FR2718M - - Google Patents

Description

FRENCH REPUBLIC

MINISTRY OF INDUSTRY

SPECIAL MEDICINAL PATENT

INDUSTRIAL PROPERTY SERVICE

P.y. No. 934.782 International Classification:

N ° 2.718 M A 61 k - C 07 c

New drug endowed in particular with antimitotic activity.

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

Requested on May 14, 1963, at 151 '34 "', Paris.

Issued by decree of August 10, 1964.

{Official Bulletin of Industrial Property [B.S.M.], No. 37 of 1964.)

A subject of the present invention is, as a new medicament, in particular for the treatment of myeloid leukemia, skin neoplasias, digestive tumors and carcinomas in general, deacetylamino N-methyl colchiceinamide of formula:

CH3ON

CH3O

H-N-CH3

packaged for use in medicinal weight and the compositions containing it.

Deacetylamino N-methyl colchiceinamide is in the form of a product crystallized in yellow prisms, soluble in alcohol, acetone, benzene and chloroform, sparingly soluble in ether, insoluble in water, acids and dilute aqueous alkalis.

Its melting point, determined on a Kofler block, is F = 210 ° C.

The principle of the preparation consists in reacting a solution of diazomethane with deacetylamino colchiceine, then methylamine with deacetylamino colchicine obtained.

The following diagram explains the reactions:

CH3ON CH:, o / X "-

CH3O

CH3O

CHsO

CHsO.

CHaO / ^ V> - / CH3O | |

0

H-N-CH3

diazomethane

(I)

(II)

methylamine

(m)

Procedure

Stage A. - Preparation of deacetylamino colchicine:

6 g of deacetylamino colchicein, I, obtained according to J. Schreiber et al., Helvetica Chim. Acta, 44, 540, (1961), dissolved in methylene chloride with a solution of diazomethane in methylene chloride until an excess persists, destroys the excess of reagent with a few drops of acetic acid and evaporates to dryness under vacuum.

The crude mixture obtained is chromatographed on magnesium silicate. By elution with methylene chloride, deacetylamino colchicine, II, (mp = 182-184 ° C) is obtained which crystallizes from ethyl acetate.

Stage B. - Preparation of deacetylamino N-methyl colchiceinamide.

100 mg of deacetylamino colchicine, II, are dissolved in 4 cm3 of 50% water methanol, 2 cm3 of a 36% aqueous solution of monomethylamine is added and left for sixteen hours at room temperature. Poured into water saturated with sodium chloride, extracted with methylene chloride, the methylene solution washed with water, which is dried over sodium sulfate, filtered and evaporated to dryness under vacuum.

Is obtained by recrystallization in ether 85 mg of deacetylamino N-methyl colchiceinamide in the form of a product crystallized in yellow prisms, soluble in alcohol, acetone, benzene and chloroform, poorly soluble in ether, inso-

65 2191 0 73 340 3

Price of the booklet: 2 francs

Claims (49)

[2.718 M] - lubricated in water, dilute aqueous acids and alkalis, melting at 210 ° C. Analysis for C20H23O4N = 341.4: Calculated: C, 70.36%; H, 6.8%; N, 4.1%; Found: C, 70.6%; H, 6.8%; N, 4.2%. The product has interesting pharmacological properties. In particular, it has an important antimitotic action. It can be used for the treatment of myioid leukemia, skin neophases, digestive tumors and carcinomas in general. Deacetylamino N-methyl colchiceinamide is used buccally, transcutaneously or in local applications. It can be in the form of injectable solutions or suspensions, packaged in ampoules, in multi-dose vials; sterile powders to be prepared at the time of use in an appropriate solvent, tablets and ointments. The useful dosage ranges between 1 and 25 mg per day in adults depending on the route of administration. The pharmaceutical forms such as injectable solutions or suspensions, sterile powders, tablets and ointments are prepared according to the usual methods. Pharmacological study of the drug object of the invention: Antimitotic activity. The antimitotic activity of the drug, object of the invention, was studied according to the method described by R. Jequier, D. Branceni and M. Peterfalvi (Arch. Int. Pharmacodyn. 1955, 103, 243). This method is based on the following facts: In the 3rd rat, the mitotic index of the femoral bone marrow (cells in mitosis / total number of cells) is substantially the same on smears made in various regions and on several fields of the same smear; this mitotic index is normally between 10 and 20 ° / 00 After subcutaneous injection of an antimitotic colchicium such as, for example, colchicine which blocks the division of cells at an intermediate stage of mitosis, this index rises and reaches its maximum around the sixth hour. The observed increase is a function of the administered dose; the correlation is clearly manifested by an S-shaped curve whose inflection point is around the 100% 0 mitotic india. As a measure of the stathmokinetic activity of a product is therefore chosen, the antimitotic dose 100 (DAM 100) defined as being that which provides 100 mitoses per 1000 cells. The standard technique used is as follows: 1. Subcutaneous injection of several doses of the substance to be studied into groups of 2 or 3 rats, the volume injected always being 0.2 cm3 per 100 g of body weight. 2 - 2. Animal sacrifice, six hours after injection; removal of the femoral marrow preparation of smears and staining with May Grunwald-Giemsa; count of 1000 cells on each preparation; 3. Determination of the DAM 100 from the graph representing the mitotic indices found as a function of the logarithm of the dose. The MAH100 of deacetylamino N-methyl colchiceinamide is 0.4 mg / kg. Under the same conditions, the antimitotic dose (DAM100) is 0.7 mg / kg for colchicine. Determination of toxicity: The toxicity test was carried out on mice of the Rockland strain, weighing between 18 and 22 g. The aqueous suspension of deacetylamino N-methyl colchiceinamide was administered intraperitoneally to groups of mice at increasing doses. The animals were kept under observation for a week. The lethal dose (LD50) is approximately 50 mg / kg. By way of comparison, the LD50 of colchicine is equal to 2 mg / kg. The comparison of the active doses (DAM100) and the toxic doses (LD50) of deacetylamino N-methyl colchiceinamide and colchicine shows for the compound which is the subject of the patent a markedly more favorable therapeutic margin than that of colchicine. ABSTRACT The invention relates to, as a new drug endowed in particular with antimitotic activity: Deacetylamino N-methyl colchiceinamide of the formula: CHsO. \ / 3 I y V CH3O o Mp = 210 ° C H-N-CH3 Deacetylamino N-methyl colchiceinamide packaged for medicinal use, in particular in the form of injectable solutions or suspensions, packaged in ampoules, in multi-dose vials or sterile powders to be prepared at the time of use in a solvent suitable: tablets and ointments. Company known as: ROUSSEL-UCLAF - 3 - [2.718 M] 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: - French patent n ° 1.214.102. For the sale of booklets, contact the Imprimerie Nationale, 27, rue de la Convention, Paris (15 *),