DE2312428A1 - NEW ANDROSTERONE DERIVATIVE, PROCESS FOR ITS MANUFACTURING AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

Dr. F. Zumsteln sen. - Dr. E. Assmann
Dr. R. Koenigsberger - Dlpl.-Phys. R. Holzbauer - Dr. F. Zumstefn Jun.

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Cas 1523 D

ROUSSEL-UCLAF, Paris / France

New androsterone derivative, method for its
Manufacture and pharmaceutical compositions

The invention relates to the diacid androsterone phosphate
formula

a process for the preparation of this compound as well as pharmaceutical Compositions containing this compound.

It is known that androsterone is hypocholesterolemic
Possesses properties. However, the androsterone is inactive even when administered buccally; it is only effective when administered parenterally. The disadvantages of such administration are well known, especially when the administration has to be repeated.

Certain androsterone derivatives, which are hypocholesterolemic Have properties are known. These derivatives are each

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but either very little effective when administered buccally, such as the o-methyl derivative of androsterone [RRCounsell, "J.Med.Chem. ¹¹ , 7, 119 (1964)], or they are only effective when administered parenterally, such as dirnethylaminoethoxyiminoandrosterone [ "Chem. Pharm. Bull"., Tokyo 14 (1) 174 (1966)],

The diacid phosphate of androsterone, on the other hand, shows hypocholesterolemic Properties both buccal and parenteral administration. This unexpected result shows numerous advantages and makes this product considerably easier to use in therapy.

The hypocholesterolemic properties of diacid phosphate of androsterone cause its use in the treatment of hypercholesterolemia and its related Complaints »the diacid androsterone phosphate is still used in the treatment or prevention of atheromatosis, the coronary insufficiency and the arteritis of the lower Extremities. ·

The pharmaceutical compositions contain the diacid androsterone phosphate as active ingredient together with an excipient suitable for buccal, parenteral or rectal administration. They may take the form of simple or coated tablets, gel beads, capsules ₉ suspensions or syrups, in the form of injectable solutions or suspensions or in the form of suppositories.

For example, the average dose for adults can be between 50 and 500 mg per day with one to three administration times per day.

The process for the preparation of the disauric androsterone phosphate is characterized in that the androsterone is Subjected to the action of a phosphorylating agent.

Such an agent can be Z ₀ E ₀ phosphorus oxychloride, phosphorus pentachloride or a functional derivative of phosphoric acid, such as a

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OR dialkyl- or di-aralkyl "-ha log en. Phosphate of the formula X-P ^

I OR 0

where X is a halogen atom and preferably chlorine and R is a lower-alkyl or -aralkyl radical, be, what are followed by hydrolysis.

According to a preferred embodiment of the invention Process is the phosphorylating agent phosphorus oxychloride, and the working conditions are the following:

a) One works in the presence of a cyclic, aromatic base, preferably in the presence of pyridine}

b) one works in an ether medium, whereby ethyl ether, tetrahydrofuran or dioxane are preferred;

c) one works at low temperature, preferably at. a temperature close to -15 C *

The following examples illustrate the invention without, however, restricting it.

example 1 Production of the disauric androsterone phosphate

4 g of androsterone and 17 ecm of pyridine are added to 170 ecm of ether under nitrogen. The mixture is cooled to -15 ° C. and a solution of 1.36 ecm of phosphorus oxychloride in 85 ecm of ether is added dropwise. The suspension thus obtained is stirred for 2 hours at a temperature of -10 ° C. and then allowed to warm to room temperature. Water is added, stirred for 15 hours at +5 ⁰ C are added and then ether. The ether phase is extracted with 0.1N sodium hydroxide and the alkaline extract is then acidified with 0.5N hydrochloric acid. The precipitate obtained is filtered off with suction, washed with water and taken up with 1N sodium hydroxide. The insoluble fraction is removed by extraction with ethyl acetate and the basic solution is acidified by adding 1N hydrochloric acid. The precipitate is filtered off with suction and washed with water

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_ 4 -

dry it in vacuo at 50 ° C for 24 hours. 2.45 g of a product are obtained which are dissolved in a water / alcohol mixture (50/50) and passed over an ion exchange resin (in the acidic form). The eluate is collected and evaporated to dryness in vacuo. The residue obtained is recrystallized from aqueous ethanol. This gives 1.470 g of the diacidic Androsteronphosphats, F = 200 ⁰ C. Concentration of the mother liquors gives a second crop of 0.430 g of Androsteronphosphats, F = 20Q ° C, [α] ^ ° = + 74.5 ° + 2 ° Cc «1 % chloroform). The product is soluble in methylene chloride, chloroform, ethanol and acetone and insoluble in water.

Analysis: C ^ H ^ OrP = 370.43

Calculated: C 61.60 H 8.43 'P 8.36 %
Found: 61.4 8.7 8.7 %

Example 2 Pharmaceutical preparation

Tablets with 100 mg active ingredient:.

(Formulation for 1000 tablets)

Androsterone disauric phosphate 100 g

Excipient 200 g

(Composition of the excipient: lactose, starch, talc,

Magnesium stearate)

Investigation of the hypocholesterolemic activity of the diacid phosphate of androsterone (compound A) in normal female rats

Several groups of female rats weighing an average of about 200 grams are used for each experiment and are rendered hypercholesterolemic by administration of a hypercholesterolemic diet containing 1% cholesterol and 0.25 % cholic acid.

One group of rats is used for comparison and receives only the hypercholesterolemic agent that the other groups receive

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the compound A at a daily dose of 20 mg / kg and the hypercholesterolemic diet at the same time. The treatment lasts 10 days. On the 11th day, the animals are sacrificed and blood samples are used to determine the levels of the serum sterols taken.

The results obtained are summarized in the table below.

Used
product dose Meet
ching
path Serum-
sterols
in g / l modification
of the serum
steringeh. 1.Ver
search 0 (comparison)
A.
A. 20 mg / kg
20 mg / kg buccal
subcutaneous 2.07
1.52
1.43; -27 %
-31 % 2nd ver
search 0 (comparison)
A. 20 mg / kg buccal 1.24
0.92 -26 % 3rd ver
search comparison
A. 20 mg / kg buccal 1.21.
0.89 -26%

These experiments show the effectiveness of disauric androstereone phosphate on both buccal and parenteral Administration,

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Claims (4)

Claims 1.) Androsterone disauric phosphate of the formula 2.) Process for the preparation of the disauric androsterone phosphate according to claim 1, characterized in that the androsterone is subjected to the action of a phosphorylxer. 3.) Method according to claim 2 _P, characterized in that the Phosphoryliertmgsmittei is phosphorus oxychloride. 4.) Pharmaceutical compositions containing the diacid androsterone phosphate according to claim 1 as an active ingredient together with an E>: cipients _o