GB2087894A

GB2087894A - Immunotherapeutic 3-(substituted amino) steroids of the pregnane and 19-norpregnane series

Info

Publication number: GB2087894A
Application number: GB8135218A
Authority: GB
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1980-11-21
Filing date: 1981-11-23
Publication date: 1982-06-03
Also published as: DK514981A; NL8105260A; DK161093C; PT74015B; IL64224A0; AU546100B2; FR2494698A1; ES507309A0; JPH0247479B2; CH651056A5; FI77871C; ZA817806B; ES8207195A1; JPS57116099A; IT8149746A0; CA1175415A; SE8105995L; GB2087894B; HU184896B; KR830007716A

Abstract

The title compounds of formula I and their salts are, with certain exceptions, new: <IMAGE> W is H or OH; X is ethyl, 1-hydroxyethyl, or acetyl; or W + X = ethylidene; R, is H or Me; R2 and R3 are each H, alkyl or hydroxyalkyl, R3 alternatively being acyl (including alkoxycarbonyl and radicals derived from amino acids and peptides), and at least one of R2 and R3 being other than H. Preparation: from the corresponding primary amines (R2 = R3 = H) Use: treatment of autoimmune diseases. <IMAGE>

Description

SPECIFICATION New 3-amino steroid compounds, their production and pharmaceutical compositions containing them The present invention relates to new 3-amino steroid compounds, their production, their use as medicaments and pharmaceutical compositions containing them.

Accordingly, the invention provides a compound which is a steroid of formula I:

or a salt thereof, in which W represents a hydrogen atom or a hydroxyl radical or, together with X, represents an ethylidene radical, X represents an ethyl radical or a group

or, together with W, an ethylidene radical, the wavy lines signify that the corresponding radical is in configuration a or ss, R, represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms and R3 represents a hydrogen atom, an alkyl radical containing 1 to 5 carbon atoms, a hydroxyalkyl radical containing 2 to 5 carbon atoms, an acyl or alkoxycarbonyl radical containing 2 to 8 carbon atoms or an acyl radical corresponding to an aamino carboxylic acid, an N-alkylated a-amino carboxylic acid or to a peptide containing 2 or 3 a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units, with the proviso that at least one of R2 and R3 does not represent a hydrogen atom, and with the further provisos: (i) when at the same time R, represents a methyl radical, W and R2 each represent a hydrogen atom and X represents the radical

then R3 cannot represent methyl, acyl of 2 to 8 carbon atoms or an acyl radical corresponding to an a-amino carboxylic acid or an N-alkylated a-amino carboxylic acid, (ii) when at the same time R, represents a methyl radical, W represents a hydrogen atom, R2 represents a methyl radical and X represents the radical

then R3 cannot represent a methyl or acetyl radical, (iii) when at the same time R, represents a methyl radical, R2 and W each represent a hydrogen atom, X represents a group

whose hydroxyl is of (S) configuration and the -NR2R3 radical is at position 3a, then R3 cannot represent a methyl, acetyl or glycyl radical, (iv) when W represents a hydrogen atom, X represents a group

and the -NR2R3 radical is at position 3a, then the substituents R,, R2, and R3 do not each represent at the same time a methyl radical, (v) when at the same time R2 and W each represent a hydrogen atom, R1 represents a methyl radical, X represents a group

whose hydroxyl is of (R) configuration and the -NR2R3 radical is at position 3a, then R3 does not represent an ethoxycarbonyl, methyl or acetyl radical, and (vi) when at the same time R1, R2 and R3 each represent a methyl radical and the -NR2R3 radical is at position 3a, then W and X cannot together represent an ethylidene radical.

The a-amino carboxylic acid residue which R3 can represent can be N-alkylated. The N can be mono- or di-alkylated eg by alkyl containing 1 to 5 carbon atoms. Similarly some or all of the aamino carboxylic acid units in the peptide residue which R3 can represent can be N-alkylated, the N being mono- or di-alkylated eg by alkyl containing 1 to 5 carbon atoms.

In formula I and in the following the term alkyl radical containing 1 to 5 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl; the term hydroxyalkyl radical containing 2 to 5 carbon atoms includes hydroxyethyl or hydroxypropyl; the term acyl radical containing 2 to 8 carbon atoms includes acetyl, propionyl, n-butyryl, isobutyryl, benzoyl or nicotinoyl; the term alko, ycarbonyl radical containing 2 to 8 carbon atoms includes methoxy-, ethoxy-, or propoxycarbonyl; the acyl radical corresponding to an a-amino carboxylic acid can be a radical corresponding for example to Ala, Val, Ival, Leu, lie, Asp, Asn, Glu, Glen, Ser, Thr, Cys, Met, Lys, Arg, Phe, Tyr, Trp, His, Pro, Nva, Nle, Hyp, Orn, these acids being in the D or L form or Sar or Gly; the acyl radical corresponding to an N-alkylated a-amino carboxylic acid can be a radical corresponding to an N-allcylated derivative of any of these specified a-amino carboxylic acids; when R3 represents an acyl radical corresponding to a peptide containing 2 or 3 a-amino carboxylic or N-alkylated a-amino carboxylic acid units, the units can be for example of the aamino carboxylic acids and N-alkylated a-amino carboxylic acids referred to above.

By convention, the symbols of the a-amino carboxylic acids represent these acids in their D or L configuration (for example, the term Ala signifies alanine in D form or in L form). Unless indicated otherwise, the nomenclature used in the present Specification is the IUPAC nomenclature, whose rules are published especially in Biochem. J. (1972) 126, 773-780.

The salts of the steroid can be addition salts with mineral or organic acids for example hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acids, alkane sulphonic acids such as methane or ethane sulphonic acids, arylsulphonic acids such as benzene or paratoluene sulphonic acids or arylcarboxylic acids.

Among the present compounds, there may be mentioned especially those wherein X represents the group

Among these, there may be mentioned particularly the compounds wherein X represents the group

and R2 represents a hydrogen atom or a methyl radical. Particular compounds are specified in the Examples and include: (2S) 2-amino N-[(20S)-20-hydroxy (5a)-pregnan-3a-yl] propanamide; (2S) 2-amino N-[(20S)-20-hydroxy (5a)-pregnan-3a-yl] 1 H-indol 3-propanamide; 2-amino N-[(20S)-20-hydroxy- 1 9-nor(5a)-pregnan-3a-yl acetamide; 2-amino N-[(20S)-20-hydroxy (5a)-pregnan-3a-yl N-methyl acetamide; and their salts.

The invention also provides a process for preparing the present compounds, which process comprises reacting an amine of formula II.

in which the wavy line, W, X and R, are as defined above either with a halide of formula Ill: Hal-R'3 Ill in which Hal represents a chlorine, bromine or iodine atom and R'3 represents an alkoxycarbonyl radical containing 2 to 8 carbon atoms, to obtain a steroid of formula I in which R2 represents a hydrogen atom, R3 represents an alkoxycarbonyl radical containing 2 to 8 carbon atoms and W, X R1 and the wavy line are as defined above, which sterois is salified if desired, or with an acylating agent which is the acid R'30H or an acid functional derivative thereof, in which R'3 represents an acyl radical containing 2 to 8 carbon atoms, to obtain a steroid of formula I in which R2 represents a hydrogen atom, R3 represents an acyl radical containing 2 to 8 carbon atoms and W, X, R, and the wavy line are as defined above, which steroid is salified if desired or with an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or a peptide containing 2 or 3 a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units, the amine function of these acids or units being protected if necessary by an easily-cleavable protecting group substituted thereon, in which case the protecting group is subsequently removed, to obtain a steroid of formula I in which R2 represents a hydrogen atom, R3 represents an acyl radical corresponding to an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or to a peptide containing 2 or 3 a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units and W, X, R, and the wavy line are as defined above, which steroid is salified if desired, or with an alkyl halide containing 1 to 5 carbon atoms or a hydroxyalkyl halide containing 2 to 5 carbon atoms, in both cases the halogen being a chlorine, bromine or iodine atom, to obtain a steroid of formula I, in which R2 and R3 are the same or different and each represents a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms and W, X, R1 and the wavy line are as defined above, which steroid of formula I is salified if desired, and optionally where R3 represents a hydrogen atom the steroid is reacted (a) with a halide of formula IV:: Hal-R"3 IV in which R"3 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms or an alkoxycarbonyl radical containing 2 to 8 carbon atoms and Hal is as defined above, to obtain a steroid of formula I in which R2 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms, R3 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms or an alkoxycarbonyl radical containing 2 to 8 carbon atoms and W, X, R, and the wavy line are as defined above, which steroid is salified if desired, or (b) with an acylating agent which is the acid R"30H or an acid functional derivative thereof, in which R"3 represents an acyl radical containing 2 to 8 carbon atoms, to obtain a steroid of formula I in which R2 represents alkyl of 1 to 5 carbon atoms or hydroxyalkyl of 2 to 5 carbon atoms, R3 represents an acyl radical containing 2 to 8 carbon atoms and W, X, R1 and the wavy line are as defined above, which steroid is salified if desired, or (c) with an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or a peptide containing 2 or 3 a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units, the amine function of these acids or units being protected if necessary by an easily cleavable protecting group substituted thereon, in which case the protecting group is subsequently removed, to obtain a steroid of formula I in which R2 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms, R3 represents an acyl radical corresponding to an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or to a peptide containing 2 or 3 a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units and W, X, R, and the wavy line are as defined above, which steroid is salified if desired, or with an alkyl haloformate to obtain a carbamate of the amine of formula II, which is then reduced to obtain a steroid of formula I in which R3 represents a methyl group, which steroid is satified if desired, or with an acetylating agent to obtain the N-monoacetylated steroid, which is then reduced to obtain a steroid of formula I in which R3 represents an ethyl group, which steroid is salified if desired, and the steroid is optionally reacted again with an acetylating agent and then reduced, to obtain a steroid of formula I in which R2 and R3 each represents an ethyl group, which steroid is salified if desired, or with acetone in the presence of a reducing agent, to obtain a steroid of formula I in which R2 represents isopropyl and R3 represents a hydrogen atom or isopropyl, which steroid is salified if desired.

In the reaction of the amine of formula II with the a-amino carboxylic acid, N-alkylated aamino carboxylic acid or peptide, it is usually necessary to protect the amino function in the acid or the peptide unit, so that the amine of formula Il reacts with the acid function to produce the desired compound. When the amino function is already protected by being N,N-dialkylated, no further protection is necessary. The easily cleavable protecting group is especially such a group which can be removed by acid hydrolysis.

Under preferred conditions for carrying out the present process, it has one or more of the following features: (1) The reaction of the amine of formula Il with the halide of formula Ill is preferably carried out in the presence of an acid fixing agent, in particular an alkali metal hydroxide, an alkali metal (for example potassium) carbonate, an alkali metal bicarbonate, an alkali metal acetate, an alkaline-earth carbonate, a tertiary amine (for example a trialkylamine or pyridine) or an alkali metal alcoholate (for example sodium ethylate).

(2) In the reaction of the amine of formula II or the steroid of formula I in which R3 represents a hydrogen atom with an acylating agent, the acylating agent is preferably an acyl halide of formula Hal B'3 in which Hal is as defined above and R'3 represents an acyl radical containing 2 to 8 carbon atoms; in that event, the reaction is preferably carried out in the presence of an acid fixing agent such as those specified above. The acylating agent can be, however, the free acid B'3OH or an acid funtional derivative other than the halide, especially an acid anhydride (R'3)2O.

When the free acid is used, it is preferred to carry out the conversion into an amide with an activation agent such as a carbodiimide. Other techniques can be used such as those described for example in "The Peptides" Vol. 1, Academic Press 1 979.

The reaction with the halide of formula Ill or the acylating agent which is the acid R3OH or an acid functional derivative thereof can be carried out for example in inert solvents or suspension media such as dioxan, dimethylformamide, benzene, toluene or methylene chloride.

(3) The reaction of the amine of formula II or of the steroid of formula I in which R3 represents a hydrogen atom and R2 represents an alkyl or hydroxyalkyl radical, with the a-amino carboxylic acid N-alkylated a-amino carboxylic acid or peptide, protected as necessary, preferably takes place in the presence of a condensation agent, which activates the acid function of the acid or peptide.

As condensation agent there may be used a carbodiimide of formula: A-N = C = N-B in which A and B represent an alkyl radical containing 1 to 8, eg 1 to 5, carbon atoms, possible bearing a dialkylamino radical or they represent a cycloalkyl radical.

There may be used, for example, dicyclohexylcarbodiimide or 1-ethyl 3-(3-dimethylaminopropyl) carbodiimide, preferably the latter.

A 2-chloro N-methyl pyridinium halide such as the iodide can also be used.

An alkyl chloroformate such as, for example, methyl, ethyl or isobutyl chloroformate can also be used; an alkyl pyrophosphite such as, for example, ethyl pyrophosphite can also be used.

As easily-cleavable protecting group there may be used, as desired according to the compound, for example the benzyloxycarbonyl group or the (Z) tertbutyloxycarbonyl group (BOC).

It is especially preferred that the protecting group is the tertbutyloxycarbonyl radical.

To eliminate the easily-cleavable protecting group, there is used preferably as cleaving agent an acid such as hydrochloric acid; an alkanolic solution of hydrochloric acid can be employed or anhydrous hydrochloric acid can be employed by bubbling it into nitromethane containing the protected substance. Acids such as paratoluene sulphonic acid, formic acid or trifluoroacetic acid can also be used. Hydrogen in the presence of palladium can also be used for the protecting group (Z) for example.

(4) The reaction of the amine of formula II with the alkyl or hydroxyalkyl halide preferably takes place in the presence of the same acid fixing agents and solvents as in the case of the reaction with the halide of formula Ill.

The hydroxy function of the hydroxyalkyl radical is advantageously blocked by a protecting group which is easily cleavable especially by acid hydrolysis. This protecting group is advantageously a tetrahydropyranyl radical. It can be cleaved under the same conditions as those discussed above for the group protecting the amino acid.

(5) The reaction of the steroid of formula I in which R3 represents a hydrogen atom, R2 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms and W, X, R, and the wavy line are as defined above with the halide of formula IV is preferably carried out under the conditions discussed above for the reaction of the amine of formula II with the halide of formula Ill or with the alkyl halide.

(6) For the preparation of the N-alkylated steroids of formula I, one can preferably proceed as follows: -to prepare a N-monomethylated steroid of formula I, a carbamate of the amine of formula II can be prepared for example by the action of an alkyl haloformate and especially an ethyl haloformate, then reduction of the carbamate for example with the aid of lithium aluminium hydride; -to prepare a N-monoethylated steroid of formula I, the corresponding N-acetylated steroid can be prepared then reduced; -to prepare the N-diethylated steroid, the proceedure can be repeated.

In these three cases under item (6), when X represents a group

it may be necessary to prepare the ketal at position 20, for example by the action of ethylene glycol, then, after reduction, to hydrolyse the said ketal, for example with the aid of a mineral acid.

-to prepare a N-mono- or di-isopropylated steroid of formula I, a steroid of formula Il can be reacted with acetone in the presence of a reducing agent such as sodium cyanoborohydride.

In the present process, protection of the amine functions is clearly not necessary when these amine functions are alkylated.

The steroids of formula I, with the exception of those in which R3 represents an acyl or alkoxycarbonyl radical, are basic in nature and hence form salts with acids. The addition salts of the steroids can advantageously be prepared by reacting, in substantially stoichiometric proportions, a mineral or organic acid with the steroid. The salts can be prepared without isolating the corresponding bases.

The present compounds possess very interesting pharmacological properties; they are en dowed especially with remarkable immunotherapeutic properties. They are, in particular, capable of stimulating immune reactions.

These properties indicate the use of the steroids of formula I and their pharmaceutically acceptable salts as medicaments for use in humans or animals. Use in humans is of especial interest.

Accordingly, the invention provides the present compounds or their pharmaceutical compositions for use in a method of treatment of the human or animal body by therapy.

Preferably, the present compounds are the steroids of formula I in which X represents a group

and their addition salts with pharmaceutically acceptable acids. Among these compounds, especially preferred are the steroids of formula I in which X represents a group

and R2 represents a hydrogen atom or a methyl radical, and their addition salts with pharmaceutically acceptable acids.

Particularly preferred is: 2-amino N-[(20S)-20-hydroxy (5ev)-pregnan-3a-yl] propanamide; (2S) 2-amino N-[(20S)-20-hydroxy (5a)-pregnan-3a-yl] 1 H-indole 3-propanamide; 2-amino N-[(20S)-20-hydroxy-1 9-nor (5a)-pregnan-3a-yl] acetamide; or 2-amino N[(20S)-20-hydroxy (5a)-pregnan-3a-yl] N-methyl acetamide; or an addition salt of any of these with a pharmaceutically-acceptable acid.

The present medicaments are useful, for example, in the treatment of autoimmune diseases resulting from a deficiency in certain lymphocytes, whether they be non-specific diseases of the connective tissue of an organ such as, for example, rhumatoid arthritis or systemic lupus erythematous or whether they be specific diseases of an organ such as thyroiditis, pemphigus or haemolytic anaemia.

The present medicaments can, therefore, be used as adjuvant treatment of antibiotherapy and of anticancer chemotherapy.

The usual dose, which depends on the compound used, the subject treated and the complaint concerned, can be, for example, from 10 mg to 1 g per day, by oral route in man, eg for the product of Example 1 4 used as adjuvant to antibiotherapy.

The invention provides pharmaceutical compositions which contain at least one of the present compounds as active principle.

The present compounds can be incorporated in pharmaceutical compositions intended for the oral or parental route.

The pharmaceutical compositions can be, for example, solid or liquid and can be presented in the pharmaceutical forms currently used in human medicine such as, for example, plain or sugar-coated compressed tablets, gelatin capsules, granules, suppositories and injectable preparations; they can be prepared according to the usual methods. The active compound or compounds can be incorporated in excipients usually employed in pharmaceutical compositions.

Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols.

These excipients may be compounded with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.

The starting amines of formula II, when they are not known, can be prepared as follows; A product of formula V:

in which R, and the wavy line are as defined above, is reacted with an excess of ethyl triphenylphosphonium bromide and of potassium tert-butylate to obtain a product of formula VI:

in which R, and the wavy line are as defined above, which is converted, for example, by conversion to the tosylate then the action of sodium azide or directly by reaction with diphenyl azidophosphate in the presence of ethyl azodicarboxylate and triphenylphosphine, into the azide of formula VII::

in which RX and the wavy line are as defined above, and the configuration at position 3 is inverted with respect to that of the compounds V and VI, which is reduced, for example with the aid of lithium aluminium hydride, to obtain an amine of formula IIA:

in which R, and the wavy line are as defined above, which -either is used itself, -or is reduced for example by hydrogenation in the presence of a catalyst based on rhodium, platinum or palladium, to obtain a product of formula IIB:

in which R, and the wavy line are as defined above, -or is hydrated for example with the aid of diborane to obtain a product of formula llc::

in which R, and the wavy lines are as defined above, which can be used itself or subjected to oxidation for example with the aid of chromic acid, to obtain a product of formula IID:

in which R, and the wavy line are as defined above, -or is subjected to cis-dihydroxylation, for example with the aid of osmic anhydride in the presence of trimethyloxamine, after protection or non-protection of the amine by an easily hydrolysable group such as a trifluoroacetyl group, to obtain a product of formula IIE::

in which R represents a protecting group defined above or a hydrogen atom, and R, and the wavy line are as defined above, which either, when R represents a hydrogen atom, can be used itself, or, when R represents a protecting group, is subjected to an agent for cleaving the said protecting group, for example by alkaline hydrolysis in the case of a trifluoroacetyl group, then the free amine obtained can be used itself, or, is subjected to oxidation, for example with the aid of chromic acid, to obtain a product of formula IIF::

in which R, R, and the wavy line are as defined above, which either, when R represents a hydrogen atom, can be used itself, or, when R represents a protecting group, is subjected to an agent for cleaving the said protecting group, then the free amine obtained can be used itself, or, is reduced, for example with the aid of sodium borohydride, to obtain a product of formula IIG:

in which R, R, and the wavy lines are as defined above, which either, when R represents a hydrogen atom, can be used itself, or, when R represents a protecting group, is subjected to an agent for cleaving the said protecting group, to produce the free amine which can be used.

Examples of the production of amines of formula II appear hereinafter.

The following Examples illustrate the invention.

Example 1: (2S) 2-amino N-U20S)-20-hydroxy 5er-pregnan-3eY-yq propanamide (hydrochloride and base).

Stage A: 2-[1, l-dimethyl ethoxy carbonylaminoj N-f(20S)-20-hydroxy (5a)-prngnan-3a-yU propanamide.

1.92 g of (20S) 3a-amino 5a-pregnan-20-ol and 2.27 g of tertbutyloxycarbonyl-L-alanin (BOC-L-alanine) were dissolved in 60 cm3 of chloroform and 1 2 cm3 of pyridine. The solution was agitated at O' C to + 5" C under inert atmosphere and 1.14 g of 1-ethyl 3(dimethylaminopropyl) carbodiimide hydrochloride were added.At the end of 1 hour 1 5 minutes, 1.1 5 g of 1ethyl 3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the agitation was maintained for 50 minutes at 0 C to + 5" C, the mixture was brought to dryness, taken up with an aqueous solution of sodium acid carbonate, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride then with a normal aqueous solution of hydrochloric acid and again with a saturated aqueous solution of sodium chloride, dried, brought to dryness, crystallized from isopropyl ether, separated, washed with isopropyl ether and dried at 60 C under reduced pressure. The title product of this Stage was obtained.

M. Pt.= 171 C.

Stage B: Hydrochloride and base of (2S) 2-amino N-[20S)-20-hydroxy 5a-prngnan-3a-ylJ propanamide.

variant 1: Under inert atmosphere, 1.55 g of the product obtained in Stage A were suspended in 100 cm3 of nitromethane, hydrogen chloride was bubbled in for 10 minutes, the mixture was agitated at 20"-25" C for 35 minutes, the excess hydrochloric acid was eliminated, the residue was separated, washed with ethyl ether, dried at 60 C under reduced pressure and recrystallized from methanol. 990 mg of the title hydrochloride of this Stage were obtained.

M.Pts220" C.

variant 2: Under inert atmosphere, 2.7 g of the product obtained in Stage A was dissolved in 10 cm3 of ethanol, 40 cm3 of hydrochloric ethanol (3.5N) were added, the mixture was agitated for 8 hours, brought to dryness, taken up with ethyl acetate, chilled, separated, washed with ethyl acetate, dried at 60 C under reduced pressure and recrystallized from methanol. 2.2 g of the title hydrochloride of this Stage were obtained. M.Pt.--220" C.

Preparation of the base: 1 .74g of the hydrochloride were dissolved in 100 cm3 of tetrahydrofuran containing 30% of water, 4 cm3 of 2N sodium hydroxide were added, the mixture was brought to dryness, taken up with 100 cm3 of chloroform, washed with water, dried, brought to dryness and recrystallized from ethyl acetate. 1 .27g of the base were obtained. M.Pt = 224" C.

By proceeding analogously to the process described above, the steroids (and their hydrochlorides) listed in the Table below were prepared.

No. of Starting Example Variant amino acid R3 Melting Point

2 1 and BOC-L-glutamic 220"C see note acid OCH-CH2-CH2- COOH (S) (hydrochloride) below NH2 3 1 BOC-L-serine OACH-CH20H I 210"C NH2 (hydrochloride) 4 1 BOC-L-phenyl- o ,CH-CH2t (S) 240"C alanine NH2 (hydrochloride) 5 1 BOC-L-trypto- o; CH-CIl2 X {5) 135"C phan NH2 H (S) (base) 6 2 BOC-L-proline o Ct (S) 275"C 2 (hydrochloride) 7 CF3COOH BOC-glycol a 240"C glycine OCH2- NH- CO - C H2- NH 2 hydrochloride 200 then 252"C base Note regarding Example 2 The second acid function of L-glutamic acid was blocked by forming its benzyl ester; it was released by catalytic hydrogenation in acetic acid in the presence of palladium, before cleavage of the BOC.

Example 8: N-U20S)-20-h ydroxy 5a-prngnan-3a-ylJ 3-pyridine carboxamide.

Under inert atmosphere, 960 mg of (20S) 3a-amino 5a-pregnan-20-ol and 813 mg of nicotinic acid were dissolved in 30 cm3 of chloroform and 6 cm3 of pyridine, and 582 mg of 1-ethyl 3-(3-dimethylaminopropyl) carbodiimide hydrochloride were added. After 3 hours 30 minutes, under agitation, 291 mg of 1-ethyl 3-(3-dimethylaminopropyl) carbodiimide hydrochloride were added, the mixture was agitated for 16 hours, brought to dryness, taken up with 30 cm3 of water, chilled, separated, washed with water, dried at 80 C under reduced pressure and recrystallized from methanol. 920 mg of title product were obtained.

M. Pt. = 258 C.

[α]D = + 14.5 + 1 (c= 1% pyridine).

Example 9: 2-amino N-f(20S) 1 70r,20-dihydroxy Sa-pregnan 3a-yl] acetamide hydrochloride.

By proceeding analogously to Example 1, variant 2, but starting with BOC-glycine and (20S) 3a-amino 5a-pregnan 17a,20-diol, the title product was obtained.

M.Pt.#200 C [α]D = + 4 # 1 (c = 1.5% ethanol 95 ).

The starting (20S) 3a-amino 5a-pregnan-1 7a,20-diol can be prepared as follows: Stage 1: (Z) (5a) pregn- 1 7 (20)-en 3fi-ol 59.4 g of triphenylethylphosphonium bromide was added to 16.1 g of potassium tertbutylate in solution in 160 cm of tetrahydrofuran, the mixture was agitated for 30 minutes, 23.2 g of epiandrosterone were added, the mixture was agitated for 15 minutes, poured into iced water, extracted with ethyl acetate, washed with water, dried, distilled to dryness, purified by chromatography on silica (eluant:cyclohexane/ethyl acetate, 7:3 by volume), crystallized from methanol, chilled, separated and dried, 23.1 g of the title product of this Stage were obtained.

MPt = 160 C.

Stage 2: (Z) 3a-azido (50r)-pregn-1 7(20)-ene 1.92 g of ethyl azodicarboxylate and 3.02 g of diphenyl azidophosphate were added to a solution of 1.66 g of the product above in 30 cm3 of benzene and 5 cm3 of tetrahydrofuran, the mixture was agitated in an ice bath, a solution of 2.88 g of triphenylphosphine in 30 cm3 of benzene was added over 20 minutes, the mixture was agitated further for 40 minutes at 10 C, washed with a 2N solution of hydrochloric acid, then with water, dried and distilled to dryness, and purified by chromatography on silica (eluant:heptane then heptane/ethyl ether, 1:1 by volume). 1.67 g of crystals of the title product are obtained.

M.Pt. = 114" C after recrystallization from methanol.

Stage 3: (Z) 5a-pregn 1 7(20)-ene3a-amine (and hydrochloride).

14.5 g of (Z) 3a-azido (5a)-pregn-1 7(20)-ene as obtained above were dissolved in 290 cm3 of tetrahydrofuran, the mixture was agitated, with heating, at 25-27" C, 800 mg of lithium aluminium hydride were added over 1 hour, the mixture was agitated further for 1 hour, the excess hydride was eliminated with methanol, the residue was filtered, the filtrate was washed with an aqueous solution of Seignette salt then with a saturated aqueous solution of sodium chloride, dried and distilled to dryness. 1 3.1 g of crystals of the title amine of this Stage were obtained.

M.Pt-"'90' C.

The base was dissolved in 1 50 cm3 of ethyl acetate and 30 cm3 of methylene chloride, 27 cm3 of 1.7N hydrochloric ethyl acetate were added, the mixture was separated and washed with ethyl acetate and the crystals obtained were dried under reduced pressure.

1 3.2 g of crystals of the hydrochloride were obtained.

M.Pt > 300 C.

[(Y]D at 1% in pyridine containing 10% of water = + 38.5 + 1.5'.

Stage 4: N-f(Z, 5a)-pregn 17(20)-en 3a-yl] trifluoroacetamide.

Under inert atmosphere, 1 6.5 g of the hydrochloride obtained in Stage 3 above were suspended in 1 65 cm3 of methylene chloride and 1 6.5 cm3 of pyridine, the mixture was cooled to about 5" C, 1 6.5 cm3 of triflouroacetic anhydride were introduced over 5 minutes, the mixture was agitated for 1 5 minutes at ambient temperature and distilled to dryness under reduced pressure, 200 cm3 of water were added, the mixture was separated, washed with water and dried under reduced pressure. 18.1 g of crystals were obtained.

M.Pt. = 204 C.

Stage 5: N-F(20S) I 7a,20-dihydroxy (5a)-pregnan-3a-yl] trifluoroacetamide.

Under inert atmosphere, 18.1 g of the product obtained in Stage 4 above were dissolved in 100 cm3 of methylethylketone, 9 g of dihydrated trimethylamine N-oxide were added together with a solution of 360 mg of osmium tetroxide in 71 cm3 of methylethylketone, the mixture was agitated for 2 hours at reflux and allowed to cool, 200 cm3 of 10% solution of sodium thiosulphate in water were added, the mixture was agitated for 30 minutes at ambient temperature, decanted, washed with water, dried on magnesium sulphate, filtered and distilled to dryness under reduced pressure. The oil obtained was purified by chromatography on silica (eluant:benzene/ethyl acetate, 7:3 by volume). 14 g of the title product of this Stage were obtained.

M.Pt. = 172"C then 192"C.

Stage 6: (20S) 3a-amino 5o'-pregnan- 1 7a,20 diol.

Under inert atmosphere, 4 g of the product obtained above were dissolved in 20 cm3 of methanol, 8 cm3 of sodium hydroxide solution were added, the mixture was agitated for 1 hour 30 minutes, 50 cm3 of water were added, the mixture was agitated for 10 minutes, separated, washed with water and dried under reduced pressure at 40"C. 3 g of the title product of this State were obtained.

M.Pt = 210"C.

Example 10: 2-amino N-(20S)-20-hydroxy 19-nor (5a)-pregnan-3a-yl] acetamide hydrochloride.

Proceeding analogously to Example 1, variant 1, but starting with BOC-glycine and (20S) 3a-amino-19-nor (5a)-pregnan-20-ol, the title product was obtained.

M.Pt-270"C with sublimation.

Cal, f 39.5" f 1.5" (c = 1 % methanol).

The starting (20S) 3a-amino-1 9-nor (5a)-pregnan-20-ol can be prepared as follows: Proceeding analogously to Example 9, Stages 1, 2 and 3, for the preparation of (Z) Sa- pregn-1 7(20)-en-3a-amine, but starting with 1 9-nor-epiandrosterone, (Z) 5a-1 9 nor pregn 17(20)-en-3α-amine was prepared.

Under nitrogen, 156 mg of sodium borohydride were suspended in 5 cm of tetrahydrofuran, a solution of 0.5 cm3 of boron trifluoride etherate in 2.5 cm3 of tetrahydrofuran was added drop by drop at + 5 C, the mixture was agitated for 1 hour in an ice bath, 296 mg of (Z) 5α-19 nor-pregn 17(20)-en-3α;-amine in solution in 3 cm of tetrahydrofuran were added, the mixture was agitated for 1 hour 30 minutes at ambient temperature and then cooled in an ice bath, 2 cm3 of 6N sodium hydroxide were added slowly, the mixture was agitated for 5 minutes at ambient temperature and decanted, the aqueous phase was extracted with tetrahydrofuran, the organic phase was washed with water, 4 cm3 of 5N sodium hydroxide and 2 cm3 of hydrogen peroxide of 110 volumes were added, and the mixture was agitated for 45 minutes, extracted with ethyl acetate, washed with water, dried and distilled to dryness under reduced pressure.The dry extract was taken up in 10 cm3 of methanol with 5 cm3 of N hydrochloric acid, heated for 30 minutes in a water bath at 50 C, poured into a saturated solution of sodium bicarbonate, extracted with methylene chloride, washed with water, dried and evaporated under reduced pressure. 257 mg of crystals of the expected product were obtained. M.Pt-1 90'C.

Example 11: 2-amino N-[17α-hydroxy 20-oxo 5α-pregnan-3α-yl]acetamide hydrochloride.

Proceeding analogously to Example 1, variant 2, but starting with BOC-glycine and 3a- amino 1 7a-hydroxy 5a-pregnan-20-one, the title product was obtained.

M.Pt. > 300 C.

]D= + 50 + 1 (e = 1% ethanol 95").

The starting 3a-amino 1 7a-hydrnxy 5a-pregnan-20-one can be prepared as follows: By perchromic oxidation of the product obtained in Stage 5 of Example 9, N-(1 7a hydroxy-20-oxo-Sa-pregnan-3a-yl] trifluoroacetamide was prepared (M.Pt = 1 78"C then 186"C), which was treated as described in Stage 6 of Example 9 to obtain 3a-amino 17ahydroxy 5Oc-pregnan-20-one. M.Pt. = 216"C (after crystallization from water).

Example 12: 2-amino N-U20R)-20-hydroxy 5a-pregnan-3a-yU acetamide hydrochloride.

Proceeding analogously to Example 1, variant 1, but starting with BOC-glycine and (20R) 3a-amino 5a-pregnan-20-ol, the title product was obtained.

M.Pt=210 C then 260 C.

[a]D = + 22 # 1 (c = 0.8% pyridine containing 10% of water).

Example 13: Ethyl N-[(20S)-20-hydroxy(5α)-pregnan-3α-yl] carbamate Drop by drop over 10 minutes, under inert atmosphere, 5 g of (20S) 3a-amino 5apregnan-20-ol in solution in 500 cm3 of methylene chloride were added to 1 S cm3 of ethyl chloroformate and 45 cm3 of methylene chloride, the mixture was agitated for 30 minutes, 20 cm3 of N sodium hydroxide were added, the mixture was agitated further for 30 minutes, decanted, extracted with methylene chloride, washed with water, dried, filtered, evaporated to dryness under reduced pressure, taken up with ethyl ether and separated. 5.7 g of the title product were obtained.

M.Pt"'1 98 C = = + 25 # 1.5 (c = 1% methylene chloride).

Example 14: 2-amino N-f(20S)-20-hydroxy 5a-pregnan-3a:-yl] N-methyl acetamide hydrochloride.

By reduction of the product of Example 13, (20S) 3a-methylamino 5a-pregnan-20-ol (M.Pt = 1 70 C), described by Vetter and colieagues in Bull. Soc. (1963) 1324, was prepared. This was reacted with BOC-glycine by a process analogous to that of Example 1, variant 2, to obtain the title hydrochloride. M.Pt~250 C.

Example 15: 2(S) 2-amino N-methyl Nj(20S) 20-hydroxy-5a-pregnan-3a-yl] propanamide hydrochloride.

(20S) 3a-methylamino 5a-pregnan-20-ol was reacted with BOC-L-alanine by a process analogous to that of Example 1, variant 1, to obtain the title hydrochloride M.Pt > 270 C.

Example 16: 2(R) 2-amino N-methyl N-f(20S) 20-hydroxy-5a-pregnan-3a-yl] propanamide hydrochloride.

(20S) 3α-methylamino-5α-pregnan-20-ol was reacted with BOC-L-alanine by a process analogous to that of Example 1, variant 1, to obtain the title hydrochoride.

Example 17: (20S) 3e-ethylamino 5a-pregnan-20-ol hydrochloride.

(20S) 3a-amino 5a-pregnan-20-ol was reacted with ethyl iodide in the presence of sodium carbonate, to obtain the base of the title product. M.Pt = 1 29"C after recrystallization from ethyl acetate.

The hydrochloride was prepared by the addition of hydrochloric ethyl acetate.

M.Pt. > 270"C.

Example 18: 2-amino N-ethyl N- f(2 05) 20-hydroxy 5a-pregnan 3a-ylj acetamide hydrochloride.

The base of the product of Example 1 7 was reacted with BOC-L-glycine by a process analogous to that of Example 1, variant 1, to obtain the title hydrochloride. M.Pt-230"C.

Example 19: (20S) 3a-f(2-hydroxyethyl) amino] 5a-pregnan-20-ol hydrochloride.

7 g of (20S) 3a-amino Sa-pregnan-20-ol and 7 g of sodium carbonate were suspended in 100 cm3 of anhydrous dioxan, 6.6 cm3 of 3-[2-bromoethoxy] tetrahydropyran were added and the mixture was refluxed for 24 hours under inert atmosphere. The resultant mixture was cooled to ambient temperature, diluted with water, extracted with ether, dried, distilled to dryness under reduced pressure and purified by chromatography on silica (eluant:chloroform/methanol/acetic acid, 85:5:10 by volume). 7.7 g of yellow oil were collected.

Hydrolysis of the protecting group 3 g of the product prepared as above were dissolved in 30 cm3 of ethanol and 15 cm3 of 2N hydrochloric acid, the mixture was agitated under reflux for 1 hour 30 minutes, cooled, poured into 100 cm3 of aqueous sodium bicarbonate solution, chilled for 15 minutes, separated, washed with water, dried at 40"C under reduced pressure, dissolved in 350 cm3 of methylene chloride containing 10% of methanol, filtered and concentrated to about 50 cm3, 100 cm3 of ethyl acetate were added, the mixture was concentrated by half and the precipitate was separated. It was disolved in 100 cm3 of methanol, the solution was filtered and concentrated to about 30 cm3, 70 cm3 of ethyl acetate was added, the mixture was concentrated by half, separated and dried at 40"C under reduced pressure. 1.65 g of the expected base were obtained.

M.Pt = 215"C.

Formafion of the hydrochloride.

1.5 g of the base prepared as above were dissolved in 40 cm3 of methanol, a 1.6N solution of hydrochloric ethyl acetate was added until the pH was acid, 60 cm3 of ethyl acetate were added, the mixture was concentrated under reduced pressure, separated and dried at 40"C under reduced pressure. 1.5 g of the expected hydrochloride were obtained.

M.Pt > 260"C.

Example 20: -dimethylamino N- f(2 OS) 20-hydroxy 5er-pregnan-30r-yl] acetamide.

Proceeding analogously to Stage A of Example 1, but using 2.552 g of (20S) 3a-amino 5a-pregnan-20-ol and 3.350 g of N,N-dimethyl glycine hydrochloride, produced 4 g of crude product containing the title product and its O,N-disubstituted derivative. By saponification with sodium hydroxide in methanol, the title product was obtained.

M.Pt= 206"C.

Coil, = + 29" ii" (C = 1 % 1% CHCl3).

Example 21: Compressed tablets were prepared, of formula: (2S) 2-amino N-20S)-20-hydrnxy 5a-pregnan-3a-yl propanamide hydrochloride 20 mg; excipient q.s. for one compressed tablet up to 100 mg.

(Detail of the excipient:lactose, starch, talc, magnesium stearate).

Example 22: Compressed tablets were prepared of formula: 2-amino N(20S)-hydrnxy 5a-pregnan-3a-yl N-methyl acetamide hydrochloride 15 mg; excipient q.s. for one compressed tablet up to 100 mg.

(Detail of the excipient:lactose, starch, talc, magnesium stearate).

Pharmacological study 1. Anaphylactic shock adjuvant Principle: The effect of administering to animals a product capable of stimulating the activity of the immune systems is measured by an increase in the shock in response to the administration of an antigen to which the animal has been sensitized.

Male mice weighing 30 to 35 g are sensitized by intra-plantar route with beef serum albumin. 8 days later they receive this antigen by intravenous route. Under conditions of minimum sensitization the control animals do not suffer any mortal shock at the time of this last administration.

The product to be tested is injected by intraplantar route, mixed with the antigen: if this product is an adjuvant it will increase the sensitization and the result of this will be a mortal shock at the time of administration by intravenous route.

The dose which causes mortality in 50% or more of the animals is considered as the active dose.

Results Product of Example Dose per animal in mg 1 0.5 2 4 5 5 5 6 2 7 1 8 5 9 1 10 0.5 13 5 14 0.5 The products in this Table and the following 2 Tables are in the form of their hydrochlorides except for the products of Examples 5, 8 and 13, which are in the form of their bases.

2. Test of rosettes with red corpuscles from sheep.

Principle: The effect of administering to animals a product capable of stimulating the activity of the immune systems is measured by an increase in their capacity for reaction to the injection of an immunogenic product.

Male rats, 3 months old, are sensitized by intra-peritoneal route with erythrocytes from sheep (day 0). 7 days later (day 7) their spleens are removed and the splenocytes are put into contact with erythrocytes from sheep: the percentage of leucocytes around which the erythrocytes have formed rosettes is then counted.

The product to be studied is administered per os daily from day - 1 to day 1.

The dose of product which multiplies by about 2 the percentage of rosettes observed in the control animals is regarded as immunostimulating dose.

Results Dose per animal in Product of Example mg/kg per os 1 1 5 2 6 8 5 10 5 11 5 14 10 3. Study of the acute toxicity The lethal doses LDo of the products tested were evaluated by administration orally to the mouse.

The maximum dose not causing any mortality at the end of 8 days is called Ludo.

The results are as follows: Product of Example LDo in mg/Kg 1 200 2 > 400 3 2400 4 2400 5 21000 6 2800 7 3400 9 2600 10 2400 11 21000 12 2400 13 2400 14 2200

Claims

1. A compound which is a steroid of formula I:

or, together with W, an ethylidene radical, the wavy lines signify that the corresponding radical is in configuration a or ss, R, represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms and R3 represents a hydrogen atom, an alkyl radical containing 1 to 5 carbon atoms, a hydroxyalkyl radical containing 2 to 5 carbon atoms, an acyl or alkoxycarbonyl radical containing 2 to 8 carbon atoms or an acyl radical corresponding to an aamino carboxylic acid an N-alkylated a-amino carboxylic acid or to a peptide containing 2 or 3 a-amino carboxylic acid, or N-alkylated a-amino carboxylic acid units, with the proviso that at least one of R2 and R3 does not represent a hydrogen atom, and with the further provisos:: (i) when at the same time R1 represents a methyl radical, W and R2 each represent a hydrogen atom and X represents the radical

and the -NR2R3 radical is at position 3a, then the substituents R1, R2, and R3 do not each represent at the same time a methyl radical, (v) when at the same time R2 and W each represent a hydrogen atom, R1 represents a methyl radical, X represents a group

2. A compound according to claim 1 wherein X represents a group

3. A compound according to claim 2 wherein X represents a group

and R2 represents a hydrogen atom or a methyl radical.

4. A steroid claimed in claim 1 which is named in any one of the Examples.

5. A salt of the steroid claimed in claim 4.

6. (2S)2-amino N-20S)-20-hydrnxy (5a)-pregnan-3a-yl] propanamide or a salt thereof.

7. (2S) 2-amino N-20S)-20-hydrnxy (5a)-pregnan-3a-yl] 1 H-indol 3-propanamide or a salt thereof.

8. 2-amino N-[(20S)-20-hyd roxy-l 9 nor (5a)-pregnan-3a-yl acetamide or a salt thereof.

9. 2-amino N-[20S)-20-hydroxy (5a)-pregnan-3a-yI N-methyl acetamide or a salt thereof.

1 0. Process for preparing a compound claimed in any one of claims 1 to 9, which process comprises reacting an amine of formula II:

in which the wavy line, W, X and R1 are as defined in claim 1 either with a halide of formula III: Hal-R'3 Ill in which Hal represents a chlorine, bromine or iodine atom and R'3 represents an alkoxycarbonyl radical containing 2 to 8 carbon atoms, to obtain a steroid of formula 1 in which R2 represents a hydrogen atom, R3 represents an alkoxycarbonyl radical containing 2 to 8 carbon atoms and W, X, R, and the wavy line are as defined above, which steroid is salified if desired, or with an acylating agent which is the acid R'30H or an acid functional derivative thereof, in which R'3 represents an acyl radical containing 2 to 8 carbon atoms, to obtain a steroid of formula I in which R2 represents a hydrogen atom, R3 represents an acyl radical containing 2 to 8 carbon atoms and W, X, R1 and the wavy line are as defined above, which steroid is salified if desired, or with an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or a peptide containing 2 or 3a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units, the amine function of these acids or units being protected if necessary by an easily-cleavable protecting group substituted thereon, in which case the protecting group is subsequently removed, to obtain a steroid of formula I in which R2 represents a hydrogen atom, R3 represents an acyl radical corresponding to an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or to a peptide containing 2 or 3 a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units and W, X, R1 and the wavy line are as defined above, which steroid is salified if desired, or with an alkyl halide containing 1 to 5 carbon atoms or a hydroxyalkyl halide containing 2 to 5 carbon atoms, in both cases the halogen being a chlorine, bromine or iodine atom, to obtain a steroid of formula I in which R2 and R3 are the same or different and each represents a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms and W, X, R, and the wavy line are as defined above, which steroid of formula I is salified if desired, and optionally where R3 represents a hydrogen atom the steroid is reacted (a) with a halide of formula IV:: Hal-R"3 IV in which R"3 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms or an alkoxycarbonyl radical containing 2 to 8 carbon atoms and Hal is as defined above, to obtain a steroid of formula I in which R2 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms, R3 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms or an alkoxycarbonyl radical containing 2 to 8 carbon atoms and W, X, R, and the wavy line are as defined above, which steroid is salified if desired, or (b) with an acylating agent which is the acid R"30H or an acid functional derivative thereof, in which R"3 represents an acyl radical containing 2 to 8 carbon atoms, to obtain a steroid of formula I in which R2 represents alkyl of 1 to 5 carbon atoms or hydroxyalkyl of 2 to 5 carbon atoms, R3 represents an acyl radical containing 2 to 8 carbon atoms and W, X, R, and the wavy line are as defined above, which steroid is salified if desired, or (c) with an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or a peptide containing 2 or 3a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units, the amine function of these acids or units being protected if necessary by an easily cleavable protecting group substituted thereon, in which case the protecting group is subsequently removed, to obtain a steroid of formula I in which R2 represents an alkyl radical containing 1 to 5 carbon atoms or a hydroxyalkyl radical containing 2 to 5 carbon atoms, R3 represents an acyl radical corresponding to an a-amino carboxylic acid, an N-alkylated a-amino carboxylic acid or to a peptide containing 2 or 3a-amino carboxylic acid or N-alkylated a-amino carboxylic acid units and W, X, R1 and the wavy lines are as defined above, which steroid is salified if desired, or with an alkyl haloformate to obtain a carbamate of the amine of formula II, which is then reduced to obtain a steroid of formula I in which R3 represents a methyl group, which steroid is salified if desired, or with an acetylating agent to obtain the N-monoacetylated steroid, which is then reduced to obtain a steroid of formula I in which R3 represents an ethyl group, which steroid is salified if desired, and the steroid is optionally reacted again with an acetylating agent and then reduced, to obtain a steroid of formula I in which R2 and R3 each represents an ethyl group, which steroid is salified if desired, or with acetone in the presence of a reducing agent, to obtain a steroid of formula I in which R2 represents isopropyl and R3 represents a hydrogen atom or isopropyl, which steroid is salified if desired.

11. A pharmaceutical composition comprising a pharmaceutically-acceptable excipient together with a compound claimed in any one of claims 1 to 9 or prepared by a process claimed in claim 10.

1 2. A pharmaceutical composition comprising a pharmaceutically-acceptable excipient together with (2S) 2-amino N-[(20S)-20-hydroxy (Sa)-pregnan-3a-yl] propanamide, (2S) 2-amino N-[(20S)-20-hydroxy (Sa)-pregnan-3a-yl] 1 H-indol 3-propanamide, 2-amino N-[(20S)-20-hydroxy-1 9-nor (5a)-pregnan-3a-yl] acetamide, or 2-amino N-[(20S)-20-hydroxy (Sa)-pregnan-3a-yI] N-methyl acetamide, or a pharmaceutically acceptable salt of any of these.

1 3. A compound claimed in any one of claims 1 to 9 or a composition claimed in claim 11 or 12, which compound or composition is for use in a method of treatment of the human or animal body by therapy.