FR309F - New drug especially for the treatment of hyperandrogenism. - Google Patents

Description

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1

In its special drug patent application, No. PV 131,869, filed on December 12, 1967, the Applicant Company described, as a new drug, in particular for the treatment of hyperandrogenism, 3-oxo 12-methyl estra 4, 9,11-trienes, of general formula:

in which R represents hydrogen, the acyl residue of an organic carboxylic acid or a lower alkyl radical and R 'represents hydrogen or an alkyl radical having 1 to 4 carbon atoms.

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the present Addition, in the realization of which participated PIM. NELE1EC Lucien and G-A3G Jean-Claude, has for object, as a new drug, notably for the treatment of hyperandrogenism, a compound corresponding to the general formula of the patent application, 3-oxo 12, 17cx-dimethyl 17p-hydroxy estra 4,9,11-triene, of formula:

containing.

3-Oxo 12,17a-dimethyl 17 | 3-hydroxy estra 4,9,11-triene occurs as a yellow solid, soluble in alcohol and chloroform and insoluble in water.

Its melting point, determined on a Kofler block, is: P. = 156 ° C.

20

Its rotatory power is: / a / D = -140 ° + 2 ° (c = 1%, chloroform).

The principle of the preparation consists in blocking the 3-ketone function of 3-oxo 12-methyl 17f3-hydroxy estra 4,9,11-triene, for example in the form of an oxime; the 3-oximino 12-methyl 17 | 3-hydroxy estra 4,9,11-triene thus formed is xidized by means of a ketone in the presence of aluminum isopropoxide, the 3-cximino 12- is processed. methyl 17-oxo estra '4,9,11-triene obtained by methylmagnesium halide or methyl lithium to form 3-oximino 12,17a-dirnethyl 17P-hydroxy estra 4,9,11-triene, releases the function 3-ketone by acid hydrolysis or function exchange and obtains the sought 3-oxo 12,17a-dimethyl 17p-hydroxy estra 4,9,11-triene.

The attached diagram explains the reactions.

Procedure:

Stage A: 3-oximino 12-methyl 17 ^ -hydrox ^; estra 4.9.11-triene, III

8.3 g of 3-oxo 12-methyl 17P-hydroxy estra 4,9,11-triene, II, are dissolved in 220 cm3 of ethanol, a solution of 24.5 g of sodium acetate and 11, added. 4 g of hydroxylamine hydrochloride in 115 cm3 of water and refluxed for two hours with stirring and under nitrogen; after cooling, the reaction mixture is poured into ice water,

stir for thirty minutes, filter, wash the precipitate with water and dry at 60 ° C; 8.6 g of 3-oximino 12-methyl 17P-hydroxy estra 4,9, 11-triene, III are obtained in the form of pale yellow crystals, soluble in ethanol and chloroform, insoluble in water, melting at 120 ° -130 ° G (Yield: 98%), The compound obtained is a mixture of syn and anti oximes.

U.V. spectrum (ethanol):

Max. at 237-238 E]% = 117

l cm

Max. at 328 m | i E] ^ = 1160 or s = 34 700

l cm

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Infl. around 335 ml ^ E] ^ = 1125

i cm

I.R. spectrum ("chloroform):

Absence of G = 0 conjugate Presence of free OH at 3580cm- ^

5 Presence of C = C conjugated at 1601 and 1578cm ~ ^

The starting material, 3-oxo 12-methyl 17p-hydroxy estra 4,9,11-triene, is obtained according to the process described in the main patent filed on December 12, 1967.

Stage B: 3-oximino 1.2-methyl J_7-oxo_e ^ stra_4_t_9A11_-trieneA IV 6.8 g of 3-oximino 12-methyl 17P-hydroxy estra 4,9,11- are dissolved.

triene, III, in 1 liter of toluene and 130 cm3 of cyclohexanone at reflux, with stirring and under nitrogen, drives off 20 cm3 of solvent and adds a solution of 30 g of aluminum isopropoxide in 2 liters of toluene, while distilling 2 liters of solvent; 200 cm3 of water are added and then entrained with steam for one hour and thirty minutes; after cooling the mixture, 200 cm3 of methylene chloride are added, the alumina is filtered off and washed with methylene chloride; the organic phase is washed with water, the aqueous phase is reextracted with methylene chloride and the combined organic phases are evaporated to dryness; the residue is chromatographed on silica gel, eluted with 20 chloroform of ajsetone to obtain 4 g of 3-oximino 12-methyl 17-oxo estra 4,9,11-triene, IV, in the form of orange crystals, soluble in alcohol and chloroform, insoluble in water, melting at 210-220 ° C (Yield: 59%).

I.R. spectrum (chloroform):

25 Presence of cyclopentanone at 1725cm- ^

Presence of oxime "

Presence of C = C conjugated at 1570 and 1598cm- ^

U..V spectrum. (ethanol):

Max. at 237 mH E] = 115

30 Infl. Arei's 310 m | i E] / û = 838

i cm

Max. at 325 mH S 1% = 1145 or> = 34,000

1 cm

Infl. around 334 mu E] ^ = 1055

1 cm

Stage 0: 3-oximino 1,2j_17a-dimethyl 1_7g_-hydrox £ estra 4.9 »11-triene, V In 650 cm3 of a 2 M ethereal solution of methylmagnesium bromide, with stirring and under nitrogen, a solution is added. 3.7 g of 3-oximino 12-methyl 17-oxo estra 4,9,11-triene, IV, in 225 cm3 of benzene and refluxed for two hours; after cooling, 1 liter of saturated aqueous solution of ammonium chloride is added, decanted and the aqueous phase reextracted with ethyl acetate; the 40 organic phases are washed with water, dried and evaporated to dryness; the residue is chromatographed on silica gel and eluted with acetone chloroform; 3.3 g of 3-oximino 12,17a-dimethyl 17 (3-hydroxy estra 4,9,11-triene, V, are obtained in the form of yellow crystals, soluble in alcohol, inso-

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fads in water, melting at about 230 ° C (Yield: 76? £).

Analysis: = 313.44

Calculated: N 4.67

Found: 4.0

5 U.V. spectrum (ethanol):

Max. at 338-339 m | i E] ^ = 107

1 cm

Infl. around 312 mM E} = 873

1 cm

Max. at 327 mM E] "/ o = 1180 or r" 37,000

1 cm

Infl. around 335 m | i E] ^ = 1130

1 cm

Stage D: 3-oxo 12 ^ 17a-dimethyl 17 (3-hydroxy estra 4.9.11-triene. I

3.1 g of 3-oximino 12,17a-dimethyl 17 (3-hydroxy estra 4,9,11-triene, V, with stirring and under nitrogen, are introduced into a mixture of 120 cm3 of acetic acid, 120 cm3 of water- and 12 cm3 of pyruvic acid and refluxed for one hour; after cooling, the reaction mixture is poured into a mixture of 1.5 liters of water, 200 g of sodium bicarbonate and 200 cm3 of ether; the organic phase is decanted and washed with water until the washing water is neutral; the aqueous phase is re-extracted with ethyl acetate and the combined organic phases are evaporated to dryness; the residue is dissolved in methylene chloride at 20 $ ether, pass 1a, solution on a column of silica gel and elute with methylene chloride to 15 ether; 1.9 g of 3-oxo 12,17a- are obtained.

dimethyl 17 ^ -hydroxy estra 4,9,11-triene, m.p. 156 ° C.

Analysis: G2GH26 ^ 2 = ^ 98.42 Calculated: G <? <, 80.49 H fc 8.75

Found: 80.3 8.8.

I.R. spectrum (chloroform) s Presence of OH at 3610cm- ^

Presence of 0 = 0 + C = C conjugated at 1669, 1661, 1651, 1643, 1635, 1600 and

1568cm ~ 1

30 U.V. spectrum (ethanol}

Max. at 245 mM

Max. at 270 mM

Max. at 285 mM

Max. at 355 mM E ^ = 1035 or c = 30,900 The product has interesting pharmacological properties.

In particular, it has a significant antiandrogenic action.

It can be used for the treatment of prostatic adenoma, prostate cancer, hyperandrogenism, acne, ltiirsutism, amenorrhea, dysmenorrhea.

40 3-Oxo 12,1 7a-dimethyl 17f3-hydroxy estra 4,9,11-triene is used buccally, perlingually, transcutaneously, rectally and topically. It can come in the form of solutions or suspensions

E

cm

224

E

he

119

E

> cm

122

E

cm

1035

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injectable, packaged in ampoules, multi-dose vials, tablets-, coated tablets, sublingual tablets, capsules, suppositories, ointments and creams.

The useful dosage ranges between 50 and 200 mg per dose and per day in adults, depending on the route of administration.

Pharmaceutical forms such as: injectable solutions or suspensions, tablets, coated tablets, sublingual tablets, capsules, suppositories, ointments and creams are prepared according to the usual methods.

10 Pharmacological study of the drug, object of the invention 2 10 Exogenous antiandrogenic activity:

The exogenous antiandrogenic activity was determined against testosterone propionate in castrated male rats, according to the LERNER method, described by D0RFMAN in: "Methods in Hormones Research", II, page 320.

Young male rats of about four weeks old are castrated; treatment begins the day after castration and lasts for seven days; on the eighth day, the animals are sacrificed and the following organs are removed: prostate, seminal vesicles, and levator ani. 3-oxo 12,17a-dimethyl 17f3-hydroxy estra 4,9,11 -triene is administered at a dose of 1 mg per rat per day, subcutaneously, in solution in olive oil. supplemented with 5% of benzyl alcohol. Testosterone propionate is administered at a dose of 50% per rat per day, subcutaneously. The following groups of rats were formed: a) a control group which received the solvent;

b) a group of rats to which 50 µl of testosterone propionate is administered subcutaneously;

c) a group of rats to which 1 mg of the product studied is administered subcutaneously;

D) a group of rats which receives 1 mg of the test product, subcutaneously and 50 µ of testosterone propionate subcutaneously.

The following table summarizes the results obtained:

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Treatment

Daily doses

Levator fresh ani mg

Seminal vesicles mg

Prostate mg

Witnesses

0

22.8

7.3

15.3

Testosterone propionate

50 y

29.2

42.4

CO

_i>

3-oxo 12,17o-dimethyl 17p-hydroxy estra 4,9,11-triene.

1 mg

18.8

16.9

28.7

3-oxo 1 2.1 7cx-dimethyl 17 (3-hydroxy estra 4.9 »1 1-triene

Testosterone propionate

1 mg +

50 y

22.2 (-24? S)

40.7

55.2 (-34%)

In the second experiment, the product studied was administered at a daily dose of 400 µ, under the same experimental conditions. The following results were obtained:

Treatment

Daily doses

Levator fresh ani mg

Seminal vesicles mg

Prostate mg

Witnesses

0

24.2

7.6

11.3

Testosterone propionate

50 y

32.9.

49.2

62.8

3-oxo 12,17a-dimethyl 170-hydroxy estra 4,9,11 -triene

400 y

18.3

18.0

13.2

3-oxo 12.1 7a-dimethyl 17 (3-

hydroxy estra 4,9,11-triene +

Testosterone propionate

400 y +

50 y

30.2

45.4

(-9%)

42.0 (■ 33 *)

It can be seen, from these results, that the product studied exerts a clear antiandrogenic activity vis-à-vis 50 μ of testosterone propionate and that, administered alone, it does not exhibit a significant androgenic effect.

It can therefore be deduced from this that 3-oxo 12,1 7a-dimethyl 17 | 3-hydroxy estra 4,9,11-triene exhibits a marked inhibitory action vis-à-vis the androgenic action of testosterone propionate.

2 ° Search for an estrogenic action:

The estrogenic activity of 3-oxo 12,17a-dimethyl 17P-hydroxy estra 4, 9,11-triene was investigated by the RUBIN test (Enio., 1951.49.429).

19-21 day old female mice are treated once

Claims (27)

309 7 per day for three days; the animals are sacrificed on the fourth day and the uteri are removed, dissected and weighed. The product, used in solution in olive oil with the addition of 5% benzyl alcohol, was administered subcutaneously in total doses of 10, 30 and 90% under the volume of 0.1 cm3. The following table brings together the results obtained: Lots Total doses Uterine weight in mg Witnesses 0 10.2 Product studied 90 y 91.5 Witnesses 0 11.2 Product studied 10 y 30 y 19.8 45.6 The estrogenic effect is about 300 times lower than that of ethynyl estradiol. ABSTRACT The purpose of the Addition is, as a new medicinal product, in particular for the treatment of hyperandrogenism, 1 ° -3-oxo 12,17a-dimethyl 170-hydroxy estra 4,9,11-triene, of formula: PO F. = 156 ° C, / a / £ = -140 ° + 2 ° (c = 17 °, chloroform), packaged for use at medicinal weight. 2 ° 3-oxo 1 2,1 7a-dimethyl 17 [3-hydroxy estra 4,9,11-triene presented in particular in the form of injectable solutions or suspensions, packaged in ampoules, in multiple dose vials, tablets, coated tablets , sublingual tablets, capsules, suppositories, ointments and creams.