FR2417M - - Google Patents

Description

FRENCH REPUBLIC

MINISTRY OF INDUSTRY

INDUSTRIAL PROPERTY SERVICE

SPECIAL MEDICINAL PATENT

P.V. n ° 923.183 International Classification:

N ° 2.417 M A 61 k - C 07 c

New drug endowed in particular with anabolic activity.

Company known as: ROUSSEL-UCLAF residing in France (Seine).

Requested on January 30, 1963, at 151 '40m, in Paris.

Issued by decree of March 23, 1964.

(Official Bulletin of Industrial Property [B.S.M.], No. 17 of 1964.) (Patent resulting from the division of the invention patent application, P.V. No. 916,520, filed November 24, 1962.)

A subject of the present invention is, as a new medicament, 17 a-methyl 17 (3-hydroxy A3 5a-androstene and its esters, of general formula:

/ \

/ \

GOLD

CHs

V \ /

h

R being H or a residue of lower aliphatic acid or aromatic acid packaged for use at medicinal weight and compositions containing it.

17α-Methyl 17 (3-hydroxy A3 5a-androstene (R = H) occurs as a compound

crystallized in colorless needles, soluble in alcohol, ether, acetone, benzene, chloroform, insoluble in water, dilute aqueous acids, dilute aqueous alkalis.

Its melting point, determined on a Kofler block, is F. 140 ° C, / ot / S ° = + 25 ° ± 5 (c = 1% chloroform).

17 a-methyl 17 (3-hydroxy A3 5 a-androstene and its esters are prepared as was shown in the patent application filed in France on November 24, 1962 by the applicant company and entitled: "New steroids alcoylés, alcoy -lenes or alkynes and method of preparation ”.

The principle of the preparation consists in reacting 17-oxo A3 5a-androstene with methyl lithium in 3.5% solution in ether, obtaining 17a-methyl 17 (3-hydroxy A3 5a -androstene which is converted, if necessary, into an ester:

/ \

/ \

_ /

■ 0

/ \

CHaLi-ether w

H

\ /

,OH

\

/ \

ch3

esterif.

OR CH3

H

V

h

R being a residue of lower aliphatic acid or aromatic acid.

Procedure. - In a flask are mixed 20 cm3 of a solution of methyl lithium at 3.5% in ether, at room temperature, with a solution of 1 g of 17-oxo A3 5a-androstene in 5 cm3 of benzene. Rinsed with benzene, stirred for one hour at room temperature, the reaction mixture is poured over ice, extracted several times with methylene chloride, the organic phases washed twice with water and dried over magnesium sulfate. Stirred with a little alumina, decolorized by passing to black and filtering.

It is evaporated to dryness, the residue is taken up in acetone, water is slowly added to the acetone solution which crystallizes; on ice, the crystalline precipitate is separated, washed with a water-acetone solution and dried at 75 ° C.

The weight obtained is 1 g.

The product is purified by two recrystallizations from a water-acetone solution, mp 140 ° C, / a / ° + 25 ° ± 5 (c = 1%, chloroform).

Analysis: C20H32O = 288.46.

Calculated: C = 83.27%; H, 11.18%.

Found: C = 83.00%; H, 11.10%.

65 2191 0 73 203 3

Price of the booklet: 2 francs

[2.417 M] - 2

As indicated in the above-mentioned patent application, the product is endowed with valuable pharmacological properties. It has in particular a remarkable protein-anabolic action, while exhibiting only a very low androgenic activity.

H can be used for the treatment of disorders of protein anabolism, asthenia, thinness, osteoporosis, senescence, delayed consolidation of fractures, metabolic disorders of prolonged corticosteroid therapy.

17α-Methyl 17 [3-hydroxy A3 5a-androstene and its esters are used buccally, perlin-guale, transcutaneously and rectally.

It can be in the form of injectable solutions or suspensions, packaged in ampoules, in multi-dose vials, implants, tablets, glossettes and suppositories.

The useful dosage ranges between 5 and 10 mg per dose and 5 and 40 mg per day in adults depending on the route of administration. The pharmaceutical forms such as injectable solutes or suspensions, implants, tablets, glossettes or suppositories are prepared according to the usual methods.

Pharmacological study of the subject drug

From the results obtained, it is found that 17a-methyl 17p-hydroxy A3 5a-androstene exerts at 200 y the same net anabolic action as 17a-methyl 19-nor testosterone at 500 y. Has these of the invention. - Determination of androgenic and anabolic activity: the tests were carried out according to the technique of Herschberger (Proc. Soc. Exp, Biol. Med., 1953, 83, 175) slightly modified. Male rats castrated at 25 days of age are administered the test compound daily for 10 days. The animals are treated from the day after castration and are sacrificed on the eleventh day, twenty-two to twenty-six hours after the last administration. They are autopsied during the sacrifice and the organs concerned are removed and weighed, in particular the levator ani muscle (Ievator ani) for the study of the anabolic action, the ventral prostate and the seminal vesicles for the study of 'a simultaneous androgenic effect.

17α-Methyl 17 | 3-hydroxy A3 5a-androstene, used in aqueous suspension, was administered orally at daily doses of 200 µg, 500 µg, 1 mg, 2 mg and 5 mg per rat per day.

The results obtained are summarized in the following table in comparison with those obtained with 17α-methyl testosterone and 17α-methyl 19-nor-testosterone.

doses, the two products are practically devoid of androgenic effects; at 500 y, the anabolic effect of 17α-methyl testosterone is substantially nonexistent.

Treatment

Daily dose

Duration of treatment

Weight c Initial orporel Final

Seminal vesicles

Ventral prostate

Fresh ani levator

Lf

Levator ani sec

Ls t2i

g g

mg mg mg

mg

Witnesses.

-

10

44

86

7.6

11.4

17.1

0.199

2.7

0.031

500 y

//

46

87

11.0

32.2

20.9

0.241

5.7

0.065

17a-Methyl tested

1 mg

//

49

97

15.2

61.8

38.4

0.395

12.3

0.124

rone

2mg

//

46

93

19.2

59.0

20.0

0.213

5.7

0.060

5 mg

//

46

83

61.0

99.0

31.6

0.377

7.2

0.085

17a-Methyl 19-nor-testosterone

500 y u

48.8

83.2

8.6

26.0

28.1

0.342

6.2

0.076

1 mg u

46

82

20.4

41.5

29.7

0.365

7.0

0.085

5 mg

//

49

93

40.3

78.4

56.4

0.609

13.8

0.148

200 y

//

46.6

90.6

7.2

18.8

29.2

0.320

6.6

0.071

17a-Metiyl, 17 (3-

500 y

//

48.8

76.8

10.9

30.7

27.5

0.370

6.1

0.082

hydroxy A3, 5a- <

1 mg

//

49

97

15.3

40.6

43.1

0.447

11.7

0.122

androstene

2 mg

/;

43

83

19.8

44.2

41

0.50

7.4

0.09

5 mg ti

44

98

47.9

68.7

50.4

0.516

10.1

0.103

Lf: ratio of the weight of the fresh ani ivator X 103 to the body weight. Ls: ratio of the weight of the dry ani levator x 103 to body weight.

- 3

[2.417 M]

Determination of toxicity: 17a-methyl 17 (3-hydroxy A3 5x-androstene, suspended in carboxymethyl cellulose, was administered orally to 2 groups of 10 mice of the Rockland strain weighing 18 to 22 g at respective doses of 50 and 100 mg / kg, in a volume of 0.4 cm3 per mouse of 20 g.

No signs of intoxication or mortality were observed in the mice kept under observation for a period of 8 days.

17oc-methyl 17 (3-hydroxy A3 5 "-androstene is therefore well tolerated by mice at doses of 50 and 100 mg / kg, administered orally.

ABSTRACT

A subject of the invention is, as a new medicament, in particular for the treatment of protein anabolic disorders:

1 ° 17oc-methyl 17f3-hydroxy A3 5 <x-androstene and its esters of general formula:

/ \

/ \

, OR \ CHS

\ / \ /

H

R being H or a residue of lower aliphatic acid or aromatic acid, M.p. 140 ° C, M10 = + 25 ° rt 5 (c = 1%, chloroform) (R = H].

2 ° 17a-methyl 17 (3-hydroxy A3 5a-androstene and its esters, packaged for medicinal use, in particular in the form of injectable solutions, injectable suspensions, packaged in ampoules, in multi-dose vials, implants, tablets, glossettes and suppositories.

Company known as: ROUSSEL-UCLAF

DOCUMENTARY NOTICE ON THE NEW FEATURE

Documents likely to affect the novelty of the medicinal product: none.

Documents illustrating the state of the art in this area:

Chemistry and Industry, vol. 48, p. 1962 (1961), J.A. Edwards and A. Bowers.

For sale of booklets, contact the Imprimerie Nationale, 27, rue de la Convention, Paris (15 ").