FR298M - New drug, in particular for the treatment of spasms of coronary origin. - Google Patents

Description

FRENCH REPUBLIC

MINISTRY OF INDUSTRY

INDUSTRIAL PROPERTY SERVICE

SPECIAL MEDICINAL PATENT

P.y. No. 836.865

International classification

N ° 298 M A 61 k - C 07 c

New drug, in particular for the treatment of spasms of coronary origin.

Company: LES LABORATOIRES FRANÇAIS DE CHIMIOTHÉRAPIE residing in France (Seine).

Requested on August 26, 1960, at 3:27 p.m., in Paris.

Issued by decree of March 13, 1961.

fOfficial Bulletin of Industrial Property [5.S.M.], No. 8 of 1961.)

(Patent resulting from division of invention patent application, P.V. No. 830,184, filed June 16, 1960.)

The present invention relates, as a new medicament, to compositions based on 3a-hydroxy 20,20-6fs- (nitratomethyi) 21-nitrato 11-oxo 55-pregnane and its esters, and in particular on 3a-acetoxy 20 , 20-èis- (nitratomethyl) 21-nitrato 11-oxo 5/3-pregnane of the general formula:

0.

\ / \

CH2ONO2 CH2ONO2 CH2ONO2

R0- '

in which R represents H or the organic or inorganic acyl radical.

The active principle (R = COCH3) is in the form of a colorless solid compound, soluble in acetone, benzene and chloroform, sparingly soluble in alcohol and isopropyl ether. Its melting point determined with the Kofler block is F = 162-163 ° C.

3a-acetoxy 20,20-èis- (nitratomethyl 21-nitrato 11-oxo 5/3-pregnane (II) is prepared as was indicated in the patent application filed in France on June 16, 1960 by the applicant company and entitled "New polyhydroxy steroids and production of these compounds", the principle of the preparation consisting of the following reaction:

yCHaOH 0, „-CH2OH '

V / V— ^ CH.OH

0;

V / \

Z

CH2ONO2 CH2ONO2 CH2ONO2

Co'

/ w

Co-'

(D

As it emerges, the synthesis is characterized by the action of nitric acid fuming in acetic medium on 3a-acetoxy 20,20-bis-hydroxymethyl 21-hydroxy 11-oxo 5/3-pregnane (I) , which gives the desired compound, 3a-acetoxy 20,20-bis- (nitrato-methyl) 21-nitrato 11-oxo 5/3-pregnane (II).

According to an embodiment of the aforementioned synthesis, is introduced into 1.5 cm3 of acetic anhydride cooled to - 10 ° C, 0.5 cm3 of fuming nitric acid and then added over one minute, under nitrogen and with stirring, 0.058 g of compound I. The temperature of the reaction mixture is maintained for twenty

(II)

minutes at - 10 ° C then poured over ice. The precipitate is filtered off and washed with water until the washing water is neutral.

The crude product is chromatographed on silicagel eluting with methylene chloride at 1% acetone and then crystallized by adding ethanol.

0.056 g of compound II is obtained, Mp = 162-163 ° C.

Analysis: C25H37O12N3 = 571.57

Calculated: C% 52.53 H% 6.52.

Found: 52.7 6.6.

This compound is not described in the literature.

1 - 41150

Price of the booklet: 1 NF

Claims (55)

[298 M] - As indicated in the above-mentioned patent application, the product is endowed with valuable pharmacological properties. In particular, it has an action on the coronary flow. The activity of 3a-acetoxy, 20,20-bis- (nitratomethyl 21-nitrato 11-oxo 5jS-pregnane, already at the extremely low concentration of 0.0001 f / g per cubic centimeter on the coronary flow of the isolated heart of rabbit, together with its low toxicity, make it possible to recommend its use in the treatment of angina pectoris and coronary heart disease.It is not excluded that it also has a peripheral vasodilator action and antispasmodic effects allowing its use in asthma, bronchial spasms, arterial spasms. Said compound may be used orally in the form of a 1 mg tablet (daily dose: 1 to 5 mg), or parenterally intramuscularly, in the form of an aqueous suspension or an oily solution at a unit dose of 1 to 2 mg or even by venous route in solution in acetyl methylamine at a dose of 1 to 2 mg, or alternatively by rectal route. It can be in the form of injectable solutions, injectable suspensions packaged in ampoules, vials, syringes ready for injection, in the form of tablets, drops and suppositories. Preferably, it will be used in the form of injectable solutions, injectable suspensions packaged in ampoules, in vials, syringes ready for injection, tablets, drops and suppositories. The useful dosage ranges between 1 and 5 mg per dose per day in adults depending on the route of administration. Pharmaceutical forms such as injectable solutions, injectable suspensions, tablets or suppositories are prepared according to methods known in pharmacy. Pharmacological study of 3a-acetoxy 20,20- bis- (nitraiomethyl) 21-nitrato 11-oxo 5fi-pregnane. Action on coronary flow. - The study of the action of said compound on coronary flow was carried out on the isolated rabbit heart, using a technique inspired by Langendorff (Arch. Gesam. Physiol., 1895, 61, 291) .-. In this method, the heart is suspended by the aorta from a cannula and the coronary system is perfused, by means of this cannula, under a constant pressure of 5 cm of mercury, with Locke's serum of pH 7.2 to 7 , 3, heated to 37 °. The studied body is dissolved in ethanol; this solution is diluted with Locke's serum, to a suitable concentration. With a suitable device, the coronary flow is recorded and, at the same time, the ventricular contractions. We systematically sought the initial concentration of said compound which clearly increases the coronary flow of such a preparation and the attached table provides the results obtained with this body as well as with trinitrin and papaverine, under the same experimental conditions. Acute toxicity. - The toxicity test was carried out on Rockland strain mice weighing between 18 and 22 g. The body was used as a suspension at 10 mg per cubic centimeter in a suitable dispersive solution. H was injected in this form by the subcutaneous route, into two groups of ten mice, at doses of 50 and 100 mg / kg respectively. The animals were kept under observation for a week. No symptoms of intoxication or mortality were noted during this period. Said compound is therefore devoid of toxicity, even at a dose of 100 mg / kg. Body studied Introductory active concentration of f £ g / em3 in the infusion fluid Increase in coronary flow as% of normal flow Duration of action Effects on ventricular contractions On the amplitude On frequency Trinitrine Papaverine 1 10 0.0001 0.001 10 20 10 40 mn 2 to 20 15 Durable in plateau> 30 0 0 0 0 I o o o in • ^ a 3 a-acetoxy 20, 20-bis - (nitratomethyi) 21-nitrato 11-oxo 5 i-pregnane. ABSTRACT The subject of the invention is, as a new medicament, in particular for the treatment of spasms of coronary origin: 1 ° Compositions based on 3 "-hydroxy 20, 20-bis> - (nitratomethyi) 21-nitrato 11-oxo 5/3-pregnane and its esters, in particular on 3a-aeetoxy 20, 20-bis- (nitratomethyl ) 21-nitrato 11-oxo 5/3-pregnane of the general formula: RO / \ / V ' 3 - [298 M] CH2ONO2 nitrato 11-oxo 5/3-pregnane and its esters such as CHaONOa in particular 3a-acetoxy 20,20-bis- (nitratomethyi) CH2ONO2 21-nitrato 11-oxo 5/3-pregnane, packaged for medicinal use in particular in the form of injectable solutions, injectable suspensions, packaged in ampoules, vials, syringes ready for injection, tablets, drops and suppositories . in which R represents H or an acyl radical of an organic or inorganic acid, F = 162-163 ° C (R = COCH3). 2 ° 3a-hydroxy 20, 20-bis- (nitratomethyl) 21- Company: THE FRENCH CHEMOTHERAPY LABORATORIES Vicarious : G. Bkrixawski To sell the booklets, contact the Imprimerie Nationale, 27, rue de la Convention, Paris (15 *).