FR2649M - - Google Patents

Description

FRENCH REPUBLIC

MINISTRY OF INDUSTRY

INDUSTRIAL PROPERTY SERVICE

SPECIAL MEDICINAL PATENT

P.y. No. 911.197 International Classification:

N ° 2.649 M A 61 k - C 07 d

Medicinal product based on pyrazole derivative.

Public limited company known as: LABORATOIRE MILLOT residing in France (Seine).

Requested October 3, 1962, 16 "llm, Paris.

Issued by decree of July 15, 1964.

(Official Bulletin of Industrial Property [5.S.M.], No. 33 of 1964.)

This medicinal product comprises, as an active substance, a new compound which is 3-methyl-5-phenyl pyrazole, corresponding to the formula:

HC-

-C-CH3

,NOT

NOT/

I

H

This compound can be prepared by applying the general known methods of synthesizing pyrazole compounds, in particular the condensation of the appropriate α, [} ethylene ketone, i.e. benzalacetone with hydrazine, to obtain 3-methyl. 5-phenyl pyrazoline, according to the equation:

VS

HC-CO-CHs

"V 11

V - CH + NH2

HaC C-CH3

H2N

which is then converted into pyrazole, for example by heating with sulfur, or alternatively by condensation of the appropriate β-diketone, that is to say benzoylacetone, with hydrazine (in the form of a hydrate), with intense heating, according to the equation:

o-

H2C ~ CO-CH3 I

-co + NH2

HC-

-C-CHs

O

HaN

-C N

\NOT/

I

H

The following examples illustrate the invention. Example 1. - After synthesis of 3-methylphenyl-5 pyrazoline from benzalacetone and hydrazine, 32 g of the compound obtained are heated with 32 g of sulfur (medium temperature approximately 200 °): a powerful reaction is produced. release of hydrogen sulphide which stops after thirty 65 2191 0 73 271 3

minutes. Heating is continued for an additional twenty to thirty minutes to complete the reaction and the reaction mixture is distilled in vacuo. 27.9 g of 3-methyl-phenyl-5 pyrazole are obtained in the form of yellowish crystals (melting point: 127 °) after recrystallization from a mixture of octane and benzene (1: 1). Yield: 89.0%.

Example 2 - Benzoylacetone and hydrazine are reacted in equimolecular proportion by heating to a temperature of 150 °, without solvent.

The 3-methyl-5-phenyl pyrazole formed can be recrystallized from very hot water. It is obtained in the form of crystalline needles which, by drying out, form a felted fabric, which can only be triturated with difficulty.

It is easier to isolate the base with ether and to purify it by distillation. It distills around 316-317 °. The distillate solidifies in needles (melting point: 127 °).

From the base, for example by passing dry hydrochloric gas through an ethereal solution of this base, one can easily prepare the hydrochloride which is a white crystalline powder, odorless and of burning flavor, having an instantaneous melting point of 165 -167 ° at the Kofler bank. Its maximum absorption, in alcoholic solution, is X - 252 m [z. (EJ = 790).

The hydrochloride is sparingly soluble in cold but soluble in hot water, soluble in alcohol in cold, very soluble in chloroform in cold and insoluble in ether.

The pharmacodynamic properties of the new pyrazole derivative, tested as hydrochloride in aqueous solution, are as follows:

1 ° Toxicity:

It was calculated by the probit method in mice. The LD 50, by the intravenous route, is 113 dt 4.2 mg / kg for the hydrochloride administered in aqueous solution. The oral LD 50 is 680 rb 20 mg / kg, the LD 100 approximately 800 mg / kg and the LD 0 approximately 500 mg / kg for the base administered in suspension at 4% in gum.

Price of the booklet: 2 francs

Claims (58)

[2.649 M] - 2 ° Sedative and protective action with regard to convulsants: at. Strychnine. The strychnine is injected into the mouse intravenously, at a dose of 1 mg / kg, thirty minutes after oral administration of methyl-3-phenyl-5 pyrazole hydrochloride. Calculated by the probits method, the ED 50 of protection against strychnine by 3-methyl-5-phenyl-pyrazole hydrochloride administered orally is: 190 zb 12 mg / kg for protection against attacks and 175 ± 11 , 5 mg / kg for protection against death. b. Amphetamine: Amphetamine administered subcutaneously to mice at a dose of 25 mg / kg causes intense agitation. Amphetamine is injected one hour after oral administration of 3-methyl-5-phenyl-pyrazole hydrochloride. At a dose of 300 mg / kg of this hydrochloride, 50% of the mice are protected against agitation. vs. Maximum electroshock: In this experiment, we seek to determine the action of the new compound on the threshold of tonic electrical convulsive seizures (stiffening and extension of the hind legs). The rise in the threshold is considered to be significant when it reaches or exceeds 50% of the initial threshold. At a dose of 100 mg / kg (hydrochloride in aqueous solution) administered orally one hour before the electroshock, complete protection of the animal is obtained. The lower doses make it possible to consider that the threshold of activity against electroshock is certainly notably below 100 mg / kg. 3 ° Potentiation of barbiturates: Potentiation of barbiturates is an important factor in sedative activity. The mice are injected with a dose of 40 mg / kg, intraperitoneally, of pentobarbital inducing a short sleep of about twenty-five minutes. Upon awakening, the new compound is administered orally at varying doses but not by themselves inducing sleep. We note the number of animals that go back to sleep and the duration of this new sleep: 100 mg / kg of 3-methyl-5-phenyl-pyrazole hydrochloride; 100% of the mice go back to sleep for about two hours; 50 mg / kg of 3-methylphenyl-5-pyrazole hydrochloride; 100% of the mice go back to sleep for about forty minutes; 25 mg / kg of 3-methyl-5-phenyl-5-pyrazole hydrochloride; 30% of the mice go back to sleep for about twenty minutes. In conclusion, the ED 50 of potentiation with barbiturates is between 50 and 25 mg / kg. 4. Action on rectal temperature. Variable doses of the new compound are administered orally and, by means of a thermoelectric couple, the rectal temperature of the animals is measured. At a dose of 100 mg / kg, 3-methyl-5-phenyl-pyrazole hydrochloride lowers the rectal temperature by an average of 3 degrees in mice with a maximum action one hour and a half after administration. 3-methyl-5-phenyl pyrazole can be used therapeutically as a sedative and hypothermic agent in conditions accompanied by hyperthermia and agitation. It can be used in the form of one of the salts which this basic compound gives with pharmaceutically acceptable acids, in particular in the form of the hydrochloride. It may be presented in combination with a solid or liquid excipient for oral administration or an excipient for endorec-tal administration. A typical example of sugar-coated tablets containing 30 mg of active ingredient is as follows: 3-methyl-5-phenyl-5-pyrazole hydrochloride 30 mg Icing sugar 9 mg Kaolin 10 mg Gum arabic powder 7 mg Hydrated alumina 40 mg Wheat starch 27 mg Talc 5 mg Magnesium stearate 2 mg for one 130 mg tablet. Coating for a sugar-coated tablet of approximately 200 mg. The medicament may also, for oral administration be in the form of a solution to be administered in drops, at 10 g in 100 ml of 20% ethyl alcohol. Suppositories for adults can weigh about 2.5 g and be dosed at 50 mg of active ingredient. The daily dosage is 2 to 4 sugar-coated tablets per day, including 2 in the evening, or a suppository (at bedtime) or 10 drops twice a day. ABSTRACT 1 ° Sedative and hypothermic drug, which comprises as active substance 3-methyl-5-phenyl pyrazole corresponding to the formula: HC C-CHs 0 \ „/ N I H 2 ° Forms of realization of the drug specified under 1 °, presenting the following particularities, taken separately or in combinations: at. The pyrazole derivative appears in the form of one of the salts which it gives with pharmaceutically acceptable acids, in particular in the form of the hydrochloride; b. The active substance is combined with an excipient 3 - [2.649 M] for oral administration, in particular a solid excipient for tablets or a hydrc-alcoholic excipient for absorption in drops, or alternatively to an excipient for suppositories. Public limited company known as: LABORATOIRE MILLOT Vicarious : J. Casanova (Young Ahmenc-aud cabinet) DOCUMENTARY NOTICE ON THE NEW FEATURE Documents likely to affect the novelty of the medicinal product: - M. Negwer “Organisch-Chemische Atchnei-mittel und ihre Synonyma” (1961), p. 134. For sale of booklets, contact the Imprimerie Nationale, 27, rue de la Convention, Paris (15 ").