EP0613483A1 - New lupane derivatives, preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

New lupane derivatives of general formula (I) in which R is (A), in which R ′ and R ″ identical or different are H or alkyl, X is a bond, carbamoyl or aminocarbonyl optionally substituted, Y is a bond or phenylene , R ° and R °° identical or different are H or alkyl or R ° is OH, hydroxyalkyl, phenyl, benzyl, carbamoylmethyl, or forms a heterocycle with the nitrogen of X when X is carbamoyl and Y is a bond, and, n, m, and p are integers from 0 to 16, 4 m + n + p 16, R1 is methyl, R2 is hydroxy, methyl, hydroxymethyl, -CH2OR'2, -CH2SR'2 or -CH2NHR'2 or, R2 is amino substituted or dialkoylamino, the alkyl parts of which can form a heterocycle, R3 is H or forms with R1 or R2 methylene or oxo, R4 and R5 are different and represent H or hydroxy, or together form oxo, hydroxyimino or alkyloxyimino which can be substituted, and R6 and R7 are H, or O2, R4 and R5, and R6 and R7 together form oxo radicals, alkyl radicals (1 to 4C) being straight or branched, as well as their salts when they exist and their preparation. The new products according to the invention are particularly advantageous in the field of AIDS.

Description

 NOVEL DERIVATIVES SAID LUPANE, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS WHERE CONTAINING THEM

The present invention relates to new lupane derivatives, of general formula:

their salts, their preparation and the pharmaceutical compositions containing them.

In Japanese patent application J 01 143 832, betulin derivatives of the general formula have been described:

wherein R ₁ and R ₂ are hydroxy or acyloxy and R ₃ is in particular methyl. These derivatives are useful in the field of anticancer agents.

It has now been found that the lupane derivatives of general formula (I) in which: R represents a radical of general formula

 in which R 'and R ", which are identical or different, are hydrogen atoms or alkyl radicals,

X is a bond or represents a carbamoyl, N-methyl carbamoyl, aminocarbonyl or N-methylaminocarbonyl radical,

Y is a bond or represents a phenylene radical,

R ° and R °° identical or different are hydrogen atoms or alkyl radicals (it being understood that R ° and R °° are not necessarily identical on each unit -CR ° R °° -), or R ° is hydroxy, hydroxyalkyl, phenyle, benzyl, carbamoylmethyl or alternatively, when Y is a bond and X is carbamoyl, Rº can form a 5 or 6-membered ring with the nitrogen atom contained in X, this cycle being able moreover to include a other heteroatom chosen from oxygen or sulfur and, n, m and p are whole numbers from 0 to 16 such that m + n + p is between 4 and 16,

R ₁ is a methyl radical, or forms with R ₃ a methylene radical or an oxo radical,

R ₂ is a hydroxy, methyl, hydroxymethyl radical or a -CH ₂ OR ' ₂ , -CH ₂ SR' ₂ or -CH ₂ NHR ' ₂ radical for which R' ₂ is alkyl, hydroxyalkyl, dihydroxyalkyl, acetamidoalkyl, or acetyl, or R ₂ is an amino radical substituted by a hydroxyalkyl or carboxyhydroxyalkyl radical, or a dialkoylamino radical, the alkyl parts of which may form, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocycle optionally containing another chosen heteroatom among oxygen, sulfur or nitrogen and optionally N-alkylated, R ₃ is a hydrogen atom or forms with R ₁ or R ₂ a methylene radical or an oxo radical. R ₄ and R ₅ are different and represent a hydrogen atom or a hydroxy radical, or together form an oxo, hydroxyimino or alkyloxyimino radical optionally substituted (by a carboxy or dialkoylammo radical in which the alkyl parts can form with the atom nitrogen to which they are attached, a 5 or 6-membered heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen or sulfur and optionally substituted by an alkyl radical) and

R ₆ and R ₇ are hydrogen atoms, or else R ₄ and R ₅ , and R ₆ and R ₇ together form oxo radicals, and their pharmaceutically acceptable salts, when they exist, exhibit a cytoprotective effect on infected cells by an HIV virus (Human Immunodeficiency Virus) as well as an activity inhαbitrice of the production of reverse transcriptase of an HIV virus. In the general formula above, it is understood that the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms.

According to the invention, the products of general formula (I) can be obtained by the action of an amino acid of general formula: H ₂ N - R (III) in which R is defined as above and of which, where appropriate, the function acid has been previously protected, on the acid chloride of general formula:

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are defined as above, followed, where appropriate, by transformation into an ester for which the symbol R 'is alkyl, then by removal of protective radicals.

It is understood that when R ₂ , R ₄ or R ₅ represent or contain a hydroxy radical, the latter is protected beforehand; the same applies if R ₂ contains a carboxy radical or if the substituent -CR ₁ R ₂ R ₃ in position 19 is a carboxy radical. The reaction of the amino acid on the chloride of lupen-20 (29) oic-28 acid of general formula (IV) is carried out according to the usual methods which do not alter the rest of the molecule. The operation is carried out in particular in the presence of an organic nitrogenous base such as a trialkylamine (triethylamine for example) in an organic solvent such as a chlorinated solvent (chloroform, 1,2-dichloroethane, dichloromethane) or in tetrahydrofuran or in a mixture of these solvents, at a temperature between 15 and 30 ° C.

The acid function of the amino acid of general formula (III) is protected by any compatible radical and the establishment and elimination of which does not alter the rest of the molecule. Likewise, the radicals R ₂ , R ₄ or R ₅ of the lupane derivative of general formula (IV) are protected by compatible radicals which can be put in place and eliminated without touching the rest of the molecule. By way of example, the protective groups can be chosen from the radicals described by TW GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscier.ee Publication (1991) or by Me Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). It is in particular advantageous to use protective radicals which can be eliminated simultaneously. We will choose radicals which can be eliminated in neutral, basic or acidic medium. The protections can advantageously be carried out in the form of esters. In this case, the removal of the protective radicals is carried out by hydrolysis in a basic medium, in particular in the presence of soda at a temperature between 10 and 50 ° C.

For example, the hydroxy radicals can be protected in the ester state (formyloxy, acetoxy, i.butoxy, trichloracetyloxy, phenoxyacetyloxy, benzyloxy), in the ketone state, in the form of carbonate by a radical - COOR _a in which R _a is an alkyl or benzyl radical optionally substituted or also by a trialkylsilyl radical; the acid protecting radicals can be chosen from alkyl (methyl, ethyl, t.butyl), substituted alkyl (trichlorethyl, haloethyl, p. toluenesulfonylethyl, benzyl, benzyl substituted by a nitro radical, benzhydryl, triphenylmethyl, benzyloxymethyl. .), alkyloxyalkyl (methoxymethyl), tetrahydropyranyl or trimethylsilyl. The lupane derivatives of general formula (I) in which the radical R has a chiral center, have isomeric forms. It is understood that these isomeric forms and their mixtures fall within the scope of the present invention. The preparation of one or the other of these forms depends on the choice of the starting amino acid. Where appropriate, the transformation into an ester for which R ′ is an alkyl radical is carried out according to the usual methods which do not alter the rest of the molecule. In particular, one operates by the action of an alkyl iodide.

According to the invention, the lupane derivative of general formula (I) for which R ₄ and R ₅ together form a hydroxyimino or alkyloxyimino radical optionally substituted as defined above, and the other radicals are defined as previously can also be obtained by the action of l hydroxylamine or one of its derivatives of general formula: R ₈ -O-NH ₂ (V) in which R ₈ is a hydrogen atom or an alkyl radical optionally substituted (by a carboxy or dialkoylamino radical in which the alkyl parts can form with the nitrogen atom to which they are attached , a 5 or 6-membered heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen or sulfur and optionally substituted by an alkyl radical), on a lupane derivative of general formula (I) in which R ₄ and R ₅ together form an oxo radical, then optionally release of the protective radicals.

It is understood that if R ₈ contains a carboxy radical or if the lupane derivative of general formula (I) contains carboxy or hydroxy radicals, the latter are protected beforehand. The protection and the release of the protective radicals are carried out according to the methods mentioned above.

The reaction is advantageously carried out using the hydrochloride of the derivative of general formula (V) in pyridine at the reflux temperature of the reaction mixture, or in an alcohol in the presence of an alkaline carbonate at the reflux temperature of the reaction mixture. According to the invention the lupane derivative of general formula (I) for which R ₁ and R ₂ are methyl radicals, R ₃ is a hydrogen atom and the other radicals are defined as above can also be obtained by reduction of a lupane derivative of general formula (I) for which R ₁ and R ₃ together form a methylene radical and R ₂ is defined as above.

The reduction is carried out by any known method which does not affect the rest of the molecule. In particular, the process is carried out by catalytic hydrogenation in the presence of palladium on carbon, at atmospheric pressure, at a temperature between 15 and 25 ° C. in a solvent such as an alcohol (methanol, ethanol for example).

If necessary, the radicals liable to interfere with the reaction are protected beforehand. Protection and disposal protective radicals are carried out according to the methods mentioned above.

According to the invention the lupane derivative of general formula (I) for which R ₂ is a hydroxy radical, R ₁ is a methyl radical, R ₃ is a hydrogen atom and the other radicals are defined as above can also be obtained by reduction of a lupane derivative of general formula (I) for which R ₂ and R ₃ together form an oxo radical and R ₁ is a methyl radical.

The reduction is carried out by any known method which does not affect the rest of the molecule. In particular, the reduction is carried out with an alkaline borohydride (sodium borohydride for example) in the presence of tetrabutylammonium chloride or tetraethylammonium, in a solvent such as an aromatic hydrocarbon (toluene for example), at a temperature between 50 ° C. and the reflux temperature of the reaction mixture.

If necessary, the radicals liable to interfere with the reaction are protected beforehand. The protection and removal of protective radicals is carried out according to the methods mentioned above. According to the invention, the lupane derivative of general formula (I) for which R ₁ and R ₃ together form an oxo radical, R ₂ is a hydroxy radical and the other radicals are defined as previously can also be obtained by oxidation of a lupane derivative of general formula (I) for which R ₁ and R ₃ together form an oxo radical and R ₂ is a methyl radical.

The reaction is generally carried out by the action of a hypochlorite or a hypobromite. For example by the action of sodium hypobromite which can be prepared in situ, in a hydroorganic medium, in particular in dioxane, at a temperature between -10 and 20 ° C. If necessary, the radicals liable to interfere with the reaction are protected beforehand. Protection and disposal protective radicals are carried out according to the methods mentioned above.

According to the invention the lupane derivative of general formula (I) for which X (in the radical R) represents a carbamoyl radical and the other radicals are defined as above, can also be obtained from a lupane derivative of formula general:

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are defined as above and R ₉ represents a radical of general formula:

in which n and R "are defined as above, by the action of an amine of general formula:

in which R ', R °, R °°, m and p are defined as above then, if necessary, transformation of the acid obtained into an ester for which R' is an alkyl radical and elimination if necessary of the protective radicals.

It is understood that the radicals representing or containing radicals which can interfere with the reaction are protected beforehand. The protection and the release of the protective radicals are carried out as described above. The amine of general formula (VIII) is preferably condensed from the hydrochloride of the amine. The reaction is carried out according to the usual methods of condensation of an amine on an acid. In particular, one operates in the presence of an acid acceptor such as a nitrogenous organic base (trialcoylamine, pyridine, N-methylmorpholine, diaza-1,8 bicyclo [5.4.0] undecene-7, diaza-1,5 bicyclo [4.3.0] nonene-5 for example) in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example) or an amide (dimethylformamide for example). It is also possible to operate in the presence of a condensing agent such as a carbodiimide (dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for example) and optionally in the presence of a catalyst such as N-hydroxybenzotriazole or N-hydroxysuccinimide, at a temperature between -20 and 40 ° C. The amino acid of general formula (III) and the lupane derivative of general formula (IV) can be prepared as described below in the examples.

In particular, the lupane derivatives of general formula (IV) for which R ₁ is a methyl radical, R ₂ is a hydroxy or methyl radical and R ₃ is a hydrogen atom can be prepared according to the reduction process described above for the preparation of the products of general formula (I) for which R ₂ is a hydroxy radical.

The lupane derivatives of general formula (IV) for which R ₁ is a methyl radical and R ₂ and R ₃ together form an oxo radical can be prepared according to the method described by A. VYSTRCIL et al., Collect. Czech. Chem. Comm., 35, 295 (1970).

The lupane derivatives of general formula (IV) for which R ₂ is a hydroxy radical and R ₁ and R ₃ together form an oxo radical can be prepared by analogy with the method described for the preparation of the corresponding products of general formula (I) , by oxidation of the corresponding methyl ketone. It is understood that the protection of the acid in position -19 thus obtained is essential for the implementation in the following reaction. The lupane derivatives of general formula (IV) for which R ₂ is a hydroxymethyl radical can be prepared by the action of silver acetate on the corresponding bromine derivative for which R ₂ is bromomethyl and for which, if necessary, the radical R ₄ or R ₅ is previously protected. The reaction is advantageously carried out in an organic solvent such as, for example, toluene, at a temperature between 20 ° C. and the reflux temperature of the reaction mixture. The starting bromine derivative can be obtained by the action of a brominating agent such as, for example, tetrabutylammonium tribromide or N-bromosuccinimide on the corresponding derivative of lup-20 (29) -en-28-oic acid. The reaction is carried out in a chlorinated solvent such as methylene chloride, chloroform, or carbon tetrachloride at a temperature in the region of 25 ° C.

The lupane derivatives of general formula (IV) for which R ₂ is a substituted amino radical and R ₁ and R ₃ together form an oxo radical can be prepared by the action of the corresponding amine on the lupane derivative of general formula (IV ) for which R ₂ is a hydroxy radical and R ₁ and R ₃ together form an oxo radical. The reaction is carried out by any known method to obtain an amide from an acid, without affecting the rest of the molecule. One operates in particular by action of the amine on the chloride of the acid of general formula (IV), in a chlorinated solvent, at a temperature between -20 and 40ºC. It is understood that the functions which can interfere with the reaction are protected beforehand, in particular when the substituted amino radical is a carboxy hydroxy alkyl radical, it is necessary to protect the carboxy radical.

The lupane derivatives of general formula (IV) for which R ₂ is a substituted amino radical and R ₁ and R ₃ together form an oxo radical can be prepared by the action of the corresponding amine on the lupane derivative for which R ₂ is a bromomethyl radical in the presence of tetra [triphenylphosphine] palladium and a nitrogenous base.

The lupane derivatives of general formula (IV) for which R ₂ is a radical -CH ₂ OR ' ₂ or -CH ₂ SR' ₂ and R ₁ and R ₃ together form a methylene radical can be prepared from the lupane derivative for which R ₂ is bromomethyl, by the action of the corresponding alcoholate or thiolate.

3α-hydroxylup-20 (29) -en-28-oic acid (3α-betulιnιque acid) and its derivatives substituted in position 20 or 30 can be obtained according to or by analogy with the method described by W. HERZ, Phytochemistry, 11, 3061 (1972).

The lupane derivatives of general formula (IV) for which R ₄ and R ₅ together form an oxo radical, can be prepared by oxidation of the lupane derivative of general formula (IV) for which R ₄ and R ₅ represent respectively an atom d hydrogen and a hydroxy radical. The oxidation is advantageously carried out by an oxidizing agent such as chromic anhydride.

The lupane derivatives of general formula (IV) for which R ₄ and R ₅ , and R ₆ and R ₇ together form oxo radicals, can be prepared by oxidation of the lupane derivative of general formula (IV) for which R ₄ and R ₅ together form an oxo radical.

The lupane derivatives of general formula (IV) for which R ₄ and R ₅ together form a hydroxyimino or alkyloxyimino radical optionally substituted (by a carboxy or dialkoylamino radical in which the alkyl parts can form with the nitrogen atom to which they are attached , a 5 or 6-membered heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen or sulfur and optionally substituted by an alkyl radical) can be prepared by analogy with the process described above for the preparation of lupane derivatives of general formula (I) for which R ₄ and R ₅ together form a radical = NOR ₈ .

The acid chloride of the lupane derivative of general formula (IV) can be prepared according to known methods. For example, the reaction is carried out by the action of oxalyl chloride or thionyl chloride, in a chlorinated solvent such as chloroform, dichloroethane or dichloromethane. The lupane derivatives of general formula (VI) can be prepared by analogy with the method described for the preparation of the products of general formula (I), starting from a product of general formula (IV). The products of general formula (VIII) can be prepared according to or by analogy with the methods described below in the examples.

The new lupane derivatives of general formula (I) can be purified if necessary by physical methods such as crystallization or chromatography.

The products according to the invention can be transformed into metal salts or into addition salts with a nitrogenous base according to the methods known per se. These salts can be obtained by the action of a metal base (for example alkaline or alkaline earth), ammonia or an amine on a product according to the invention, in a suitable solvent such as water or an alcohol . The salt formed precipitates after optional concentration of the solution; it is separated by filtration.

Examples of pharmaceutically acceptable salts which may be mentioned are the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), the ammonium salt, the salts of nitrogenous bases (ethanolamine, diethanolamine, trimethylamine , triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzylphenethylamine, NN'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine).

The new lupane derivatives according to the present invention are particularly useful for the prophylaxis and treatment of AIDS (acquired immunodeficiency syndrome) and associated syndromes [ARC (AIDS related complex)]. By prophylaxis we mean the treatment of subjects who have been exposed to HIV viruses, in particular asymptomatic seropositive people who present the risk to develop the disease in the months or years to come after the first infection.

The products according to the invention, which are inhibitors of the cytopathogenic effect of HIV and inhibitors of the production of reverse transcriptase in cell culture at concentrations devoid of cytotoxic or cytostatic effect, are of particular interest.

The activities were highlighted in the following tests:

Activity vis-à-vis the pathopathogenic effect of the HIV virus

The powdered products were dissolved in a proportion of 2 mg of product per 2 ml (approximately 4 × 10 ^-3 M) in a mixture of dimethylformamide (DMF) and L-lysine (base) at (1:19, theft: theft). First add 1 volume of DMF and dissolve the product as best as possible, then add 9 volumes of a solution of L-lysme base at 4 × 10 ^-3 M in distilled water. In this way, a stock solution of product containing 10% of DMF and containing a molar ratio (product / lysine) close to 1 is obtained. The test is carried out on the lymphoblastoid line CEM clone 13. In a 96-well microplate, 25 μl / well of a solution of product to be tested in isotonic phosphate buffer (TPI) or TPI alone in the case of the controls. The products are studied at different concentrations (often 8), due to

6 wells per concentration. 125 μl of a suspension of CEM cells (8 × 10 ⁴ cells mL ml) are then added to the RPMI medium containing

10% fetal calf serum, 100 IU / ml of penicillin, 100 μg / ml of streptomycin and 2 μmoles / ml of glutamine and the microplates are incubated for one hour at 37 ° C., under an atmosphere containing 5% carbon dioxide. For each concentration, the test is divided into two parts: one part (3 wells) on infected cells, for determining the antiviral activity and the other part (3 wells) on non-infected cells, to determine the cytotoxicity of the products. The first series is then infected with HIV-1 (100 μl per well of a suspension of LAV-1-BRU virus containing 200-300 TCID50) while the other series receives 100 μl of RPMI medium as defined above. After 7 days of incubation, 100 μl of cells are removed to measure cell viability [determined according to a modification of the technique described by R. Pauwels et al.,

J. Virol. Meth., 20, 309-321 (1988)]. We add to this sample

10 μl of a solution containing 7 mg of MTT [3- (4,5-dimethyl 2-thiazolyl) -2,5-diphenyltetrazolium bromide] per ml of isotoπic phosphate buffer. After 3 hours of incubation at 37 ° C the supernatant is removed. MTT is converted to a formazan salt

(blue) only inside living cells. 100 μl of isopropanol (containing 0.04 mole / l of hydrochloric acid) are then added and the microplates are agitated until the formazan blue is dissolved. The absorbance at 540 nm is read with an automatic reader of ELISA reactions in microplates. This absorbance is proportional to the quantity of living cells.

The protection rate (in%) of a given product is determined from the optical densities (OD) by the formula: DO (cell, treated and inf.) - DO (cell, untreated and inf.)

 DO (cell treated and not inf.) - DO (cell not treated and inf.)

If necessary, the inhibitory concentration 50% is determined.

The results demonstrate that for concentrations of the tested product of between 0.5 and 30 μg / ml, a significant reduction in the cytopathogenic effect is obtained.

The protection rate provided by the products according to the invention is between 20 and 100%.

The 50% inhibitory concentration of the products according to the invention is between 0.30 and 100 μg / ml when it can be determined. Recovery of viral multiplication because assay of HIV virus reverse transcriptase

The activity of reverse transcriptase is measured directly on 50 μl of culture supernatant. According to the method described by O. Schwartz et al., AIDS Research, and Human Retrovirus 4 (6). 441-448 (1988). 10 μl of buffer containing 0.5 M of KCl, 5 mM of dithiothreitol (DTT) and 0.5% of triton X-100 are added to all microwells containing the 50 μl of supernatant to be tested. 40 μl of buffer containing the 1.25 mM ethylene glycol-bis (2-aminoethyl ether) tetraacetic acid (EGTA), 0.125 mM Tris. HCl pH 7.8, 12.5 mM MgCl ₂ , 3 μCi of ( ³ H) thymidine triphosphate (TTP), 0.05 DO ₂₆₀ of polyadenylic acid - thymidylic acid (poly rA-oligo dT) are then added. The microplate is covered with a plastic film and incubated for 60 minutes at 37 ° C.

The reaction is stopped by adding 20 μl of an ice-cold solution of 120 mM Na ₄ P ₂ 0 ₇ in 60% of trichloroacetic acid and the samples are placed for 15 minutes on the ice bed.

The precipitates are filtered through glass fibers using a cell washer (Skatron) and the filters are washed with a solution of 12 mM Na ₄ P ₂ O ₇ in 5% trichloroacetic acid.

The filters are dried and the radioactivity is counted after adding a scintillating liquid.

Inhibitions of the production of reverse transcriptase associated with the virus are observed, between 20 and 100% at the concentrations tested (0.30 to 100 μg / ml).

Of particular interest are the products of general formula (I) in which:

R represents a radical of general formula:

in which R ′ and R ″ which are identical or different are hydrogen atoms or alkyl radicals, X is a bond or represents a carbamoyl, N-methyl carbamoyl, ammocarbonyl radical,

Y is a bond or represents a phenylene radical, R ° and R °° identical or different are hydrogen atoms or alkyl radicals (it being understood that R ° and R °° are not necessarily identical on each unit -CR ° Rºº-), or R ° is hydroxy, hydroxyalkyl, phenyl, benzyl, carbamoylmethyl or, when Y is a bond and X is carbamoyl, R ° can form a 5 or 6-membered ring with the nitrogen atom contained in X and, n, m and p are whole numbers from 0 to 16 such that m + n + p is between 4 and 16,

R ₁ is a methyl radical, or forms with R ₃ a methylene radical or an oxo radical,

R ₂ is a hydroxy, methyl, hydroxymethyl radical or a -CH ₂ SR ' ₂ or -CH ₂ NHR' ₂ radical for which R ' ₂ is alkyl, hydroxyalkyl, acetamidoalkyl, or acetyl, or R ₂ is a substituted amino radical by a hydroxyalkyl or carboxyhydroxyalkyl radical, or a dialkoylamino radical, the alkyl parts of which may form, with the nitrogen atom to which it is attached, a 5 or 6-membered heterocycle optionally containing another nitrogen atom and optionally N-methylated,

R ₃ is a hydrogen atom or forms with R ₁ or R ₂ a methylene radical or an oxo radical,

R ₄ and R ₅ are different and represent a hydrogen atom or a hydroxy radical, or together form an oxo or alkyloxyimino radical optionally substituted (by a carboxy or dialkoylamino radical in which the alkyl parts can form with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle possibly containing another nitrogen atom optionally substituted by a methyl radical) and

R ₆ and R ₇ are hydrogen atoms, or

R ₄ and R ₅ , and R ₆ and R ₇ together form oxo radicals. it being understood that the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms, as well as their salts when they exist.

And among these products, more especially active are: - N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -β-alanme;

- N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-ala¬nme;

- N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-threonme;

- N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-amιnooctanoyl] -L-statin;

- N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-ammoheptylcarbamoylacetic acid. The following examples, given without limitation, illustrate the present invention.

Example 1

650 mg of methyl 5-ammopentanoate hydrochloride are added and then

1.07 cm ³ of triethylamme to 50 cm ³ of a chloroformic solution of 3β-acetoxylup-20 (29) en-28-oyl chloride (prepared from

1.7 g of 3β-acetoxylup-20 (29) -en-28-oic acid). The solution is then stirred for 20 hours at a temperature in the region of 20 ° C. After adding 60 cm ³ of distilled water, the organic phase is decanted and the aqueous phase is washed with 40 cm ³ in total of chloroform. The combined organic phases are washed with a total of 40 cm of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.9 g of a yellow meringue are obtained, which is chromatographed on a 2.2 cm diameter column containing 38 g of silica (0.02-0.045 mm) eluted with dusopropyl ether, collecting fractions of 10 cm ³ . After elimination of the first 23 fractions, the following 17 are combined and concentrated under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. 1.1 g of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -5-aminopentanoate are thus obtained in the form of a white meringue (Rf = 0.35; thin layer chromatography silica; eluent: diisopropyl ether).

18 cm ³ of 4N sodium hydroxide are added to a solution of 1.1 g of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -5-aminopentanoate in 18 cm ³ of methanol and 9 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature in the region of 20 ° C. Diluted with 40 cm of distilled water and stirred again for about 15 minutes. The suspension is then acidified to a pH close to 2 using 21 cm of 4N hydrochloric acid. After 1 hour of stirring, the solid is separated by filtration, washed 5 times with 100 cm ³ in total of distilled water until elimination of the chloride ions (silver nitrate test) and dried under reduced pressure (13, 5 Pa) at a temperature in the region of 20 ° C. 820 mg of N- [3β-hydroxylup-20 (29) -en-28-oyl] -5-aminopentanoic acid are thus obtained in the form of a white meringue, melting at around 160 ° C. 3β-acetoxylup-20 (29) -en-28-oyl chloride is prepared according to J. PROVITA and A.VYSTRCIL, Collect. Czech. Chem. Commun., 41, 1200 (1976).

EXAMPLE 2 0.53 cm ³ of triethylamine and 380 mg of methyl 6-aminohexanoate hydrochloride are added to a solution of 1 g of 3β-acetoxylup-20 (29) -en-28-oyl chloride dissolved in 50 cm ³ of methylene chloride, stirring is continued for 20 hours at a temperature in the region of 20 ° C., then 100 cm of distilled water are added.

The organic phase is decanted, the aqueous phase is extracted with a total of 75 cm of methylene chloride, the organic extracts are combined, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The residue obtained is purified by HPLC in fractions of 250 mg, on a column 5 cm in diameter containing 200 g of grafted silica C ₁₈ (0.01 mm) eluted with a mixture of acetonitrile, water and tetrahydrofuran 75-10-15 by volume, collecting 75 cm ³ fractions. The first 3 fractions are eliminated; the next 2 are combined and concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 35 ° C. 838 mg of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -6-ammohexanoate are thus obtained in the form of a white meringue [Rf = 0.3; thin layer chromatography on silica; eluent: cyclohexane-ethyl acetate (80-20 by volume)].

A solution of 800 mg of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -6-methyl ammo hexanoate in 13 cm ³ of methanol, 6.5 cm ³ of tetrahydrofuran and 1.6 cm 4N sodium hydroxide is stirred for 15 hours at a temperature in the region of 20 ° C. After adding 2 cm ³ of 5N hydrochloric acid and 20 cm ³ of distilled water, stirring is continued for 30 minutes. The solid is separated by filtration,

 3

washed with a total of 50 cm of distilled water and air dried. 750 mg of N- [3β-hydroxylup-20 (29) -èn-28-oyl] -6-hexanoic acid are thus obtained in the form of a white solid, melting at around 135 ° C.

Example 3

320 mg of methyl 7-ammoheptanoate hydrochloride are added, then 0.62 cm ³ of triethylamme to a solution of 1 g of 3β-acetoxylup-20 (29) -en-28-oyl chloride in 30 cm ³ of dichloromethane. The solution is stirred for 20 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The 1.77 g of beige meringue obtained are chromatographed on a column 3 cm in diameter containing 80 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80-20 (in volumes) by collecting 60 cm fractions. The first 23 fractions are eliminated; the following 8 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 930 mg of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -7-methyl ammoheptanoate are thus obtained in the form of a white meringue [Rf = 0.2; thin layer chromatography on silica; eluent: cyclohexane-ethyl acetate 80-20 (by volume)]. A volume of 1.9 cm ³ of 7N sodium hydroxide is added over approximately 5 minutes to a solution of 930 mg of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -7- aminoheptanoate in 7 cm of methanol and 10 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of

30 ° C. The residue is diluted in 40 cm of distilled water and acidified to a pH close to 2 using 5N hydrochloric acid. After 20 minutes of stirring, the solid is separated by filtration, washed with 100 cm ³ in total of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. 740 mg of N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptanoic acid, thus melting at around 134 ° C., are thus obtained.

Methyl 7-aminoheptanoate is prepared according to CF. HORN, B.T. FREURE, H. VINEYARD, H.J. DECKER, Angew. Chenu, 74, 531 (1962). Example 4

0.53 cm of triethylamine and 490 mg of hydrochloride are added.

Methyl 8-aminooctanoate in a solution of 1 g of 3β-acetoxylup-20 (29) -en-28-oyl chloride dissolved in 50 cm ³ of methylene chloride and maintains stirring for 20 hours at a neighboring temperature 20 ° C. After adding 100 cm ³ of distilled water, the organic phase is decanted, the aqueous phase is extracted with 75 cm ³ in total of methylene chloride, the organic extracts are combined, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained is purified by HPLC, in fractions of 250 mg on a column 5 cm in diameter containing 300 g of C ₁₈ grafted silica (0.015-0.020 mm) eluted with a mixture of acetonitrile, water and tetrahydrofuran 70-15-15 (by volume), under a pressure of 370 Psi, collecting 75 cm fractions. The first 3 fractions are eliminated; the next 2 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 750 mg of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -8-ammooctanoate are thus obtained in the form a white meringue [Rf = 0.3; thin layer chromatography on silica; eluent: cyclohexane ethyl acetate 80-20 in (volumes)].

A solution of 750 mg of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -8-amino octanoate in 12 cm ³ of methanol, 6 cm ³ of tetrahydrofuran and 1.5 cm ³ of 4N sodium hydroxide is stirred for 15 hours at a temperature in the region of 20 ° C. After adding 10 cm of methanol, 2 cm of 5N hydrochloric acid and then 25 cm of distilled water, stirring is continued for 30 minutes at a temperature in the region of 20 ° C and the solid is separated by filtration, washed with 50 cm ³ in total of distilled water, and dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. We thus obtain

710 mg of N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoic acid, in the form of a white solid, melting at around 140 ° C.

The methyl 8-amιnooctanoate hydrochloride can be obtained in the following manner:

To a solution of 1 g of 8-ammooctanoic acid in 40 cm ³ of methanol, 0.7 cm ³ of thionyl chloride is added at a temperature in the region of -20 ° C. and the stirring is continued for

12 hours at a temperature close to 20 ° C. The solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 1.48 g of methyl 8-ammooctanoate hydrochloride are thus obtained, in the form of a white solid.

Example 5

310 mg of methyl 10-ammodecanoate hydrochloride are added, then 0.35 cm ³ of triethylamme to 11 cm ³ of a chloroform solution of 3β-acetoxylup-20 (29) -en-28-oyl chloride (prepared from of

550 mg of 3β-acetoxylup-20 (29) -en-28-oic acid). The solution is then stirred for 15 hours at a temperature close to 20 ° C. After adding 15 cm ³ of distilled water, the reaction mixture is stirred for 1 hour, the organic phase is decanted and the aqueous phase is extracted with 20 cm ³ in total of chloroform. The combined organic phases are washed with 20 cm ³ in total of distilled water, dried over anhydrous sodium sulfate and concentrated to dry under reduced pressure (2.7 kPa) at a temperature close to

30 ° C. 730 mg of a yellow meringue are obtained, which is chromatographed on a 2.1 cm diameter column containing 35 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 60- 40 (by volume) by collecting 5 cm ³ fractions. After elimination of the first 21 fractions, the following 17 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 600 mg of methyl N- [3β-acetoxylup-20 (29) - en-28-oyl] -10-methyl aminodecanoate are thus obtained in the form of a white meringue [Rf = 0.72; thin layer chromatography on silica; eluent: cyclohexane-ethyl acetate 60-40 (by volume)].

8.7 cm of 4N sodium hydroxide are added to a solution of 600 mg of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -10-aminodecanoate in 9 cm ³ of methanol and 4.5 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature in the region of 20 ° C. Diluted with 40 cm ³ of distilled water and acidified with 10 cm ³ of 4N hydrochloric acid. After 1 hour of stirring, 15 cm ³ of ethyl ether are added and the organic phase is isolated. The aqueous phase is extracted with a total of 30 cm of ether. The combined organic phases are washed with a total of 30 cm of distilled water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 550 mg of N- [3β-hydroxyiup-20 (29) -en-28-oyl-10-aminodecanoic acid, which melts at around 100 ° C, are thus obtained. Methyl 10-aminodecanoate hydrochloride can be prepared as described in German patent application 971,392.

Example 6

580 mg of methyl 11-aminoundecanoate hydrochloride is added, then 0.62 cm of triethylamine to a solution of 1.03 g of 3β-acetoxylup-20 (29) -en-28-oyl chloride in 30 cm ³ of dichloromethane . The solution is then stirred for 48 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 20 ° C. 2 g of a yellow meringue are obtained which is chromatographed on a 2.7 cm diameter column containing 80 g of silica (0.02-0.045 mm) eluted with dusopropyl ether, collecting 20 cm ³ fractions. After elimination of the first 10 fractions, the following 6 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 1.29 g of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -11-methyl undeca¬noate are thus obtained in the form of a white meringue.

4.5 cm of 4N sodium hydroxide are added to a solution of 1.28 g of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -11-ammoundecanoate in

8 cm ³ of methanol and 13 cm ³ of tetrahydrofuran, the reaction mixture is stirred for 24 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue is suspended in

60 cm of distilled water. Aciαify at a pH close to 2 using

3.6 cm of 5N hydrochloric acid. After 20 minutes of stirring, the solid is separated by filtration, washed with distilled water to a pH in the region of 7 and air dried at a temperature in the region of 20 ° C. 1.2 g of N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-ammoundecanoic acid are thus obtained in the form of a white solid, melting at around 115 ° C. Methyl 11-ammonoundecanoate is prepared according to H. ZAHN, J. KUNDE, Chem. Ber., 94., 2470 (1961).

Example 7

243 mg of methyl 11-ammoundecanoate hydrochloride are added, then 0.27 cm ³ of triethylamme in 20 cm ³ of a tetrahydrofuran / chloroform 50-50 mixture (by volume), containing 453 mg of

3α-acetoxylup-20 (29) -èn-28-oyle. The solution is stirred for 20 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue is taken up in 60 cm ³ of ethyl ether and 25 cm ³ of distilled water, the organic phase is decanted and the aqueous phase is extracted with 25 cm ³ in total of ethyl ether. The combined organic phases are washed with 45 cm ³ in total of distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The 600 mg of me light yellow rings obtained are chromatographed on a column 2.5 cm in diameter containing 56 g of silica (0.063-0,200 mm) eluted with a mixture of cyclohexane and ethyl acetate 85-15 (in volumes), collecting fractions of 7 cm ³ . The first 10 fractions are eliminated; the following 17 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 810 mg of methyl N- [3α-acetoxylup-20 (29) -èn-28-oyl] -11-aminoundecanoate are thus obtained in the form of a white meringue.

5.8 cm of 4N sodium hydroxide are added over approximately 5 minutes to a solution of 400 mg of methyl N- [3α-acetoxylup-20 (29) -èn-28-oyl] -11-aminoundecanoate in 7 cm ³ of methanol and 3.5 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 24 hours at a temperature in the region of 20 ° C. Diluted with 35 cm ³ of distilled water and the organic solvents are evaporated under reduced pressure (4.05 kPa) at a temperature in the region of 30 ° C. The aqueous suspension is then acidified to a pH of 1 to 1 using 6.8 cm ³ of 4N hydrochloric acid. After

1 hour of stirring, the aqueous phase is extracted with 50 cm of ethyl ether. The organic phase is decanted and washed with a total of 45 cm ³ of distilled water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure (4.05 kPa) at a temperature in the region of 30 ° C. 384 mg of a whitish meringue are thus obtained which is suspended in 12 cm ³ of diisopropyl ether, separated by filtration and washed with 8 cm ³ in total of diisopropyl ether. The solid (320 mg) is resuspended in 10 cm ³ of diisopropyl ether, 3 cm ³ of ethyl ether are added and the mixture is left stirring for 1 hour. The solid is separated by filtration, washed with a total of 10 cm of diisopropyl ether and dried under reduced pressure (13.5 Pa) at a temperature in the region of 35 ° C. 290 mg of N- [3α-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid are thus obtained in the form of a white solid, melting at around 220 ° C.

3α-acetoxylup-20 (29) -en-28-oyl chloride can be prepared as follows:

A solution of 267 mg of oxalyl chloride and 437 mg of 3α-acetylbetulinic acid in 14 cm of chloroform is kept under stirring at a temperature in the region of 20 ° C for 18 hours and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue is taken up in 20 cm of cyclohexane and the solvent is evaporated to dryness under reduced pressure under the same conditions. This operation is repeated 2 times. 453 mg of 3α-acetoxylup-20 (29) -en-28-oyl chloride are thus obtained.

3α-acetoxylup-20 (29) -en-28-oic acid can be obtained in the following manner:

A solution of 490 mg of anhydride (3α-acetoxylup-20 (29) -en-28 oic) acetic αans 49 cm ³ of 70% ethanol is heated for 1 hour 30 minutes at reflux in the presence of 4.9 cm d 4N ammonia. The suspension is cooled to around 20 ° C., the insoluble material is separated by filtration, washed with 20 cm ³ in total of absolute ethanol, and the combined filtrates are concentrated to dryness under reduced pressure (2.7 kPa) at a similar temperature. 30 ° C. 452 mg of 3a-acetoxylup-20 (29) -en-28-oic acid are obtained in the form of a cream solid.

Acetic (3α-acetoxylup-20 (29) -en-28-oic) anhydride can be prepared as follows:

A mixture of 445 mg of 3α-hydroxylup-20 (29) -en-28-oic acid (3α-betulmic acid), 1.14 g of sodium acetate and 4.5 cm of acetic anhydride is heated 1 hour 15 minutes at reflux. The solution is then cooled to around 20 ° C. and then 15 cm ³ of distilled water are added dropwise, and stirring is continued for

1 hour. The solid formed is separated by filtration and washed using a total of 25 cm ³ of distilled water. The residue is then dissolved in

50 cm ³ of ethyl ether, 10 cm ³ of distilled water are added, the organic phase is decanted, washed with 10 cm of distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2, 7 kPa) at a temperature in the region of 30 ° C. 0500 mg of anhydride (3α-acetoxylup-20 (29) -èn-28-oïque) acetic are thus obtained in the form of a white meringue.

3α-betulmιque acid is obtained according to W. HERZ, Phytochemistry, 11, 3061 (1972). Example 8

610 mg of methyl 11-aminoundecanoate hydrochloride are added, then 0.68 cm ³ of triethylamine to 20 cm ³ of a chloroform solution of 3-oxolup-20 (29) -en-28-oyl chloride (prepared from 1 g of 3-oxolup-20 (29) -en-28-oic acid). The solution is then stirred for 15 hours at a temperature in the region of 20ºC. After addition of 40 cm ³ of distilled water, the organic phase is decanted and the aqueous phase is extracted with 30 cm in total of chloroform. The combined organic phases are washed with a total of 30 cm ³ of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of

40 ° C. 1.5 g of a yellow meringue are obtained, which is chromatographed on a 3.5 cm diameter column containing 150 g of silica.

(0.02-0.045 mm) eluted with a mixture of methylene chloride and methanol 98-2 (by volume), collecting 20 cm ³ fractions.

After elimination of the first 45 fractions, the following 30 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. 1.1 g of methyl N- [3-oxolup- (29) -èn-28-oyl] -11-aminoundecanoate are thus obtained in the form of a white meringue [Rf = 0.5; thin layer chromatography on silica; eluent: dichloromethane-methanol 98-2 (by volume)]. 9 cm ³ of 4N sodium hydroxide are added to a solution of 600 mg of methyl N- [3-oxolup-20 (29) -èn-28-oyl] -11-aminoundecanoate in 9 cm ³ of methanol and 4.5 cm of tetrahydrofuran and the reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C. Diluted with 20 cm of distilled water and acidified with 12 cm of 4N hydrochloric acid. After 15 minutes of stirring, the suspension is added with 25 cm of ethyl acetate and the organic phase is separated. The aqueous phase is extracted with 30 cm in total of ethyl acetate, the combined organic phases are washed with 30 cm in total of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (13.5 Pa) at a temperature close to 30 ° C. 340 mg of N- [3-oxolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid are thus obtained in the form of a white powder melting at around 90 ° C. 3-oxolup-20 (29) -èn-28-oyl chloride can be prepared as follows: To a solution of 2 g of 3-oxolup-20 (29) -èn-28-oic acid in 44 cm ³ of chloroform, 0.76 cm of oxalyl chloride is added with stirring and the stirring is maintained at a temperature close to

20 ° C for 20 hours. The solvent is then evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The traces of oxalyl chloride are removed by suspending the residue in 10 cm ³ of cyclohexane and evaporating the solvent to dryness under reduced pressure (2.7 kPa) at a temperature close to

35 ° C. 2.2 g of 3-oxolup-20 (29) -en-28-oyl chloride are obtained in the form of a yellow meringue.

The 3-oxolup-20 (29) -en-28-oic acid is prepared according to R. KAWAGUCHI, K. W. KIM, J. Pharm. Soc. Jpn, 60, 595, 1940. Example 9

380 mg of methyl 11-aminoundecanoate hydrochloride and then 0.56 cm ³ of triethylamme are added to a solution of 800 mg of 30-acetoxy-3-oxolup-20 (29) en-28-oyl chloride in 40 cm dichloromethane. The solution is then stirred for 1 hour and 30 minutes at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained is chromatographed on a column 4 cm in diameter and containing 125 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 6-4 (by volume), collecting 25 cm fractions ³ . The first 9 fractions obtained are eliminated, the following 6 are concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. 960 mg of methyl N- [30-acetoxy-3-oxolup-20 (29) -èn-28-oyl] -11-methyl ammoundeca-noate are thus obtained in the form of a colorless lacquer. 1.6 cm ³ of 4N sodium hydroxide are added to a solution of 930 mg of methyl N- [30-acetoxy-3-oxolup-20 (29) -èn-28-oyl] -11-aminoundecanoate in

13 cm 3 of methanol and 6.5 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature close to 20ºC. Acidified with 1.3 cm ³ of 5N hydrochloric acid and diluted with 100 cm ³ of distilled water. After 1 hour of stirring, the solid is separated by filtration, washed with a total of 30 cm of distilled water. There is thus obtained 730 mg of N- [30-hydroxy-3-oxo lup- 20 (29) -èn-28-oyl] -11-aminoundecanoic acid melting at a temperature in the region of 100 ° C.

The 30-acetoxy chloride 3-oxolup-20 (29) -èn-28-oyl is prepared in the following manner:

To a solution of 770 mg of 30-acetoxy-3-oxolup-20 (29) -en-28- oic in 38.5 cm ³ of dichloromethane, 0.22 cm ³ of oxalyl chloride is added. After 15 hours of stirring at a temperature in the region of 20 ° C, the solvent is evaporated off under reduced pressure

(2.7 kPa) at a temperature in the region of 35 ° C. 800 mg of 30-acetoxy-3-oxolup-20 (29) -en-28-oyl chloride are obtained in the form of a white meringue which is used without further purification.

The 30-acetoxy-3-oxolup-20 (29) -en-28-oic acid is obtained in the following manner:

A solution of

1.6 g of chromic anhydride in 1.6 cm ³ of distilled water and 16 cm ³ of pyridine cooled to 0 ° C, in a solution of 2.34 g of acid

30-acetoxy-3β-hydroxylup-20 (29) -en-28-oic in 28 cm ³ of pyridine to

0 ° C. The reaction mixture is stirred for 1 hour at 0 ° C., then 12 hours at a temperature in the region of 20 ° C. and diluted with 250 cm ³ of distilled water. 100 cm ³ of ethyl acetate are added and the organic phase is decanted. The aqueous phase is extracted with 2 times 100 cm ³ of ethyl acetate, the organic phases are combined, washed with 200 cm total distilled water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The residue obtained (2.4 g) is chromatographed on a column 5 cm in diameter containing 200 g of silica (0.020-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 6-4 (by volume ) by collecting 80 cm ³ fractions. The first 9 fractions are eliminated, the following 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. 1.55 g of 30-acetoxy-3-oxolup-20 (29) -en-28-oic acid are thus obtained in the form of a white meringue.

30-acetoxy-3β-hydroxylup-20 (29) -en-28-oic acid can be prepared as follows:

A mixture of 4.44 g of 30-bromo-3β-hydroxylup-20 (29) -èn-28-oique acid, 2.08 g of silver acetate in 250 cm of toluene is heated for half an hour at reflux. The insoluble material is filtered hot and rinsed with a total of 75 cm of boiling toluene. The combined filtrates are then evaporated under reduced pressure (2.7 kPa). The residue (4.32 g) is chromatographed on a column 6 cm in diameter and containing 350 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 7-3 (in volumes) by collecting 100 cm fractions. The first 14 fractions obtained are eliminated, the next 11 are concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 45 ° C. 2.34 g of 30-acetoxy-3β-hydroxylup-20 (29) -en-28-oic acid are thus obtained in the form of a white meringue. [Rf = 0.26; thin layer chromatography on silica; eluent: cyclohexane-ethyl acetate 70-30 (by volume)]. The 30-bromo 3β-hydroxylup-20 (29) -en-28-oic acid is obtained in the following manner:

A solution of 4 g of 3β-hydroxylup-20 (29) -en-28-oic acid and 4.32 g of tetrabutylammonium tribromide in 80 cm of chloroform and 80 cm of tetrahydrofuran is stirred for 2 days at a temperature close to 25 ° C. The reaction mixture is washed successively

2 times with 50 cm ³ of distilled water, 2 times with 25 cm ³ of a 0.1N sodium thiosulfate solution and with 2 times 25 cm ³ of distilled water and then dried over anhydrous magnesium sulfate. The organic phase is evaporated under reduced pressure (2.7 kPa) and at a temperature in the region of 40 ° C. A yellow pasty solid (5.01 g) is obtained which is chromatographed on a column 6 cm in diameter, containing 350 g of silica (0.02-0.045 mm) and eluted with a mixture of methylene chloride and acetate of ethyl 90-10 (by volume), collecting 50 cm ³ fractions. The first 5 fractions obtained are eliminated, the following 70 are evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 4.44 g of 30-bromo 3β-hydroxy-lup-20 (29) -en-28-oic acid are thus obtained in the form of a white solid. [Rf = 0.3; thin layer chromatography on silica; eluent: methylene chloride-ethyl acetate 90-10 (by volume)].

Example 10

580 mg of methyl 11-aminoundecanoate hydrochloride are added, then 0.65 cm 3 of triethylamine to 20 cm ³ of a chloroform solution of 2,3-dioxolup-20 (29) -en-28-oyl chloride (prepared from 1 g of 2,3-dioxolup-20 (29) -en-28-oic acid). The solution is agitated

24 hours at a temperature close to 20 ° C. 40 cm of distilled water are added, stirring is continued for 15 minutes then the organic phase is decanted and the aqueous phase is extracted with 30 cm ³ in total of chloroform. The combined organic phases are washed with 30 cm ³ in total of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.4 g of a yellow meringue are obtained which is chromatographed a first time on a 2.7 cm diameter column containing 70 g of silica (0.02-0.045 mm), eluting with a mixture of cyclohexane and 80-20 ethyl acetate (by volume) and collecting 10 cm ³ fractions. After elimination of the first 33 fractions, the following 12 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C.

The 700 mg of pale yellow oil obtained are chromatographed again on a column 2.8 cm in diameter containing 70 g of silica (0.020-0.045 mm). Eluted with a mixture of methylene chloride and ethyl acetate 90-10 (by volume), collecting 15 cm ³ fractions. The first 14 fractions are eliminated; the following 7 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 470 mg of methyl N- (2,3-dioxolup-20 (29) -en-28-oyl) -11-aminodecanoate are obtained in the form of a yellow meringue [Rf = 0.37; thin layer chromatography on silica; eluent: chloroform-methanol 95-5 (volumes)]. 7 cm of 4N sodium hydroxide are added to a solution of 470 mg of methyl N- [2,3-dioxolup-20 (29) -èn-28-oyl] -11-ammoundecanoate in 7 cm ³ of methanol and 3.5 cm of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature in the region of 20 ° C. Diluted with 15 cm ³ of distilled water, acidified to a pH close to 3-4 using 9 cm ³ of 4N hydrochloric acid, stirring is continued for 15 minutes and 30 cm ³ of chloroform are added. After decanting the organic phase, the aqueous phase is extracted with 20 cm ³ in total of chloroform. The combined organic phases are washed with 20 cm ³ in total of distilled water, dried over anhydrous sodium sulfate and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The mineral salts are eliminated, taking up the residue with 20 cm ³ of ethyl acetate and 10 cm ³ of 1N hydrochloric acid. The aqueous phase is extracted with 20 cm in total of ethyl acetate. The combined organic phases are washed with 30 cm ³ in total of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 420 mg of a white meringue are thus obtained which is chromatographed on a 2.2 cm diameter column containing 40 g of silica (0.060 mm). Eluted with a mixture of chloroform and methanol 95-5 (by volume), collecting 5 cm ³ fractions. The first 16 fractions are eliminated; the following 6 are combined and concentrated under reduced pressure (12.5 Pa) at a temperature in the region of 35 ° C. 230 mg of N- [2,3-dioxolup-20 (29) -èn-28-oyl] -11-ammoundecanoic acid are obtained in the form of a white meringue, melting at around 90 ° C. (sticky).

2,3-dιoxolup-20 (29) -èn-28-oyl chloride can be prepared as follows:

To a solution of 1 g of 2,3-dexoxolup-20 (29) -en-28-oic acid in 21 cm 3 of chloroform, 0.72 cm3 of oxalyl chloride is added with stirring and the mixture is stirred at a temperature close to

20 ° C for 18 hours. The solvent is then evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue is suspended in 10 cm ³ of cyclohexane and the solvent is evaporated under reduced pressure (2.7 kPa) at a temperature close to 30 ° C. This operation is repeated 2 times. 940 mg of 2,3-dioxolup-20 (29) -en-28-oyl chloride is obtained in the form of a yellow meringue. [Rf = 0.62; thin-layer chromotography ; eluent cyclohexane-ethyl acetate 80-20 (by volume)]. 2,3-dioxolup-20 (29) -en-28-oic acid is prepared as follows:

3.48 g of potassium terbutylate are added to a solution of 5.27 g of 3-oxolup-20 (29) -en-28-oic acid in 248 cm of terbutanol and then a stream of oxygen is passed through for 23 hours at a temperature close to 25 ° C. 31 cm ³ of 1N hydrochloric acid are then added. After 15 minutes with stirring, the insoluble material is removed by filtration and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue is taken up in 50 cm 3 of cyclohexane and the solvent is evaporated .. a .. dry under the same conditions; this operation is repeated 3 times. The 7.7 g of meringue obtained are chromatographed on a 4.5 cm diameter column containing 385 g of silica (0.020-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 80-20 (in volumes), collecting 50 cm ³ fractions. The first 23 fractions are eliminated, the following 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 3.3 g of 2,3-dioxolup-20 (29) -en-28-oic acid are thus obtained in the form of a yellow meringue. [Rf = 0.2; thin layer chromatography on silica; eluent: cyclohexane-ethyl acetate 80-20 (in volumes)].

Example 11

280 mg of methyl 11-aminoundecanoate hydrochloride and 0.28 cm of triethylamme are added to 25 cm of a dichloromethane solution of 3β, 30-diacetoxylup-20 (29) -en-28-oyl chloride (prepared from 560 mg of 3β, 30-diacetoxylup-20 (29) -en-28-oic acid). The solution is then stirred for 12 hours at a temperature in the region of 20 ° C. 10 cm of distilled water are added. The organic phase is separated and then washed with 20 cm ³ in total of distilled water. The combined organic phases are dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The colorless oil obtained (750 mg) is chromatographed on a column 1.7 cm in diameter and containing 15 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80- 20 (by volume) by collecting fractions of 15 cm ³ . The first 2 fractions obtained are eliminated, the next 5 are concentrated to dryness under reduced pressure (22 kPa) at a temperature in the region of 40 ° C. 650 mg of N- [3β, 30-dιacétoxylup-20 (29) -èn-28-oyl] -11-methyl ammoundeca-noate are thus obtained in the form of a white lacquer [Rf = 0.28; thin layer chromatography on silica; eluent: cyclohexane ethyl acetate 80-20 (by volume)].

 3

10 cm of 4N sodium hydroxide are added to a solution of 650 mg of N- [3β, 30-dιacétoxylup-20 (29) -èn-28-oyl] -11-methyl aminoundécanoate 10 cm of methanol and 5 cm of tetrahydrofuran and the reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C. Acidification to a pH of this 1-2 is carried out using a 5N hydrochloric acid solution. After 1 hour of stirring, the solid is separated by filtration, washed with a total of 30 cm of distilled water. The solid obtained is dissolved in a mixture of dichloromethane and 90-10 ethanol (by volume). The insoluble material is filtered and the filtrates are concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. An oil is thus obtained which is stirred with 20 cm of ethyl ether. After 12 hours of stirring at a temperature in the region of 20 ° C., the solid formed is filtered and then rinsed with 10 cm ³ in total of ethyl ether and dried under reduced pressure (13.5 Pa). 400 mg of N- [3β, 30-dιhydroxylup-20 (29) -èn-28-oyl] - 11-ammoundecanoic acid are thus obtained, melting at a temperature in the region of 174 ° C.

The 3β, 30-acetoxylup-20 (29) -en-28-oyl chloride is prepared as follows:

0.22 cm ³ of oxalyl chloride is added to a solution of 560 mg of 3β, 30-dιacétoxylup-20 (29) -èn-28-oïque acid in 25 cm of dichloromethane. After 15 hours of stirring at a temperature close to

20 ° C, the solvent is evaporated under reduced pressure (22 kPa) and at a temperature close to 40 ° C. 600 mg of a white meringue is obtained which is used without further purification.

The 3β, 30-diacetoxylup-20 (29) -en-28-oic acid is obtained in the following manner: A suspension of 1.8 g of 3β-acetoxy-30-bromolup-20 (29) -enic acid -28- oic and 800 mg of silver acetate in 50 cm ³ of toluene is agitated

48 hours at a temperature close to 20 ° C then filtered. The solution obtained is then concentrated to dryness under reduced pressure (2 kPa).

The residue is dissolved in 50 cm of ethyl acetate. The organic phase is decanted and washed with a total of 60 cm ³ of distilled water, dried over anhydrous magnesium sulphate, then concentrated under reduced pressure (2.7 kPa) at an Vosine temperature of 40 ° C. The white solid obtained (1.7 g) is chromatographed on a column 1.7 cm in diameter and containing 35 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80 -20 (by volume), collecting 15 cm ³ fractions. The first 4 fractions obtained are eliminated, the following 10 are concentrated to dryness under reduced pressure (13.5 Pa) at a temperature in the region of 40ºC. 1.1 g of 3β, 30-diacetoxylup-20 (29) -en-28-oic acid are thus obtained in the form of a white meringue sufficiently pure for subsequent transformations.

The 3β-acetoxy-30-bromolup-20 (29) -en-28-oic acid is obtained in the following manner:

A solution of 2.5 g of 3β-acetoxy-lup-20 (29) -en-28-oic acid and 2.41 g of tetrabutylammonium tribromide in 50 cm ³ of chloroform is stirred for 5 days at a temperature close to 25 ° C. The reaction mixture is washed successively 2 times with 25 cm ³ of distilled water, 2 times with 25 cm ³ of a sodium thiosulfate solution

0.1N and with 2 times 25 cm ³ of distilled water and then dried over anhydrous magnesium sulfate. The organic phase is concentrated to dryness under reduced pressure (2.7 kPa) and at a temperature in the region of 40 ° C. A yellow pasty solid (4 g) is obtained which is chromatographed on a column 3.2 cm in diameter containing 100 g of silica (0.02-0.045 mm) and eluted with a mixture of cyclohexane and acetate of ethyl 85-15 (by volume), collecting 20 cm ³ fractions. The first 5 fractions obtained are eliminated, the following 10 are evaporated under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 2.7 g of 3β-acetoxy-30-bromolup-20 (29) -en-28-oic acid are thus obtained in the form of a white solid melting at a temperature in the region of 190 ° C.

3β-acetoxylup-20 (29) -en-28-oic acid can be prepared according to Bruckner, Kovacs and Koczka, J. Chem. Soc, 948 (1948).

Example 12 After having heated under reflux for 3 hours a mixture of 190 mg of 11-ammoundecanoic acid and 308 mg of chlorotrimethylsilane in 50 cm ³ of dichloromethane, the solution is cooled to around 20 ° C. and 750 mg of chloride of 30 are added. -acetoxy-3-oxolup-20 (29) -èn-28-oyle then 0.72 cm of triethylamme. Stirring is continued for 48 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue is chromatographed on a column 4 cm in diameter containing 125 g of silica (0.02-0.045 mm), eluted in the presence of the methylene chloride methanol 80-20 mixture (by volume), collecting 50 cm ³ fractions . The first 20 fractions are eliminated, the following 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 330 mg of N- [30-acetoxy-3-oxolup-20 (29) -èn-28-oyl] -11-ammoundecanoic acid are thus obtained in the form of a white meringue. To a solution of 330 mg of N- [30-acetoxy-3-oxolup-20 (29) -èn-28¬oyl] -11-ammoundecanoic acid in 13 cm ³ of methanol, 90 mg of sodium cyanoborohydride is added. then drop by drop, in about 5 minutes, 1.46 cm of a 15% aqueous solution of titanium chloride

III. The solution is kept stirring for 15 hours at a temperature in the region of 20 ° C. and 75 cm of distilled water are added,

50 cm ³ of ethyl acetate and 10 cm ³ of 1N hydrochloric acid. The organic phase is separated, the aqueous phase is extracted with 30 cm ³ in total of ethyl acetate, the organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated under pressure reduced (2.7 kPa) at a temperature close to 40 ° C. The residue obtained (370 mg) is chromatographed on a column 4 cm in diameter containing 125 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 60-40 (by volume) collecting 50 cm ³ fractions. The first 10 fractions are eliminated; the next 7 are combined and concentrated under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. The white solid obtained is dissolved in 0.5 cm ³ of ethanol and diluted with 22 cm ³ of distilled water. After 10 minutes of stirring, the solid is separated by filtration, washed with a total of 20 cm of distilled water and air dried. 260 mg of N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] - 11-methyl aminoundecanoate are obtained in the form of a white solid, melting at around 80 ° C.

Example 13 To a solution of 150 mg of 20,29,30-trinor 3β-acetoxy-19 - [(2-acetoxyethyl) carbamoyl] lupan-28-oic acid in 10 cm ³ of chloroform, a solution of 0 is added. , 03 cm ³ of oxalyl chloride in 5 cm ³ of chloroform. The reaction mixture is stirred for 12 hours at a temperature in the region of 20 ° C. and then concentrated under reduced pressure (15 kPa). The residue is taken up in 5 cm ³ of chloroform. To the solution obtained, 80 mg of methyl 11-aminoundecanoate hydrochloride are added and

0.09 cm of triethylamine. The solution is then stirred for 12 hours at a temperature in the region of 20 ° C. 10 cm of distilled water are added and then the reaction mixture is brought to a pH close to 2 using a 4N hydrochloric acid solution. The organic phase is separated and the aqueous phase is extracted 2 times 15 cm ³ of chloroform.

The combined organic phases are washed with 60 cm ³ in total of distilled water and then dried for 3 hours over anhydrous magnesium sulfate and filtered. The organic phase is concentrated to dryness under reduced pressure (10 kPa) at a temperature in the region of 40 ° C. The 200 mg of pale yellow meringue obtained are filtered through a column 2.7 cm in diameter, containing 50 g of silica (0.02-0.045 mm) eluted with a mixture of chloroform, methanol and ammonia at 28 % 24-6-1 (by volume). The filtrate is concentrated to dryness under reduced pressure (13.5 Pa). 120 mg of N- {20.29, 30-trinor 3β-acetoxy- are thus obtained. 19 - [(2-acetoxyethyl) carbamoyl] methyl lupan-28-oyl} -11-aminoundecanoate in the form of a white lacquer [Rf = 0.90 thin layer chromatography on silica; eluent: chloroform, methanol, 28% ammonia 24-6-1 (by volume)].

 3

5 cm of 4N sodium hydroxide are added to a solution of 200 mg of N¬

{20, 29, 30-trmor 3β-acetoxy-19 - [(2-acetoxyethyl) carbamoyl] lupan-28oyl} -11 -methyl amoundoundecanoate in 10 cm ³ of methanol and 5 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature close to 20 ° C. The reaction mixture is then acidified to a pH close to 2 using 4N hydrochloric acid and diluted with 50 cm of distilled water. After 2 hours with stirring at a temperature in the region of 20 ° C, the solid is separated by filtration, washed with 20 cm ³ in total of distilled water and then dissolved in 10 cm of ethanol. The solution obtained is filtered and then concentrated to dryness under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. The solid is taken up three times with 15 cm ³ of ethanol and the solution is concentrated to dryness under reduced pressure. The solid residue is suspended in 50 cm ³ of chloroform. The suspension is brought to a temperature in the region of 40 ° C. and filtered while hot. The filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The residue is triturated with 5 cm of diisopropyl ether, filtered and then rinsed with 6 cm of diisopropyl ether. The solid is dried under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. 90 mg of N- {20, 29, 30-trinor 3β-hydroxy-19 - [(2-hydroxyethyl) carbamoyl] lupan-28-oyl} -11-ammoundecanoic acid are thus obtained in the form of a white solid melting at a temperature close to 170 ° C.

The acid 20, 29, 30-trmor 3β-acetoxy-19- [2-acetoxyethyl) carbamoyl] lupan-28-oic can be obtained in the following way: With a solution of 450 mg of acid 20, 29, 30 -trmor 3β-acetoxy-19 - [(2-hydroxyethyl) carbamoyl] lupan-28-oic in 60 cm ³ of chloroform is added 30 mg of 4-dιméthylamιnopyrιdme, 0.35 cm ³ of triethylamme and

0.1 cm of acetic anhydride. The reaction mixture is stirred for 72 hours at a temperature in the region of 20 ° C. and then brought to a pH in the region of 1-2 using a 4N hydrochloric acid solution. The organic phase is decanted and then washed with a total of 30 cm of distilled water, dried for 1 hour over anhydrous magnesium sulfate and concentrated under reduced pressure (40.5 kPa) at a temperature in the region of 40 ° C. The solid residue is triturated with 5 cm ³ of oxide of

 3

 diisopropyl, filtered, rinsed with a total of 4 cm of diisopropyl ether and then dried under reduced pressure (100 Pa) at a temperature in the region of 40 ° C. 350 mg of acid are thus obtained.

20,29,30-trinor 3β-acetoxy-19 - [(2-acetoxyethyl) carbamoyl] lupan-28- oic in the form of a white solid melting at a temperature in the region of 190 ° C.

The 20,29,30-trinor 3β-acetoxy-19 - [(2-hydroxyethyl) carbamoyl] lupan-28-oic acid can be obtained in the following manner:

To a solution of 500 mg of 29.30-dinor 3β-acetoxylupan-20.28-dioic acid in 50 cm ³ of chloroform is added 0.11 cm ³ of oxalyl chloride. The mixture is stirred for 12 hours at a temperature in the region of 20 ° C, then it is concentrated under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The residual solid is dissolved in 15 cm ³ of chloroform and a solution of 0.18 cm ³ of ethanolamine in 5 cm ³ of chloroform is added over 10 minutes. After

3 days of stirring at a temperature in the region of 20 ° C, 20 cm ³ of distilled water are added and then the pH is brought to around 1-2 by means of a 4N hydrochloric acid solution. The organic phase is decanted, washed with a total of 80 cm of distilled water, dried over anhydrous magnesium sulfate, filtered and then evaporated under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The 600 mg of pale yellow meringue obtained are chromatographed on a column 1.8 cm in diameter, containing 20 g of silica (0.02-0.045 mm), eluted with a mixture of dichloromethane and methanol 95-5 (by volume ). The first 7 fractions are eliminated, the following 12 are concentrated to dryness under reduced pressure (13.5 Pa). 230 mg of 20,29,30-trinor 3β-acetoxy-19- [(2-hydroxyethyl) carbamoyl] lupan-28-oic acid are thus obtained in the form of a white meringue [Rf = 0.30 layer chromatography thin silica; eluent: dichloromethane methanol 95-5 (by volume)]. 29.30-dinor 3β-acetoxyiupan-20.28-dioic acid can be obtained according to the method described by JK GUIDER et al., J. Chem. Soc, 3024 (1953 ;.

Example 14

To a solution of 300 mg of 20, 29, 30-trmor 3β-acetoxy-19- (2acetoxy-1-methoxycarbonylethylcarbamoyl) lupan-28-oic acid in 20 cm ³ of chloroform, a solution of 0 is added in 1 minute. 0.05 cm ³ of oxalyl chloride in 5 cm ³ of chloroform. The reaction mixture is stirred for 12 hours at a temperature in the region of 20 ° C. and then concentrated under reduced pressure (25 kPa). The residue is taken up in 15 cm of chloroform. To the solution obtained, 140 mg of methyl 11-ammo-undecanoate hydrochloride and 0.15 cm ³ of triethylamme are added. The solution is then stirred for 12 hours at a temperature close to

20 ° C. 10 cm of distilled water are added, then the reaction mixture is brought to a pH close to 1 by means of a 4N hydrochloric acid solution. The organic phase is separated and the aqueous phase is extracted with 2 times 10 cm of chloroform. The combined organic phases are washed with a total of 30 cm of distilled water and then dried for 3 hours over magnesium sulfate and filtered. The organic phase is concentrated to dryness under reduced pressure (25 kPa) at a temperature in the region of 40 ° C. The 450 mg of pale yellow lacquer obtained are chromatographed on a column 1.7 cm in diameter, containing 20 g of silica (0.02-0.045 min. Eluted using a mixture of dichloromethane and methanol 97.5- 2.5 (by volume) 10 cm ³ fractions are collected, the first 10 fractions are eliminated, the next 15 are concentrated to dryness under reduced pressure (13.5 Pa). The 300 mg of solid obtained are chromatographed on a column 2.8 cm in diameter, containing 50 g of silica (0.02-0.045 mm), eluted using a mixture of chloroform, methanol and 28% ammonia 24-12-1 (in 10 cm ³ fractions are collected. The first 7 fractions are eliminated, the following 10 are concentrated to dryness under reduced pressure (13.5 Pa). This gives 200 mg of N- [20,29,30 -trιnor 3β-acetoxy-19- (2-acetoxy-1-methoxycarbonylethylcarbamoyl) methyl lupan-28-oyl] -11-methyl aminoundecanoate in the form of a white lacquer [Rf = 0.80 chromatog raffia on thin layer of silica; eluent: chloroform, methanol, 28% ammonia 24-6-1 (by volume)].

5 cm ³ of 4N sodium hydroxide are added to a solution of 200 mg of N- [20,29,30-trinor 3β-acetoxy-19- (2-acetoxy-1-methoxycarbonylethylcarbamoyl) lupan-28-oyl] -11-ammoundecanoate ) of methyl in 10 cm ³ of methanol and 5 cm of tetrahydrofuran and the reaction mixture is stirred for 15 hours at a temperature in the region of 20 ° C. The reaction mixture is then acidified to a pH close to 2 using 4N hydrochloric acid. Diluted with 50 cm ³ of distilled water. The mixture is stirred for 2 hours at a temperature in the region of 20 ° C. The solid is separated by filtration, washed with a total of 25 cm of distilled water and then air dried. The 160 mg of solid are chromatographed on a column 1.2 cm in diameter, containing 5 g of silica (0.02-0.045 mm) using a mixture of chloroform, methanol and 28% ammonia 12 -6-1 (by volume), collecting 10 cm ³ fractions. The first 9 fractions are eliminated, the following 13 are concentrated to dryness under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. The residue is triturated with 5 cm ³ of diethyl ether, filtered, rinsed with 6 cm ³ in total of diethyl ether and then dried under reduced pressure (10 kPa). The 80 mg of solid obtained is dissolved in 2 cm ³ of dioxane and then added

0.5 cm ³ of an aqueous solution of 4N hydrochloric acid and 15 cm ³ of distilled water. The solid is filtered, washed 4 times with 2 cm of distilled water and then dissolved in 10 cm of ethanol. The solution obtained is filtered and then evaporated under reduced pressure (8 kPa) at a temperature in the region of 35 ° C. The addition of ethanol and the evaporation is repeated 3 times. The residue is dissolved in a mixture of

30 cm ³ of chloroform and 3 cm ³ of tetrahydrofuran. The solution is filtered and then concentrated under reduced pressure (8 kPa) at a temperature in the region of 40 ° C. The residue is triturated with 5 cm of diisopropyl ether, filtered, rinsed 3 times with 2 cm of diisopropyl ether, then dried under reduced pressure (13.5 Pa). 50 mg of N- [20,29,30-trinor! 9- (1-carboxy-2-hydroxyethylcarbamoyI) -3β-hydroxylupan-28-oyl] -11-aminoundecanoic acid are thus obtained in the form of a solid white melting at a temperature close to 208 ° C. The 20,29,30-trmor 3β-acetoxy-1- (2-acetoxy-19-methoxycarbonylethylcarbamoyl) lupan-28-oic acid can be obtained in the following manner:

To a solution of 300 mg of acid 20, 29,30-trinor 3β-acetoxy-19- (2-hydroxy-1-methoxycarbonylethylcarbamoyl) lupan-28-oïque in 25 cm ³ of chloroform is added 30 mg of 4-dιméthylamιnopyrιdme and 0.35 cm of triethylamme and 0.21 cm of acetic anhydride. The reaction mixture is stirred for 12 hours at a temperature in the region of 20 ° C. 20 cm of distilled water are added and then brought to a pH in the region of 2-3 using a 4N hydrochloric acid solution. The organic phase is decanted and then washed with a total of 60 cm of distilled water, dried for 1 hour over anhydrous magnesium sulfate and concentrated under reduced pressure (15 kPa) at a temperature in the region of 40 ° C. To the colorless oil obtained, 2 cm ³ of dioxane and 20 cm ³ of water are added. It is triturated and cooled to a temperature close to 0 ° C. The solid is filtered, washed with 3 times 5 cm ³ of distilled water and then dried under reduced pressure (100 Pa) at a temperature in the region of 40 ° C. 300 mg of 20, 29, 30-trmor 3β-acetoxy-19- (2-acetoxy-1-methoxycarbonylethylcarbamoyl) lupan-28-oic acid are thus obtained in the form of a white solid melting at a temperature close to 180 ° C.

The 20, 29, 30-trιnor 3β-acetoxy-19- (2-hydroxy-1-methoxycarbonyl¬ethylcarbamoyl) lupan-28-oic acid can be obtained in the following manner:

To a solution of 1.8 g of 29.30-dιnor 3β-acetoxylupan-20.28-dioic acid in 150 cm ³ of chloroform is added 0.38 cm of oxalyl chloride. The mixture is stirred for 12 hours at a temperature in the region of 20 ° C, then concentrated under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The residual solid is dissolved in 40 cm of chloroform and a solution of 700 mg of methyl L-sermate hydrochloride and 1.5 cm ³ of triethylamme is added over 10 minutes. After 12 hours of stirring at a temperature in the region of 20 ° C., 50 cm ³ of distilled water are added and then the pH is brought to around 1-2 by means of a 4N hydrochloric acid solution. The organic phase is decanted, washed with 30 cm ³ of distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The 600 mg of pale yellow meringue obtained are chromatographed on a column 2.4 cm in diameter, containing 50 g of silica (0.02-0.045 mm), eluted using an ethyl acetate / dichloromethane 1- mixture. 1 (by volume). The first 14 fractions are eliminated, the following 9 are concentrated to dryness under reduced pressure (13.5 Pa). 800 mg of a solid are thus obtained which is triturated with 10 cm ³ of acetonitrile, filtered, washed with 2 times 2 cm of acetonitrile and dried under reduced pressure (13.5 Pa). 800 mg of 20,29,30-trinor acid are thus obtained

3β-acetoxy-19- (2-hydroxy-1-methoxycarbonyl-ethylcarbamoyl) lupan-28- oic in the form of a white meringue melting at a temperature in the region of 230 ° C.

Example 15 2.2 cm ³ of triethylamme and 1.94 g of methyl 11-amino undecanoate hydrochloride are added to 195 cm of a chloromethyl solution of 30-nor 3β-acetoxy-20-oxolupan-28-oyl chloride . The solution is then stirred for 72 hours at a temperature in the region of 20 ° C. The reaction mixture is diluted with 100 cm ^{3 of} dichloromethane, the organic phase is washed with 3 times 150 cm ³ of distilled water. The combined organic phases are dried for 3 hours over magnesium sulfate and filtered. The organic phases are concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The pale yellow oil obtained (5.7 g) is chromatographed on a column 4 cm in diameter, 60 cm high and containing silica (0.02-0.045 mm) eluted successively with a mixture of cyclohexane and ethyl acetate 70-30 (by volume) for fractions 1 to 50 and a mixture of cyclohexane and ethyl acetate 50-50 (by volume) for the following fractions. 100 cm ³ fractions are collected. The first 30 fractions are eliminated; the following 32 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. This gives 5 g of a white meringue which is crushed with 2 times

100 cm of diisopropyl ether and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. This gives 4.75 g methyl N- (30-nor 3β-acetoxy-20-oxolupan-28-oyl) -11-aminoundecanoate in the form of a white meringue [Rf = 0.23; thin layer chromatography on silica; eluent: cyclohexane ethyl acetate 8-2 (by volume)]. 10 cm of 5N sodium hydroxide are added to a solution of 700 mg of N- (30-nor

Methyl 3β-acetoxy-20-oxolupan-28-oyl) -11-aminoundecanoate in

15 cm ³ of methanol and 15 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 48 hours at a temperature in the region of

20 ° C. A mixture of 10 cm ³ of methanol and 10 cm ³ of tetrahydrofuran is successively added three times and at 24 hour intervals, leaving the reaction mixture to stir at a temperature in the region of 20 ° C. The reaction mixture is then acidified to a pH close to 2 using 4N hydrochloric acid. 150 cm of distilled water are added. After 2 hours with stirring at a temperature in the region of 20 ° C, the solid is separated by filtration, washed with a total of 180 cm of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C . 500 mg of a white solid are thus obtained. The aqueous phase is extracted with 200 cm ³ in total of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulphate and then evaporated under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. We thus obtain

150 mg of a pale yellow oil. The solid and the oil are combined and chromatographed on a column 2 cm in diameter, 40 cm high, containing silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 50 -50 (by volume), collecting 10 cm ³ fractions. The first 15 fractions are eliminated; the next 10 are combined and concentrated under reduced pressure

(2.7 kPa) at a temperature in the region of 35 ° C. 400 mg of a pale yellow oil are thus obtained. This oil is dissolved in 1.5 cm ³ of tetrahydrofuran. After 20 minutes with stirring at a temperature in the region of 20 ° C., 1.5 cm ³ and 10 cm ³ of diisopropyl ether are added at 20 minute intervals. The solid is separated by filtration and dried under reduced pressure (13.5 Pa) at a temperature close to

40 ° C. 200 mg of N- (30-nor 3β-acetoxy-20-oxolupane-28-oyl) -11-ammoundecanoic acid are thus obtained in the form of a white solid melting at around 150 ° C. The 30-nor 3β-acetoxy-20-oxolupan28-oyl chloride is obtained in the following manner:

1.5 cm 3 of oxalyl chloride is added over 5 minutes to 150 cm ³ of a solution in dichloromethane of 30-nor 3β-acetoxy-20-oxolupanoic acid. The solution is then stirred for 20 hours at a temperature in the region of 20 ° C. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The white meringue obtained is triturated with 2 times 200 cm of cyclohexane. The solid is filtered and dried under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 3.7 g of 30-nor 3β-acetoxy-20-oxolupan-28-oyl chloride are thus obtained in the form of a white meringue.

The 30-nor 3β-acetoxy-20-oxolupan-28-oic acid is prepared according to A. VYSTRCIL and M. BUDESINSY, Collect. Czech. Chem. Commun., 35, 295 (1970).

Example 16

370 mg of methyl 12-aminododecanoate hydrochloride are added, then 0.4 cm ³ of triethylamine to a solution of 660 mg of 3β-acetoxylup-20 (29) -en-28-oyl chloride in 13.2 cm ³ of chloroform and 13 cm ³ of tetrahydrofuran. The solution is stirred for 20 hours at a temperature in the region of 20 ° C and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 60 cm ³ of ethyl ether and 25 cm ³ of distilled water are added to the residue. The organic phase is decanted and the aqueous phase is extracted with 40 cm in total of ethyl ether. The combined organic phases are washed with a total of 60 cm of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure

(2.7 kPa) at a temperature close to 30 ° C. The 860 mg of cream-colored meringue obtained are chromatographed on a column 2 cm in diameter containing 52 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80-20 (in volumes) by collecting fractions of 7 cm ³ . The first 7 fractions are eliminated; the following 7 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. We thus obtain 650 mg of methyl N- [3β-acetoxylup-20 (29) -en-28-oyl] -12-ammododecanoate, in the form of a white meringue.

8.1 cm of 4N sodium hydroxide are added in approximately 5 minutes to a solution of 570 mg of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -12-methyl amnododecanoate in 9 cm ³ of methanol and 4.5 cm ³ of tetrahydrofuran. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. Diluted with 40 cm ³ of distilled water and acidified to a pH close to 1 using 9.5 cm ³ of 4N hydrochloric acid. After 15 hours of stirring at a temperature in the region of 20 ° C., 120 cm ³ of ethyl ether are added and the organic phase is decanted. The aqueous phase is again extracted with 50 cm ³ of ethyl ether, the combined organic phases are washed with 75 cm in total of distilled water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa ) at a temperature close to 30 ° C. The residue is suspended in 9 cm ³ of diisopropyl ether, the solid is separated by filtration, washed with a total of 4 cm of diisopropyl ether and dried under reduced pressure (13.5 Pa) at a temperature close to 30 ° C. 470 mg of N- [3β-hydroxylup-20 (29) -en-28-oyl] -12-ammododecanoic acid, melting at around 182 ° C., are thus obtained.

Methyl 12-ammododecanoate is prepared according to H. ZAHN, H.D. STOPER, Chem. Ber., .21 (10), 3251 (1965).

EXAMPLE 17 0.24 cm of triethylamme and 500 mg of methyl aminohexadecanoate hydrochloride are added to a solution of 820 mg of methyl chloride.

3β-acetoxylup-20 (29) -en-28-oyl in solution in a mixture composed of 20 cm ³ of chloroform and 20 cm ³ of tetrahydrofuran. After

20 hours of stirring at a temperature in the region of 20 ° C., 40 cm of distilled water are added and the organic phase is decanted. The aqueous phase is extracted with 75 cm in total of chloroform, the organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained is first chromatographed times on a column 4 cm in diameter containing 150 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80-20 (by volume) and collecting 10 cm fractions ³ . The first 80 fractions are eliminated; the following 23 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 568 mg of a beige meringue are thus obtained which is chromatographed a second time (column 4 cm in diameter; 15 g of silica (0.02-0.045 mm), fractions of 30 cm ³ ). The eluent system is composed of a mixture of methylene chloride and methanol 99-1 (by volume). The first 30 fractions are eliminated, the following 6 are combined and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The 363 mg obtained are chromatographed a third time on a column 1.7 cm in diameter, containing 20 g of silica (0.02-0.045 mm), eluting with a mixture of cyclohexane and ethyl acetate 80-20 in volumes). 3 cm ³ fractions are collected. The first 13 fractions are eliminated the following 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 380 mg of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] - 16-aminohexadecanoate are thus obtained in the form of a white meringue [Rf = 0.3; thin layer chromatography on silica; eluent: methylene chloride ethyl acetate 97-3 (by volume)].

A solution of 380 mg of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -16-amino methyl hexadecanoate in a mixture of 5 cm ³ of methanol, 2.5 cm of tetrahydrofuran and 0, 62 cm of 4N sodium hydroxide solution is stirred for 15 hours at a temperature in the region of 20 ° C. The solvent is then evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The white residue is suspended in 25 cm ³ of distilled water. 1 cm ³ of 5N hydrochloric acid is added and stirring is continued for 20 minutes. The solid is separated by filtration, washed with a total of 50 cm of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. The solid obtained is suspended in 20 cm of distilled water and filtered. 292 mg of acid are thus obtained which is purified by chromatography on a column 1.7 cm in diameter containing 20 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane, ethyl acetate, and methylene chloride 50-40-10 (by volume), collecting 2 cm fractions. The first 10 fractions are eliminated, the following 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 280 mg of N- [3β-hydroxylup-20 (29) -en-28-oyl] -16-ammohexadecanoic acid are thus obtained in the form of a white solid, melting at around 85 ° C.

Methyl 16-ammohexadecanoate can be prepared in the following manner: A solution of 1.3 g of methyl 16-phthalιmιdohexadecanoate in 50 cm ³ of methanol is stirred for 3 hours, at a temperature in the region of 80 ° C., in the presence 170 mg of hydrazme hydrate. The solution is cooled to around 20 ° C. and 2 cm of 5N hydrochloric ether are added. The solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is taken up in 50 cm of distilled water. The solid is separated by filtration. The filtrates are concentrated to dryness under reduced pressure at a temperature in the region of 35 ° C. 320 mg of a white solid are obtained. The solid separated by filtration is washed with a total of 25 cm of distilled water, suspended in 20 cm of distilled water and 1 cm ³ of 5N hydrochloric acid is added. After 15 minutes with stirring, the crystals are separated by filtration, washed with 20 cm of 1N hydrochloric acid and 20 cm ³ of distilled water. This batch (1.2 g) added to the 320 mg obtained after evaporation of the filtrates is chromatographed on a column 2 cm in diameter containing 30 g of silica (0.020¬

0.045 mm), eluted with a mixture of chloroform and methanol 90-10

(in volumes) by collecting 20 cm fractions. The first 3 fractions are eliminated, the following 6 are combined and evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is suspended in 20 cm of a saturated sodium bicarbonate solution, and stirred for 15 minutes. The solid is separated by filtration, washed with a total of 50 cm of distilled water and dried under reduced pressure (13.5 Pa) at a temperature close to

20 ° C. 500 mg oe 16-methyl ammohexadecanoate are thus obtained in the form of a white solid. Methyl 16-phthalimidohexadecanoate can be prepared as follows:

To a mixture of 1.36 g of methyl 16-hydroxyhexadecanoate, 847 mg of phthalimide, 1.49 g of triphenylphosphine, in 2.6 cm ³ of tetrahydrofuran, a solution of 0.89 cm ³ d is added dropwise. 'ethyl azidodicarboxylate in 2.6 cm of tetrahydrofuran.

Stirring is continued for 15 hours at a temperature in the region of 20 ° C and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The 5.4 g of residue obtained are chromatographed on a column 3 cm in diameter containing 100 g of silica (0.020-0.045 mm) eluted with methylene chloride. The first 18 fractions are eliminated, the following 36 are combined and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 1.5 g of methyl 16-phthalimidohexadecanoate are thus obtained in the form of a white solid.

Example 18

0.31 cm of triethylamine and 660 mg of methyl 17-aminoheptadecanoate hydrochloride are added to a solution of 1 g of 3β-acetoxylup-20 (29) -en-28-oyl chloride in a mixture of 20 cm ³ of chloroform and 20 cm of tetrahydrofuran. After 20 hours of stirring at a temperature in the region of 20 ° C., 40 cm ³ of distilled water are added. The organic phase is decanted and the aqueous phase is extracted with 100 cm in total of chloroform. The organic extracts are combined, dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue obtained is chromatographed for the first time on a column 4 cm in diameter containing 100 g of silica

(0.02-0.045 mm). The eluent mixture is composed of methylene chloride and ethyl acetate 95-5 (by volume), the fractions are 30 cm ³ . After elimination of the first 5 fractions, the following 19 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 "C. This gives 750 mg of a white meringue which is chromatographed a second time: column 2.2 cm in diameter, 40 g of silica (0.02-0.045 mm), eluting with a mixture of methylene chloride and ethyl acetate 98-2 by volume and collecting 10 cm ³ fractions. The first 16 fractions are eliminated, the following 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The 540 mg obtained are chromatographed a third time on a column 2 cm in diameter containing 40 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80-20 (by volume) collecting 5 cm ³ fractions. After elimination of the first 4 fractions, the following 10 are combined and concentrated to dryness under reduced pressure at a temperature in the region of 30 ° C (2.7 kPa). The 443 mg obtained are chromatographed a last time on a 1.4 cm diameter column containing 20 g of silica (0.020-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80-20 (by volume) , collecting 5 cm ³ fractions. After elimination of the first 2 fractions, the following 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. 210 mg of N- [3β-acetoxylup-20 (29) -en-28-oyl] -17-methyl ammoheptadecanoate are obtained in the form of a white meringue [Rf = 0.4; thin layer chromatography on silica; eluent: cyclohexane, ethyl acetate 80-20 (by volume)].

A solution of 210 mg of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -17-ammo methyl heptadecanoate in 2.7 cm ³ of methanol, 1.3 cm ^{3 of} tetrahydrofuran and 0 , 34 cm ³ of 4N sodium hydroxide solution is stirred for 15 hours at a temperature in the region of 20 ° C. The solvent is then removed under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C. The residue is dissolved in 12.5 cm of distilled water and 0.5 cm ³ of 5N hydrochloric acid is added. After 20 minutes of stirring, the solid is separated by filtration, washed with 50 cm ³ in total of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. 194 mg of acid are thus obtained which is chromatographed on a column of 1.7 cm in diameter containing 20 g of silica (0.020-0.045 mm), eluted with a mixture of cyclohexane, ethyl acetate and chloride of methylene 50-40-10 (by volume), collecting 5 cm ³ fractions. The first 10 fractions are eliminated, the following 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The solid obtained is suspended in 20 cm of distilled water and separated by filtration. 220 mg of N- [3β-hydroxylup-20 (29) -en-28-oyl] -17-aminoheptadecanoic acid are thus obtained in the form of a white solid, melting at around 82 ° C.

Methyl 17-aminoheptadecanoate is prepared in the following manner:

0.37 cm ³ of thionyl chloride is added to 23 cm ³ of methanol cooled to -20 ° C and 980 mg of 17-aminoheptadecanoic acid is added. The solution is stirred for 12 hours at a temperature close to

20 ° C and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.08 g of methyl 17-ammoheptadecanoate hydrochloride are thus obtained, in the form of a white solid. 17-aminoheptadecanoic acid can be prepared as follows:

A solution of 3.4 g of 17-phthalimidoheptadecanoic acid in 60 cm of methanol is stirred for 1 hour, at a temperature in the region of 80 ° C, in the presence of 1.67 g of hydrazine hydrate. The solution is cooled to around 20 ° C. and the solid is separated by filtration and dried in air. The residue (1.92 g) is taken up in 180 cm of distilled water. The solid is separated by filtration, washed with a total of 45 cm of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 980 mg of 17-aminoheptadecanoic acid is obtained in the form of a white solid.

17-phthalimidoheptadecanoic acid can be prepared as follows: To 2.14 g of phthalimide potassium in 40 cm ³ of N, N-dimethylformamide, 2 g of 17-bromoheptadecanoic acid is added and the mixture is heated for 6 hours. temperature in the region of 80 ° C. The solution is cooled to around 20 ° C., it is poured into 100 cm ³ of distilled water and 10 cm of 2N hydrochloric acid are added dropwise. The solid formed is separated by filtration. 5.13 g of a residue are obtained which is chromatographed on a column 4 cm in diameter containing 250 g of silica (0.020-0.045 mm) eluted with a mixture of methylene chloride and methanol 95-5 (by volume) . The first 4 fractions are eliminated, the following 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 3.39 g of 17-phthalimidoheptadecanoic acid are thus obtained in the form of a white solid.

EXAMPLE 19 To a solution of 0.54 g of 11 -amιno-2, 2-methylmethylundecanoate and 0.28 cm ³ of triethylamme in 50 cm ³ of dichloromethane, a solution of 1.1 g of 3β chloride is added. acetoxylup-20 (29) -èn¬

28-oyl (prepared from 1 g of 3β-acetoxylup-20 (29) -en-28-oyl acid) in 50 cm ³ of dichloromethane. The solution is stirred for 15 hours at a temperature in the region of 20 ° C. 100 cm ³ of dichloromethane are added. The organic phase is washed with 300 cm ³ in total of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of

40 ° C. The 2 g of oil obtained are chromatographed on a column 3 cm in diameter and 50 cm high in silica (0.02-0.045 mm) eluted with a mixture of dichloromethane and ethyl acetate 95-5 (in volumes), collecting 50 cm ³ fractions. The first 12 fractions are eliminated, the following 4 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 60 ° C. The yellow oil obtained is dissolved in 100 cm ³ of dichloromethane. The organic phase is washed with 150 cm total distilled water, dried over magnesium sulfate and then concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The 1.1 g of yellow oil obtained are chromatographed on a column 2 cm ³ in diameter and 40 cm ³ high containing silica (0.02-0.045 mm), eluted with dichloromethane, collecting fractions of 50 cm ³ . The first 25 fractions are eliminated. The following 21 are combined and concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 0.80 g of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -11-ammo-2,2-dιméthylundécanoate are obtained. methyl in the form of a white lacquer (Rf = 0.12; chromatography on a thin layer of silica; eluent dichloromethane).

19 cm of 4N sodium hydroxide are added in approximately 5 minutes to a solution of 1.4 g of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -11-amino-2,2-dimethyl ndecanoate methyl in 40 cm ³ of methanol and 40 cm ³ of tetrahydrofuran and the reaction mixture is stirred for 48 hours at a temperature in the region of 20 ° C. The reaction mixture is acidified to a pH close to 2 using 4N hydrochloric acid and then 200 cm ³ of distilled water are added. After 30 minutes of stirring, the aqueous phase is decanted, the solid is separated by filtration and rinsed with 90 cm in total of distilled water. The filtrate is taken up in 100 cm of ethyl acetate. The organic phase is dried for 2 hours over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The 1.4 g of white meringue obtained are chromatographed on a column 2.7 cm in diameter and 36 cm high containing silica (0.02-0.045 mm) eluted successively with dichloromethane (fractions 1 to 25), a mixture of dichloromethane and ethyl acetate 95-5 (by volume)

(fractions 26 to 80) and a mixture of dichloromethane and ethyl acetate 9: 1 (by volume) (fractions 81 to 120), collecting fractions of 50 cm ³ . The first 95 fractions are eliminated, the

20 following are combined and concentrated under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. 1 g of a white meringue is thus obtained which is triturated with 15 cm ³ of n-heptane, filtered, washed with 20 cm total of n-heptane and then dried under reduced pressure (13.5 Pa) at a temperature close to 40 ° C. 750 mg of N- [3β-hydroxylup-20 (29) -en-28-oyl] -11-amino-2,2-methyl undecanoic acid melting at a temperature in the region of

120 ° C. Methyl 11-amino-2,2-dimethylundecanoate is prepared in the following manner:

A solution of 15.4 g of methyl 11-phthalimido-2,2-dimethylundecanoate and 2.33 cm ³ of 98% hydrazine hydrate in 500 cm ³ of methanol is stirred for 12 hours at a temperature close to 20 ° C. We add 32 cm of 5N hydrochloric methanol. The solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue is taken up in 150 cm ³ of distilled water. After 20 minutes of stirring, the solid is separated by filtration, washed with 90 cm ³ in total of distilled water. The aqueous phase is brought to a pH close to

9-10 using a 10% sodium carbonate solution, extracted with a total of 500 cm ³ of diisopropyl ether, dried over magnesium sulphate and then concentrated under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The residue is taken up in a mixture of 15 cm ³ of methanol and 50 cm ³ of diethyl ether. 10 cm ³ of 5N hydrochloric methanol are added and then evaporated to dryness under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. The yellow oil obtained is taken up in 100 cm ³ of distilled water. 2 cm ³ of 4N hydrochloric acid are added and then brought to a pH in the region of 9-10 using a 10% sodium carbonate solution. Extraction is carried out with 450 cm ³ in total of ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure

(13.5 Pa) at a temperature in the region of 40 ° C. 6.8 g of methyl 11-amιno-2,2-dιméthylundécanoate are thus obtained in the form of a yellow viscous oil [Rf = 0.54; thin layer chromatography on silica; eluent: chloroform, methanol, 28% ammonia 24-6-1 (by volume)].

Methyl 11-phthalιmιdo-2,2-dιméthylundécanoate is obtained in the following way: At 8.2 g of phthalimide potassium in 70 cm of N, N-dιméthylformamide, 12.3 g of 11 -bromo-2 are added, 2-methylmethylundecanoate in solution in 70 cm of N, N-methylmethylformamide and the mixture is heated for 3 hours at a temperature in the region of 80 ° C. The solution is cooled to a temperature in the region of 20 ° C. and then poured into 1400 cm of distilled water. Acidified to a pH close to 2 using 4N hydrochloric acid and then extracted with 1000 cm ³ in total of ethyl acetate. The organic phase is washed with a total of 450 cm of distilled water, dried over magnesium sulfate, then concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 60 ° C. 15.4 g of 11-phthalιmιdo-2,2-dιméthylundécanoate are thus obtained. methyl in the form of a pale yellow viscous oil [Rf = 0.38; thin layer chromatography on silica - eluent: 8-2 cyclohexane ethyl acetate (by volume)].

Methyl 11-bromo-2,2-dimethylundecanoate was obtained in the following manner:

To a solution of 25 cm ³ of diisopropylamine in 90 cm ³ of tetrahydrofuran cooled to a temperature in the region of -78 ° C, 110 cm ³ of a 1.6 M solution of n-butylithium in hexane are added in 25 minutes . It is left for 1 hour at a temperature in the region of -78 ° C. 18.5 cm of methyl isobutyrate are added over 25 minutes. We shake

1 hour at a temperature close to -70 ° C before adding in

15 minutes a solution of 70.4 g of 1,9-dibromononane in 45 cm of tetrahydrofuran. The mixture is left to stir for 2 hours at a temperature in the region of -70 ° C. and then 12 hours at a temperature in the region of 20 ° C. Concentration is carried out under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 200 cm ³ of IN hydrochloric acid are added, then extraction is carried out with 250 cm of dichloromethane. The organic phase is washed successively with 160 cm ³ in total of 1N hydrochloric acid, 160 cm ³ in total of distilled water, 30 cm ³ of a saturated aqueous solution of sodium bicarbonate and finally 80 cm ³ in total of distilled water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The 74 g of an orange oil obtained are distilled under reduced pressure (20 Pa), collecting the fraction which distills between 120 and 130 ° C. 33.2 g of an oil are thus obtained which is redistilled under reduced pressure (10 Pa). The fraction which distills between 114 ° C and 122 ° C is collected. 25 g of 11-bromo-2,2-dimethylundecanoate demethyle are thus obtained.

EXAMPLE 20 A solution of 1 g of methyl N- [3-oxolup-20 (29) -èn-28-oyl] -11-aminoundecanoate, 440 mg of methyl aminoxyacetate hydrochloride is heated at reflux for 3 hours. in 20 cm of pyridine, then the solution is cooled to a temperature in the region of 20 ° C. and added with 100 cm ³ of distilled water and 50 cm ³ of acetate ethyl. The organic phase is decanted, the aqueous phase extracted with 100 cm in total of ethyl acetate, the organic extracts are combined, washed with 50 cm in total of distilled water, dried over anhydrous magnesium sulfate and evaporated under pressure reduced (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained is chromatographed on a column 5 cm in diameter containing 200 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 80-20 (by volume), collecting 30 cm fractions. The first 11 fractions are eliminated; the following 16 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 940 mg of an oil are thus obtained which is purified by HPLC in 2 steps, on a column 5 cm in diameter containing 300 g of silica grafted with C ₁₈ (0.015-0.025mm), eluted with a mixture of 'acetonitrile, water, tetrahydrofuran 50-30-15 then 65-20-15 (by volume). The first 18 fractions are eliminated, the next 2 are combined and concentrated to dryness under reduced pressure (13.5 Pa) at a temperature in the region of 35 ° C. 450 mg of N- [3- (methoxycarbonylmethoxyimino] lup-20 (29) -èn-28-oyl] -11-methyl aminoundecanoate are thus obtained in the form of a colorless lacquer [Rf = 0.4 ; ethyl acetate (75-25 by volume)].

A solution of 454 mg of N - [- (methoxycarbonylmethoxyimino) lup-20 (29) -èn-28-oyl] -11-methyl aminoundecanoate in 6 cm ³ of methanol, 3 cm of tetrahydrofuran and 0.77 cm of sodium hydroxide 4N is stirred for 15 hours at a temperature in the region of 20 ° C. and acidified with 1 cm of 5N hydrochloric acid. After 2 hours of stirring, the solid is separated by filtration, washed with a total of 30 cm of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 320 mg of N- [3- (carboxymethoxyimino) lup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid (mixture of Z and E isomers) are thus obtained in the form of a solid. white melting around 100 ° C.

Example 21

A solution of 1.35 g of methyl N- [3-oxolup-20 (29) -èn-28-oyl] -11-aminoundecanoate, 210 mg of 2- (4 hydrochloride) is heated at reflux for 1 hour. -methyl-1-piperazmyl) ethoxyamine in 25 cm of pyridine, then the solution is cooled to a temperature close to

20 ° C. 200 cm ³ of distilled water are added, then 11 cm ³ of IN soda

 3

and 100 cm of ethyl acetate. The organic phase is decanted, the aqueous phase is extracted with 200 cm ³ in total of ethyl acetate, the organic extracts are combined, washed with 60 cm in total of distilled water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure (13.5 kPa) at a temperature in the region of 35 ° C. The residue obtained (1.65 g) is chromatographed on a column 5 cm in diameter containing 200 g of silica (0.02-0.045 mm) eluted with a mixture of ethyl acetate and methanol 50-50 (in volumes), collecting 30 cm fractions. The first 17 fractions are eliminated; the following 18 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 1.34 g of methyl N- {3- [2- (4-methyl-1-piperazi-nyl) ethoxyimino] lup-20 (29) - en-28-oyl} -11-aminoundecanoate are thus obtained in the form a white meringue [Rf = 0.3; thin layer chromatography on silica; eluent: ethyl acetate methanol 50-50 (by volume)].

A solution of 1.34 g of methyl N- {3- [2- (4-methyl-1-piperazinyl) ethoxyimino] lup-20 (29) -èn-28-oyl} -11-aminoundecanoate in 20 cm ³ of methanol, 10 cm ³ of tetrahydrofuran and 1.05 cm ³ of 4N sodium hydroxide is stirred for 15 hours at a temperature in the region of 20 ° C and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 25 cm ³ of ethyl acetate are then added, the solid is separated by filtration and washed with 15 cm ³ in total of ethyl acetate. 760 mg of N- {3- [2- (4-methyl-1-piperazinyl) ethoxyimino] lup-20 (29) -èn-28-oyl} -11-aminoundecanoic acid (mixture of Z isomers) are thus obtained. and E), in the form of a beige solid, melting at around 97 ° C.

Example 22 A solution of 1 g of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -11-amino undecanoate in 50 cm ³ of ethanol is hydrogenated, under atmospheric pressure and at a temperature around 20 ° C, in the presence of 0.1 g of 5% palladium on carbon (by weight), for

4 hours. The catalyst is filtered, washed with a total of 30 cm of absolute ethanol and the filtrates are evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 810 mg of a colorless oil are obtained which is chromatographed on a column 4 cm in diameter containing 100 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane, methylene chloride and acetate. 80-10-10 ethyl (by volume), collecting 30 cm ³ fractions. After elimination of the first 17 fractions, the following 6 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 600 mg of a 50-50 mixture of N- [3β-acetoxylupan-28-oyl] -11-methyl-ethyl aminoundecanoate are obtained in the form of a colorless oil [Rf = 0.5; thin layer chromatography on silica; eluent: cyclohexane, ethyl acetate 80-20 (by volume)].

A solution of 600 mg of N- [3β-acetoxylupan-28-oyl] -11-ammo methyl undecanoate in 4.3 cm 3 of methanol and 8.5 cm3 of tetrahydrofuran is added with 1 cm of 4N sodium hydroxide, stirred while

15 hours at a temperature in the region of 20 ° C, acidified to a pH in the region of 3-4 using 0.9 cm of 4N hydrochloric acid and diluted with

25 cm of distilled water. After 15 hours with stirring, the solid is separated by filtration, washed with a total of 50 cm of distilled water and dried under atmospheric pressure at a temperature in the region of 20 ° C.

410 mg of N- [3β-hydroxylupan-28-oyl] -11-ammo undecanoic acid are thus obtained, melting at around 110-115 ° C.

Example 23

A solution of 1.4 g of N- (30-nor 3β-acetoxy-20-oxolupan-28-oyl) + methyl 11-ammoundecanoate, 100 mg of sodium borohydride and 700 mg of tetrabutylammonium chloride, in 120 cm toluene, is heated to a temperature close to reflux. After 9 hours, 100 mg of sodium borohydride and 700 mg of tetrabutylammonium chloride are added and the mixture is brought to a temperature close to reflux for 9 hours. After adding 100 mg of sodium borohydride and 700 mg of tetrabutylammonium chloride once more, the reaction mixture is heated for 24 hours at a temperature close to reflux. 1 c ^m3 of distilled water is added and the temperature. After 8 hours, 100 mg of sodium borohydride and 700 mg of tetrabutylammonium chloride are added successively 3 times at 8 hour intervals. The solution is then stirred for 48 hours at a temperature in the region of 20 ° C. 50 cm ³ of distilled water are then added over 1 hour. The organic phase is decanted, the aqueous phase is extracted with 80 cm ³ in total of ethyl acetate, the combined organic phases are washed with 90 cm ³ in total of distilled water, dried for 2 hours over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. The residue obtained is chromatographed on a column 3 cm in diameter containing 80 g of silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 6-4 (by volume), collecting fractions 50 cm ³ . The first 12 fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 800 mg of a solid are thus obtained which is dissolved in 20 cm ³ of diethyl ether. The ethereal solution is washed successively with 10 cm of a 2N hydrochloric acid solution and then with 4 times 10 cm ³ of distilled water. The organic phase is dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 500 mg of N- (30-nor 3β-acetoxy-20-hydroxylupan-28-oyl) -11-methyl aminoundecanoate are thus obtained in the form of a white meringue.

A solution of 500 mg of N- (30-nor 3β-acetoxy-20-hydroxylupan-28-oyl) -11-methyl aminoundecanoate in 10 cm ³ of methanol, 5 cm ³ of tetrahydrofuran and 5 cm of 4N soda for 12 hours at a temperature close to 20 ° C. The suspension is then acidified to a pH close to 1-2 using 4N hydrochloric acid and then diluted with 20 cm of distilled water. After 30 minutes of stirring, the solid is separated by filtration, washed successively by 5 times

10 cm ³ of distilled water and 3 times 5 cm ³ of diethyl ether and then dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 400 mg of a solid are thus obtained which is dissolved in 5 cm ³ of dioxane. To the solution obtained, 15 cm ³ of distilled water are added. The white solid obtained is filtered, washed with 2 times 3 cm ³ of a dioxane-distilled water 1-3 mixture (by volume) and then dried under pressure. reduced (13.5 Pa) at a temperature in the region of 40 ° C. 250 mg of N- (30-nor 3β, 20-dιhyαroxylupan-28-oyl) -11-ammoundecanoic acid are thus obtained, melting at around 170 ° C.

Example 24 To a solution of 2.6 g of sodium hydroxide in 18 cm ³ of distilled water, cooled to -5 ° C, 0.7 cm of bromine is added. The reaction mixture is stirred for 15 minutes at -5 ° C. and then 12 cm ³ of dioxane are added. The solution obtained is added in approximately 10 minutes to a solution of

2.3 g of methyl N- (30-nor 3β-acetoxy-20-oxolupan-28-oyl) -11-aminoundecanoate in 50 cm ³ of dioxane. The solution is stirred at a temperature in the region of 10 ° C for 15 hours, then a solution of 0.5 g of sodium sulfite in 5 cm of distilled water is added and the solution is acidified to a pH of 1 using hydrochloric acid 4N.

After 30 minutes, diluted with 50 cm of distilled water and the solid is separated by filtration, washed with a total of 50 cm of distilled water and air-dried at atmospheric pressure at a temperature in the region of 20 ° C. 2 g of a white solid are thus obtained which is dissolved in a mixture of 10 cm ³ of dioxane and 5 cm ³ of distilled water. The mixture is left for 48 hours at a temperature in the region of 20 ° C. The solid is filtered, rinsed successively with 2 cm of dioxane and twice 5 cm of diethyl ether and then dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 800 mg of N- (30-nor 3β-hydroxy-20-oxolupan-28-oyl) -11-ammoundecanoic acid are thus obtained, melting at around 160 ° C. Methyl N- [30-nor 3β-acetoxy-20-oxolupane-28-oyl] -11-aminoundecanoate can be prepared as follows: 2.2 cm ³ of triethylamme and 1.94 g of hydrochloride 11- methyl ammoundecanoate are added to 195 cm ³ of a solution in dichloromethane of 30 nor chloride 3β-acetoxy-20-oxolupan28-oyl. The solution is then stirred for 72 hours at a temperature in the region of 20 ° C. The reaction mixture is diluted with 100 cm of distilled water. The organic phase is extracted with 3 times 150 cm ³ of dichloromethane. The combined organic phases are dried

3 hours on magnesium sulfate, the desiccant is filtered, rinsed per 90 cm ³ in total of dichloromethane. The combined organic phases are concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The 5.7 g of pale yellow oil obtained are chromatographed on a column 4 cm in diameter, 60 cm high and containing silica (0.02-0.045 mm) eluted successively with a mixture of cyclohexane and acetate ethyl alcohol 70-30 (by volume) for fractions 1 to 50 and a mixture of cyclohexane and ethyl acetate 50-50 (by volume), for the following fractions.

100 cm ³ fractions are collected. The first 30 fractions are eliminated; the following 32 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. This gives 5 g of a white meringue which is crushed with 2 times

100 cm 3 of diisopropyl ether then dried under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. 4.75 g of N- (30-nor 3β-acetoxy-20-oxolupan-28-oyl] -11-methyl aminoundecanoate are thus obtained in the form of a white meringue [Rf = 0.23; thin layer chromatography silica; eluent: cyclohexane ethyl acetate 8-2 (volumes)].

The 30-nor 3β-acetoxy-20-oxolupan-28-oyl chloride is obtained in the following manner:

1.5 cm 3 of oxalyl chloride are added over 5 minutes to 150 cm ³ of a solution in dichloromethane of 30-nor 3β-acetoxy-20-oxolupan-28-oic acid. The solution is then stirred for 20 hours at a temperature in the region of 20 ° C. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The white meringue obtained is triturated with 2 times 200 cm ³ of cyclohexane then the solvent is evaporated to dryness under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. 3.7 g of 30-nor 3β-acetoxy-20-oxolupan-28-oyl chloride are thus obtained in the form of a white meringue.

The 30-nor 3β-acetoxy-20-oxolupan-28-oic acid is prepared according to A. VYSTRCIL and M. BUDESINSY, Collect. Czech. Chem. Commun., 35, 295 (1970).

Example 25 To a solution of 1 g of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -β-alanine in 100 cm of dichloromethane, 420 mg of methyl 8-amnooctanoate hydrochloride, 240 mg are added 1-hydroxybenzotriazole hydrate, 760 mg of 1-ethyl 3- (3-dimethylammopropyl) carbodiimide hydrochloride and 1 cm ³ of triethylamme. The solution is stirred for 12 hours at a temperature in the region of 20 ° C. and then 100 cm ³ of distilled water are added. The organic phase is decanted and the aqueous phase is extracted with 150 cm ³ in total of methylene chloride.

The organic extracts are combined, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained (1.4 g) is chromatographed on a column 4 cm in diameter containing 125 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 60-40 ( by volume), collecting 50 cm ³ fractions. The first 36 fractions are eliminated; the following 15 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 1.1 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -3-ammopropιonoyl] -8-methyl ammooctanoate are thus obtained in the form of a white meringue [Rf = 0.5; thin layer chromatography on silica; eluent: methylene chloride methanol 90-10 (by volume)].

A solution of 1.1 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -3-aminopropionoyl] -8-methyl ammooctanoate in 15 cm of methanol,

7.5 cm ³ of tetrahydrofuran and 1.9 cm ³ of 4N sodium hydroxide is stirred for 15 hours at a temperature in the region of 20 ° C. and then 20 cm ³ of

 3

methanol, 3 cm 5N hydrochloric acid and 50 cm ³ of distilled water.

After 30 minutes of stirring, the solid formed is separated by filtration, washed with a total of 50 cm of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 845 mg of N- [N- (3β-hydroxylup-20 (29) -èn-28-oyl) -3-ammopropionoyl] -8-ammooctanoic acid are thus obtained in the form of a white solid melting towards 115 ° C.

N- [3β-acetoxylup-20 (29) -èn-28-oyl] -3-ammopropιonιque acid can be prepared as follows: After having heated under reflux for 3 hours a mixture of 190 mg of 3-aminopropionic acid and 410 mg of chlorotrimethylsilane in 50 cm of dichloromethane, the solution is cooled to around 20 ° C. and 1 g of 3-acetoxylup chloride is added. 20 (29) -èn-28-oyl dissolved in 30 cm of dichloromethane then 0.81 cm of triethylamine dissolved in 15 cm 3 of dichloromethane. Stirring is continued for 15 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is chromatographed on a column 5 cm in diameter containing 250 g of silica (0.02-0.045 mm), eluted in the presence of the methylene chloride methanol 90-10 mixture (by volume), collecting 50 cm fractions . The first 9 fractions are eliminated, the following 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 1.04 g of N- (3β-acetoxylup- 20 (29) -en-28-oyl) -3-aminopropionic acid are thus obtained in the form of a white meringue [Rf = 0.3; thin layer chromatography on silica; eluent: methylenemethanol chloride 90-10 (by volume)].

Example. 26

410 mg of hydrochloride are added to a solution of 1 g of N- (3β-acetoxylup-20 (29) -en-28-oyl) glycine in 100 cm ³ of dichloromethane.

Methyl 8-aminooctanoate, 243 mg of 1-hydroxybenzotriazole hydrate, 690 mg of 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.5 cm of triethylamine. The solution is stirred for 12 hours at a temperature in the region of 20 ° C. and then 100 cm of distilled water are added. The organic phase is decanted and the aqueous phase is extracted with 150 cm in total of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained (1.26 g) is chromatographed on a column 5 cm in diameter containing 200 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 50-50 ( by volume) by collecting fractions of

50 cm ³ . The first 17 fractions are eliminated; the following 27 are combined and concentrated under reduced pressure (2.7 kPa) to a temperature close to 35 ° C. 1.2 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) glycyl] -8-methyl ammoocta-noate are thus obtained in the form of a white meringue [Rf = 0.2; thin layer chromatography on silica; eluent: cyclohexane ethyl acetate 50-50 (by volume)].

A solution of 1.2 g of methyl N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) glycyl] -8-ammooctanoate in 17 cm of methanol,

8.5 cm ³ of tetrahydrofuran and 2.1 cm ³ of 4N sodium hydroxide is stirred for 15 hours at a temperature in the region of 20 ° C. and then 20 cm ³ of methanol, 4 cm ³ of 5N hydrochloric acid and 50 cm ^{3 are added.} distilled water and

50 cm of ethyl acetate. The organic phase is decanted and the aqueous phase is extracted with 200 cm in total of ethyl acetate.

The organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is dissolved in 4 cm ³ of ethanol and 40 cm ³ of distilled water are added. After 30 minutes of stirring, the solid is separated by filtration, washed with 50 cm ³ in total of distilled water and dried under reduced pressure

(13.5 Pa) at a temperature in the region of 40 ° C. 883 mg of N- [N- (3β-hydroxylup-20 (29) -èn-28-oyl) -glycyl] -8-ammooctanoic acid are thus obtained in the form of a white solid, melting at about 130 °. vs.

N- (3β-acetoxylup-20 (29) -èn-28-oyl) glycine can be prepared as follows:

After having heated at reflux for 6 hours 30 minutes, a mixture of 830 mg of glycine and 2.28 g of chlorotrimethylsilane in 300 cm ³ of dichloromethane, the solution is cooled to around 20 ° C. and added

5.17 g of 3-acetoxylup-20 (29) -en-28-oyl chloride and then 3.54 cm of triethylamme. Stirring is continued for 48 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is chromatographed on a column 5 cm in diameter containing 250 g of silica (0.02-0.045 mm), eluted with a mixture of methylene chloride and methanol 90-10 (by volume), collecting 50 cm ³ fractions . The first 10 fractions are eliminated, the 15 following are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 "C. This gives 1.04 g of N- [3β-acetoxylup-20 (29) -en-28- oyl] glycine in the form of a white meringue [Rf≈ 0.3; chromatography on a thin layer of silica; eluent: methylene chloride methanol (90-10 by volume)].

Example 27

To a solution of 1.13 g of N- (3β-acetoxylup-20 (29) -en-28-oyl) - 8-aminooctanoic acid, in 100 cm ³ of dichloromethane, 250 mg of glycinate hydrochloride are added. methyl, 240 mg of 1-hydroxybenzotriazole hydrate, 690 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.5 cm of triethylamine. The solution is stirred for 12 hours at a temperature in the region of 20 ° C. and then 100 cm of distilled water are added. The organic phase is decanted and the aqueous phase is extracted with 150 cm ³ in total of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure

(2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained (1.3 g) is chromatographed on a column 4 cm in diameter containing

125 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 30-70 (by volume), collecting 50 cm ³ fractions. The first 15 fractions are eliminated; the following 17 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 1.2 g of methyl N- [3β-acetoxylup-20 (29) -èn-28-oyl] -8-aminooctanoylglycinate are thus obtained in the form of a white meringue [Rf = 0.3; thin layer chromatography on silica; eluent: cyclohexane ethyl acetate (50-50 by volume)].

A solution of 1.2 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -8-aminooctanoyl] methyl glycinate in 17 cm ³ of methanol, 8.5 cm ³ of tetrahydrofuran and 2.1 cm ³ of 4N sodium hydroxide solution is stirred for 15 hours at a temperature in the region of 20 ° C. and then 10 cm ³ of methanol, 2.5 cm ³ of 5N hydrochloric acid and 40 cm ³ of distilled water are added .

After 30 minutes of stirring, the solid is separated by filtration, washed with a total of 50 cm ³ of distilled water and air dried at a temperature close to 20 ° C. 1.03 g of N- [N- (3β-hydroxylup-20 (29) -èn-28-oyl) -8-ammooctanoyl] glycine acid is thus obtained in the form of a white solid, melting towards 132 ° C.

N- [3β-acetoxylup-20 (29) -en-28-oyl] -8-amιnooctanoic acid can be prepared in the following manner:

After heating at reflux for 3 hours, a mixture of 330 mg of 8-ammooctanoic acid and 410 mg of chlorotrimethylsilane in

3

50 cm of dichloromethane, the solution is cooled to around 20 ° C. and 1 g of 3β-acetoxylup-20 (29) -en-28-oyl chloride and then 0.81 cm of triethylamme are added. Stirring is continued for 15 hours at a temperature in the region of 20 ° C and the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is chromatographed on a column 5 cm in diameter containing 200 g of silica (0.02-0.045 mm), eluted in the presence of the cyclohexane-ethyl acetate mixture 60-40 (by volume), collecting fractions of 50 cm ³ . The first 18 fractions are eliminated, the following 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 1.1 g of N- [3β-acetoxylup-20 (29) -èn-28-oyl] -8-aminooctanoic acid are thus obtained in the form of a white meringue [Rf = 0.4; thin layer chromatography on silica; eluent: cyclohexane ethyl acetate 60-40 (by volume)].

Example 28

To a solution of 1.05 g of N- [3β-acetoxylup-20 (29) -en-28-oyl] 4-ammobutanoic acid in 60 cm of tetrahydrofuran, 0.4 g of methyl 4-ammophenylacetate is added then 0.31 g of 1-hydroxybenzotriazole. After 15 minutes of stirring at a temperature in the region of 20 ° C., 0.84 g of 1- (3-dimethylammopropyl) -3-ethylcarbodumide hydrochloride and then 1 cm of triethylamme are added. The solution is stirred 240 hours at a temperature in the region of 20 ° C. The reaction mixture is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. To the residual pasty solid, 100 cm of dichloromethane are added. The organic phase is washed with a total of 150 cm of distilled water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The cream solid obtained (1.4 g) is chromatographed on a column 2 cm in diameter and 40 cm high in silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 1- 1 (by volume), collecting fractions of 70 cm ³ . The first 8 fractions are eliminated, the next 2 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. We obtain

750 mg of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -4 aminobutanoyl] -4- methyl aminophenylacetate in the form of a viscous pale yellow oil [Rf = 0.69 ; thin layer chromatography on silica: eluent: cyclohexane / - ethyl acetate 1-1 (by volume)].

10 cm of 4N sodium hydroxide are added in approximately 5 minutes to a solution of 1.1 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -4 aminobutanoyl] -4- aminophenylacetate methyl in 20 cm ³ of methanol and 20 cm 3 of tetrahydrofuran and the reaction mixture is stirred for

72 hours at a temperature close to 20 ° C. The reaction mixture is acidified to a pH close to 2 using 5N hydrochloric acid and then 100 cm of distilled water are added. After 3 hours of stirring, the solid is separated by filtration and rinsed with 100 cm ³ in total of distilled water. The solid is triturated with 30 cm of diisopropyl ether, filtered, rinsed with 30 cm in total of diisopropyl ether, then dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 500 mg of N- [N- (3β-hydroxylup-20 (29) -èn-28-oyl) -4-aminobutanoyl] -4-aminophenylacetic acid are thus obtained, melting at a temperature in the region of 190 ° C (pasty) .

N- (3β-acetoxylup-20 (29) -en-28-oyl) -4-aminobutanoic acid can be obtained in the following manner:

After heating for 4 hours at reflux, a mixture of 0.7 g of 4arainobutyric acid and 1.68 cm ³ of chlorotrimethysilane in 180 cm ³ of chloroform, the solution is cooled to around 20 ° C. and a solution of 3.3 is added. g of 3-acetoxylup-20 (29) -en-28-oyl chloride in

90 cm ³ of chloroform, then 3 cm ³ of triethylamine. Stirring is continued for 30 hours at a temperature in the region of 20 ° C. The reaction mixture is washed with 450 cm total of distilled water. The organic phase is dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained (4.3 g) is chromatographed on a column 3 cm in diameter and 40 cm high containing silica (0.02-0.045 mm), eluted with a mixture of dichloromethane and methanol 95-5 ( by volume), collecting 50 cm ³ fractions. The

First 6 fractions are eliminated; the following 44 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 2.3 g of N- [3β-acetoxylup-20 (29) -en-28-oyl] 4-ammobutanoic acid are thus obtained in the form of a white meringue [Rf = 0.51; thin layer chromatography on silica; eluent: dichloromethane-methanol 9-1 (by volume)].

Methyl 4-ammophenylacetate can be obtained according to H. Salkowski Chem. Ber., 28, 1917, (1895). Example 29

To a solution of 1.05 g of N- (3β-acetoxylup-20 (29) -en-28-oyl) 4-aminobutanoic acid in 100 cm ³ of tetrahydrofuran, 0.4 g of 4-ammomethylbenzoate is added. methyl then 0.31 g of 1-hydroxybenzotriazole. After 15 minutes of stirring at a temperature in the region of 20 ° C., 0.84 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and then 1 cm ³ of triethylamme are added. The solution is stirred for 72 hours at a temperature in the region of 20 ° C. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. To the residual pasty solid, 100 cm ³ of dichloromethane are added. The organic phase is washed with a total of 150 cm of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The cream solid obtained (1.4 g) and chromatography on a column 2 cm in diameter and 40 cm high in silica (0.02-0.045 mm) eluted with a mixture of cyclohexane and ethyl acetate 1- 1 (by volume), collecting fractions of 70 cm ³ . The first 15 fractions are eliminated, the following 24 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.15 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -4- are obtained. methyl aminobutanoyl] -4-ammomethylbenzoate in the form of a white meringue [Rf = 0.15; thin layer chromatography on silica; eluent 1: 1 cyclo-hexane-ethyl acetate (by volume)].

15 cm ³ of 4N sodium hydroxide are added in approximately 5 minutes to a solution of 1.1 g of N- [N- (3β-acetoxylup-20 (29) -èn-28-oyl) -4-aminobutanoyl] -4- methyl amino methylbenzoate in 30 cm ³ of methanol and 30 cm ³ of tetrahydrofuran and the reaction mixture is stirred for

24 hours at a temperature close to 20 ° C. The reaction mixture is acidified to a pH close to 2 using 5N hydrochloric acid and then 150 cm of distilled water are added. After 3 hours of stirring, the solid is separated by filtration and rinsed with 150 cm ³ in total of distilled water. The solid is triturated with 30 cm of diisopropyl ether, filtered, rinsed with 75 cm ³ in total of diisopropyl ether, then dried under reduced pressure (13.5 Pa) at a temperature in the region of 40 ° C. 900 mg of N- [N- (3β-hydroxylup-20 (29) -èn-28-oyl] -4- aminobutanoyl] -4-aminomethylbenzoic acid, thus melting at a temperature in the region of 180-190 ° C, are obtained. pasty).

Methyl 4-aminomethylbenzoate can be obtained in the following manner: At 30 cm ³ of methanol cooled to a temperature close to -30 ° C., 3.3 cm ³ of thionyl chloride are added over 10 minutes. Stirring is continued for 30 minutes at a temperature in the region of -23 ° C., then 4.7 g of 4-aminomethylbenzoic acid are added. It is left to return to a temperature in the region of 20 ° C. in 1 hour. 15 cm of methanol are added to the mixture and the stirring is continued for 15 hours at a temperature in the region of 20 ° C. The solid is separated by filtration, rinsed with 90 cm ³ in total of methanol and then 150 cm ³ in total of diethyl ether. The solid is dried under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. 3.2 g of methyl 4-aminomethylbenzoate hydrochloride are thus obtained in the form of a white solid melting at a temperature in the region of 270 ° C.

Examples 30 to 49 By operating by analogy with Example 27, the following derivatives were prepared:

30)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -β-alanine, was prepared from N- [3β-acetoxylup-20 ( 29) -en-28-oyl] -8-aminooctanoic acid and methyl β-alaninate, mp = 138 ° C, (R = 51%).

31)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-aspartic acid was prepared from N- [3β-acetoxylup- acid 20 (29) -en-28-oyl] -8-aminooctanoic and dibenzyl L-aspartate, mp = 140 ° C, (R = 47%).

32)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-phenylglycine, was prepared from N- [3β-acetoxylup-20 ( 29) -en-28-oyl] -8-aminooctanoic acid and methyl L-phenylglycinate, mp = 135 ° C, (R = 45%).

33)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-alanine, was prepared from N- [3β-acetoxylup-20 ( 29) -en-28-oyl] -8-aminooctanoic and benzyl L-alanmate, mp = 120 ° C, (R = 34%).

34)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -D-serine, was prepared from N- [3β-acetoxylup-20 acid ( 29) -en-28-oyl] -8- aminooctanoic acid and methyl D-serumate, mp = 252 ° C, (R = 8%). 35)

Sodium N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-homoserinate, was prepared from N- [3β-acetoxylup- acid 20 (29) -en-28-oyl] -8-ammooctanoic and α-amino-γ-butyrolactone, mp = 130 ° C, (R = 45%).

36)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -D, L-isoserine was prepared from N- [3β-acetoxylup-20 acid (29) -en-28oyl] -8-ammooctanoic and of D, methyl L-isoserinate, mp = 140 ° C, (R = 56%).

37)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-lysine, was prepared from N- [3β-acetoxylup-20 acid ( 29) -en-28-oyl] -8- aminooctanoic acid and methyl N-trifluoroacetyl-L-lysinate, (R = 16%).

38)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-asparagine, was prepared from N- [3β-acetoxylup-20 ( 29) -en- 28-oyl] -8-aminooctanoic acid and p-nitrobenzyl L-asparaginate, mp = 120 ° C, (R = 34%).

39)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] sarcosine, was prepared from N- [3β-acetoxylup-20 (29) - acid en-28-oyl] -8-aminooctanoic acid and ethyl sarcosinate, mp = 120 ° C, (R = 85%).

40)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-proline, was prepared from N- [3β-acetoxylup-20 acid ( 29) -ên-28-oyl] -8-aminooctanoic and methyl L-prolinate, mp = 142 ° C, (R = 72%).

41)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-phenylalanine was prepared from N- [3β-acetoxylup-20 (29 ) -ên-28- oyl] -8-aminooctanoic and methyl L-phenylalaninate, mp = 116 ° C, (R = 58%).

42)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-valine, was prepared from N- [3β-acetoxylup-20 ( 29) -en-28-oyl] -8-aminooctanoic acid and methyl L-valinate, mp = 145 ° C, (R = 80%).

43)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -3-amino-2-hydroxy-3-phenylpropionic acid (2S, 3S), was prepared from methyl N- [3β-acetoxylup-20 (29) -en-28-oyl] -8-aminooctanoic acid and methyl 3-amino-2-hydroxy-3-phenylpropionate (2S, 3S), pF = 120 ° C, (R = 58%).

44)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -4-aminobutyryl] -6-aminohexanoic acid was prepared from N- [3β-acetoxylup-20 acid (29) -en-28-oyl] -4-aminobutyric acid and methyl 6-aminohexanoate, mp = 140 ° C, (R = 100%).

N- [3β-acetoxylup-20 (29) -en-28-oyl] -4-aminobutyric acid was prepared from 3β-acetoxylup-20 (29) -en-28-oyl chloride and 4-aminobutyric acid, [Rf = 0.43; thin layer chromatography on silica; eluent: methylene chloride, methanol 90-10 (by volume)].

45)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -5-aminopentanoyl] -5-aminopentanoic acid was prepared from N- [3β-acetoxylup-20 acid (29) -en-28-oyl] -5-aminopentanoic acid and methyl 5-aminopentanoate, mp = 132 ° C, (R = 85%).

N- [3β-acetoxylup-20 (29) -en-28-oyl] -5-aminopentanoic acid was prepared from 3β-acetoxylup-20 (29) -en-28-oyl chloride and 5-aminopentanoic acid, [Rf = 0.51; layer chromatography thin silica; eluent: methylene chloride, methanol 90-10 (by volume)].

46)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptanoyl] -3- aminopropionic acid was prepared from N- [3β-acetoxylup- 20 acid (29) -en-28-oyl] -7-aminoheptanoic acid and methyl 3-aminopropionate, mp = 194 ° C, (R = 36%).

N- [3β-acetoxylup-20 (29) -en-28-oyl] -7-aminoheptanoic acid was prepared from 3β-acetoxylup-20 (29) -en-28-oyl chloride and 7-aminoheptanoic acid, [Rf = 0.26; thin layer chromatography on silica; eluent: cyclohexane, ethyl acetate 60-40 (by volume)].

47)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -6-aminohexanoyl] -4- aminobutyric acid was prepared from N- [3β-acetoxylup- 20 acid (29) -en-28-oyl] -6-aminohexanoic acid and methyl 4-aminobutyrate, mp = 206 ° C, (R = 10%).

N- [3β-acetoxylup-20 (29) -èn-28-oyl] -6-aminohexanoic acid was prepared from 3β-acetoxylup-20 (29) -èn-28-oyl chloride and 6-aminohexanoic acid, [Rf = 0.2; thin layer chromatography on silica; eluent: cyclohexane, ethyl acetate 60-40 (by volume)].

48)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -3-aminopropionic acid was prepared from N- [3β-acetoxylup-20 acid (29) -en-28-oyl] -8-aminooctanoic and methyl 3-aminopropionate, mp = 138 ° C, (R = 51%).

49)

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -4-aminobutyric acid was prepared from N- [3β-acetoxylup- acid 20 (29) -èn-28-oyl] -8-amιnooctanoιque and methyl 4-ammobutyrate, mp = 168 ° C, (R = 23%).

Example 50

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-thréomne can be obtained as follows: to a solution of 1 g of N acid - [3β-acetoxylup-20 (29) -èn-28-oyl] -8-aminooctanoique, in 50 cm of dichloromethane, 470 mg of benzyl L-threonmate hemioxalate is added under a stream of argon,

240 mg of 1-hydroxybenzotriazole hydrate, 600 mg of 1- (3-dιméthylamιnopropyl) -3-ethylcarbodnmιde hydrochloride and 0.88 cm ³ of triethylamme. The solution is stirred for 12 hours at a temperature in the region of 20 ° C. and then 60 cm of distilled water are added. The organic phase is decanted, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. The residue obtained (1.36 g) is chromatographed on a column 4 cm in diameter containing 100 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 30-70 ( by volume) by collecting 40 cm fractions. The first 10 fractions are eliminated; the following 10 are combined and concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. 1.12 g of a white meringue are thus obtained which is dissolved in a mixture of 13.5 cm ³ of methanol, 6.7 cm ³ of tetrahydrofuran and 1.4 cm ³ of 5N sodium hydroxide.

After 15 hours with stirring at a temperature in the region of 20 ° C., 1.4 cm ³ of 5N hydrochloric acid and 15 cm ³ of distilled water are added. The methanol is removed under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. After 30 minutes of stirring, the solid obtained is separated by filtration, washed with 35 cm ³ in total of distilled water and air-dried at a temperature in the region of 20 ° C. 880 mg of N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-threum are thus obtained in the form of a white solid, melting towards 130 ° C.

Example 51 N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] -L-statin can be obtained as follows:

To a solution of 500 mg of N- [3β-acetoxylup-20 (29) -en-28-oyl] - 8-aminooctanoic acid, in 30 cm of dichloromethane, 211 mg of methyl L-statinate hydrochloride are added , 105 mg of 1-hydroxybenzotriazole hydrate, 298 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.38 cm ³ of triethylamine. The solution is stirred for 18 hours at a temperature in the region of 20 ° C. and then 50 cm of distilled water are added. The organic phase is decanted, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue obtained (570 mg) is dissolved in a mixture of 15 cm of methanol, 10 cm ³ of tetrahydrofuran and 10 cm ³ of 5N sodium hydroxide.

After 15 hours with stirring at a temperature in the region of 20 ° C., 5 cm ³ of methanol are added, then 10 cm ³ of 5N hydrochloric acid and

5 cm ³ of distilled water. The mixture is extracted with 60 cm ³ of diethyl ether. The organic phase is decanted and washed with a total of 30 cm ³ of distilled water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure (4.0 kPa) at a temperature

3 close to 40 ° C. The residue (520 mg) is suspended in 10 cm of diethyl ether. After 1 hour of stirring, the solid obtained is separated by filtration, washed with 5 cm ³ of diethyl ether and dried under reduced pressure (13.5 Pa) at a temperature in the region of 20 ° C. 340 mg of N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L-statin are thus obtained in the form of a white solid, melting towards

158 ° C.

Methyl L-statinate can be prepared according to the method described by Y. TAKEMOTO et al., Tetrahedron Lett., 31 (2), 217, 1990.

Example 52 By operating by analogy with Example 11.

N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -10-aminodecanoic acid was prepared from 3β, 30-diacetoxylup-20 (29) -èn-28- chloride oyl and methyl 10-ammodecanoate, mp = 130-140 ° C, (R = 14%). Example 53

By operating by analogy with Example 11 and Example 27, N '- [N- [3β, 30-dιhydroxylup-20 (29) -èn-28-oyl] -8-amιnooctanoyl] glycine is prepared, pF = 154 ° C, (R = 83%). Example 54

The N- [3β, 30-dιhydroxylup-20 (29) -èn-28-oyl] -1O-methyl ammodecanoate can be obtained in the following way:

A solution of 760 mg of N- [3β, 30-dιhydroxylup-20 (29) -èn-28-oyl] -10-ammodecanoic acid, 0.48 cm of methyl iodide, 0.45 cm of 1, 8-dιazabι-cyclo [5.4.0] undéc-7-ene in 6 cm of N, N-dimethylformamide is stirred for 4 hours at a temperature in the region of 20 ° C. After adding 60 cm of distilled water and 25 cm ³ of chloroform, the organic phase is decanted. The aqueous phase is extracted with a total of 25 cm of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The yellow oil obtained (1.34 g) is chromatographed on a column 3.2 cm in diameter containing 90 g of silica (0.02-0.04 mm) eluted with a mixture of dichloromethane and acetate. ethyl 50-50 (by volume), collecting 10 cm ³ fractions. After elimination of the first 52 fractions the following 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The 800 mg of meringue obtained are dissolved in 8 cm ³ of methanol and 8 cm ³ of distilled water are added dropwise. After 30 minutes of stirring, the crystals obtained are separated by filtration, washed with 10 cm ³ in total of distilled water and dried under reduced pressure (13.5 Pa) at a temperature close to

30 ° C. 800 mg of N- [3β, 30-dιhydroxylup-20 (29) -en- 28-oyl] -10-methyl ammodecanoate are thus obtained in the form of a white solid, melting at around 100 ° C.

Example 55 and 56 By operating by analogy with Example 54, the following products are prepared:

55)

The methyl N '- [N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] glycinate was prepared from N' - [N- [3β, 30-dihydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] glycine, mp = 115 ° C, (R = 77%).

56)

Methyl N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] glycinate was prepared from N' - [N- [3β-hydroxylup- 20 (29) -en-28-oyl] - 8-aminooctanoyl] glycine, mp = 100 ° C, (R = 90%).

Example 57

By operating by analogy with Example 19, the following product is prepared: N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -11-amino 2,2-dimethylundecanoic acid is prepared from methyl 11-amino-2,2-dimethylundecanoate and 3β, 30-diacetoxylup-20 (29) -en-28-oic acid. mp = 190 ° C.

Example 58

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoylacetic acid can be obtained in the following manner:

To a solution of 3.5 g of 3β-acetoxylup-20 (29) -en-28oyl chloride in 60 cm ³ of chloroform, 1.3 g of ethyl 7-aminoheptylcarbamoylacetate are added with stirring, then 1, 1 cm ³ of triethylamine. After 12 hours with stirring at a temperature in the region of 25 ° C, 50 cm ³ of distilled water are added, the organic phase is decanted and the aqueous phase is extracted with 25 cm ³ in total of chloroform. The organic extracts are combined, washed with a total of 40 cm ³ of distilled water, dried over anhydrous magnesium sulfate and the solvent is evaporated off under reduced pressure (2.7 kPa) at) a temperature close to 35 ° C. The beige meringue obtained (1.8 g) is chromatographed on a column 3 cm in diameter containing 90 g of silica (0.02-0.045 mm), eluted with a mixture of ethyl acetate and cyclohexane 75-25 (by volume), collecting 10 cm ³ fractions. The first 42 fractions are eliminated, the following 15 are combined and concentrated under reduced pressure

(2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained (830 mg) is dissolved in a mixture of 8 cm ³ of methanol,

4 cm 3 of tetrahydrofuran and 2.75 cm ³ of 4N sodium hydroxide. After 12 hours with stirring at a temperature in the region of 25 ° C, the solvent is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue is taken up in 40 cm ³ of distilled water and acidified with 3 cm ³ of 4N hydrochloric acid. The crystals obtained are separated by filtration, washed with 90 cm ³ in total of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 35 ° C. 670 mg of N- [3β-hydroxylup- 20 (29) -èn-28-oyl] -7-ammoheptylcarbamoylacétιque acid are thus obtained in the form of a white solid, melting at around 140 ° C.

Ethyl 7-ammoheptylcarbamoylacetate can be prepared as follows: 1.3 cm ³ of ethyl malonate chloride are added dropwise to a mixture of 3.4 g of mono N-benzyloxycarbonyl- 1,7-heptyldιamme,

1.68 cm ³ of triethylamme in 120 cm ³ of tetrahydrofuran and the solution is stirred for 48 hours at a temperature in the region of 25 ° C. After adding 400 cm ³ of distilled water and 200 cm ³ of chloroform, the organic phase is decanted and the aqueous phase is extracted with 400 cm total of chloroform. The organic extracts are combined, washed with a total of 400 cm of distilled water, dried over anhydrous sodium sulfate and evaporated under reduced pressure (12.7 kPa) at a temperature in the region of 35 ° C. The orange oil obtained (4.0 g) is chromatographed on a column 3.5 cm in diameter containing 200 g of silica (0.02-0.045 mm), eluted with ethyl acetate, collecting fractions of 15 cm ³ . The first 47 fractions are eliminated, the following 17 are combined and concentrated under reduced pressure (2.7 kPa) at a similar temperature 35 ° C. The yellow oil obtained (1.62 g) is dissolved in a mixture of 5 cm ³ of acetic acid and 5 cm ³ of hydrobromic acid at

30% (in solution in acetic acid) and is stirred for 15 minutes at a temperature in the region of 25 ° C. The solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. 1.23 g of ethyl 7-aminoheptylcarbamoylacetate are thus obtained in the form of a thick honey used as it is.

The mono N-benzyloxycarbonyl-1,7-heptyldiamine can be prepared as follows: To a solution of 10 g of N-benzyloxycarbonyl-8-aminocaprylic acid in 500 cm of methylene chloride, 2 g of chloride d ammonium, 5.2 g of 1-hydroxybenzotriazole hydrate, 13 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 9.6 cm ³ of triethylamine. The solution is stirred for 18 hours at a temperature in the region of 20 ° C., then 1 liter of distilled water and 12 cm ³ of 4N hydrochloric acid are added. The organic phase is decanted and the aqueous phase is extracted with 200 cm ³ in total of chloroform.

The organic extracts are combined, washed with a total of 200 cm of distilled water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The white powder obtained (7.1 g) is dissolved in a mixture of 92 cm ³ of acetonitrile and 30 cm ³ of distilled water and 3.6 g of bis (trifluoroacetoxy) iodobenzene are added.

After 24 hours with stirring at a temperature in the region of 20 ° C., 400 cm ³ of distilled water, 120 cm ³ of 4N ammonia and 100 cm ³ of chloroform are added. The organic phase is decanted, the aqueous phase is extracted with 200 cm ³ in total of chloroform. The organic extracts are combined, washed with 100 cm ³ of distilled water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. We thus obtain

3.47 g of mono N-benzyloxycarbonyl-1,7-heptyldiamine, in the form of an orange oil [Rf = 0.5; thin layer chromatography on silica; eluent: chloroform, methanol, 20% ammonia 12-3-0.5

(in volumes)]. N-Benzyloxycarbonyl-8-ammocaprylιque acid can be prepared according to: A. KAPOOR, LW GERENCSER, J. Pharmac. Sci., 1969, 53. (8), 976.

Example 59 The N- [3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oyl] -11-ammoundecanoic acid is prepared in the following manner:

By analogy with Example 7, methyl N- [3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -èn-28-oyl] -11-ammoundecanoate is prepared from 3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -en-28-oyl chloride. 3.1 cm of 4N sodium hydroxide are added to a solution of 250 mg of N- [3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -èn-28-oyl] -11- methyl ammoundecanoate in

20 cm ³ of tetrahyrofuran and 10 cm ³ of methanol. The reaction mixture is stirred for 12 hours at a temperature in the region of 20 ° C and then acidified to a pH in the region of 3 using 4N hydrochloric acid and then diluted with 200 cm of distilled water. After 2 hours of stirring, the solid is separated by filtration, washed with 90 cm ³ in total of distilled water and then dried under reduced pressure (10 kPa) at a temperature in the region of 40 ° C. 150 mg of N- [3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid are thus obtained in the form of a white solid melting at a temperature close to 170 ° C.

The chloride of 3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -en-28-oic acid is prepared in a similar manner to that described in Example 11: from 300 mg of '3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -en-28-oic acid, 350 mg of a colorless lacquer is thus obtained which is used without further purification.

3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -en-28-oic acid can be obtained as follows: A mixture of 400 mg of 3β-hydroxy-30- acid ( 2'-hydroxyethyl) thiolup- 20 (29) -èn-28-oïque, 930 mg of sodium acetate and 4.3 cm of anhydride

3 acetic acid is heated for 15 minutes at reflux. 4.3 cm of anhy- steep acetic, and heated to reflux for 15 minutes. It is cooled to a temperature in the region of 5 ° C. and 50 cm of distilled water are added dropwise over 3 hours. After 12 hours of stirring at a temperature in the region of 25 ° C, the solid formed is separated by filtration, washed with a total of 50 cm ³ of distilled water and dried under vacuum (20 kPa) at a temperature in the region of 25 ° C . The

500 mg of creamy white solid obtained are suspended in

30 cm ³ of ethanol. 3 cm ³ of ammonia (density 0.8) are added. The mixture is stirred for 12 hours at a temperature in the region of 25 ° C. The solvent is evaporated under reduced pressure (2.7 kPa). The residue is chromatographed on a column 2 cm in diameter, containing 200 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 7-3 (by volume), collecting fractions of 10 cm ³ . The first 18 fractions are eliminated, the following 7 are combined and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. 300 mg of 3β-acetoxy-30- (2'-acetoxyethyl) thiolup-20 (29) -en-28-oic acid are thus obtained in the form of a white solid [Rf = 0.49; thin layer chromatography on silica; eluent: cyclohexane, ethyl acetate 7-3 (by volume)]. 3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oic acid can be prepared as follows:

After having stirred for 3 hours at a temperature in the region of 25 ° C., a solution of 215 mg of 2-hydroxyethanethiol and 200 mg of ethyl¬

3

sodium late in 15 cm of ethanol, the mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. To the residual solid are successively added 20 cm ³ of tetrahydrofuran and 480 mg of 3β-hydroxy-30-bromolup-20 (29) -en- 28-oic acid. The suspension obtained is stirred for 48 hours at a temperature in the region of 25 ° C. and then 10 cm of distilled water are added. The mixture is acidified to a pH close to 2 using an aqueous solution of 2N hydrochloric acid and then diluted with 300 cm of distilled water. The white solid formed is separated by filtration, washed successively with 300 cm 3 in total of distilled water and 25 cm ³ of diethyl ether. The white solid obtained is dried under reduced pressure (20 kPa) at a temperature in the region of 35 ° C. 400 mg are thus obtained 3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oic acid in the form of a white solid melting at a temperature in the region of 220 ° C.

Examples 60 and 61 By following a procedure analogous to Example 59, the following derivatives were prepared:

60)

N- [3β-hydroxy-30-methylthiolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid from 3β-hydroxy-30-bromolup-20 (29) -èn- acid 28-oic and methanethiol, mp = 148 ° C.

61)

N- [3β-hydroxy-30- (2'acetylammoethyl) thiolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid from 3β-hydroxy-30-bromolup-20 acid ( 29) -en-28-oic and N-acetylaminoethanethiol, mp = 150 ° C. Example 62

N- [3β-hydroxy-30-diethylaminolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid is prepared in the following manner:

Methyl N- [3β-acetyl-30-diethylaminolup-20 (29) -èn-28-oyl] -11-aminoundecanoate is prepared in a similar manner to that described in Example 11 from 11-aminoundecanoate hydrochloride methyl and 3β-acetyl-30-diethylaminolup-20 (29) -en-28-oic acid.

2.4 cm of 1N sodium hydroxide are added to a solution of

450 mg of methyl N- [3β-acetyl-30-diethylaminolup-20 (29) -èn-28-oyl] -11-amino undecanoate in 10 cm ³ of methanol and 5 cm ³ of tetrahydrofuran. The reaction mixture is stirred for 12 hours at a temperature in the region of 20 ° C. and then acidified to a pH in the region of 4-5 using solid citric acid and then diluted with 100 cm of distilled water. The aqueous phase is extracted with 100 cm ³ in total of chloroform. The combined organic phases are washed with 75 cm ³ in total of distilled water, then dried over magnesium sulfate. We evaporate the solvent under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The residue (400 mg) is chromatographed on a column 2.8 cm in diameter, containing 40 g of silica (0.02-0.045 mm), eluted with a mixture of chloroform, methanol and ammonia 24-6- 1 (by volume), collecting 20 cm ³ fractions. The first 4 fractions are eliminated, the following 6 are combined and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. The residue obtained is taken up in 8 cm ³ of acetonitrile. The solid obtained is separated by filtration, washed with a total of 4 cm of acetonitrile and dried under reduced pressure

(2.7 kPa) at a temperature close to 40 ° C. 140 mg of N- [3β-hydroxy-30-diethylaminolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid are thus obtained in the form of a white solid, mp = 130 ° C.

3β-acetyl-30-diethylaminolup-20 (29) -en-28-oic acid can be prepared in the following manner:

A solution of 200 mg of 3β-acetyl-30-diethylaminolup-20 (29) -en-28- methyl oate and 800 mg of lithium iodide in 60 cm ³ of collidine is heated for 8 hours to a temperature close to reflux. . The solvent is evaporated off under reduced pressure (15 Pa) at a temperature in the region of 70 ° C. The residue is taken up in 50 cm of dichloromethane. The organic phase is washed with 100 cm ³ in total of distilled water. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to

35 ° C. 152 mg of 3β-acetyl-30-diethylaminolup20 (29) -en-28-oic acid are thus obtained, which is used without further purification.

Methyl 3β-acetyl-30-diethylaminolup-20 (29) -en-28-oate can be obtained in the following manner:

 3

To 30 cm of tetrahydroturan, 30 mg of palladium acetate, 140 mg of triphenylphosphine and 0.02 cm ³ of triethylamine are added. The mixture is allowed to stir for 30 minutes at a temperature close to

25 ° C. The yellow solid obtained is added to a solution of 770 mg of

Methyl 3β-acetyl-30-bromolup-20 (29) -èn-28-oate, 70 cm of tetrahydrofuran and 0.4 cm of diethylamine. The reaction medium is heated for 30 hours at a temperature close to reflux. After evaporation of the solvent under reduced pressure (2.7 kPa) at a temperature close to 40ºC, the residual solid is taken up in 50 cm ³ of dichloromethane. The organic phase is washed with 45 cm ³ in total of distilled water, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure (2.7 kPa) at a temperature close to

40 ° C. The residue is chromatographed on a 2.3 cm diameter column containing 60 g of silica (0.02-0.045 mm) eluted with a mixture of chloroform and methanol 9-1 (by volume), collecting 15 cm fractions . The first 8 fractions are eliminated, the following 50 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C. We thus obtain

400 mg of methyl 3β-acetyl-30-diethylaminolup-20 (29) -en-28-oate.

Methyl 3β-acetyl-30-bromolup-20 (29) -en-28-oate was synthesized according to B. Pradham, Indian J. Chem. 22B, 1983, 12-16. Examples 63 to 65

The following derivatives were prepared analogously to the method described in Example 62.

63)

N- [3β-hydroxy-30-pyrrolidinolup-20 (29) -èn-28-oyl] 11-aminoundecanoic acid is prepared from 3β-acetyl-30-bromolup-20 (29) -èn28-oate methyl and pyrrolidine, mp = 146 ° C.

64)

N- [3β-hydroxy-30- (2 '-hydroxyethyl) aminolup-20 (29) -èn-28-oyl] -1 1 -aminoundecanoic acid is prepared from 3β-acetyl-30-bromolup20 (29 ) -en-28-methyl and 2-acetyloxyethanamine, mp = 21 4 ° C.

65)

N- [3β-hydroxy-30- (4'-methylpiperazino) lup-20 (29) -èn-28-oyl] 11 -aminoundecanoic acid is prepared from 3β-acetyl-30-bromolupp¬20 (29 ) -en-28-methyl and N-methylpiperazine, mp = 160 ° C. Example 66 N- [30-acetoxy-3β-hydroxylup-20 (29) -èn-28-oyl) -11-aminoundecanoic acid;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -2-aminoisobutyric acid; N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -4-amino-3 (R, S) -hydroxybutyric acid;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] -4-amino-4-benzyl-3-hydroxybutyric acid (3S, 4S);

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] -4-amino-4-cyclohexylmethyl-3-hydroxybutyric acid (3R, 4S);

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] -5-hydroxy-2-piperidinecarboxylic acid (2S, 5R);

Propionic acid 3 - [[N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl]; 3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl] - 2 (R) -hydroxypropionic acid;

3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyll-7-aminoheptylcarbamoyl] - 2 (S) -hydroxypropionic acid;

3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl] - 2 (R, S) -hydroxypropionic acid;

3- [EN- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -3 (R) -hydroxypropionic acid;

3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl) - 3 (S) -hydroxypropionic acid; 3- [N- [3β-hydroxylup-20 (29) -èn-28-oyl} -7-aminoheptylcarbamoyl-3 (R, S) -hydroxypropionic acid;

3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl] -2 (R), 3 (R) -dihydroxypropionic acid; 3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-ammoheptylcarbamoyl] -2 (S), 3 (S) -dihydroxypropionic acid;

3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl] -2 (R), 3 (S) -dihydroxypropionic acid; 3 - [[N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl] -2 (S), 3 (R) -dihydroxypropionic acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -butyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -4 (R) -hydroxybutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -4 (S) -hydroxybutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -4 (R, S) hydroxybutyric acid; 4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -2 (R) -hydroxybutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -2 (S) -hydroxybutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -2 (R, S) -hydroxybutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -2 (R, S) -phenylbutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -3 (R, S) -phenylbutyric acid; 4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -4 (R, S) phenylbutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -3 (R, S) -methylbutyric acid; 4- [N- [3β-hydroxylup-20 (29) -ën-28-oyl] -7-aminoheptylcarbamoyl] - 3 (R, S) -hydroxybutyric acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 3,3-dimethylbutyric acid; 4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2,2-dimethylbutyric acid;

4- [N- {3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 4,4-dimethylbutyric acid;

4- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptylcarbamoyl] - 3-hydroxy-3-methylbutyric acid 3 (R, S);

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 3,4-dihydroxybutyric acid, 3 (R, S), 4 (R, S);

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2,3-dihydroxybutyric acid, 2 (R, S), 3 (R, S); 4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] 4-isobutyl-3-hydroxybutyric acid, 3 (R, S), 4 (R, S);

[N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] acetic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-amino-2 (R, S) -methylundecanoic acid;

N '- [N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L statin;

N '- [N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L serine; N '- [N- [3β, 30-dihydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L threonine;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptanoyl] -L statin; N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-amιnoheptanoyl] -L threonine;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -7-aminoheptanoyl] -L serine;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoyl] -glycine; N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoyl] -L statin;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoyl] -L threonine;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -11-aminoundecanoyl] -L serine; N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoyl] -D statin;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -D statin;

N '- [N- [3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -glycine; N '- [N- [3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L statin;

N '- [N- [3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L threonme;

N '- [N- [3β-hydroxy-30- (2'-hydroxyethyl) thiolup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -L serine;

N- [3β-hydroxy-30-methoxylup-20 (29) -èn-28-oyl] -11-aminoundéca¬noïque acid;

N- [30-t.butyloxy-3β-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid; N- [3β-hydroxy-30- (2 ', 3'-dihydroxypropyl) oxylup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid; N- [3β-hydroxy-30- (2'-hydroxyethyl) oxylup-20 (29) -èn-28-oyl] -11- aminoundecanoic acid; N- [3β-hydroxy-30- (2 ', 3'-dihydroxypropyl) thiolup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid; N- [3β-hydroxylup-20 (29) -èn-28-oyl] -3- (8-aminooctamido) phenylacetic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -4- (8-aminooctamido) phenylacetic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -2- (8-aminooctamido) phenylacetic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -3- (11-aminoundecanamido) phenylacetic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -4- (11-aminoundecanamido) phenylacetic acid; N- [3β-hydroxylup-20 (29) -èn-28-oyl] -2- (11-aminoundecanamido) phenylacetic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -3- (8-aminooctamido) methylbenzoic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -2- (8-aminooctamido) methyl¬benzoic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -4- (8-aminooctamido) methylbenzoic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -3- (11-aminoundecanamido) methylbenzoic acid; N- [3β-hydroxylup-20 (29) -èn-28-oyl] -2- (11-aminoundecanamido) methylbenzoic acid;

N- [3β-hydroxylup-20 (29) -èn-28-oyl] -4- (11-aminoundecanamido) methylbenzoic acid. N '- [N- (3β-hydroxylup-20 (29) -en-28-oyl) -8-aminooctanoyl] -2-aminoisobutyric acid;

N '- [N- (3β-hydroxylup-20 (29) -en-28-oyl) -8-aminooctanoyl] -5-hydroxy-2-piperidinecarboxylic acid (2-R, S); N '- [N- (3β-hydroxylup-20 (29) -en-28-oyl) -8-aminooctanoyl] -3-aminobenzoic acid;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] -2-aminobenzoic acid;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] -4-aminobenzoic acid;

N '- [N- (3β-hydroxylup-20 (29) -en-28-oyl) -8-aminooctanoyl] -3- (R, S) -amino-3-phenylpropionic acid;

N '- [N- (3β-hydroxylup-20 (29) -en-28-oyl) -8-aminooctanoyl] -3-aminoisobutyric acid (2-R, S); N '- [N- (3β-hydroxylup-20 (29) -en-28-oyl) -8-aminooctanoyl] -3-aminobutyric acid (3-R, S);

N '- [N- (3β-hydroxylup-20 (29) -èn-28-oyl) -8-aminooctanoyl] -N'-hydroxycarbonylethylpropionic acid;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -trans-4-hydroxy-L proline;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -9-aminononanoyl] glycine;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-aminooctanoyl] -nipecotic acid;

N '- [N- [3β-hydroxylup-20 (29) -en-28-oyl] -8-ammooctanoyl] -4-amino-6-methylheptanoic acid (4S);

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctanoyl] -4-amino-5-phenyl-3-hydroxypentanoic (3S, 4S); 2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamόyl] - 2 (R) -propionic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2 (S) -propionic acid; 2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2 (R, S) -propionic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2,2-dimethylacetic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2 (R) -benzylacetic acid;

2- [N- [3β-hydroxylup-20 (29) -ën-28-oyl] -7-aminoheptylcarbamoyl] - 2 (S) -benzylacetic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] - 2 (R, S) -benzylacetic acid; [N- [3β-hydroxy-30- (2'-hydroxyethyl) thio-lup-20 (29) -èn-28-oyl] - 7-aminoheptylcarbamoyl] acetic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -benzoic acid;

3- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -benzoic acid;

N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-aminoheptylcarbamoyl] -benzoic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctylcarbamoyl] - 2 (R) -propionic acid; 2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctylcarbamoyl] -2 (S) -propionic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-aminooctylcarbamoyl] -2,2-dimethylacetic acid; 2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] -2 (R) -benzylacetic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] -2 (S) -benzylacetic acid; 2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] -2 (R, S) -benzylacetic acid;

[N- [3β-hydroxy-30- (2'-hydroxyethyl) thιo-lup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] acetic acid;

2- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] -benzoic acid;

3- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] -benzoic acid;

4- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctylcarbamoyl] -benzoic acid. The present invention also relates to pharmaceutical compositions containing at least one product of general formula (I) optionally in the form of a salt, in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants, or with another agent for the treatment of AIDS, an antiviral, immunomodulatory or antimicrobial agent.

The composition according to the invention is capable of keeping cells infected with an HIV virus alive and therefore of reducing the progression to AIDS or of reducing its severity in subjects already infected by reducing the mortality of the infected cells. The compositions can be used orally, parenterally or rectally.

The compositions can be used for curative or preventive purposes in subjects having an immunodeficiency and / or infected with an HIV virus. Of course, the constitution of these components sitions will be adapted to the specific case of the digestive tract of the immunocompromised.

As solid compositions for oral administration, tablets, pills, capsules, powders or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.

These compositions can include substances other than diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

The compositions for parenteral administration can be sterile solutions or emulsions. As solvent or vehicle, propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, can be used.

These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers.

Sterilization can be done in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

In human therapy, the doctor will determine the dosage he considers most appropriate based on preventive or curative treatment, depending on the age, weight, degree of infection and other factors specific to the subject. treat. Generally, the doses are between 10 and 100 mg / kg intravenously for an adult.

The present invention also relates to combinations consisting of one or more lupane derivatives of general formula (I), and / or where appropriate their salts, and of another active principle known for its anti-retrovirus activity, optionally in the presence pharmaceutically acceptable excipients.

The anti-retrovirus agents which can be combined are chosen from agents which are compatible and inert with respect to the lupane derivative of general formula (I). Without limitation, these agents are chosen from reverse transcriptase inhibitors [zidovudme (AZT), didanosme (DDI), dideoxycytidme (DDC), TIBO, nevirapme, PMEA, HEPT ...], among protease inhibitors [ such as, for example, A 77003], or among these inhibitors of the tat protein [such as, for example, RO 24-7429].

The following example illustrates a composition according to the invention.

Example

Ampoules containing a solution containing 10 mg of N- [3β-hydroxylup-20 (29) -èn-28-oyl] -11-aminoundecanoic acid are prepared by adding 2% glycine and 0.1% cysteme to 500 cm of a 0.2% solution of N- [3β-hydroxylup-20 (29) en-28-oyl) -11 -aminoundecanoic acid in isotonic phosphate buffer. The solution is divided and aseptically distributed in ampoules. Each ampoule contains 10 mg of active product.

Claims

1 - New lupane derivative of general formula:

 in which :

R represents a radical of general formula:

 in which R 'and R ", which are identical or different, are hydrogen atoms or alkyl radicals,

X is a bond or represents a carbamoyl, N-methyl carbamoyl, ammocarbonyl or N-methylaminocarbonyl radical,

Y is a bond or represents a phenylene radical,

R ° and R °° identical or different are hydrogen atoms or alkyl radicals (it being understood that R ° and R °° are not necessarily identical on each unit -CR ° R °° -), or R ° is hydroxy, hydroxyalkyl, phenyl, benzyl, carbamoylmethyl or, when Y is a bond and X is carbamoyie, R ° can form a 5 or 6-membered ring with the nitrogen atom contained in X, this cycle being able moreover to include another heteroatom chosen from oxygen or sulfur and, n, m and p are whole numbers from 0 to 16 such that m + n + p is between 4 and 16, R ₁ is a methyl radical, or forms with R ₃ a methylene radical or an oxo radical,

R ₂ is a hydroxy, methyl, hydroxymethyl radical or a -CH ₂ OR ' ₂ , -CH ₂ SR'2 or -CH ₂ NHR' ₂ radical for which R ' ₂ is alkyl, hydroxyalkyl, dihydroxyalkyl, acetamidoalkyl, or acetyl, or R ₂ is an amino radical substituted by a hydroxyalkyl or carboxyhydroxyalkyl radical, or a dialkoylamino radical in which the alkyl parts can form, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocycle optionally containing another chosen heteroatom among oxygen, sulfur or nitrogen and optionally N-alkylated,

R ₃ is a hydrogen atom or forms with R ₁ or R ₂ a methylene radical or an oxo radical,

R ₄ and R ₅ are different and represent a hydrogen atom or a hydroxy radical, or together form an oxo, hydroxyimino or alkyloxyimino radical optionally substituted (by a carboxy or dialkoylamino radical in which the alkyl parts can form with the atom nitrogen to which they are attached, a 5 or 6-membered heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen or sulfur and optionally substituted by an alkyl radical) and

R ₆ and R ₇ are hydrogen atoms, or

R ₄ and R ₅ , and R ₆ and R ₇ together form oxo radicals, it being understood that the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms, as well as their salts when they exist.

2 - New lupane derivative according to claim 1 for which: R represents a radical of general formula: in which R 'and R ", which are identical or different, are hydrogen atoms or alkyl radicals,

X is a bond or represents a carbamoyl, N-methyl carbamoyl, aminocarbonyl radical, Y is a bond or represents a phenylene radical,

R ° and R °° identical or different are hydrogen atoms or alkyl radicals (it being understood that R ° and R °° are not necessarily identical on each unit -CR ° R °° -), or R ° is hydroxy, hydroxyalkyl, phenyle, benzyl, carbamoylmethyl or, when Y is a bond and X is carbamoyie, R ° can form a 5 or 6-membered ring with the nitrogen atom contained in X and, n, m and p are whole numbers from 0 to 16 such that m + n + p is between 4 and 16,

R ₁ is a methyl radical, or forms with R ₃ a methylene radical or an oxo radical,

R ₂ is a hydroxy, methyl, hydroxymethyl radical or a -CH ₂ SR ' ₂ , or -CH ₂ NHR' ₂ radical for which R ' ₂ is alkyl, hydroxyalkyl, acetamidoalkyl, or acetyl, or R ₂ is a substituted amino radical by a hydroxyalkyl or carboxyhydroxyalkyl radical, or a dialkoylamino radical, the alkyl parts of which can form, with the nitrogen atom to which it is attached, a 5 or 6-membered heterocycle optionally containing another nitrogen atom and optionally N-methylated,

R ₃ is a hydrogen atom or forms with R ₁ or R ₂ a methylene radical or an oxo radical,

R ₄ and R ₅ are different and represent a hydrogen atom or a hydroxy radical, or together form an oxo or alkyloxyimino radical optionally substituted (by a carboxy or dialkoylamino radical in which the alkyl parts can form with the nitrogen atom to which they are attached, a heterocycle of 5 or 6 links optionally containing another nitrogen atom optionally substituted by a methyl radical) and

R ₆ and R ₇ are hydrogen atoms, or

R ₄ and R ₅ , and R ₆ and R ₇ together form oxo radicals, it being understood that the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms, as well as their salts when they exist.

3 - A lupane derivative according to claim 1, characterized in that it is N '- [N- [3β-hdroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] - β-alanme.

4 - A lupane derivative according to claim 1, characterized in that it is N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] - L-alanme.

5 - A lupane derivative according to claim 1, characterized in that it is N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] - L-threonme.

6 - A lupane derivative according to claim 1, characterized in that it is N '- [N- [3β-hydroxylup-20 (29) -èn-28-oyl] -8-ammooctanoyl] - L-statme. 7 - A lupane derivative according to claim 1, characterized in that it is N- [3β-hydroxylup-20 (29) -èn-28-oyl] -7-ammoheptylcarbamoylacetic acid.

8 - Process for the preparation of a new lupane derivative according to claim 1, characterized in that an amino acid of general formula is made to act:

H ₂ N - R in which R is defined as in claim 1, and where appropriate, the acid function has been previously protected, on the chloride of the acid of general formula:

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are defined as in claim 1, it being understood that the hydroxy or acid functions represented or contained in these radicals are previously protected, then transforms if necessary into an ester, removes the protective radicals and optionally transforms the product obtained into a salt.

9 - Process for the preparation of a lupane derivative according to claim 1, for which R ₄ and R ₅ together form an optionally substituted hydroxyimino or alkyloxyimino radical as defined in claim 1, and the other radicals are defined as in claim 1 , characterized in that the hydroxylamine or one of its derivatives of general formula is made to act:

R ₈ -O-NH ₂ in which R ₆ is a hydrogen atom or an alkyl radical optionally substituted (by a carboxy or dialkoylamino radical, the alkyl parts of which can form, with the nitrogen atom to which they are attached, a heterocycle with 5 or 6 members optionally containing another heteroatom chosen from oxygen, nitrogen or sulfur and optionally substituted by an alkyl radical), on a lupane derivative according to claim 1 for which R ₄ and R ₅ together form a oxo radical, then if necessary, eliminates the radi protective waters and possibly transforms the product obtained into a salt.

10 - Process for the preparation of a lupane derivative according to claim 1, for which R ₁ and R ₂ are these methyl radicals, R ₃ is a hydrogen atom and the other radicals are defined as in claim 1, characterized in reducing a lupane derivative according to claim 1 for which R ₁ and R ₃ together form a methylene radical and R ₂ is a methyl radical, then if necessary, eliminates the protective radicals and optionally transforms the product obtained into a salt.

11 - Process for the preparation of a lupane derivative according to claim 1, for which R ₂ is a hydroxy radical, R ₁ is a methyl radical, R ₃ is a hydrogen atom and the other radicals are defined as in claim 1, characterized in that the reduction of a lupane derivative according to claim 1 is carried out, for which R ₂ and R _{3 together} form an oxo radical and R ₁ is a methyl radical, then if necessary, eliminates the protective radicals and optionally transforms the product obtained into a salt.

12 - Process for the preparation of a lupane derivative according to claim 1, for which R ₁ and R ₃ together form an oxo radical, R ₂ is a hydroxy radical and the other radicals are defined as in claim 1, characterized in that that a lupane derivative according to claim 1 is oxidized, for which R ₁ and R ₃ together form an oxo radical and R ₂ is a methyl radical, then, if appropriate, eliminates the protective radicals and optionally transforms the product obtained into a salt.

13 - Process for preparing a lupane derivative according to claim 1, for which X (in the radical R) represents a carbamoyie radical and the other radicals are defined as in claim 1, characterized in that one makes act a soul of general formula: in which R ', R °, R °°, m and p are defined as in claim 1, on a lupane derivative of general formula:

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are defined as in claim 1 and R ₆ represents a radical of general formula:

in which n and R "are defined as in claim 1, then eliminates protective radicals where appropriate and optionally transforms the product obtained into a salt. 14 - Pharmaceutical composition characterized in that it contains at least one product according to claim 1, in the pure state or in combination with any compatible and pharmaceutically acceptable diluent or adjuvant and / or in combination with another antiviral, immunomodulatory or antimicrobial active principle.