Untitled record

FRENCH REPUBLIC _Λ MINISTRY

INDUSTRIAL AND SCIENTIFIC DEVELOPMENT

INDUSTRIAL PROPERTY SERVICE

SPECIAL MEDICINAL PATENT

PV n ° 133.219 Transi. n ° 163 Μ N ° 7.524.M International classification: A 61 k // C 07 d

New pharmaceutically active piperonyl-piperazine amide derivatives.

Company known as: LABORATOIRES F. BOUCHARD (request filed by Messrs. André BUZAS and René PIERRE) resident: 1^er in France (Paris); the 2^e in France (91).

Carried out on March 12, 1968, by post.

Issued by decree of December 15, 1969.

{Official Bulletin of Industrial Property [BSM], No. 4 of January 26, 1970.) (Patent resulting from the division of the patent application,

PV n ° 133.219, deposited on December 20, 1967, at 10/15^{> m}.)

The present invention relates to novel amide derivatives of piperonyipiperazine as novel antidepressant drugs and stimulants of the nervous system. These molecules have the general formula:

O

<img file="FR7524M_D0001.tif" />

where R represents:

(See table in column opposite)

They can be prepared by reacting piperonyipiperazine on the corresponding phenoxy acetic acid chloride in the presence of a tertiary base such as pyridine and in a suitably chosen solvent such as tetrahydrofuran, chloroform, dioxane, benzene and isopropyl ether.

O

To a solution of 22.03 g (0.1 mole) of piperonylpiperazine, in 200 ml of dry tetrahydrofuran, 7.9 g (0.1 mole) of dried and distilled pyridine are successively added, then, little by little, with stirring. 22.5 g (0.11 mole) of chloride of the para para chlorophenoxy acetic acid, taking care that the temperature does not exceed 20 degrees. When the addition is complete, the mixture is heated for 1 hour at reflux. The mixture is left to return to ambient temperature, then the tetrahydrofuran is removed under vacuum. The residue is

210032 7

<td>R</td><td>Molecule</td>

<td>^q-^&lt;^^{r =}^ -O-^CH2-</td><td>AT</td>

<td>CFs /</td><td>D</td>

<td>f- /⁼⁼⁼^ -o-ch₂-</td><td>E</td>

<td>HaC-O - ^^^ - O-CHü-</td><td>F</td>

<td>O</td><td></td>

<td>HaC-C-HN- ^ ^ -O-CHü-</td><td>G</td>

We give below an example illustrating this method:

Para chlorophenoxy acetyl-piperonylpiperazide hydrochloride:

Vo-CHs-CN

<img file="FR7524M_D0002.tif" />

dissolved in 100 ml of chloroform; washed with 10% sodium carbonate, then with water. The chloroform layer is then transferred to a flask and stirred vigorously in the presence of 10% hydrochloric acid. Pyridine hydrochloride goes into solution in water while para chlorophenoxy acetylpiperonylpiperazide hydrochloride precipitates. This precipitate is drained under vacuum, washed, then recrystallized from water.

Yield 26 grams F 230 - 232 ° (Kofler) [7.524 Μ] -

The LD 50 in mice by subcutaneous route is between 300 and 400 mg / kg for derivatives E, F and G; it is higher (between 1 g and

1.5 g / kg) for derivatives A and D. In the same animal, orally, these new drugs are not very toxic since the never lethal maximum dose is several grams (for example 4 g / kg for derivative A ).

The pharmacological study has shown that these bodies have thymoanaleptic and psychostimulating properties:

They are convulsive in mice at a dose of 100 mg / kg intraperitoneally, more intensely for derivatives A, E and F;

They protect the mouse against the effects of tremorine, the derivatives A, D, E and G almost completely, the derivative F at 50%;

Derivatives A, D, E and G reduce by one third to half the mortality caused by amphetamine in "grouped" mice;

The derivatives A, E, F, G have an antireserpinic activity by halving approximately the gastric ulcers of the rat as well as the ptosis of the mouse, induced by reserpine.

Clinical studies have shown that, when administered to humans in capsules, derivatives E, F and G at the daily dose of 50 to 100 mg, derivatives A and D at the daily dose of 300 to 500 mg have a beneficial action on nervous fatigue, on asthenia and on the depressed.