjected to the action of an organometallic derivative, in which the organic radical is represented by R 1, which leads to the corresponding 12-methyl-17Ji-R ₃ -17fi-hydroxy-estra-4,9,11-triene, the keto group of which is in the 3-position is released by acid hydrolysis, the sought-after 3-oxo-12-methyl-17 ^ R, -17 / i-hydroxy-estra-4,9, ll-triene is isolated, which is optionally subjected to the action of an esterifying or etherifying agent, the corresponding derivative esterified or etherified in 17 / i -slcllung is obtained. 3. 3 - oxo - 12 - methyl - 17 // - hydroxy - estra-4,9,11-triene. 4. 3 - Oxo - 12 ■ »- methyl - 17 // - hydroxy - oestra-5 (10), 9 (l l) -serve. 5. S-oximino - ^ - methyl-n / f-hydroxy-estra- 4,9.11-trien. 6. S-Oximino - ^ - methyl-n-oxo-östra ^ / J.l I- trien. 7. 3-Oximino-12,17 - »- dimethyl-17 / i-hydnmöstra-4,9,11-triene. 8. 3-Oximino-12-methyl-17, i-ethinyl-17 / (- hydroxy-estra-4,9,11-triene. 9. Therapeutic compositions, characterized in that they contain at least one compound according to claim I and contain a pharmaceutical carrier. OR, OR, Oll represents wherein R, the residue of an organic carboxylic acid having 1 to 18 carbon atoms or 55 The invention relates to 3- oxo] 2-methyl-estra-4.9,1-l-ynes Vcrbindungen the general Formally ho according to claim 1. A method for their production, Therapeutic compositions containing them and the intermediates according to claims 3 till 8. The organic carboxylic acid residue in formula I. ('S with 1 to 18 carbon atoms can be derived from an aliphatic Acid, an aromatic acid, a cycloaliphatic one !! Acid or a heterocyclic Sourced from acid.