FR2531964A1 - 14-Aminosteroid derivatives, preparation process and use in therapy - Google Patents

Abstract

The invention relates to new 14-aminosteroid derivatives represented by the general formula: in which R represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms and R1 represents a sugar residue, as well as their salts with acids. Use in therapy, in particular for the treatment of heart failure.

Description

The present invention, made in the CERES Laboratories - Center
European Scientific Research concerns new steroid derivatives, and more particularly new amino-14 steroid derivatives substituted in position 3 by a sweet derivative, a process for their preparation and their therapeutic application.

French patent application 2,464,270 describes compounds of the amino-14 steroid type, and in particular hydroxylated derivatives of amino-14 androstane and amino-14 nor-21 pregnane. Also known are steroid alkaloids of the pregnane and androstane series substituted in position 14 by an amino group, and for example the amino-14 $ pregnanediol-3X, 20x is described by A. Astier et al., Bull . Soc. Chim.

 No. 9-10, P.1581-1582 (1976); other amino-14ss pregnanes and amino-148 androstanes are also described by A. Astier et al., Tetrahedron vol.34, p.1481-1486, (1978). However, no pharmacological property nor any therapeutic application of these derivatives has been described.

Amino derivatives of steroids useful in therapy are also known, and for example French patent applications 2,494,697 and 2,494,698 describe amino-3 (5x) pregnanediol-17, 20, amino-3 (5x) nor -19 pregnanol-20 and amino derivatives, presented as having immunotherapeutic properties allowing their application as medicaments for the treatment of autoimmune diseases resulting from a deficiency in certain lymphocytes.

The work carried out by the applicant has made it possible to surprisingly find that new derivatives of amino steroids, and more particularly derivatives of the pregnanol-20 and nor-21 pregnanol-20 series, substituted in position 14 by an amino group and in position 3 by a sugar residue, have positive inotropic properties as well as supraventricular antiarrhythmic properties.

The present invention therefore relates to new amino-14 steroid derivatives substituted in position 3 by a sweet derivative as well as their addition salts with mineral or organic acids.

The invention also relates to a process for the preparation of amino-14 steroids substituted in position 3 by a sweet derivative, from a dihydroxy-3.20 amino-14 steroid.

The invention also relates to the application of new amino-14 steroid derivatives substituted in position 3 by a sweet derivative, in human and veterinary therapy, as cardiotonic drugs for the treatment of heart failure, as well as the pharmaceutical compositions containing as active principle at least one of the new amino-14 steroid derivatives, or a pharmaceutically acceptable salt, in combination with one or more suitable excipients.

dans laquelle R représente un atome d'hydrogène ou un groupe alkyle inférieur de 1 à 4 atomes de carbone, et R1 représente un reste de sucre, substitué le cas échéant.The new amino-14 steroid derivatives in accordance with the present invention can be represented by the general formula (I):

in which R represents a hydrogen atom or a lower alkyl group of 1 to 4 carbon atoms, and R1 represents a sugar residue, substituted where appropriate.

The new amino-14 steroid derivatives of general formula (I) have in their molecule several asymmetric carbon atoms, in particular the carbons in positions 3, 5, 14, 17 and 21, and can therefore exist in various stereoisomeric forms; the invention relates to new products of general formula (I) in the form of separate isomers or as a mixture.

The invention also relates to the salts of the amino-14 steroids of general formula (I), and in particular the salts obtained by the action of a mineral or organic acid, according to the usual methods of the technique.

The acid used can be chosen from hydrochloric acid, oxalic acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, p-toluene sulfonic acid, formic acid , hydrobromic acid, maleic acid, sulfamic acid, etc.

In the general formula (I) above, R preferably represents a hydrogen atom or a methyl group.

The sugar residue represented by R1 in the general formula (I) may be a residue of monosaccharide, oligosaccharide or polysaccharide, substituted if necessary.

R1 can be, for example, a residue of monosaccharide, and in particular a pentose or a hexose modified or substituted if necessary, to form for example a 2-deoxy or a 6-deoxy-hexose, a 2,6-dideoxy hexose, a deoxy- 2 amino-2 hexose, a deoxy-3 amino-3 hexose, a deoxy-3 methoxy-3 hexose, etc.

As examples of monosaccharides which can be used in the invention, mention may in particular be made of glucose, rhamnose, fructose, galactose, mannose, arabinose, digitoxose, cymarose, xylose, lyxose, ribose, digitalose, deoxy-6 glucose, glucosamine, 4-amino trideoxy-2,4,6 lyxohexopyranose, 4-amino dideoxy-2,6 glycopyranose, etc, and preferably the anomers ss-D or aL. It is also possible to use disaccharides such as sucrose, maltose or lactose or also various polysaccharides containing several oses.

Among the compounds of general formula (I) above, the invention preferably relates to those for which the sweet residue represented by R1 is a residue of glucose, rhamnose, galactose, fucose, or digitoxose.

The invention particularly relates to amino-I4 steroid derivatives consisting of O- (aL-rhamnopyranosyl) -3 amino-14B nor-21 pre gnan- (5) diol-38,20, 0- (oL -rhamnopyranosyl) -3 amino-14ss pregnan- (5 diol-3ssS20a and its 20ss isomer, 0- (ss-D-digitoxosyl) -3 amino-14B pre gnan- (58) diol-3ss, 20 α and the 0 - (4-amino-tridesoxy-2,3,6 α; - L-lyxohexopyra- nosyl) -3 amino-14ss pregnan- (5ss) diol-3ss, 20 ç
As indicated above, the amino-14 steroid derivatives according to the invention can exist in various stereoisomeric forms resulting from the presence of several asymmetric carbon atoms in the steroid backbone. The invention preferably relates to the derivatives of general formula (I) in which the substituent -OR1 in position 3, the hydrogen atom in position 5, the group -NH2 in position 14, and the substituent -CHROH in position 17 have the ss configuration. This configuration is not limiting, and for example the hydrogen atom in position 5 can be in configuration a.

dans laquelle R est un atome dthydrogène ou un groupe alkyle inférieur, et de préférence un groupe méthyle, en protégeant le groupe -NH2 en position 14 et le groupe -OH en position 20, en effectuant une réaction de couplage avec un sucre activé de formule R1-X ou R1 est défini comme ci-dessus et X représente un atome d'halogène ou un groupe acétyle, et en éliminant ensuite, le cas échéant, les groupements protecteurs.The new amino-14 steroid derivatives of general formula (I) can be prepared from the amino-14 steroid represented by the general formula (II) below:

in which R is a hydrogen atom or a lower alkyl group, and preferably a methyl group, by protecting the group -NH2 at position 14 and the group -OH at position 20, by carrying out a coupling reaction with an activated sugar of formula R1-X or R1 is defined as above and X represents a halogen atom or an acetyl group, and then eliminating, where appropriate, the protective groups.

The activated sugars can be, for example, tri-0-acetyl digitoxose, tri-0-acetyl aL-rhamnosyl bromide, O-benzoyl-3-tridesoxy-2,4,6 trifluoroacetamido-4 ass-L-lyxohexopyranoside, 2,3-di-acetyl-2,3-dideoxy-4,6-trifluoroacetamido-4 glycopyranosyl bromide, tetra-0-acetyl α-D-glycosyl bromide, etc.

The protection of the -NH2 group in position 14 and of the -OH group in position 20 is carried out by the usual techniques, and for example. the -NH2 group can be transformed into a trifluoroacetamido group -NHCOCF3 by the action of trifluoroacetic acid anhydride in the presence of triethylamine, or into a formamido group by the action of acetic anhydride in formic acid. The -OH group can be acetylated by the action of acetic anhydrous in a suitable solvent such as pyridine.

The functional groups of the sweet derivatives are preferably protected before carrying out the coupling reaction with the amino-14 sterold.

The hydroxyl groups of the sugar derivatives can be protected by the usual methods, in particular by acylation or by benzoylation. For example, the hydroxyl groups of a digitoxose or a rhamnose can be transformed into acetoxy groups by acetylation by means of acetic anhydride. We can in particular refer to the method described by E.

Fisher et al. in Chem. Ber. n053, p.2362 (1920) for the sugar protection technique.

The protective groups are then removed, after coupling between the sugar derivative and the amino-14 sterold, according to the usual techniques, for example by heating in basic medium.

The coupling reaction is carried out by reacting at its anomeric carbon atom, the sugar derivative previously protected, with the hydroxy group in position 3 of the amino-14 steroid on which protective groups have been introduced at the level of the substituents at positions 14 and 20, in a suitable organic solvent I1 may be advantageous to add the excess sweet derivative, and for example, between 1.5 and 2.5 moles of sweet derivative may be used for one mole of amino-14 steroid.

The operating conditions can be chosen according to the usual methods, and for example the coupling method described by D.M. von Niekerk et al. in Experientia n028 p.123 (1972), or the method described by W. Meyer et al. in Chem. Ber. n0104 p.l (1971) especially in the case of an amino sugar. When a sugar such as 2,6-dideoxy hexose or 4-amino trideoxy-2,4,6 hexose is used, it is advantageous to carry out the coupling according to the method described by J. Boivin, C. Monneret and Mr.

 Païs in Tetrahedron Letters p.lill (1980).

The coupling reaction can be carried out according to the above techniques, in a solvent such as benzene or toluene, acetonitrile, methylene chloride, or dioxane, alone or as a mixture, at room temperature, but it it may be useful to heat the reaction medium to activate the reaction, depending on the reagents used.

The amino-14 steroids of general formula (II) used as starting materials, can be prepared as indicated in the French patent application 82.14038 in the name of the applicant, by reduction then acetylation of a dihydroxy-3,14 steroid carrying in position 17 an acyl group -COR, R being a hydrogen atom or an alkyl group, in order to form a trihydroxy-3,14,20 steroid O-acetylated in positions 3 and 20, which is treated with an azothydric acid-boron trifluoride complex before carrying out a reduction with a metal hydride or by catalytic hydrogenation.

For example, amino-14-S pregnan- (5ss) diol-3B, 20a represented by formula (II) where R is a methyl group, can be obtained from oxo-20 pregnan- (5ss) diol-3ss, 14ss on which reduction is carried out with potassium borohydride, then acetylation with acetic anhydride in pyridine to form di-0-acetyl-3.20 pregnan- (5ss) triol -gg, 14a208 which is treated with azothydric acid in the presence of summer boron trifluoride spleen, to then carry out a reduction by the mixed lithium and aluminum hydride. One can also use the method described by Astier et al. in Tetrahedron n034 p.1481-1486 (1978).

As indicated above, the amino-14 steroid derivatives represented by the general formula (I) have interesting pharmacological properties, in particular positive inotropic properties and supraventricular antiarrhythmic properties described in more detail below allowing their application. in human and veterinary therapy for the treatment of heart failure.

The examples described below illustrate the invention without limiting its scope.

EXAMPLE 1
O- (BD-digitoxosyl) -3 amino-145 nor-21 pregnan- (5ss) diol-3ss, 20
To a solution of 3.2 g of amino-14ss nor-21 pregnan- (5ss) diol-3ss, 20 in 40m1 of pyridine cooled to OOC, one ml of acetic anhydride is added with stirring.

After 30 minutes of stirring at OOC, the reaction medium is added with an ice-cold sodium bicarbonate solution, left under stirring for another 10 minutes, then extracted with methylene chloride and evaporated to dryness.

By crystallization of the residue (3.629) in the benzene / hexane mixture, 3.09 of 20-O-acetyl-20 amino-14 $ nor-21 pregnan- (53) diol-3ss, 20 are obtained (yield 83 o).

To a solution of 3.669 of the above derivative in 100 ml of anhydrous methylene chloride cooled to OOC, 3.4 ml of triethylamine and 3.1 ml of trifluoroacetic anhydride are added with magnetic stirring. The mixture is stirred for a further 20 minutes, leaving to return to room temperature, then evaporated to dryness. The residue is dissolved again in methylene chloride and the solution obtained is washed with a saturated solution of sodium bicarbonate, then with water, finally dried in the usual manner and evaporated to dryness. The product obtained is dissolved in 600ml of methanol, then passed slowly over 5 hours. on a column of 300 ml of IR 45 resin (OH phase). The column is washed with 300 ml of methanol. The collected solutions, evaporated to dryness, provide 4.529 of O-acetyl-20 trifluo roacetamido-14r nor-21 pregnane- (5>) diol-3ss, 20 by thin layer chromatography, which does not crystallize.

To a solution of 0.339 of the above derivative and 0.40 g of tri-O-acetyl digitoxose in 30 ml of benzene, 0.359 of dry p-toluene sulfonic acid is added. After 1h. stirring at room temperature, the reaction medium is supplemented with a saturated sodium bicarbonate solution, and extracted with methylene chloride. The residue (0.69) is chromatographed on Merck H60 silica (eluent hexane / AcOEt 75/25). 0.49 is obtained from a mixture of O- (di-O-acetyl-3,4 α a and ss-D-digitoxosyl) -3
O-acetyl-20 trifluoroacetamido-14ss nor-21 pregnane- (5ss) diol-3ss, 20.

To a solution of this mixture in 16 ml of methanol, 4 ml of 5N sodium hydroxide are added, with stirring, and the mixture is refluxed for 2 h 30 min. After this time, it is diluted with water and extracted with methylene chloride. The product obtained (0.279) is chromatographed on Merck H60 silica (eluent CH2C12 / MeOH / NH40H 93/7 / 0.4). 0.159 of the ss-D derivative which crystallizes in the methanol / ether mixture is thus obtained, as well as 0.119 of the a-D isomer, which crystallizes in the same mixture of solvents.

Melting point F = 198-1990C (ss-D anomer).

 2260C (anomer A-D).

= = -31 (c = l, CHC13)
NMR spectrum (CDC13) 6 = 0.93 (CH3-19) 0.98 (CH3-18) 1.30 (CH3-6 ')
4.87 (H-1) ppm (-D anomer).

6 = 0.95 (CH3-19) 1.00 (CH3-18)
1.31 (CH3-6 ') 4.99 (H-1') ppm (-D anomer).

EXAMPLE 2
- 0- (oL-rhamnopyranosyl) -3 amino-14ss nor-21 pregnan- (5ss) diol-3ss, 20
To a solution containing 4.69 of 20-acetyl trifluoroacetamido-146 Nor-21 pregnan- (5ss) diol-3ss, obtained as indicated in Example 1, and 6.959 of tri-0-acetyl-2 bromide, 3.4 aL-rhamnosyl in 235 ml of acetonitrile, 4.969 of mercuric cyanide is added. After 1 hour. stirring at room temperature, diluted with methylene chloride and extracted by washing with a saturated solution of sodium hydrogencarbonate. The crude product obtained (7.829) is chromatographed on Merck H60 silica (eluent
CH2C12 / MeOH 0.3 o).

We obtain 5.369 of 0- (tri-0-acetyl-2,3,4 Ct -L-rhamnopyranosyl) -3ss
O-acetyl-20 trifluoroacetamido-14 $ Nor-21 pregnan- (5ss) diol-3ss, 20 pure which does not crystallize.

To 4.69 of the above derivative in solution in 130 ml of methanol, 32 ml of 5N sodium hydroxide are added and the mixture is heated at reflux for 4 h. Then diluted with methylene chloride and washed with water, then with a semi-saturated sodium chloride solution (maintaining a sufficient methanol concentration). 39 of pure product are obtained by thin layer chromatography, which crystallizes from a methanol / ether mixture.

Melting point F = 2440C = = 530 (c = l, CHC13 / MeOH 80/20)
NMR spectrum (CDC13) 6 = 0.90 (CH3-19) 0.95 (CH3-18)
1.20 (CH3-6 ') 4.82 (H-1') ppm.

EXAMPLE 3
O- (4-amino dideoxy-4,6 ss-D-glucopyranosyl) -3
amino-14ss nor-21 pregnan- (5ss) diol-3ss, 20
To a benzene solution containing 0.69 of 0-acetyl-20 trifluoroaceta mido-14 nor-21 pregnan- (5ss) diol-3ssS20 obtained as indicated in Example 1, 0.359 mercuric cyanide and 0.24 g of bromide are added mercuric. It is brought to reflux and Os27g of 2,3-diacetyl-dideoxy-4,6 trifluoroacetamido-4 glucopyranosyl bromide in solution in 6 ml of is added. benzene. After 1 hour of boiling at reflux, the same amount of bromosugar (0.27 g in 6 ml of benzene) is added again and after another 1 h 0.279 of bromosugar in 4 ml of benzene. The mixture is allowed to reflux for 2.5 h, then cooled, diluted with methylene chloride and extracted by washing with a saturated sodium bicarbonate solution. The evaporated organic solvent leaves a residue (1.059) which is chromatographed on Merck H60 silica (eluent CH2C12 / MeOH 0.4la). 0.469 pure product is obtained in TLC, which crystallizes from the acetone-hexane mixture.

To a solution of 0.359 of the above product in 14 ml of methanol, 3.5 ml of 5N sodium hydroxide is added and the mixture is refluxed for 3 h., Then diluted with water and extracted with methylene chloride. 0.189 product is obtained which crystallizes from the ethanol-ether mixture.

Melting point F -2330C = = -34 "(c = l, -CHCl3)
EXAMPLE 4
O- (4-amino-tridesoxy-2,4,6 aL-lyxohexopyranosyl) -3
amino-14 nor-21 pregnan- (5ss) diol-3ss, 20
To a solution of 1.89 amino-14 $ nor-21 pregnan- (58) diol-3ss, 20 described in Example 6 of French patent 2,464,270, in 39.6 ml of formic acid, the following is added at room temperature, 24ml of acetic anhydride. The temperature of the medium is brought to 600C for 30 minutes, then to 1000C. 8 ml of acetic anhydride are then added and the mixture is left to react for approximately one hour at the same temperature.

After cooling and diluting with water, extraction is carried out with dichloromethane, washing with bicarbonate water, drying over sodium sulfate and evaporating to dryness under vacuum.

 2.179 formed from a mixture of the two neutral products, to which 42 ml of 0.25N ethanolic soda cooled to + 50C are added. After one hour at ordinary temperature, diluted with water, extracted with methylene chloride and after washing, 2.289 of a residue is obtained in the form of a foam (quantitative gross yield).

Cooled to -150C with an ice-salt bath, a solution of 2.189 of the above product in 12ml of pyridine. 0.559 acetic anhydride is added and the mixture is allowed to return to room temperature without removing the bath for two hours; two additions of acetic anhydride of 0.169 are then carried out each time, at −150 ° C., allowing the temperature to rise between each addition.

120 ml of water are added. It is extracted with benzene, washed with citric acid in aqueous solution at 5, then with water.

The crude product thus obtained is chromatographed on a silica column; a dichloromethane / methanol mixture (98/2) is used as eluent to separate, after crystallization from the benzene / isopropyl ether mixture, 1,239 of -acetyl-20-formylamino-14B nor-21 pregnan- (5ss) diol (-3ss, 20 (yield 60%).

To a solution of 0.609 of the above product and 1.169 of 0-benzoyl-3-trideoxy-2,4,6 trifluoroacetamido-4 a, & -lyxo-hexopyranoside of acetyl in 80 ml of a mixture with equal parts of benzene and methylene chloride, 0.59 dry p-toluene sulfonic acid is added and the mixture is left to stir at ambient temperature for 3 h., then a saturated aqueous solution of sodium bicarbonate is added and extracted with methylene chloride. The crude product obtained (1.669) is chromatographed on 509 of Merck H60 silica (eluent. 3/1 hexane / acetone) and provides 0.849 of a mixture of the Ct and ss-L anomers. By crystallization from the acetone / hexane mixture, separates the pure Ct-L anomer, ie 0.509.

The Ct-L anomer is dissolved in 24 ml of methanol, 6 ml of 5N sodium hydroxide are added and the mixture is heated at reflux for 1 hour. It is diluted with water and extracted with chloroform. The protective groups are thus eliminated and 0.369 of the desired product is obtained, which crystallizes from the methanol / ether mixture.

Melting point F = 219-2200C = D / = -91 (c = l, CHC13)
NMR spectrum (CDC13) 6 = 0.93 (CH3-19) 1.00 (CH3-18)
1.17 (CH3-6 ') 4.91 (H-l') ppm.

EXAMPLE 5
O- (ss-D-digitoxosyl) -3 amino-14ss pregnan- (5ss) diol-3ss, 20a 20a
According to the process described in Example 1, 1.79 damino-14ss pregnan- (5ss) diol-3ss, 20a are treated with acetic anhydride, then the product obtained (not crystallized) is reacted with trifluoroacetic anhydride to form 2.49 of O-acetyl-2O trifluoroacetamido-14 $ pregnan- (5ss) diol-3ss, 20 α which crystallizes in the ether / hexane mixture.

By proceeding as in Example 1, 1.1 g of tri-O-acetyl digitoxose are reacted with 0.9 g of the above product in 120 ml of benzene in the presence of Q, 8 g of dry p-toluene sulfonic acid.

After washing and extraction, then treatment with sodium hydroxide with heating at reflux, then purification, 0.359 of the ss-D anomer is obtained as well as 0.269 of the aD anomer, which both crystallize in the methanol / diethyl ether mixture.
Melting point F - 2080C (ss-D anomer) / CtD / = -260 (c = 1.5 CHCl3)
EXAMPLE 6
O- (ccL-rhamnopyranosyl) -3 amino-14ss pregnan- (5ss) diol-3ss, 20a
The procedure is as in Example 5, replacing the tri-0-acetyl digitoxose by tri-0-acetyl-2,3,4 aL-rhamnosyl bromide in acetonitrile, in the presence of mercuric cyanide.

After one hour of reaction at room temperature, dilution with methylene chloride and washing with a saturated solution of sodium bicarbonate, the 0- (tri-O-acetyl-2,3,4 α -L-rhamnopyranosyl) is obtained - 3ss D-acetyl-20 trifluoroacetamido-14 $ pregnan- (5ss) diol-3ss, 20 α which is purified by chromatography on a silica column.

The above product, in solution in methanol, is added with 5N sodium hydroxide and heated at reflux for 8 hours. After dilution with water and extraction with methylene chloride, the - (a-L-rhamnopy-ranosyl) -3 amino-14 $ pregnan- (5ss) diol-3ss, 20 & alpha is obtained; which crystallizes in the ethanol / diethyl ether mixture.

Melting point F = 2650C = = 490 (c = 0.8 CHC13 / MeOH 80/20
NMR spectrum (CDCl3 + CD4O) 6 = 0.96 (CH3-19) 1.00 (CH3-18) 1.06 (CH3-21)
1.28 (CH3-6 ') 4.90 (H-1') ppm.

EXAMPLE 7
O- (sL-rhamnopyranosyl) -3 amino-14ss pregnan- (5ss) diol-3ss, 20ss
By proceeding as in Example 1, the 0-acetoxy-20 tri fluoroacetamido-14B pregnan- (5 ss) diol-3ss, 20ss is prepared by causing acetic anhydride to act, then trifluoroacetic anhydride on amino- 14sspregnan- (5ss) diol-3 ss20ss.

The product obtained is reacted with trio-O-acetyl-2,3,4, aL-rhamnosyl bromide in acetonitrile in the presence of mercuric cyanide, according to the coupling procedure described in Example 2. After treatment with sodium hydroxide in methanol while heating at reflux, O- (aL-rhamnopyranosyl) -3 amino-14B pregnan- (5ss) diol-3ss, 20ss which crystallizes in ethanol is obtained.

Melting point F = 263-2640C / α D / = 520 (c = 0.7 CHC13 / MeOH 80/20)
NMR spectrum (CDCl3 + CD4O) 6 = 0.95 (CH3-19) 1.16 (CH3-18) 1.30 (CH3-21)
1.30 (CH3-6 ') 4.83 (H-l') ppm.

EXAMPLE 8
0- (α -rhamnopyranosyl) -3 amino-14ss pregnanediol-3ss, 20 α
The procedure is as in Example 6, replacing the amino-14ss pregnan- (58) diol-3S, 20a by the amino-14 $ pregnanediol-3ss, an isomer whose proton in position 5 occupies the configuration 5a, and by coupling with tri-O-acetyl-2,3S4 orL-rhamnosyl bromide under the same conditions.

After treatment with sodium hydroxide solution in methanol, under reflux, the O- (a-L-rhamnopyranosyl) -3ss amino-14 $ pregnanol-20 α which crystallizes in the ethanol / ether mixture.

Melting point F = 2710C
NMR spectrum (CDCl3 + CD4O)
= 0.78 (CH3-19) 0.98 (CH3-18) 1.03 (CH3-21)
1.25 (CH3-6 ') 4.76 (H-1') ppm.

EXAMPLE 9
O- (4-amino-tridesoxy-2,4,6 OrL-lyxohexopyranosyl) -3
amino-14ss pregnan- (5ss) diol-3ss, 20 α
The procedure is as in Example 4, replacing the amino-14ss nor-21 pre gnan- (5 ss) diol-3ss, 20 by the amino-14ss pregnan- (5ss) diol-3 $, 20to obtain the product. sought which crystallizes in the methanol / ethyl ether mixture
Melting point F = 2240C / α; D / = -79 (c = 1, CHCl3)
Experiments carried out on amino-14 steroid derivatives represented by the general formula (I) revealed in particular a positive inotropic activity as well as supraventricular antiarrhythmic properties.

More particularly, the derivatives in accordance with the present invention exhibit a positive inotropic activity greater than or equal to that of the well-known reference compounds such as ouabaine and digoxin.

The inotropic activity was verified on the isolated guinea pig atrium under the usual experimental conditions, by recording the amplitude of the contractions for various doses administered, relative to the control values.

Table 1 below indicates the increase in the contraction force as a function of the concentration for digoxin (comparison product) and for the products of the invention described in examples 6 and 7.

TABLE 1
Amplitude of contractions compared to Control values
Concentration (Moles / l)
Compound 2xlO 7 10-6 2x0-6 6x1-6 10-5
Digoxin + 38% + 100S + 114S + 128% + 128%
Ex.n06 - + 43ró + 63 ó +143 ó +148 ó
Ex.n07 + 50% 9 97% +178 ó +233 ó +206 ó
These results show that the products in accordance with the invention cause increases in the contraction force significantly greater than those caused by digoxin, for certain concentrations.

Furthermore, the amino-14 steroid derivatives according to the invention have a molecular ATPase inhibition capacity molecularly greater than or equal to that of digoxin or ouabaine taken as references.

Thus, for example, when the derivatives of the invention described in Examples 2, 6 and 7 are compared with the comparison products constituted by ouabaine and digoxin, the results set out in Table 2 below are obtained.

In this table, the value of ED50 is the dcse causing 50 Ó of inhibition of the membrane ATPase.

TABLE 2
DE50
ouabain 3.6 x 10 9M
digoxin 5.3 x 10 9M
Ex.n02 1.3 x 10-1ûM
Ex.n06 1.8 x 10 10M
Ex.n07 7.0 x 10 llM
The derivatives according to the invention differ from known substances for comparison of the digitalis series, such as digoxin and ouabqlnes by an advantageous modification of their toxic activity.

For example, the derivative of the invention described in Example 6 makes it possible to achieve, in anesthetized dogs, without toxic signs, an increase in cardiac contractility of 150%, while, under the same experimental conditions, the signs toxic appear, for digoxin, the cardiac contractility has increased by about 50. In addition, the toxicity of the derivatives in accordance with the invention is reversible, that is to say that stopping their administration is sufficient to eliminate the disorders observed on the electrocardiogram.

These results show that the derivatives according to the invention can be used in human and veterinary therapy, as medicaments in particular for the treatment of heart failure.

The derivatives of general formula (I) and their pharmaceutically acceptable salts can be administered in the usual forms, the active principle being diluted in a pharmaceutically acceptable carrier suitably chosen, for example in the form of tablet, capsule, dragee, suppository, injectable solution or syrup.

By way of example, the tablets can be prepared by mixing the derivative of general formula (I) or one of its salts, with one or more solid diluents such as lactose, mannitol, starch, polyvinylpyrrolidone, magnesium stearate, talc, etc. Where appropriate, the tablets may comprise several layers superimposed around a core, according to the usual techniques, to ensure a gradual release or a delayed effect of the active principle. The coating may for example consist of one or more layers of polyvinyl acetates, carboxymethylcellulose or cellulose acetophthalate.

The derivative according to the invention can also be administered in the form of a syrup or an oral solution obtained by dissolving the derivative of formula (I) or one of its pharmaceutically acceptable salts, in water or glycerol, by example, and if necessary adding a usual additive such as a sweetener and an antioxidant.

Injectable solutions can be prepared according to well known techniques and consist, for example, of a solute containing a derivative of formula (i) or one of its pharmaceutically acceptable salts.

dissolved in double distilled water, a hydroalcoholic solution, propylene glycol, etc., or a mixture of these solvents. If necessary, an appropriate additive such as a CD-preservative can be added.

The doses administered are determined by the doctor according to the mode of administration chosen, the level of the condition treated, the duration of treatment, etc.

Claims (11)

 in which R represents a hydrogen atom or a lower alkyl group of 1 to 4 carbon atoms and R1 represents a sugar residue, as well as their acid salts.

I. Derivatives of amino-14 steroids represented by the general formula (I): 2. 14-amino steroid derivatives according to claim 1, characterized in that R represents a hydrogen atom or a methyl group. 3. Amino-14 steroid derivatives according to any one of claims 1 and 2, characterized in that R1 is a residue of substituted or unsubstituted monosaccharide. 4. Amino-14 steroid derivatives according to claim 3, characterized in that R1 represents a residue of pentose or hexose, -modified or substituted where appropriate. 5. Amino-14 steroid derivatives according to claim 4, characterized in that R1 represents a residue of glucose, rhamnose, galactose, fucose, or digitoxose, substituted where appropriate. 6. 14-amino steroid derivatives according to claim 1, characterized in that they are chosen from O- (aL-rhamnopyranosyl) -3 amino-14ss nor-21 pregnan- (5ss) dìol-3ss, 20 le 0- (oL-rhamnopyranosyl) -3 amino-146 pre gnan- (5ss) diol-3ss, 20 a and its 20ss isomer 0- (ss-D-digitoxosyl) -3 amino-14ss pregnan- (5ss) diol- 3ss, 20 α and O- (4-amino-tridesoxy-2,3,6 α -L-lyxo-hexopyranosyl) -3 amino-14ss pregnan- (5ss) diol-3ss, 20 α. 7. A process for preparing steroid amino-14 derivatives according to claim 1, characterized in that a coupling reaction is carried out between an amino-14 steroid of general formula '(II):

 in which R is a hydrogen atom or a lower alkyl group, after having previously protected the -NH2 group in position 14 and the OH group in position 20, with an activated sugar of formula R1-X, ot R1 is a sugar residue and X is a halogen atom or an acetyl group, then the protective groups are eliminated, where appropriate. 8. Method according to claim 7, characterized in that the sweet derivative of formula R1-X is added in excess. 9. Method according to claim 7, characterized in that the group -NH2 in position 14 is previously protected by transformation into a trifluoroacetamido group by the action of trifluoroacetic anhydride in the presence of triethylamine, or into a formamido group by the action of acetic anhydride in formic acid, and the group -OH in position 20 is previously protected by acetylation with acetic anhydride in-pyridine. 10. Medicines characterized in that they consist of amino-14 steroid derivatives according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. 11. Pharmaceutical compositions characterized in that they contain a medicament according to claim 10, as active ingredient associated with one or more pharmaceutically acceptable excipients.