EP1846435A1 - Tetracyclic terpene series compounds, methods for preparing same, uses thereof as medicines and pharmaceutical compounds containing same - Google Patents

Abstract

The invention concerns a triterpene alkaloid of general formula (I). The invention also concerns a method for making same and use thereof as medicine.

Description

 TETRACYCLIC TRITERPENES SERIES COMPOUNDS, THEIR

METHODS OF PREPARATION, THEIR APPLICATIONS AS

DRUGS AND PHARMACEUTICAL COMPOUNDS

CONTAINING

The present invention relates to a triterpene alkaloid of the following general formula (I):

It also relates to its manufacturing process and its use as a drug.

In a century, life expectancy has increased by 25 years. This aging of the population has been accompanied by an increase in age-related diseases, the most prominent of which is Alzheimer's disease. This disease affects 22 million people worldwide and accounts for more than 75% of dementia in the elderly. It affects 5% to 12% of subjects over the age of 65 and 25% of the over 85s. It is the fourth leading cause of death in geriatrics. In France, there are 135,000 more cases per year and currently 800,000 people are affected.

Alzheimer's disease is characterized by behavioral and memory disorders. This disease mainly affects the elderly and is increasing in the industrialized countries because of the increase in life expectancy.

According to the cholinergic hypothesis, these memory disorders are associated with a loss of cholinergic functions in the brain following a very significant decrease in neuromediator acetylcholine. Currently the symptomatic treatment of the disease consists in increasing the level of neurotransmitter acetylcholine by inhibiting acetylcholinesterase (AChE), enzyme responsible for the degradation of acetylcholine. Of the four drugs marketed for the treatment of Alzheimer's disease, three are acetylcholinesterase inhibitors. These compounds are Aricept® (donepezil) (marketed by Eisai), Exelon® (rivastigmine) (marketed by Novartis), Réminyl® (galanthamine) (marketed by Janssen). In 2004, Ebixa (memantine), a gamma-aminobutyric acid (GABA) receptor antagonist protecting neurons against high and prolonged calcium influx, was marketed by Lundbeck Laboratories. Some marketed acetylcholinesterase inhibitors are difficult to prepare and have side effects. In addition, no inhibitor of butyrylcholinesterase (BChE) is currently marketed.

AChE, in addition to its catalytic functions, has unconventional properties. Studies have shown that the peripheral site of acetylcholinesterase was involved in the aggregation of the β-amyloid protein, a highly neurotoxic protein in the case of Alzheimer's disease. Indeed, if molecules are capable of interacting with the peripheral site of AChE, the aggregation of the β-amyloid protein is greatly reduced. The synthesis of inhibitors that can interact simultaneously with the active and peripheral AChE sites is therefore of interest.

On the other hand, very recent data have shown that butyrylcholinesterase also plays an important role in the case of Alzheimer's disease by promoting in particular the aggregation of the β-amyloid protein. The use of BChE inhibitors may prevent this phenomenon. Balearic boxwood is a plant rich in steroidal alkaloids of the tetracyclic triterpene type. During a systematic screening of the molecules of the chemistry of the Institute of Chemistry of Natural Substances (ICSN, Gif sur Yvette, France), researchers identified a potent inhibitor 1 of acetylcholinesterase. Compound 1 is derived from the chemical transformation of an alkaloid, N-3- isobutyrylcycloxobuxidine-F 2 isolated from Balearic boxwood (Buxus bakarica WiId) according to a new protocol (see examples 1 and 2).

compound (1) compound (2)

N-3-isobutyrylcycloxobuxidine-F 2 (D. Herlem-Gaulier et al., Bull S.c. Chim., 1966, 11, 3478-3486) has previously been extracted from the leaves of Buxus bakarica WiId in the 1960s either by successive chromatography on alumina deactivated with an elution gradient or by separation of the weak and strong bases of the crude alkaloids. In the latter case, tedious countercurrent separation was required to separate compound 2 from N-3-benzoylcycloxobuxidine-F 6b.

The general formula of N-3-isobutyrylcycloxobuxidine-F 2 as disclosed in D. Herlem-Gaulier et al (1966) comprises erroneous isomerism on carbon 4. The articles of J. Guilhem et al. (Tetrahedron Letters, 34, 2937-2938, 1975) and M. Sangare et al (Tetrahedron Letters, 22 and 23, 1791-1794, 1975) describe the general formula of compound 2 in which isomerism at carbon level 4 has been corrected.

On the other hand, a ¹³ C NMR (125 MHZ, CDCl ₃ ) (HMBC HMQC) study of compound 2 made it possible to correct the chemical shift of erroneous carbons 1, 4, 5, 7, 17, 19 and 20 in the publication from Sangare et al. In the context of the present invention, compound 2 has been isolated according to a new protocol making it possible to avoid the use of chromatographies (very laborious on large quantities) as well as the countercurrent process mentioned above. This process makes it possible to envisage interesting perspectives of scale-up in an industrial environment.

Moreover, the synthesis of compound 1 has been described by pyrolysis of 2 in the presence of tetramethylammonium hydroxide at 210 ° C. under 0.01 mmHg (D. Herlem-Gaulier et al, Bull Chemical Co. of France, 1968, 2, 763-773, see also the articles by J. Guilhem et al (1975) and M. Sangare et al (1975) for the correct isomerism at carbon level 4).

Finally, the inventors have surprisingly discovered a new, simpler method for synthesizing compound 1 from compound 2 using a single step. Other compounds exhibiting AChE inhibitory activity have been prepared in an original manner from the precursor alkaloid (2), which is very abundant in nature, isolated from the leaves of the Buis des Baléares.

Some of these compounds are already known as such but not in their therapeutic application.

Thus, the article by F. Khuong-Huu et al (Bull Soc Chim de France, 1, 258-262, 1969) describes the compounds of the following formulas:

Similarly, the article by D. Herlem-Gaulier et al (Bull Soc., Chim de France, 2,

763-773, 1968) describes the compounds of the following formulas:

These compounds as described in the articles by F. Khuong-Huu et al (1969) and Lem-Gaulier et al (1968) have erroneous isomerism at carbon 4; the articles of J. Guilhem et al. (1975) and M. Sangare et al (1975) describe good isomerism.

Benechie et al., Tetrahedron., 1976, 32: 701-707 describes in particular the following compounds 4b and 5b:

4b, and 5b

The inventors have thus discovered that the triterpene alkaloids according to the present invention act as potent inhibitors of acetylcholinesterase and butyrylcholinesterase, and can therefore be used in the treatment of Alzheimer's disease and other diseases of the central nervous system. as well as in the treatment of diseases of the peripheral nervous system. In addition, these alkaloids can be easily obtained on an industrial scale.

Thus, according to a first aspect, the invention relates to a triterpene alkaloid of general formula (I) below:

wherein one of the three dashed lines present in cycles a and b and only one represents a bond; R ₁ represents -CH ₂ X ₁ R ₇ , -CH = NR ₈ or -CH = O in which

X ₁ represents O, NH or S;

R ₇ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, an alkyl (in

C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ - bisftrialkyl (C ₁ -C ₁₀₎ alkylsilyl], or SO ₂ R _9, R ₉ C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkylphenyl, with the proviso that R ₇ does not represent SO ₂ R ₉ when X ₁ is S;

R ₈ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, an alkyl (in

C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ - bisftrialkyl (C ₁ -C ₁₀₎ alkylsilyl], or SO ₂ R _9, R ₉ representing a C ₁ -C ₁₀ alkyl or a (C ₁ -C ₁₀₎ phenyl; R ₂ and R ₃ represent independently of each other a hydrogen atom or

II ² ~ -C-R ₁₀

wherein X ₂ is O, NH or S and R ₁₀ is hydrogen, C ₁ -C ₁₀ alkyl, phenyl, C ₃ -C ₁₀ cycloalkyl, or C ₁ -C ₁₀ alkyl, C ₁₀ ) phenyl, with the proviso that at least one and only one of R ₂ or R ₃ represents a hydrogen atom, or R ₂ is absent, R ₁ represents -CH ₂ X ₁ R ₇ and -NR ₃ and -X ₁ R ₇ taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, or R ₂ represents an atom of hydrogen, R ₁ represents -CH ₂ X ₁ R ₇ and -NHR ₃ and -X ₁ R ₇ taken together represent

/ ^xr

~ HN - CH \ R 11 in which R ₁₁ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, a phenyl, a C ₃ -C ₁₀ cycloalkyl or a C ₁ -C ₁₀ alkyl phenyl, or R ₂ represents an atom of hydrogen, R ₁ represents - CH ₂ = NR ₈ and -NHR ₃ and taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, a phenyl, a C ₃ -C ₁₀ cycloalkyl or a C ₁ -C ₁₀ alkyl phenyl; R ₄ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl or a radical -X ₃ R ₁₂ in which X ₃ represents O, NH or S, advantageously O and R ₁₂ represents a hydrogen atom, an alkyl (C ₁ -C ₁₀ ) carbonyl, a (C ₁ -C ₁₀ ) alkyl phenyl, an alkyl

(C ₁ to C ₁₀ ) sulfonyl, a C ₁ to C ₁₀ alkylphenylsulphonyl or a C ₁ to C ₁₀ alkylsidyl (C ₁ to C ₁₀ ) silyl, advantageously an atom of hydrogen; R ₅ represents the group N-oxide N ⁺ R ₁₃ OCH ₃ or NCH ₃ R ₁₃ wherein R ₁₃ represents a hydrogen atom, a cycloalkyl C ₃ -C ₁₀ alkyl, C ₁ -C _10, phenyl or phthalimide, advantageously -CH ₃ and

- - [^

⁶ is = O, or -OR ₁₄ wherein R ₁₄ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ phenyl or (C ₁ -C ₁₀ ) alkylsulfonyl; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof, with the exception of compounds of the following formulas:

In the context of the present invention, the term "C ₁ -C ₁₀ alkyl" means any linear or branched monovalent saturated hydrocarbon radical having from one to ten carbon atoms inclusive. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.

The term "(C ₁ -C ₁₀ ) alkylphenyl" is understood to mean any radical R'R ", in which R 'is a C ₁ -C ₁₀ alkyl radical as defined herein, and R" is a phenyl radical. Examples of (C ₁ -C ₁₀ ) alkyl phenyl radicals include, but are not limited to, phenylethyl, 3-phenylpropyl and the like.

The term "C ₃ -C ₁₀ cycloalkyl" denotes any saturated monovalent carbocyclic radical consisting of one or more rings, preferably two rings, of three to ten carbon atoms per ring. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cycloheptyl and the like.

The term "(C ₁ -C ₁₀ ) alkylcarbonyl" in the present invention is understood to mean any radical RC (O) -, in which R is an alkyl radical as defined herein. Examples of (C ₁ -C ₁₀ ) alkylcarbonyl radicals include, but are not limited to, acetyl, propionyl, n-butyryl, sec-butyryl, t-butyryl, iso-propionyl, etc.

The term "C ₁ -C ₁₀ alkylsulfonyl" in the present invention is understood to mean any radical -S (O) ₂ -R, in which R is an alkyl group as defined herein. The examples alkylsulfonyl compounds include, but are not limited to, methylsulfonyl, propylsulfonyl and the like.

In the present invention, is meant by "isomers" compounds that have identical molecular formulas but differ in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereoisomers", and stereoisomers that are non-superimposable mirror images are referred to as "enantiomers", or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is called a "chiral center".

"Chiral isomer" means a compound with a chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is referred to as a "racemic mixture".

In the present invention, the term "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical. The term "pharmaceutically acceptable salts" of a compound is intended to mean salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include:

(1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, acid methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like; or

(2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; either coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid and phosphoric acid.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.

Advantageously, the general formula (T) is such that the hydrogen atoms are positioned in the following manner:

According to a particular embodiment, the triterpene alkaloid according to the invention is such that R ₁ represents -CH ₂ X ₁ R ₇

Preferably, the triterpene alkaloid according to the invention is such that X ₁ represents O. According to a preferred embodiment, the triterpene alkaloid according to the invention is represented by the following general formula (H):

wherein one of the two dashed lines present in cycles a and b and only one represents a bond;

______ "R

R ₄ , R ₅ , R ₁₁ and ⁶ are as defined above and X ₁ is as defined above or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof.

Advantageously, the general formula (H) is such that the hydrogen atoms are positioned in the following manner:

More preferably, the triterpene alkaloid according to the invention is such that

- R represents = O.

According to another preferred embodiment, the triterpene alkaloid according to the invention is represented by the following general formula QIT): wherein one of the two dashed lines present in cycles a and b and only one represents a bond; R ₄ , R ₅ and R ₁₁ are as defined above, X ₁ is as defined

- - _[ ^ above, and ⁶ is as defined above; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof.

Advantageously, the general formula (III) is such that the hydrogen atoms are positioned in the following manner:

According to another embodiment, the triterpene alkaloid is represented by the following general formula (VIII):

wherein one of the three dashed lines present in cycles a and b and only one represents a bond; R ₄ , R ₅ and R ₁₁ are as defined above, and

- 1_ ^

⁶ is as defined above; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof.

According to yet another preferred embodiment, the triterpene alkaloid according to the invention is represented by the following general formula (TV):

wherein one of the two dashed lines present in rings a and b and only one is a bond, R ₄ , R ₅ , R ₇ , X ₂ and R ₁₀ are as defined above, X ₁ is as defined above, and ⁶ is as defined above; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof. Advantageously, the general formula (III) is such that the hydrogen atoms are positioned in the following manner:

More preferably, the triterpene alkaloid according to the invention is such that X ₂ represents O.

Even more preferably, the triterpene alkaloid according to the invention is such that R ₁₀ or R ₁₁ represent, independently of one another, a C ₁ to C ₁₀ alkyl, advantageously branched.

Most preferably, the triterpene alkaloid according to the invention is chosen from one of the compounds of the following formulas:

6h 7th

7h 8a

8c 8d

8th 8f

8h 8i, and

32 33

38, 39

40, 51

52, 63

64, 68

70, 71

According to a second aspect, the subject of the invention is a process for producing the compound of general formula (IVb) below:

- R ^~ wherein R _4, R _5, R _7, R _10, X ₁ and ⁶ are as defined above and X ₂ is

O by reaction, the following compound of formula (Vb):

^"R wherein R _4, R _5, R _7, X ₁ and ⁶ are as defined above with the anhydride of formula R ₁₀ (CO) ₂ O wherein R ₁₀ is as defined above, advantageously in methanol.

Advantageously, the general formula (TVb) is such that the hydrogen atoms are positioned in the following manner:

Advantageously, the general formula (Vb) is such that the hydrogen atoms are positioned in the following manner:

According to one particular embodiment, the compound of formula (Vb) is obtained by acid hydrolysis, advantageously in MeOH with H ₂ SO ₄ , of the compound of formula (VI) below

^"R wherein R _4, R _5, R _7, X ₁ and ⁶ are as defined above. According to a particular embodiment, the process for producing the compound of general formula (TVb) according to the invention is such that the compound of general formula (VT) has the following formula (2)

Advantageously, the general formula (VT) is such that the hydrogen atoms are positioned in the following manner: ", 3

According to a third aspect, the subject of the invention is a process for producing the compound of formula (2) comprising the following successive stages: a) alkalinization of the crushed and dried leaves of Buxus bakarica WiId, b) extraction and maceration in a CH mixture ₂ Cl ₂ / EtOH to obtain a solid extract, c) extraction in dichloromethane at a pH of between 5.8 and 6 to obtain a crude extract of the compound of formula (2), d) purification of the compound of formula (2) , advantageously by recrystallization in acetone. Thus, according to the new extraction protocol, the crude alkaloids were fractionated by extraction at different pH in buffered medium. Compound 2 was separated from other alkaloids by extraction at pH = 5.8-6.0. Thus, from 11 kg of crushed and dried leaves of Buxus bakarica WiId 140 g of crude N-3-isobutyrylcycloxobuxidine-F 2 were collected, and 100 g of 2 pure were isolated after recrystallization from acetone. The extraction yield is very good (0.9%).

According to a fourth aspect, the subject of the invention is a method of manufacturing

compounds of the following general formula (IIa)

wherein R ₄ , R ₅ , R ₁₁ , X ₁ and ⁶ are as defined above comprising the following successive steps: a) pyrolysis of the compound of formula (TVb) wherein R ₁₀ = R ₁₁ and R ₄ , R ₅ , R ₁₁ , X ₁ and

⁶ are as defined above, and R ₇ and X ₂ are as defined above, at a pressure of between 10 ^"3 mm Hg and 10 ^{" 1} mm Hg, preferably at a pressure of 0.03 mm Hg with a temperature between 230 and 350 ° C, preferably between 235 and 270 ° C for 3 hours to 24 hours, preferably for 3 hours. b) thermolysis of the mixture obtained in step (a), at a pressure of between 10 ^-3 mmHg and 10 ^-1 mmHg, advantageously at a pressure of 0.03 mmHg, with a temperature of between 230 and 350 ° C, advantageously between 235 and 270 ° C and in the presence of tetraalkylammonium hydroxide (alkyl = methyl, ethyl, or butyl), preferably tetraethylammonium hydroxide.

Advantageously, the general formula (IIa) is such that the hydrogen atoms are positioned in the following manner:

According to a fifth aspect, the subject of the invention is a process for producing the compound of general formula (IIa) in which R ₅ represents -CH ₃ , R ₄ represents -OH,

⁶ represents = O, X ₁ represents O, R ₁₁ represents -CH (CH ₃ ) ₂ comprising the following successive stages: a) pyrolysis of the compound of formula (2) at a pressure of between 10 ^"3 and 10 ^{" 1} mm Hg preferably 0.03 mm Hg, with a temperature between 200 and 350 ° C, advantageously 240 ° C, b) thermolysis of the mixture obtained in step (a), at a pressure of between 10 ^"3 and 10 ^{" 1} mm Hg, advantageously 0.05 mmHg with a temperature of between 200 and 350 ° C, advantageously 240 ° C in the presence of tetraalkylammonium hydroxide (alkyl = methyl, ethyl, butyl), advantageously tetraethylammonium hydroxide.

Thus, N-3-isobutyrylcycloxobuxidine-F 1 was synthesized in two steps from N-3-isobutyrylcycloxobuxidine-F 2. Thermolysis at 240 ° C under 0.05 mmHg of 2 resulted in a mixture (82 / 18) N-3-isobutyrylcycloxobuxidine-F 1 and compound 3 resulting from the opening of the cyclopropane. This mixture is then transformed into

1 with a yield of 74% by heating at 240 ° C. under 0.05 mmHg in the presence of five equivalents of tetraalkylammonium hydroxide (alkyl = methyl, ethyl, butyl), advantageously tetraethylammonium hydroxide.

Alumina chromatography of the mixture of 1 and 3 makes it possible to transform it into only 3 with a yield of 91%.

According to a sixth aspect, the subject of the invention is a process for the manufacture of the compound of general formula (IIa) in which R ₅ represents -CH ₃ , R ₄ represents -OH, ⁶ represents = O, X ₁ represents O, R ₁₁ represents -CH (CH ₃ ) ₂ by heating at a temperature between 200 and 350 ° C, advantageously 210 ° C of the compound of formula (2) in ethylene glycol in the presence of NaOH.

Thus, N-3-isobutyrylcycloxobuxidine-F 1 can be obtained in a single step with a yield of 83% by heating 2 in ethylene glycol at 210 ° C in the presence of sodium hydroxide.

According to a seventh aspect, the subject of the invention is a process for the production of the compounds of general formula (TVa) below

- ^~ R wherein R _4, R _5, R _7, R _10, X _1, X ₂ and ⁶ are as defined above comprising the following successive steps: a) pyrolyzing the compound of formula (IVb) wherein R ₄ , R ₅ , R ₇ , R ₁₀ , X ₁ , X ₂ and

⁶ are as defined above, advantageously at a pressure of between 10 ^"3 and 10 ^{" 1} mmHg, advantageously 0.03 mmHg, with a temperature of between 200 and 350.degree. C., advantageously between 235 and 270.degree. for 3 hours to 24 hours, advantageously for 3 hours. b) Chromatography on alumina, or fractional crystallization, of the mixture obtained in step (a).

Advantageously, the general formula (TVa) is such that the hydrogen atoms are positioned in the following manner:

According to an eighth aspect, the subject of the invention is a process for the production of the compounds of the following general formula (IHa)

- ^~ R wherein R _4, R _5, R _11, X ₁ and are as defined above comprising the following successive steps: a) acid hydrolysis in methanol, preferably with H ₂ SO ₄ at 90 ° C for 2 hours, then, after evaporation of the methanol at room temperature, at 80 ° C. for 1 hour, of the compound of general formula (TVa) in which

R ₄ , R ₅ , X ₁ and ⁶ are as defined above and R ₇ , R ₁₀ and X ₂ are as defined above, to obtain the compound of formula (Va) below:

wherein R ₄ , R ₅ , X ₁ and ⁶ are as defined above and R ₇ is as defined above; b) condensation, advantageously at 50 ° C, of the compound of formula (Va) with the compound of formula R ₁₅ CHO wherein R ₁₅ CH represents R ₁₁ and R ₁₁ is as defined above.

Advantageously, the general formula (IHa) is such that the hydrogen atoms and the radical R ₁₁ are positioned in the following manner:

Advantageously, the general formula (Va) is such that the hydrogen atoms are positioned in the following manner:

According to a ninth aspect, the subject of the invention is a process for the manufacture of the compound of general formula (IIIb) below in which R ₄ , R ₅ , R ₁₁ , X ₁ and ⁶ are as defined above by condensation, advantageously at 50 ° C, of the compound of formula (Vb) in which R ₄ , R ₅ , X ₁ and ⁶ are as defined above, and R ₇ is as defined above with the compound of the formula R ₁₅ CHO wherein R ₁₅ CH is R ₁₁ and R ₁₁ is as defined above.

Advantageously, the general formula (HIb) is such that the hydrogen atoms and the radical R ₁₁ are positioned in the following manner:

According to a tenth aspect, the subject of the invention is a process for the manufacture of the following compound of formula (Hb)

- R ^~ wherein R _4, R _5, R _11, X ₁ and ⁶ are as defined above by heating at a temperature between 200 and 350 ° C, preferably at 300 ° C in the presence of tetraethylammonium hydroxide of the compound of formula (VII) below

- R ^~ wherein R ₁₀ = R ₁₁ and R _4, R _5, R _11, X ₁ and ⁶ are as defined above and R ₇ and X ₂ are as defined above.

Advantageously, the general formula (IIb) is such that the hydrogen atoms are positioned in the following manner:

Advantageously, the general formula (VII) is such that the hydrogen atoms are positioned in the following manner:

R According to a particular embodiment, the compound of formula (VII) is obtained by reaction in the presence of a Lewis acid, advantageously TiCl ₄ in dichloromethane, of the compound of formula (IVb) in which R ₁₀ = R ₁₁ , R ₄ , R ₅ , R ₁₁ , X ₁ and

- ^~ R are as defined above and R ₇ and X ₂ are as defined above.

According to an eleventh aspect, the subject of the invention is a process for manufacturing the compound of general formula (TVb) below:

wherein R ₅ , R ₁₀ and ⁶ are as defined above, R ₄ is -OR ₁₂ wherein R ₁₂ is as defined above, X ₁ is NH, R ₇ is H and X ₂ is O including the following successive steps:

reaction of the compound of general formula (IX) below:

in which R ₅ , R ₁₀ , R ₁₂ and ⁶ are as defined in the general formula

(TVb) above with benzylamine in the presence of anhydrous magnesium sulfate in dichloromethane to obtain the compound of formula (X) below:

- R ^~ wherein R _5, R _10, R ₁₂ and ⁶ are as defined in general formula

(EX) above;

reaction of the compound of formula (X) with sodium cyanoborohydride and glacial acetic acid in methanol to obtain a compound of formula

(XI) following:

in which R ₅ , R ₁₀ , R ₁₂ and ⁶ are as defined in the general formula

(X) above;

reaction of the compound of formula (XJ), in the presence of the 30% Pd / C catalyst in methanol, with ammonium formate or under hydrogen pressure with glacial acetic acid at pH 3 followed by alkalisation with ammonia solution to obtain the compound of formula (TVb). Preferably, the compound of formula (IX) in which R ₁₂ does not represent a hydrogen atom is obtained by the process comprising the following successive stages: protection of the hydroxyl group of the compound of general formula (TVb) below:

wherein R ₅ , R ₁₀ , and ⁶ are as defined above, R ₇ is H, and

X ₁ and X ₂ represent O by reaction with the compound of formula (R ₁₂ ) ₂ O in which R ₁₂ is as defined above but does not represent a hydrogen atom in a pyridine / dichloromethane mixture to obtain the compound of the following general formula (TVb):

wherein, R ₅ , R ₁₀ , and ⁶ are as defined above R ₇ is H, R ₁₂ is as above but is not hydrogen and X ₁ and X ₂ are O;

reaction of the compound of formula (TVb) as defined above with Dess-Martin periodinane in dichloromethane to obtain the compound of formula (TX) in which R ₁₂ does not represent a hydrogen atom. More preferably, the compound of formula (IX) in which R ₁₂ represents a hydrogen atom is obtained by the deprotection reaction of the compound of formula (IX) in which R ₁₂ does not represent a hydrogen atom.

According to a twelfth aspect, the subject of the invention is a process for producing the compound of formula (II) below:

in which R ₅ , R ₁₁ , and ⁶ are as defined above, X ₁ represents NH, R ₄ represents -OR ₁₂ and R ₁₂ is as defined in claim 1 by reaction of the compound of general formula (TVb) next :

in which R ₁₀ = R ₁₁ , R ₅ and ⁶ are as defined above, R ₄ represents

-OR ₁₂ wherein R ₁₂ is as defined above, X ₁ is NH, R ₇ is H and X ₂ represents O with triethylamine in butanol. According to a thirteenth aspect, the subject of the invention is a process for manufacturing a compound of formula (VIII) below:

in which R ₅ , R ₁₁ and ⁶ are as defined above, R ₄ represents -OR ₁₂ and R ₁₂ is as defined above by reaction of the compound of general formula (Wb) below:

in which R ₁₀ = R ₁₁ , R ₅ and ⁶ are as defined above, R ₄ represents

-OR ₁₂ wherein R ₁₂ is as defined above, X ₁ is NH, R ₇ is H and X ₂ represents O with ammonium formate in the presence of Pd / C 30% in methanol.

According to a fourteenth aspect, the subject of the invention is a general triterpene alkaloid mule (I) below: wherein one of the three dashed lines present in cycles a and b and only one represents a bond;

R ₁ represents -CH ₂ X ₁ R ₇ , -CH = NR ₈ or -CH = O in which X ₁ represents O, NH or S,

R ₇ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀ ) - bisftrialkyl (C ₁ -C ₁₀ ) silyl] or SO ₂ R ₉ , wherein R ₉ is C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkylphenyl, with the proviso that R ₇ does not represent SO ₂ R ₉ when X ₁ represents S;

R ₈ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ - bisftrialkyl (C ₁ -C ₁₀₎ alkylsilyl], or SO ₂ R _9, R ₉ representing an alkyl C ₁ -C ₁₀ alkyl or a (C ₁ -C ₁₀₎ phenyl;

R ₂ and R ₃ represent independently of each other a hydrogen atom or

II ² ~ -C-R ₁₀

wherein X ₂ is O, NH or S and R ₁₀ is hydrogen, C ₁ -C ₁₀ alkyl, phenyl, C ₃ -C ₁₀ cycloalkyl, or C ₁ -C ₁₀ alkyl, C ₁₀ ) phenyl, with the proviso that at least one and only one of R ₂ or R ₃ represents a hydrogen atom, or R ₂ is absent, R ₁ represents -CH ₂ X ₁ R ₇ and -NR ₃ and -X ₁ R ₇ taken together represent wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, or R2 represents a hydrogen atom hydrogen, R ₁ represents -CH ₂ X ₁ R ₇ and -NHR ₃ and - X ₁ R ₇ taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, or R ₂ represents an atom of hydrogen, R ₁ represents - CH ₂ = NR ₈ and -NHR ₃ and taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, a phenyl, a C ₃ -C ₁₀ cycloalkyl or a C ₁ -C ₁₀ alkyl phenyl;

R ₄ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl or a radical -X ₃ R ₁₂ in which X ₃ represents O, NH or S, advantageously O and R ₁₂ represents a hydrogen atom, an alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀₎ alkylsulfonyl, alkyl (C ₁ -C ₁₀₎ phenyl sulfonyl or alkyl ( C ₁ -C ₁₀ ) dialkyl (C ₁ -C ₁₀ ) silyl, preferably a hydrogen atom; R ₅ represents the group N ⁺ R ₁₃ OCH ₃ or NCH ₃ R ₁₃ wherein R ₁₃ represents a hydrogen atom, a cycloalkyl C ₃ -C ₁₀ alkyl C ₁

C ₁₀ , phenyl or phthalimide, advantageously -CH ₃ and

- 1_ ^

⁶ is = O, or -OR ₁₄ wherein R ₁₄ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ phenyl or (C ₁ -C ₁₀ ) alkylsulfonyl; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof, as a medicament.

Advantageously, the general formula (T) is such that the hydrogen atoms are positioned in the following manner:

Advantageously, any triterpene alkaloid according to the invention is useful as a medicament, including the compounds of general formulas II, III and IV. The present invention comprises pharmaceutical compositions, "or drugs", comprising at least one compound of the present invention, or an individual isomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt, or a solvate thereof. ci together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and / or prophylactic ingredients.

In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The appropriate dosage ranges are typically from 1 to 500 mg per day, preferably from 1 to 100 mg per day, and most preferably from 1 to 30 mg daily, depending on many factors such as the severity of the condition. to treat, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication to which the administration is directed, and the preferences and the experience of the medical practitioner involved. The person skilled in the treatment of such a pathology will be able, without undue experience and relying on his personal knowledge and description of this application, to ensure a therapeutically effective amount of the compounds of the present invention for a given pathology. In general, the compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including oral and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal) administration. subcutaneously and intravenously) or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a daily dosage regimen that can be adjusted according to the degree of the condition.

A compound or compounds of the present invention, together with one or more conventional adjuvants, vectors or diluents, may be placed in the form of pharmaceutical compositions and dosage units. The pharmaceutical compositions and unit dosage forms may be conventional ingredients in conventional proportions, with or without other compounds or active ingredients, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the dosage range. expected daily that one must employ. The pharmaceutical compositions can be employed in the form of solids, such as filled tablets or capsules, semi-solids, powders, sustained-release formulations, or liquids such as solutions, suspensions, emulsions, elixirs. or capsules filled for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams per tablet, are accordingly representative representative unit dosage forms. The compounds of the present invention can be formulated in a wide variety of dosage forms for oral administration. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as active components. The pharmaceutically acceptable vectors can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating material. In powders, the vector is generally a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is generally mixed with the vector having the necessary binding capacity in appropriate proportions and compacted to the desired shapes and sizes. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable vectors include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose sodium carboxymethylcellulose, a low melting point wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with an encapsulant material such as a vector, forming a capsule in which the active component, with or without a vector, is surrounded by a vector, which is in association with it. this. Similarly, the tablets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges may be in solid forms suitable for oral administration.

Other suitable forms for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted rapidly before use into liquid form preparations. The emulsions may be prepared in solutions, for example, in aqueous solutions in propylene glycol or may contain emulsifiers such as, for example, lecithin, sorbitan monooleate or gum arabic. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents. known. Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active component, dyes, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, eg, bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, infusions of small intestines. volume or multi-dose containers with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous vectors, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil), and injectable organic esters (e.g. ethyl), and may contain formulating agents such as preserving, wetting, emulsifying or suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solids or by lyophilization from a solution for constitution prior to use with a suitable vehicle, for example sterile pyrogen-free water. The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. The lotions may be formulated with an aqueous or oily base and will also generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and gum arabic or gum tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. A low melting point wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into convenient size molds, allowed to cool and solidify. The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be made in a single or multiple dose form. In the latter case of a dropper or pipette, this can be achieved by administering to the patient a predetermined appropriate volume of the solution or suspension. In the case of spraying, this can be achieved for example by means of a metering atomizer spray pump.

The compounds of the present invention can be formulated for aerosol administration, particularly to the respiratory tract and comprising intranasal administration. The compound will generally have a small particle size, for example of the order of five (5) microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active ingredient is formed in a package pressurized with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. The aerosol can conveniently also contain a surfactant such as lecithin. The dose of medication can be regulated by a metering valve. Alternatively, the active ingredients may be produced in a dry powder form, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidine (PVP). The powder vector will form a gel in the nasal cavity. The powder composition may be represented in unit dosage form for example in capsules or cartridges of, for example, gelatin or platelets from which the powder may be administered by means of an inhaler.

The compounds of the present invention may be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when prolonged release of the compound is needed and when conforming a patient with a treatment regimen is crucial. The compounds in transdermal delivery systems are frequently attached to a solid support adhering to the skin. The compound of interest may also be combined with a penetration enhancer, for example azone (1-dodecylazacyelheptan-2-one). Sustained-release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a liquid-soluble membrane, for example silicone rubber, or a biodegradable polymer, for example poly lactic acid.

The pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package containing discrete amounts of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Likewise, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical vectors and their formulation are described in Remington, The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th Edition, Easton, Pennsylvania.

According to a preferred embodiment, the triterpene alkaloid as a drug according to the invention is characterized in that it is chosen from one of the following compounds of formulas:

7th 7h

8a 8c

8d 8th

8h 8h

8i 12

32 33

38, 39

40, 51

52, 63

64, 68

70, 71

According to another preferred embodiment, the triterpene alkaloid according to the invention is characterized in that the medicament is intended for treating a subject suffering from a disease of the central or peripheral nervous system.

In the present invention, the term "subject" refers to mammals and non-mammals. Mammals mean any member of the mammal class including, but not limited to, humans, non-human primates such as chimpanzees and other monkeys and monkey species; farm animals such as cattle, horses, sheep, goats and pork; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds and the like.

On the other hand, the term "treating" or "treating" a pathological condition used in the present invention includes:

(1) to prevent the medical condition, namely, to cause the clinical symptoms of the disease state not to develop in a subject who may be exposed or predisposed to the medical condition, but has not yet experienced or exhibited symptoms of the pathological condition;

(2) inhibiting the disease state, namely, stopping the development of the disease state or its clinical symptoms; or (3) to calm the pathological state, namely to cause a temporary or permanent regression of the pathological condition or its clinical symptoms.

In the present invention, the term "central or peripheral nervous system disease" means any alteration of the state of health of the central or peripheral nervous system in a subject, attributed to internal or external causes, resulting in symptoms and symptoms. signs, and manifested by a disturbance of the functions or by lesions. Examples include, but are not limited to, Alzheimer's disease, memory disorders associated with aging or Alzheimer's disease, disorders associated with trisomy 21, body dementia of Lewy, Parkinson's dementia, vascular dementia, delirium, traumatic brain injury, myasthenia gravis of congenital or autoimmune origin to reverse neuromuscular blocking agents acting at postsynaptic muscle receptors and any cholinergic syndrome in which there is a decrease in the amount of acetylcholinesterase released, epilepsy, a brain tumor, a neurodegenerative disease such as Tay-Sachs disease, Lesch-Nyan disease, Huntington's disease, sclerosis amyotrophic lateral (or Lou Gehrig's disease), Down syndrome, or peripheral neuropathies such as diabetic peripheral neuropathy.

According to an even more preferred embodiment, the triterpene acaloid according to the invention is characterized in that the disease of the central or peripheral nervous system is selected from the group consisting of Alzheimer's disease, the memory disorders associated with the aging or Alzheimer's disease, disorders associated with trisomy 21, Lewy body dementia, Parkinson's dementia, vascular dementia, delirium, traumatic brain injury, myasthenia gravis of congenital or auto origin -immune to reverse neuromuscular blocking agents acting at postsynaptic muscle receptors and any cholinergic syndrome in which there is a decrease in the amount of acetylcholinesterase released.

The subject of the invention is also the use of a triterpene alkaloid according to the present invention for the manufacture of a medicament intended to treat a subject suffering from Alzheimer's disease, memory disorders associated with aging or Alzheimer's disease, disorders associated with trisomy 21, Lewy body dementia, Parkinson's dementia, vascular dementia, delirium, traumatic brain injury, myasthenia of congenital or autoimmune origin to reverse neuromuscular blocking agents acting at postsynaptic muscle receptors and any cholinergic syndrome in which there is a decrease in the amount of acetylcholinesterase released.

Finally, the subject of the invention is a method of treating a subject suffering from a disease of the central or peripheral nervous system, which comprises the administration of a triterpene alkaloid according to the present invention or of a pharmaceutical composition comprising a such alkaloid.

The examples which follow are intended to illustrate the invention without in any way limiting its scope.

EXAMPLES

Example 1 Isolation of N-3-isobutyrylcycloxobuxidine-F 2 or

(20S) -3-Isobutyrylamino-9,19-cyclo-4α-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-5α, 9 -pregnan-16α-ol-11-one 2:

C 3 _O H ₅ O N ₂ O ₄

Appearance: colorless solid

Molecular weight: 502.73 1.1. Protocol for extracting total alkaloids.

1.5 kg of crushed and dried leaves of Buxus Bakarica WiId are alkalinized with 600 ml of a 30% ammoniacal solution. A first extraction is carried out, with stirring, with 10 1 of a mixture of solvents CH ₂ Cl ₂ 9 / EtOH 1 overnight at room temperature. After filtration, five successive macerations are carried out with 10 1 of a mixture of solvents CH ₂ Cl ₂ 9 / EtOH 1, stirring for three hours at room temperature between each filtration.

The combined organic phases are evaporated in vacuo to afford 240 g of a dark green extract. The extract is successively taken up with 7 l of dichloromethane, washed 10 times with 1 l of 2N hydrochloric acid. The aqueous phases are alkalinized with a 30% ammonia solution and then extracted with 6 × 2 1 of dichloromethane. The organic phases are evaporated under vacuum to give 98 g of a brown powder.

From the marc exhausted by six extractions / macerations, a soxhlet is made with dichloromethane for twenty hours until a negative Meyer test is obtained. Each extract is successively taken up with 7 l of dichloromethane, washed 10 times with 1 l of 2N hydrochloric acid. The aqueous phases are alkalinized with a 30% ammonia solution and then extracted with 6 × 2 1 of dichloromethane. The organic phases are finally evaporated and give 7 g of alkaloids. Thus, 105 g of total alkaloids were isolated with a yield of 7%. This experiment was also carried out on a batch of 11 kg of crushed and dried leaves of Buxus Bakarica WiId at. the extraction plant of the I.C.S.N. at Gif-sur-Yvette.

1.2. Isolation of N-3-isobutyrylcycloxobuxidine-F 2. Preparation of the solutions: 4 liters of a 1.0 M AcOH / AcONa buffer solution at pH = 5 are prepared as follows:

17.136 g (0.2348 mol) of glacial acetic acid and 99.296 g (0.7151 mol) of sodium acetate are dissolved in 1000 ml of deionized water.

Dissolution of the total alkaloids in the four aqueous phases at pH = 5. A solution of 27.3 g of crude alkaloids in 500 ml of dichloromethane is washed with 4x1 l of buffer solution at pH = 5. Then, this organic phase is successively washed with 1 liter of a 10% ammonia solution, with 1 1 liter of a deionized water solution and 1 liter of a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. This provides a residue of 1.74g.

Progressive neutralization followed by extractions: Fractionation of alkaloids.

Then, the pH of each aqueous phase containing the starting buffer solution, in which the alkaloids are present, is increased by 1 pH unit by addition of 10% ammonia. The aqueous phases are then successively extracted with 8 x 500 ml of dichloromethane until the alkaloids are exhausted in the aqueous phases. The 8 organic phases are then successively washed with 1 liter of a 10% ammonia solution, with 1 liter of a deionized water solution and with 1 liter of a saturated aqueous solution of sodium chloride, and then dried over sodium chloride. anhydrous magnesium sulphate and evaporated under reduced pressure. Thus, 3.19 g of N-3-isobutyrylcycloxobuxidine-F 2 are extracted at pH = 5.8 with a yield of 0.8%. The pH is measured using a calibrated pH meter.

At the end we obtain the following mass balance:

This experiment was also carried out on a batch of 11 kg of crushed and dried leaves of Buxus Bakarica WiId at the I.CS.N extraction plant. at Gif-sur-Yvette and was able to isolate, after trituration of the extract at pH = 6 in acetone, 100 g of N-3-isobutyrylcycloxobuxidine-F 2 with a yield of 0.9% whose characteristics spectroscopic data are identical to those described by Herlem-Gaulier et al. (1968). PF (° C): 257

[α] _D = + 69 ° (c = 1.01, 25 ° C, CHCl ₃ )

Elemental analysis: Calculated for C ₃₀ H ₅₀ N ₂ O ₄ %: C, 71.67; H, 10.02; N, 5.57; O, 12.73; measured: C, 71.51; H, 10.14; N, 5.34; O: 12.87

IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1690 (C = O); 1654 and 1513 (CONH); 1096 (C-OH).

Mass (TE): m / z: 502.1 (M ^{+ #} ); 72.0 (Me-CH = N ⁺ (CH ₃ ) ₂ , base peak). (ESI): m / z: 503.4 ([M + H], 100); 504.4 (10). HRMS (ESI) calcd for C ₃₀ H ₅₁ N ₂ O ₄ m / z = 503.3849; measured: 503.3852.

Note on the chemical shift of methyls attached to nitrogen N _B :

At 243 ° K, the N _B (CH ₃ ) ₂ have for chemical shifts 2.07 ppm and 2.30 ppm in the form of two singlets. At 300 ° K, the inversion of the nitrogen doublet is slow due to an intramolecular hydrogen bond between the nitrogen NB and the proton of the alcohol attached to Cl 6. The N _B (CH ₃ ) ₂ have then for chemical shifts 2.20 ppm in the form of a large singlet. In ¹³ C NMR, no peak is observed at this temperature.

EXAMPLE 2 Isolation of N-3-Isobutyrylcycloxobuxidine-F1 (or (20S) -10 (9-) 1) abeo-4,14a-dimethyl-20-dimethylamino- (2'-isopropyl-4 ', 4'- dihydro [3 ', 1'] oxazine) -5a, 9 -pregn-1 (10) -en-16α-ol-11-one 1)

Appearance: light yellow solid Molecular weight: 484.71

Diagram 1

1 ^Ie method: ball-tube or tube to sublimate

100 mg (0.20 mmol, 1.0 eq.) Of N-3-isobutyrylcycloxobuxidine-F 2 are heated at 240 ° C under 0.05 mmHg in a bunker or tube to be sublimed. A solid sublimate is obtained in 3 hours. The sublimate is a mixture of opening product of cyclopropane 3 (18%) and N-3-isobutyrylcycloxobuxidine-F 1 (82%). To a solution of the sublimate in 2 ml of dichloromethane is added 515 mg (0.87 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation under vacuum, the red residue heated at 240 ° C. under 0.05 mmHg for 3 hours. hours provides 71.6 mg of 1 as a light yellow crystalline sublimate with a yield of 74%. It is also possible to carry out this synthesis with 1.0 M tetrabutylammonium hydroxide in methanol.

2 ^nd method: in solution in glycol To a suspension of 50 mg (0.10 mmol, 1.0 eq.) N-3-isobutyrylcycloxobuxidine-F 2 in 5 ml of freshly distilled ethylene glycol is added 0.8 mg of sodium hydroxide (0.02 mmol, 0.2 eq). After heating for 6 hours at 215 ° C. under argon, the mixture is basified with 60 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulfate and evaporated in vacuo to afford 40 mg of 1 as a light yellow solid in 83% yield.

PF ( ⁰ C): 281.5

[0C] D = + 71 ° (c = 0.8, 25 ° C, CHCl ₃ )

Elemental analysis: calculated for C ₃₀ H ₄₈ N ₂ O ₃ : C, 74.34; H, 9.98; N, 5.78; O, 9.90; measured C, 74.13; H, 9.91; N, 5.67; O: 9.97.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH,); 1693 (C = O); 1513 (C = H); 1043 (C-OH). Mass (ESI): m / z: 485.3 ([M + H], 95); 486.3 (100); 487.4 (50); 503.4 (2). HRMS (ESI) calcd for C ₃₀ H ₄₉ N ₂ O ₃ m / z = 485.3743; measured: 485.3721. Example 3: 10 (9-> 1) abeo-N-3-isobutyrylcycloxobux-1 (10) -enedin-F 3 (or

(20S) -10 (9-> 1) abeo-4α-hydroxymethyl-3-isobutyrylamino-4,4a-dimethyl-20-dimethylamino-5α, 9 -pregn-1 (10) -en-16α-ol-11- one 3}

C ₃₀ H ₅₀ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 502.73

1 method: in solution

A suspension of 250 mg (0.49 mmol, 1.0 eq.) N-3-isobutyrylcycloxobuxidine-F 2 in 20 ml of ethylene glycol freshly distilled over sodium hydroxide (concentration: 12 g / l) is heated to 160 ° C. for 6 hours under argon. The mixture is then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively washed with 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 98 / methanol 2) to give 105 mg of 3 in the form of a colorless powder after trituration in diethyl ether in a yield of 42.degree. % whose spectroscopic characteristics are identical to those described by Herlem-Gaulier, D. et al; (1968). 2 ^nd method: baked

100 mg (0.20 mmol, 1.0 eq) of N-3-isobutyrylcycloxobuxidine-F 2 are heated at 240 ° C under 0.05 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The solid sublimate is a mixture of the desired product 3 (18%) and N-3-isobutyrylcycloxobuxidine-F 1 (82%). The residues (pellet and sublimate) combined are chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 98 / methanol 2) to give 91 mg of 3 in the form of a powder. colorless after trituration in acetone with a yield of 91% whose spectroscopic characteristics are identical to those described by Herlem-Gaulier, D. et al; (1968).

PF (° C): 242

[α] _D = -46 ° (c = 1.0, 25 ° C, CHCl ₃ )

Elemental analysis: Calculated for C ₃₀ H ₅₀ N ₂ O ₄ -O ₅ SH ₂ O: C: 70.45;

H, 9.98; N, 5.47; measured: C, 70.84; H, 9.71; N, 5.21.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1652 and 1513 (CONH); 1043 (C-OH).

Mass (ESI): m / z: 503.3 ([M + H], 100); 504.3 (90).

HRMS (ESI) calcd for C ₃₀ H ₅₁ N ₂ O ₄ m / z = 503.3849; measured: 503.3852.

Example 4 Syntheses of Analogues of N-3-Isobutyrylcycloxobuxidine

In order to complete pharmacological studies, analogues of 1 have been synthesized and their antiacetylcholinesterase and anti-butyrylcholinesterase activities measured.

4.1. Synthesis of compounds 5, 6, 7 and 8

The common precursor of these analogs is cycloxobuxidine 5, which is obtained by acid hydrolysis of the amide function of N-3-isobutyrylcycloxobuxidine-F 2 with a yield of 94% (Scheme 2).

2 I N-3-isobutyrylcycloxobuxidine

Figure 2 The amides 6 are obtained by reaction of the amine 5 with different anhydrides.

Pyrolysis of compounds 6 at 0.03 mmHg at high temperature (235 ° C to 270 ° C) quantitatively leads to mixtures of compounds 7 and 8 in variable proportion. The chromatographies of these mixtures (7 and 8) on basic alumina make it possible to transform them into the corresponding compound 7 by hydrolysis of the dihydrooxazine function present on the compounds 8. Finally, the compounds 8 were obtained by thermolysis of the mixture of the compounds 7 and 8 corresponding under 0.03 mmHg at elevated temperature

(235 ° C to 270 ° C) in the presence of tetraethylammonium hydroxyl with good yields (30-94%) (Scheme 3 below):

R = CH ₃ (79%)

6b R = C ₆ H ₅ (91%)

6c R = C ₂ H ₅ (80%)

6d R = C ₆ H ₁₁ (68%)

6th R = (S) - (CH ₃ ) CH (C ₂ H ₅ ) (75%)

R = C ₄ H ₉ (79%)

6g R = C ₆ H ₅ CH ₂ (67%)

6 hr - R = (CH ₃ ) CH (C ₂ H ₅ ) (84%)

R = (C ₂ H ₅ ) CH (C ₂ H ₅ ) (81%)

0.03 mmHg, 235 ° C to 270 ° C thermolysis (ball oven), 3h

a R = CH ₃ (76%) 7a, 8a R = CH ₃ (98/2) b R = C ₆ H ₅ (85%) 7b, 8b R = C ₆ H ₅ (95/5) c R = C ₂ H ₅ (94%) 7c, 8c R = C ₂ H ₅ (64/36) d R = C ₆ H ₁₁ (73%) 7d, 8d R = C ₆ H ₁₁ (83/17) e R = ( SHCH ₃ ) CH (C ₂ H ₅ ) (80%) 7th, 8th R = (S) - (CH ₃ ) CH (C ₂ H ₅ ) (85/15) f R = C ₄ H ₉ (85%) 7f, 8f R = C ₄ H ₉ (100/0) g R = C ₆ H ₅ CH ₂ (81%) 7g, 8g R = C ₆ H ₅ CH ₂ (74/26) h R = TaC- (CH) ₃ ) CH (C ₂ H ₅ ) (30%) 7h, 8h R = PaC- (CH ₃ ) CH (C ₂ H ₅ ) (80/20) i R = (C ₂ H ₅ ) CH (C ₂ H) ₅ ) (49%) 7i, 8i R = (C ₂ H ₅ ) CH (C ₂ H ₅ ) (90/10)

Chromatography on alumina

7a R = CH ₃ (88%)

7b R = C ₆ H ₅ (68%)

7c R = C ₂ H ₅ (71%)

7d R = C ₆ H ₁₁ (89%)

7th R = (S) - (CH ₃ ) CH (C ₂ H ₅ ) (51%)

7f R = C ₄ H ₉ (88%)

7g R = C ₆ H ₅ CH ₂ (55%)

R = TaC- (CH ₃ ) CH (C ₂ H ₅ ) (30%)

R = (C ₂ H ₅ ) CH (C ₂ H ₅ ) (31%) • Compound 5: cycloxobuxidine-F 5 or

(20S) -3-amino-9,19-cyclo-4α-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-5α, 9 -pregnan-16α-ol-1-one

C ₂₆ H ₄₄ N ₂ O ₃

Appearance:: colorless solid

Molecular weight: 432.64

To a solution of 821 mg (1.63 mmol, 1.0 eq) of N-3-isobutyrylcyclobuxidine F 2 in 30 ml of methanol is added 30 ml (30.00 mmol, 18.4 eq.) Of an aqueous solution of 2N sulfuric acid slowly at room temperature. After stirring for 3 hours at 90 ° C., the reaction medium is cooled to room temperature and evaporated under reduced pressure at most at 25 ° C. The liquor obtained is heated for 1 hour at 70 ° C. It is colored yellow. The reaction mixture is basified with 50 ml of a 10% ammonia solution and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively washed with 40 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product is recrystallized from ethyl acetate. After filtration, washing and drying under reduced pressure, 657 mg of 5 in the form of a colorless solid are obtained in a yield of 94%, whose spectroscopic characteristics are identical to those described by Herlem-Gaulier, D. et al; (1968). PF (° C): 242

[GC] _n = + 127 ° (c = 0.6, 25 ° C, CHCl ₃ )

Elemental analysis: calculated for C ₂₆ H ₄₃ N ₂ O ₄ : C, 72.18; H, 10.25; N, 6.48; O: 11.09 measured: C, 71.99; H, 10.22; N, 6.31; O: 11.28.

IR (CHCl ₃ ) υ (cm ⁴ ): 3018 (OH, NH); 1680 (C = O); 1615 (C-NH); 1095 (C-OH).

Mass (ESI): m / z: 433.3 ([M + H], 100); 416.3 (10).

HRMS (ESI) calcd for C ₂₆ H ₄₅ N ₂ O ₃ m / z = 433.3430; measured: 433.3425.

• Compound 6a: N-3-acetylcycloxobuxidine-F 6a or

(20S) -3-acetylamino-9,19-cyclo-4α-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-5α, 9 -pregnan-1α-ol-11-one 6a

C ₂₈ H ₄₆ N ₂ O ₄ Appearance: colorless powder Molecular weight: 474.68

To a solution of 240 mg (0.55 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 63 ml (0.66 mmol, 1.2 eq) of acetic anhydride. After stirring for 5 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are successively washed with 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol and then 98 dichloromethane / methanol 2) to give 210 mg of 6a in the form of a colorless powder after trituration. in acetone with a yield of 79%.

PF (° C): 255

M _D = + 73 ° (c = 0.98, 25 ° C, CHCl ₃ )

Elemental analysis: Calculated for C ₂₈ H ₄₆ N ₂ O ₄ .0.5H ₂ O: C: 70.85; H, 9.77; N, 5.90; measured: C, 69.51; H, 9.61; N: 5.39

IR (CHCl ₃ ) υ (cm ⁴ ): 3436 (OH, NH); 1656 (C = O); 1656 and 1513 (CONH); 1049 (C-OH).

Mass (ESI): m / z: 475.3 ([M + H], 100); 476.4 (15).

HRMS (ESI) calcd for C ₂₈ H ₄₇ N ₂ O ₄ m / z = 475.3536; measured: 475.3511.

• Compound 6b: N-3-benzoylcycloxobuxidine-F 6b or

(20S) -3-Benzoylamino-9,19-cyclo-4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregnan-1α-ol-11-one 6fc

C ₃₃ H ₄₈ N ₂ O ₄ Appearance: colorless powder Molecular weight: 536.75 To a solution of 166 mg (0.38 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 95 mg (0.46 mmol, 1.1 eq) of acid anhydride. benzoic. After stirring for 4 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are washed with 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.8 dichloromethane / 0.2 methanol and then 98 dichloromethane / methanol 2) to give 156 mg of 6b in the form of a colorless powder after trituration. in acetone with a yield of 76% whose spectroscopic characteristics are identical to those described by Herlem-Gaulier, D. et al (1968).

PF (° C): 277

[α] _D = + 52 ° (c = 1.00, 25 ° C, CHCl ₃ ) Elemental analysis: calculated for C ₃₃ H ₄₈ N ₂ O ₄ -O ₅ SH ₂ O: C: 72.64; H, 9.04;

N, 13.12; O, 5.13; measured: C, 72.87; H: 9.02; N, 12.97; O: 5.14.

IR (CHCl ₃ ) υ (cm ⁴ ): 3438 (OH, NH); 1645 (C = O); 1628 and 1518 (CONH); 1040 (C-OH).

Mass (ESI): m / z: 537.4 ([M + H], 100); 538.4 (15). HRMS (ESI) calcd for C ₃₃ H ₄₉ N ₂ O ₄ m / z = 537.3692; measured: 537.3679.

• Compound 6c: N-3-propionylcycloxobuxidine-F 6c or

(20S) -9,19-Cyclo-4α-hydroxymethyl-4, 14-dimethyl-20-dimethylamino-3-propionylamino-5α, 9 -pregnan-1α-ol-1-one 6c

C ₂₉ H ₄₈ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 488.70

To a solution of 300 mg (0.69 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 98 ml (0.76 mmol, 1.1 eq) of acid anhydride. propionic acid. After stirring for 4 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are successively washed with 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol / 0.05 ammonia followed by 98 dichloromethane / methanol 2) to give 269 mg of 6c in the form of a colorless powder after trituration in acetone with a yield of 80%.

Mp (° C): Elemental analysis: Calculated for C ₂₉ H ₄₈ N ₂ O ₄ -O ₅ SH ₂ O: C: 70.02; H, 9.85;

N, 5.63; measured C, 70.63; H, 9.76; N, 5.21.

IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1653 (C = O); 1653 and 1514 (CONH); 1049 (C-OH).

Mass (ESI): m / z: 489.3 ([M + H], 100); 295.2 (15); 490.3 (5). HRMS (ESI) calcd for C ₂₉ H ₄₉ N ₂ O ₄ m / z = 489.3692; measured: 489.3655. • Compound 6d: N-3-cyclohexanecarboxylcycloxobuxidine-F 6d or

(20S) -3- (Cyclohexanecarboxylamino) -9,19-cyclo-4a-hydroxymethyl-4,4-dimethyl-20-dimethylamino-5a, 9 -pregnan-1α-ol-11-one 6d

C ₃₃ H ₅₄ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 542.79

To a solution of 300 mg (0.69 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 182 mg (0.76 mmol, 1.1 eq) of the anhydride of the cyclohexane carboxylic acid. After stirring for 4 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are successively washed with 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol and then 98 dichloromethane / methanol 2) to provide 225 mg of 6d in the form of a colorless powder after trituration. in acetone with a yield of 68%. Mp (° C): 293 [α] _D = + 61.9 ° (c = 1.09, 25 ° C, CHCl ₃ ) Elemental analysis: calculated for C ₃₃ H ₅₄ N ₂ O ₄ : C, 73.02; H, 10.03; N, 5.16; O, 11.79; measured: C, 72.76; H, 9.94; N: 5.07; O, 11.68.

IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1650 (C = O); 1650 and 1512 (CONH); 1050 (C-OH). Mass (ESI): m / z: 543.4 ([M + H], 100); 544.5 (85).

HRMS (ESI) calcd for C ₃₃ H ₅₅ N ₂ O ₄ m / z = 543.4162; measured: 543.4128.

Compound 6e: (S) -N-3-secbutyrylcycloxobuxidine-F6e or (20S) -9,19-cyclo-4a-hydroxymethyl-4, 14a-dimethyl-20-dimethylamino-3

(2S-Methylbutyrylamino) -5a, 9-pregnan-16α-ol-11-one 6e

C ₃₁ H ₅₂ N ₂ O ₄

Appearance: colorless solid

Molecular weight: 516.76

To a solution of 300 mg (0.69 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 151 ml (0.76 mmol, 1.1 eq) of acid anhydride. (S) -2-methylbutyric acid. After stirring for 3 hours at room temperature, the mixture is neutralized with a few drops of a solution of 10% sodium bicarbonate (pH =

8), then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with

3x40 ml of dichloromethane. The combined organic phases are successively washed with 30 ml of a saturated aqueous solution of sodium chloride, dried over sulphate of anhydrous sodium and evaporated under vacuum. The residue is chromatographed on Merck alumina column of activity II-III (eluent: 99.5 dichloromethane / 0.5 methanol and then 98 dichloromethane / methanol 2) to provide 266 mg of 6e in the form of a colorless powder after trituration. in acetone with a yield of 75%. PF (° C): 262

[GC] _n = + 59.0 ° (c = 0.44, 21 ° C, CHCl ₃ )

Elemental analysis: Calculated for C ₃₁ H ₅₂ N ₂ O ₄ -O ₅ SH ₂ O: C: 70.85; H, 10.09; N, 5.33; measured C, 71.45; H, 9.88; N, 5.23.

IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1651 (C = O), 1651 and 1511 (CONH); 1042 (C-OH).

Mass (ESI): m / z: 517.4 ([M + H], 100); 518.5 (75).

HRMS (ESI) calculated for C ₃₁ H ₅₃ N ₂ O ₄ m / z = 517.4005; measured: 517.4024.

• Compound 6f: N-3-pivalylcycloxobuxidine-F 6f or

(20S) -9,19-Cyclo-4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylamino-3- (2,2-dimethylpropionylamino) -5α, 9 -pregnan-16α-ol-11-one 6 [

C ₃₁ H ₅₂ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 516.76 To a solution of 300 mg (0.69 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 156 ml (0.76 mmol, 1.1 eq) of acid anhydride. pivalic. After stirring for 4 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are successively washed with 40 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is chromatographed on Merck alumina column of activity II-III (eluent: 99.5 dichloromethane / 0.5 methanol and then 98 dichloromethane / methanol 2) to provide 282 mg of 6f in the form of a colorless powder after trituration. in acetone with a yield of 79%.

PF (° C): 267

[α] _D = + 69.9 ° (c = 0.92, 25 ° C, CHCl ₃ )

Elemental analysis: Calculated for C ₃₁ H ₅₂ N ₂ O ₄ .0.5H ₂ O: C: 70.85; H, 10.09; N, 5.33; measured: C, 71.29; H, 9.93; N: 5.04.

IR (CHCl ₃ ) υ (cm ⁴ ): 3454 (OH, NH); 1637 (C = O); 1637 and 1514 (CONH); 1046 (C-OH).

Mass (ESI): m / z: 517.4 ([M + H], 100); 518.5 (75).

HRMS (ESI) calculated for C ₃₁ H ₅₃ N ₂ O ₄ m / z = 517.4005; measured: 517.3986. • Compound 6g: N-3-phenylacetylcycloxobuxidine-F 6g or

(20S) -9,19-Cyclo-4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylamino-3 - (phenylacetylamino) -5α, 9 -pregnan-1α-ol-11-one 6g

C ₃₄ H ₅₀ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 550.77

To a solution of 300 mg (0.69 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added a suspension of 194 mg (0.76 mmol, 1.1 eq) of anhydride. phenylacetic acid in 5 ml of methanol. After stirring for 4 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x30 ml of dichloromethane. The combined organic phases are successively washed with 30 ml of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is chromatographed on Merck alumina column of activity II-III ( eluent: dichloromethane 99.7 / methanol 0.3 and then dichloromethane 98 / methanol 2) to provide 255 mg of 6 g as a colorless powder after trituration in acetone with a yield of 67%.

Mp (° C): 265.5 [α] _D = + 62.1 ° (c = 0.84, 25 ° C, CHCl ₃ )

Elemental analysis: calculated for C ₃₄ H ₅₀ N ₂ O ₄ : C, 74.14; H, 9.15; N, 5.09; O, 11.62; measured: C, 73.98; H, 9.12; N, 4.97; O: 11.61.

IR (CHCl ₃ ) υ (cm ⁴ ): 3413 (OH, NH); 1650 (C = O); 1650 and 1516 (CONH); 1047 (C-OH). Mass (ESI): m / z: 551.4 ([M + H], 100); 552.5 (90); 553.5 (10).

HRMS (ESI) calculated for C ₃₄ H ₅₁ N ₂ O ₄ m / z = 551.3849; measured: 551.3816. Compound 6h: N-3-secbutyrylcycloxobuxidine-F 6h or

(20S) -9.19-cyclo-4a-bydroxymétbyl-4, 14a-dimétbyl-20-dimétbylamino-3 (2-méthylbutyrylamino) -5a, 9 -pregnan-lόa-ol-ll-one _^ 6h

C ₃₁ H ₅₂ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 516.76

To a solution of 238 mg (0.55 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 113 mg (0.60 mmol, 1.1 eq) of acid anhydride. 2-methylbutyric. After stirring for 5 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.5 dichloromethane / 0.5 methanol and then 99 / dichloromethane). methanol 1) to provide 238 mg of a mixture of two diastereoisomers (50/50) 6h in the form of a colorless powder after trituration in acetone with a yield of 84%. Mp (° C): Elemental analysis: Calculated for C ₃₁ H ₅₂ N ₂ O ₄ : C, 72.05; H, 10.14; NOT :

5.42; O, 12.38; measured: C, 71.88; H, 10.34; N, 5.31; O: 11.87. IR (CHCl ₃ ) υ (cm ⁴ ): 3436 (OH, NH); 1699 (C = O); 1661 and 1508 (CONH); 1082 (C-OH).

Mass (ESI): m / z: 517.4 ([M + H], 100); 518.4 (70).

HRMS (ESI) calculated for C ₃₁ H ₅₃ N ₂ O ₄ m / z = 517.4005; measured: 517.4001. It is a racemic mixture of two diastereoisomers.

• Compound 6i: N-3-secpentyrylcycloxobuxidine-F 6i or

(20S) -9,19-Cyclo-4α-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-3- (2-ethylbutyrylamino) -5α, 9 -pregnan-10α-ol-1-one 6i

C ₃₂ H ₅₄ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 530.78

To a solution of 207 mg (0.48 mmol, 1.0 eq) of cycloxobuxidine-F in 10 ml of methanol is added 113 mg (0.53 mmol, 1.1 eq) of acid anhydride. 2-ethylbutyric. After stirring for 5 hours at room temperature, the mixture is neutralized with a few drops of a 10% sodium bicarbonate solution (pH = 8) and then basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3x40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is chromatographed on Merck alumina column of activity II-III (eluent: 99.5 dichloromethane / methanol). 0.5 then dichloromethane 99 / methanol 1) to provide 206 mg of 6i in the form of a colorless powder after trituration in acetone with a yield of 81%.

PF (° C): 251

Elemental analysis: calculated for C ₃₂ H ₅₄ N ₂ O ₄ : C, 72.41; H, 10.25; N, 5.28; O, 12.06; measured: C, 72.14; H, 10.18; N, 5.23; O, 11.99.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1690 (C = O); 1650 and 1511 (CONH); 1048 (C-OH).

Mass (ESI): m / z: 531.3 ([M + H], 100); 532.3 (10). HRMS (ESI) calcd for C ₃₂ H ₅₅ N ₂ O ₄ m / z = 531.4162; measured: 531.4163.

• Compound 7a: 10 (9-> 1) abeo-N-3-acetylcycloxobuxi-1 (10) -enedin-F 7a or (20S) -10 (9-> 1) abeo-3-acetylamino-4a-hydroxymethyl- 4, 14α-dimethyl-20-dimethylamino-5α, 9-pregn-1 (10) -en-16α-ol-11-one 7a

C ₂₈ H ₄₆ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 474.68

221 mg (0.46 mmol, 1.0 eq) of N-3-acetylcycloxobuxidine-F 6a derivative are heated at 240 ° C under 0.03 mmHg in a bulb oven. A sublime product in 3 hours. The solid sublimate is a mixture of the desired product 7a (98%) and dihydrooxazine 8a (2%). The sublimate is chromatographed on Merck alumina column of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to provide 79.4 mg of 7a in the form of a colorless powder after trituration in acetone with a yield of 88%.

PF (° C): 253

IR (CHCl ₃ ) υ (cm ⁴ ): 3435 (OH, NH); 1694 (C = O); 1654 and 1516 (CONH); 1043 (C-OH).

Mass (ESI): m / z: 475.3 ([M + H], 100); 476.3 (60).

HRMS (ESI) calcd for C ₂₈ H ₄₇ N ₂ O ₄ m / z = 475.3536; measured: 475.3548.

• Compound 7b: 10 (9-> 1) abeo-N-3-benzoylcycloxobux-1 (10) -enedin-F 7b or

(20S) -10 (9-β) abeo-3-benzoylamino-4α-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-5α, 9 -pregn-1 (10) -en-16α-ol-11- one 7b

C ₃₃ H ₄₈ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 536.75

180 mg (0.33 mmol, 1.0 eq) of N-3-benzoylcycloxobuxidine-F 6b derivative are heated for 3 hours at 260 ° C under 0.03 mmHg in a bulb oven. No sublimate is obtained. The solid pellet is a mixture of the desired product 7b (95%) and dihydrooxazine 8b (5%). The pellet is chromatographed on Merck alumina column Activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to provide 126 mg of 7b as a colorless powder after trituration in acetone with a yield of 70%.

PF (° C): 289

IR (CHCl ₃ ) υ (cm ⁴ ): 3435 (OH, NH); 1693 (C = O); 1644 and 1519 (CONH); 1042 (C-OH).

Mass (ESI): m / z: 537.3 ([M + H], 100); 538.4 (80).

HRMS (ESI) calcd for C ₃₃ H ₄₉ N ₂ O ₄ m / z = 537.3692; measured: 537.3708.

Compound 7c: 10 (9-> 1) abeo-N-3-propionylcycloxobux-1 (10) -edin-F 7c or

(20S) -10 (9-> 1) abeo-4a-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-3-propionylamino-5a, 9 -pregn-1 (10) -en-16a-ol-1-yl one 7c

C ₂₉ H ₄₈ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 488.70

73.0 mg (0.15 mmol, 1.0 eq) of N-3-propionylcycloxobuxidine-F 6c derivative are heated at 240 ° C under 0.03 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The solid sublimate is a mixture of the desired product 7c (64%) and dihydrooxazine 8c (36%). The sublimate is chromatographed on Merck alumina column of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to give 51.6 mg of 7c in the form of a colorless powder after trituration in acetone with a yield of 71%.

PF (° C): 229.5

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1653 and 1514 (CONH); 1044 (C-OH).

Mass (ESI): m / z: 489.2 ([M + H], 100); 490.3 (80).

HRMS (ESI) calcd for C ₂₉ H ₄₉ N ₂ O ₄ m / z = 489.3692; measured: 489.3687.

Compound 7d: 10 (9-> 1) abeo-N-3-cyclohexanecarboxylcycloxobuloyl (10) -enedin-F 7d or

(20S) -10 (9-> 1) abeo-3 - (cyclohexanecarboxyamino) -4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregn-1 (10) -en-16α-ol- ll-one 7d

C ₃₃ H ₅₄ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 542.79

85.0 mg (0.15 mmol, 1.0 eq) of N-3- cyclohexanecarboxylcycloxobuxidine-F 6d derivative are heated at 260 ° C under 0.03 mmHg in a bulb oven. No sublimate is obtained after 3 hours. The pellet is a mixture of the desired product 7d (83%) and dihydrooxazine 8d (17%). The pellet is chromatographed on Merck alumina column of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to provide 80.0 mg of 7d in the form of a colorless powder after trituration in acetone with a yield of 89%. PF (° C): 285

Elemental analysis: Calculated for C ₃₃ H ₅₄ N ₂ O ₄ -O ₅ SH ₂ O: C: 71.86; H, 9.98; N, 5.08; measured: C, 72.13, H: 9.91; N, 4.92.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1647 and 1512 (CONH); 1043 (C-OH).

Mass (ESI): m / z: 543.3 ([M + H], 100); 544.4 (70).

HRMS (ESI) calcd for C ₃₃ H ₅₅ N ₂ O ₄ m / z = 543.4162; measured: 543.4158.

• Compound 7e: 10 (9-> l) abeo-N-3- (S) -secbutyrylcycloxobuxi-1 (10) -enedin-F 7th or

(20S) -10 (9-> 1) abeo-4a-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-3 - (S-2-methylbutyrylamino) -5a, 9-pregn-1 (10) -nn- 16a-ol-ll-one 7th

C ₃₁ H ₅₂ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 516.76

84.2 mg (0.16 mmol, 1.0 eq) of N-3- (S) -secbutyrylcycloxobuxidine-F 6e derivative are heated at 240 ° C under 0.03 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The sublimate is a mixture of the desired product 7e (85%) and dihydrooxazine 8e (15%). The sublimate is chromatographed on Merck alumina column of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to provide 80.0 mg of 7e in the form of a colorless powder after trituration in acetone with a yield of 95%. PF (° C): 219

Elemental analysis: calculated for C ₃₁ H ₅₂ N ₂ O ₄ : C, 72.05; H, 10.14; N, 5.42; O, 12.38; measured: C, 72.09; H, 10.06; N, 5.35; O: 12.32.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1649 and 1511 (CONH); 1043 (C-OH).

Mass (ESI): m / z: 517.3 ([M + H], 100); 518.4 (90).

HRMS (ESI) calculated for C ₃₁ H ₅₃ N ₂ O ₄ m / z = 517.4005; measured: 517.3980.

Compound 7f: 10 (9-> 1) abeo-N-3-pivalylcycloxobux-1 (10) -enedin-F 7f or

(20S) -OC (9-Ab) -4a-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-3- (2,4-dimethylpropionylamino) -5a, 9-pregn-1 (10) -en-16a -ol-ll-one 7f

C ₃₁ H ₅₂ N ₂ O ₄

Appearance: colorless powder Molecular Weight: 516.76

72.2 mg (0.14 mmol, 1.0 eq) of N-3-pivalylcycloxobuxidine-F 6f derivative are heated at 250 ° C under 0.03 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The sublimate contains 100% of the desired product 7f and is then chromatographed on a column of Merck alumina of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol). to provide 63.4 mg of 7f as a colorless powder after trituration in acetone with a yield of 88%.

PF (° C): 270

Elemental analysis: calculated for C ₃₁ H ₅₂ N ₂ O ₄ : C, 72.05; H, 10.14; N, 5.42; O, 12.38; measured C, 71.91, H: 10.16; N, 5.37; O: 12.11.

IR (CHCl ₃ ) υ (cm ⁴ ): 3454 (OH, NH); 1693 (C = O); 1639 and 1515 (CONH); 1044 (C-OH).

Mass (ESI): m / z: 517.3 ([M + H], 100); 518.4 (60).

HRMS (ESI) calculated for C ₃₁ H ₅₃ N ₂ O ₄ m / z = 517.4005; measured: 517.3990.

Compound 7g: 10 (9-> 1) abeo-N-3-phenylacetylcycloxobux-1 (10) -edenine-F 7g or

(20S) -10 (9-> 1) abeo-4a-hydroxymethyl-4, 14a-dimethyl-20-dimethylamino-3 - (phenylacetylamino) -5a, 9 -pregn-1 (10) -en-16a-ol; il-one 7g

C ₃₄ H ₅₀ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 550.77

101.8 mg (0.18 mmol, 1.0 eq) of N-3-phenylacetylcycloxobuxidine-6g derivative are heated at 270 ° C under 0.03 mmHg in a bulb oven. No sublimate is obtained after three hours. The pellet is a mixture of the desired product 7g (74%) and dihydrooxazine 8g (26%). The pellet is chromatographed on Merck alumina column of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to give 40.6 mg of 7 g in the form of a colorless powder after trituration in acetone. with a yield of 55%.

PF (° C): 261

IR (CHCl ₃ ) υ (cm ⁴ ): 3411 (OH, NH); 1693 (C = O); 1648 and 1519 (CONH); 1044 (C-OH).

Mass (ESI): m / z: 551.3 ([M + H], 100); 552.3 (70).

HRMS (ESI) calcd for C ₃₄ H ₅₁ N ₂ O ₄ m / z = 551.3817; measured: 551.3849.

• Compound 7h: 10 (9-> l) abeo-N-3-secbutyrylcycloxobux-1 (10) -eninedin-F 7h or

(20S) -10 (9-> 1) abeo-4a-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-3 - (2-methylbutyrylamino) -5a, 9-pregn-1 (10) -en-16a ol-1-one 7h

C ₃₁ H ₅₂ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 516.76

40.0 mg (0.07 mmol, 1.0 eq) of N-3-secbutyrylcycloxobuxidine-F 7h derivative are heated at 250 ° C under 0.08 mmHg in a bulb oven. A sublimate is obtained in 3 hours. Sublimate is a mixture of the desired product 7h (80%) and dihydrooxazine 8h (20%). The sublimate is chromatographed on a Merck alumina column of activity II-III (eluent: dichloromethane 99 / methanol 1) to give 12.0 mg of 7h in the form of a colorless powder after trituration in acetone with a yield of 30%.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1650 and 1511 (CONH); 1012 (C-OH).

Mass (ESI): m / z: 517.3 ([M + H], 100); 518.4 (40); 499.4 (5).

HRMS (ESI) calculated for C ₃₁ H ₅₃ N ₂ O ₄ m / z = 517.4005; measured: 517.4011.

It is a racemic mixture of two diastereoisomers.

Compound 7i: 10 (9-> 1) abeo-N-3-secpentyrylcycloxobux-1 (10) -edinine-F 7i or

(20S) -10 (9-> 1) abeo-4a-hydroxymethyl-4,4a-dimethyl-20-dimethylamino-3 - (2-ethylbutyrylamino) -5a, 9 -pregn-1 (10) -en-16a ol-1-one 7i

B \

C ₃₂ H ₅₄ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 530.78

40.0 mg (0.08 mmol, 1.0 eq) of N-3-secpentyrylcycloxobuxidine-F 7i derivative are heated at 250 ° C under 0.08 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The sublimate is a mixture of the desired product 7i (90%) and dihydrooxazine 8i (10%). The sublimate is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 99 / methanol 1) to provide 12.0 mg of 7i as a colorless powder after trituration in acetone with a yield of 31%.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1649 and 1510 (CONH); 1042 (C-OH).

Mass (ESI): m / z: 531.3 ([M + H], 100); 532.4 (50).

HRMS (ESI) calcd for C ₃₂ H ₅₅ N ₂ O ₄ m / z = 531.4162; measured: 531.4173.

Compound 8a: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2'-methyl-4 ', 4'-dihydro [3', r] oxazine) -5a 9-pregn-1 (10) -en-16α-ol-11-one 8a

C ₂₈ H ₄₄ N ₂ O ₃

Appearance: light yellow powder Molecular weight: 456.66

171 mg (0.36 mmol, 1.0 eq) of N-3-acetylcycloxobuxidine-F 6a derivative are dissolved in the minimum dichloromethane (2 ml) and then added 1059 mg (1.80 mmol, 5.0 eq. .) a solution of 25% tetraethylammonium hydroxide in methanol. The solution is colored yellow. The solvents are evaporated under reduced pressure. The dark red solid is dried and then heated at 240 ° C. to 0.03 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The pellet melted and yellowed. The sublimate is recrystallized from acetone and 125 mg of 8a as a light yellow powder are isolated with a yield of 76%. Mp (° C): 284 Elemental analysis: Calculated for C ₂₈ H ₄₄ N ₂ O ₃ CI: 73.64; H, 9.71; NOT :

6.13; measured C, 73.25, H, 9.56; N, 5.98. IR (CHCl ₃ ) υ (cm ⁴ ): 3331 (OH, NH); 1694 (C = O); 1672 (C = N); 1039 (C-

OH).

Mass (ESI): m / z: 457.4 ([M + H], 100); 458.4 (5).

HRMS (ESI) calculated for C ₂₈ H ₄₅ N ₂ O ₃ m / z = 457.3430; measured: 457.3470.

Compound 8b: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2'-phenyl-4 ', 4'-dihydro [3', r] oxazine) -5a, 9-pregn-1 (10) -en-16α-ol-11-one 8b

Appearance: light yellow solid

Molecular weight: 518.73

118 mg (0.22 mmol, 1.0 eq) of N-3-benzoylcycloxobuxidine-F 6b derivative are dissolved in the minimum dichloromethane (2 ml) are added 648 mg (1.10 mmol, 5.0 eq. ) a solution of 25% tetraethylammonium hydroxide in methanol. The solution is colorless. The solvents are evaporated under reduced pressure. The dark red solid is dried and then heated to 275 ° C at 0.03 mmHg in a bulb oven. No product sublimates in 3 hours. The pellet melted and yellowed. The product contained in the pellet is recrystallized from acetone and 97 mg of 8b as a light yellow powder are isolated in 85% yield.

Elemental analysis: calculated for C ₃₃ H ₄₆ N ₂ O ₃ : C, 73.64; H, 9.71; N, 6.13; measured: C, 73.25; H, 9.56; N: 5.98. IR (CHCl ₃ ) υ (cm ⁴ ): 3376 (OH, NH); 1694 (C = O); 1650 (C = N); 1027 (C-

OH).

Mass (ESI): m / z: 519.4 ([M + H], 100); 520.4 (10).

HRMS (ESI) calcd for C ₃₃ H ₄₇ N ₂ O ₃ m / z = 519.3587; measured: 519.3610.

Compound 8c: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2'-ethyl-4 ', 4'-dihydro [3', r] oxazine) -5a, 9-pregn-1 (10) -en-16α-ol-11-one 8c

C ₂₉ H ₄₆ N ₂ O ₃

Appearance: light yellow solid Molecular weight: 470.69

83 mg (0.17 mmol, 1.0 eq) of N-3-propionylcycloxobuxidine-F 6c are heated at 240 ° C under 0.03 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The sublimate consists of a product mixture resulting from the opening of cyclopropane 7c (64%) and dihydrooxazine 8c (36%). To a solution of the sublimate in 2 ml of dichloromethane is added 500 mg (0.85 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation under vacuum, the red residue heated at 240 ° C. under 0.03 mmHg for 3 hours gives 75 mg of 8c in the form of a light yellow crystalline sublimate with a yield of 94%.

PF (° C): 282

Elemental Analysis: Calculated for C ₂₉ H ₄₆ N ₂ O ₃ -O 2 SH ₂ O: C, 73.34; H

9.79; N, 5.90; measured: C, 73.08, H, 9.74; N, 5.91. IR (CHCl ₃ ) υ (cm ⁴ ): 3363 (OH, NH); 1694 (C = O); 1667 (C = N); 1040 (C-

OH).

Mass (ESI): m / z: 471.3 ([M + H], 100); 472.4 (70).

HRMS (ESI) calcd for C ₂₉ H ₄₇ N ₂ O ₃ m / z = 471.3587; measured: 471.3577.

Compound 8d: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2'-cyclohexyl-4 ', 4'-dihydro [3', n '] oxazine) 5a, 9-pregn-1 (10) -en-16α-ol-11-one 8d

Appearance: light yellow solid Molecular weight: 524.78

225 mg (0.41 mmol, 1.0 eq) of N-3-cyclohexanecarboxylcycloxobuxidine-F 6d are heated at 260 ° C under 0.03 mmHg in a bulb oven. No sublimate is obtained in 3 hours. The product contained in the pellet consists of a product mixture resulting from the opening of cyclopropane 7d (83%) and dihydrooxazine 8d (17). To a solution of the compound residue of the previously obtained mixture in 2 ml of dichloromethane is added 1085 mg (1.84 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation in vacuo, the red residue heated at 260 ° C under 0.03 mmHg for 3 hours provides 150 mg of 8d as a light yellow solid in the pellet with a yield of 69%.

Elemental analysis: calculated for C ₃₃ H ₅₂ N ₂ O ₃ : C: 75.53, H: 9.91; N, 5.14; measured: C, 75.74; H, 9.91; N, 5.14. IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1693 (C = O); 1659 (C = N); 1040 (C-

OH).

Mass (ESI): m / z: 525.3 ([M + H], 100); 526.4 (40); 543.4 (50).

HRMS (ESI) calcd for C ₃₃ H ₅₃ N ₂ O ₃ m / z = 525.4056; measured: 525.4041.

Compound 8e: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2 '- (5-methylpropyl) -4'-dihydro [3', r] oxazine ) -5a, 9-pregn-1 (10) -en-16a-ol-1-one 8e

C ₃₁ H ₅₀ N ₂ O ₃

Appearance: light yellow solid Molecular weight: 498.74

63 mg (0.12 mmol, 1.0 eq) of N-3- (S) -secbutyrylcycloxobuxidine-F 6e are heated at 253 ° C under 0.04 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The pellet consists of product resulting from the opening of cyclopropane 7e while the sublimate is a mixture of this product 7e (85%) and dihydrooxazine 8e (15%). To a solution consisting of the pellet and sublimate previously obtained in 2 ml of dichloromethane are added 364 mg (0.60 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation under vacuum, the red residue heated at 253 ° C. under 0.04 mmHg for 3 hours gives 49 mg of 8e in the form of a sublimed light yellow solid with a yield of 80%.

IR (CHCl ₃ ) υ (cm ⁴ ): 3433 (OH, NH); 1694 (C = O); 1659 (C = N); 1040 (C-OH). Mass (ESI): m / z: 499.4 ([M + H], 100); 500.4 (50).

HRMS (ESI) calcd. For C ₃₁ H ₅₁ N ₂ O ₃ m / z = 499.3900; measured: 499.3917.

Compound 8f: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2 '- (2,2-dimethylbibyl) -4', 4'-dibydro [3 '] oxazine) -5α, 9 -pregn-1 (10) -en-16α-ol-11-one 8 [

C ₃₁ H ₅₀ N ₂ O ₃

Appearance: light yellow solid Molecular weight: 498.74

73 mg (0.14 mmol, 1.0 eq) of N-3-pivalylcycloxobuxidine-F 6f are heated at 250 ° C under 0.03 mmHg in a bulb oven. No sublimate is obtained. The pellet consists of 100% opening product cyclopropane 7f. To a solution of the sublimate in 2 ml of dichloromethane is added 416 mg (0.70 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation under vacuum, the red residue is heated. at 250 ° C under 0.03 mmHg for 3 hours provided 60.4 mg of 8f as a sublimated light yellow solid with a yield of 85%.

IR (CHCl ₃ ) υ (cm ⁴ ): 3373 (OH, NH); 1693 (C = O); 1655 (C = N); 1015 (C-OH).

Mass (ESI): m / z: 499.4 ([M + H], 100); 500.4 (40).

HRMS (ESI) calcd. For C ₃₁ H ₅₁ N ₂ O ₃ m / z = 499.3900; measured: 499.3868. Compound 8g: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2 '- (1-benzyl) -4', 4'-dihydro [3 '] oxazine) -5a, 9-pregn-1 (10) -en-16α-ol-11-one 8g

C ₃₄ H ₄₈ N ₂ O ₃

Appearance: light yellow solid Molecular Weight: 532.76

240 mg (0.43 mmol, 1.0 eq) of N-3-phenylacetylcycloxobuxidine-F 6g are heated at 260 ° C under 0.03 mmHg in a bulb oven. No sublimate is obtained in 3 hours. The product contained in the pellet consists of a product mixture resulting from the opening of cyclopropane 7g (74%) and dihydrooxazine 8g (26%). To a solution consisting of the mixture previously obtained in 2 ml of dichloromethane is added 926 mg (1.57 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation under vacuum, the red residue heated at 260 ° C under 0.03 mmHg for 3 hours provides 125 mg of 8g as a light yellow solid in the pellet with a yield of 55%. Elemental analysis: Calculated for C ₃₄ H ₄₈ N ₂ O ₃ 1.5H ₂ O: C: 72.98; H, 9.12;

N: 5.00; measured C, 73.11; H, 8.98; N: 4.74.

IR (CHCl ₃ ) υ (cm ⁴ ): 3411 (OH, NH); 1694 (C = O); 1665 (C = N); 1039 (C-OH).

Mass (ESI): m / z: 533.3 ([M + H], 100); 534.4 (50). HRMS (ESI) calcd for C ₃₄ H ₄₉ N ₂ O ₃ m / z = 533.3743; measured: 533.3747. Compound 8h: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2 '- (1-methylpropyl) -4', 4 'dihydro [3', l '] oxazine) -5a, 9-pregn-1 (1θ) -en-16α-ol-11-one Sh

C ₃₁ Hs ₀ N ₂ O ₃

Appearance: light yellow solid Molecular weight: 498.74

105 mg (0.20 mmol, 1.0 eq) of N-3-secbutyrylcycloxobuxidine-F 6f are heated at 257 ° C under 0.10 mmHg in a bulb oven. A sublimate is obtained in 3 hours. The sublimate consists of a mixture of the desired product 7f (85%) and dihydroxazine 8f (15%). To a solution of the residue (pellet and sublimate) in 2 ml of dichloromethane is added 597 mg (1.01 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation under vacuum, the red residue heated at 260 ° C. under 0.1 mmHg for 5 hours gives 30.0 mg of a mixture of two diastereoisomers (50/50) 8f in the form of a pale yellow solid sublimed with a 30% yield.

IR (CHCl ₃ ) υ (cm ⁴ ): 3361 (OH); 1695 (C = O); 1651 (C = N); 1097 (C-OH).

Mass (ESI): m / z: 499.3 ([M + H], 100); 500.4 (20); 559.4 (40); 250.2 (20).

HRMS (ESI) calcd. For C ₃₁ H ₅₁ N ₂ O ₃ m / z = 499.3900; measured: 499.3900.

It is a racemic mixture of two diastereoisomers. Compound 8i: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2 '- (1-ethanylpropyl) -4', 4'-dibydro [3 '] oxazine) -5a, 9-pregn-1 (10) -en-16α-ol-11-one Si

Appearance: light yellow solid Molecular Weight: 512.76

85 mg (0.14 mmol, 1.0 eq) of N-3-secpentyrylcycloxobuxidine-F 6i are heated at 250 ° C under 0.08 mmHg in a bulb oven. The starting material partially sublimates in 3 hours. The sublimate consists of a mixture of the product of opening cyclopropane 7i (90%) and dihydrooxazine 8i (10%). To a solution of the residue (pellet and sublimate) in 2 ml of dichloromethane is added 472 mg (0.80 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation in vacuo, red residue heated at 260 ° C under 0.1 mmHg for 3 hours provides 40.0 mg of 8i as a sublimated light yellow solid with a yield of 49%.

IR (CHCl ₃ ) υ (cm ⁴ ): 3287 (OH); 1694 (C = O); 1658 (C = N); 1167 (C-OH). Mass (ESI): m / z: 513.3 ([M + H], 100); 514.3 (80); 531.4 (10); 257.2 (20); 257.7 (10).

HRMS (ESI) calcd for C ₃₂ H ₅₃ N ₂ O ₃ m / z = 513.4056; measured: 513.4045. 4.2. Syntheses of the compounds 9. U and 12 (tetrahydrooxazinesi The 1 ', 2', 4 ', 4'-tetrahydrooxa 2: ines 9 and 10 were prepared in an original manner. The condensation of isobutyraldehyde with cycloxobuxidine-F in 1,4-dioxane at 50 ° C led to the formation of 9 with a yield of 30% (Scheme 4).

Figure 4

Compound 11 is obtained in two stages from amide 3. In an acid medium, in the presence of 2N sulfuric acid and methanol, the isobutyraldehyde group migrates on the primary alcohol to give the corresponding ester which is then hydrolyzed (Scheme 5).

Figure 5

Compound 9: (20S) -9,19-Cyclo-4, 14α-dimethyl-20-dimethylamino- (2'-isopropyl-1 ', 2', 4 ', 4'-tetrahydro [3]] oxazine ) -5a, 9-pregnan-16α-ol-11-one 9

Appearance: colorless powder

Molecular weight: 486.73 To a suspension of 87 mg (0.20 mmol, 1.0 eq) of cycloxobuxidine-F 5 derivative in 15 ml of 1,4-dioxane is added 37 ml (0.40 mmol, 2.0 eq.) D isobutyraldehyde.

After stirring for 12 hours at 50 ° C., the reaction medium is cooled to room temperature and evaporated under reduced pressure. The liquor obtained is alkalinized with 30 ml of a 10% sodium bicarbonate solution and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product (105 mg) is triturated in diethyl ether. After filtration, washing and drying under reduced pressure, 28 mg of 9 in the form of a colorless powder are obtained with a yield of 30%. IR (CHCl ₃ ) υ (cm ⁴ ): 3319 (OH, NH); 1663 (C = O); 1096 (C-OH).

Mass (ESI): m / z: 487.3 ([M + H], 100); 488.4 (30).

HRMS (ESI) calcd for C ₃₀ H ₅₁ N ₂ O ₃ m / z = 487.3900; measured: 487.3897.

• Compound 11: 10 (9-> 1) beocycloxobuxi-1 (10) -enedin-F 11 or (20S) -10 (9-> 1) abeo-3-amino-4a-hydroxymethyl-4, 14a-dimethyl- 20-Dimethylamino-5α, 9-pregn-1 (10) -en-16α-ol-11-one 11

C ₂₆ H ₄₄ N ₂ O ₃

Appearance: colorless powder

Molecular weight: 432.64

250 mg (0.50 mmol, 1.0 eq) of N-3-isobutyrylcycloxobuxidine-F 2 are heated at 245 ° C under 0.1 mmHg in a bulb oven. A sublimate is obtained in 3 hours. Sublimate is a mixture of cyclopropane 3 opening product (18%) and dihydrooxazine 1 (82%). The remaining pellet consists of the product of opening of the cyclopropane 3. To a solution of 250 mg of the residue composed of the pellet and sublimate previously obtained in 15 ml of methanol are added 36 ml of a 2N aqueous sulfuric acid solution. drop by drop at room temperature. After stirring for 2 hours at 90 ° C., the reaction medium is cooled to room temperature and evaporated under reduced pressure at most at 25 ° C. The resulting liquor is heated at 80 ° C. It is colored yellow. The reaction mixture is basified with 40 ml of a 10% ammonia solution and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product is triturated in ethyl acetate. After filtration, washing and drying under reduced pressure, 128 mg of 11 in the form of a colorless solid are obtained with a yield of 60%, whose spectroscopic characteristics are identical to those described by Herlem-Gaulier, D. et al; (1968).

Mp (° C): 266 Elemental Analysis: Calculated for C ₂₆ H ₄₄ N ₂ O ₃ -O ₅ SH ₂ O: C: 70.71; H:

10.27; N, 6.34; O, 12.68; measured: C, 70.67; H, 10.31; N, 6.19; O, 12.08.

IR (CHCl ₃ ) υ (cm ⁴ ): 3383 (OH, NH); 1693 (C = O); 1602 (C-NH); 1038 (C-OH).

Mass (ESI): m / z: 433.3 ([M + H], 100). HRMS (ESI) calcd for C ₂₆ H ₄₅ N ₂ O ₃ m / z = 433.3430; measured: 433.3415.

Compound 12: (20S) -10 (9-> 1) abeo-4,14a-dimethyl-20-dimethylamino- (2'-isopropyl) -1,4-tetrahydro [3 ', r] oxazine ) -5a, 9-pregn-1 (1θ) -en-16α-ol-11-one 12

Appearance: light yellow solid Molecular Weight: 486.73

To a suspension of 85 mg (0.20 mmol, 1.0 eq) of the derivative (9-> 1) beocycloxobuxi-1 (10) -enedin-F 11 in 10 ml of 1,4-dioxane is added. ml (0.40 mmol, 2.0 eq) of isobutyraldehyde. After stirring for 12 hours at 50 ° C., the reaction medium is cooled to room temperature and evaporated under reduced pressure. The liquor obtained is alkalinized with 40 ml of a 10% solution of sodium bicarbonate and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product (94 mg) is triturated in diethyl ether. After filtration, washing and drying under reduced pressure, 40 mg of 12 in the form of a colorless powder are obtained with a yield of 42%. whose spectroscopic characteristics are identical to those described by Herlem-Gaulier, D. et al; (1968). Mp (° C): Elemental analysis: Calculated for C ₃₀ H ₅₀ N ₂ O ₃ : C, 74.03; H, 10.35; NOT :

5.76; O, 9.86; measured: C, 73.38; H, 10.54; N, 5.63, O, 9.93.

IR (CHCl ₃ ) υ (cm ⁴ ): 3442 (OH, NH); 1693 (C = O); 1044 (C-OH). Mass (ESI): m / z: 487.4 ([M + H], 100).

HRMS (ESI) calcd for C ₃₀ H ₅₁ N ₂ O ₃ m / z = 487.3900; measured: 487.3909. Example 5 Synthesis of Compounds 13 to 32 Synthesis of compounds having a function modified in 29:

Compounds having an imine function or ester at position 29 have been prepared from alcohol 2.

Compound 2 in the presence of benzyl bromide leads to monobenzyl compound 27 in position 29. Compounds 13 and 17 monoesterified on the alcohol function at 16 were obtained by the action of acetic or pivalic anhydride on compound 2. The alcohol function The primary compounds 13 and 17 are oxidized to the corresponding aldehyde 14 and 18. These aldehydes lead to imines 16 and 19 by reaction with benzylamine. It will be noted that the two primary and secondary alcohol functional groups of compound 2 are esterified by the action of pivalyl chloride to form compound 20 (Scheme 6).

(64%)

16Fk = COCH ₃ (90%) ssns purification 19 Fk = COGiH ₉ i purification S my 6

The primary alcohol function of the esters 13 and 17 was converted into sulfonate by the action of tosyl chloride or methanesulfonyl chloride to form the products 22 to 25 after prior protection of the tertiary amine function at the 20-position in salt form by reaction with p-toluenesulfonic acid (Scheme 7).

30miti

= PhCH ₃ (44%) PhCH ₃ (54%) = CH ₃ (13%) CH ₃ (36%)

Figure 7

Reduction of ketone in 11.

The ketone function of compound 5 was diastereoselectively reduced by the action of AlH ₄ to form the alcohol 28 (Scheme 8).

S my 8

Synthesis of Nor-N-isobutyrylcyclobuxidine-F2 30.

Compound 30 was prepared in two steps from N-isobutyrylcycloxobuxidine-F 2. The nitrogen atom of 2 is oxidized to N-oxide by the action of p-chloroperbenzoic acid to drive with a yield of 79%. This compound is then subjected to a non-classic demethylation reaction in the presence of iron salts to yield the demethylated compound in 76% yield (Scheme 9).

S my 9

Synthesis of an isomer of 1

The synthesis of an isomeric compound of 1 in which an OC, β-ethylenic ketone function is present was carried out in two stages. The first step is an opening reaction of the cyclopropane in the presence of a Lewis acid. The second step is the formation of the dihydrooxazine ring. The enone 31 thus obtained is then heated to high temperature in the presence of triethylammonium hydroxide to give the pentacyclic compound 32.

5 eq. mmHg

Figure 10

Compound 13: (20S) -16α-acetyl-3-isobutyrylamino-9,19-cyclo-4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregnan-11-one 13

C ₃₂ H ₅₂ N ₂ O ₅

Appearance: colorless powder

Molecular weight: 544.77

To a solution of 1007 mg (2.0 mmol, 1.0 eq) of N-3-isobutyrylcycloxobuxidine-F 2 in 100 ml of dichloromethane and 30 ml of pyridine are added 568 μl (6.0 mmol, 3.0 eq.) of acetic anhydride. The solution is light yellow. After stirring for 2 days at room temperature, the mixture is co-evaporated in the presence of 1,2-dichloroethane. The residue thus obtained is purified by chromatography on silica gel (eluent: dichloromethane 9 / methanol 1) to give 820 mg of 13 in the form of a colorless powder after recrystallization from acetone in a yield of 75%.

PF (° C): 312 Elemental analysis: for C ₃₂ H ₅₂ N ₂ O ₅

Calcd for C ₃₂ H ₅₂ N ₂ O ₅ % C 70.55 H 9.62 N 5.14

O, 14.68

Found% C 70.64 H 9.84 N 4.89 O

14.48 IR (diamond) υ (cm ⁴ ): 3276 (OH, NH); 1729 (C = O ester) and 1667 (C = O); 1632 and 1555 (CONH); 1044 (C-OH). Mass

(ESI): m / z: 545.4 ([M + H], 100); 546.4 (5); 503.4 (60). HRMS (ESI) calcd for C ₃₂ H ₅₃ N ₂ O ₅ m / z = 545.3954; found: 545.3960.

Compound 14: (20S) -16a-acetyl-3-isobutyrylamino-9,19-cyclo-4α-formyl-4, 14α-dimethyl-20-dimethylamino-5α, 9-pregnan-11-one 14

C ₃₂ H ₅₀ N ₂ O ₅

Appearance: colorless powder

Molecular weight: 542.75

To a solution of 200 mg (0.36 mmol, 1.0 eq.) Of 16-O-acetyl-N-3-isobutyrylcycloxobuxidine-F 13 in 20 ml of dichloromethane is added 209 mg. (0.47 mmol, 1.3 eq.) Of Dess-Martin periodinane. The solution becomes cloudy and becomes pink. After stirring for 16 hours at room temperature, the mixture is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is purified by flash chromatography on silica gel (eluent: dichloromethane 95 / methanol 5) to provide 127 mg of IA in the form of a colorless powder with a yield of 64%.

IR (CHCl ₃ ) υ (cm ⁴ ): 3497 (OH, NH); 2773 (CHO); 1728 (C = O); 1656 and 1517 (CONH);

1096 (C-OH).

Mass

(ESI): m / z: 543.4 ([M + H], 100); 501.4 (5).

HRMS (ESI) calculated for C ₃₂ H ₅₁ N ₂ O ₅ m / z = 543.3798; found: 543.3784. Compound 16: (20S) -16α-acetyl-3-isobutyrylamino-9,19-cyclo-4α-benzyliminomethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9β-pregnan-11-one 16

C ₃₉ H ₅₇ N ₃ O ₄

Appearance: colorless powder

Molecular weight: 631.89 Under argon, to a suspension of 60 mg (0.11 mmol, 1.0 eq) of aldehyde i4 in

2 ml of dichloromethane are added 50 mg of anhydrous magnesium sulphate and 12 μl

(0.11 mmol, 1.0 eq) benzylamine. After stirring for 16 hours at room temperature, the mixture is filtered and then evaporated in vacuo to give 65 mg of i6 as a colorless powder with a yield of 92%.

IR (diamond) υ (cm ⁴ ): 2939 (NH, C = N); 1730 (C = O ester); 1659 (C = O, CONH, C = C and C = N); 1532 (CONH); 1245 (C = C).

Mass (ESI): m / z: 632.4 ([M + H], 50); 633.5 (5); 590.5 (10); 545.3 (100); 546.4

(50); 503.3 (80); 504.4 (10).

HRMS (ESI) calcd for C ₃₉ H ₅₈ N ₃ O ₄ m / z = 632.4427; found: 632.4443.

• Compound 17: (20S) -16α-pivalyl-3-acetylamino-9,19-cyclo-4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregnan-11-one 17

C ₃₅ H ₅₈ N ₂ O ₅

Appearance: colorless powder

Molecular weight: 586.85

To a solution of 400 mg (0.80 mmol, 1.0 eq) of N-3-isobutyrylcycloxobuxidine-F 2 in 2.0 ml of pyridine is added 0.48 ml (2.40 mmol, 3.0 eq. .) pivalic anhydride. The solution is light yellow. After stirring for 5 hours at 90 ° C., the mixture is co-evaporated in the presence of 1,2-dichloroethane. The residue thus obtained is purified by flash chromatography on silica gel (eluent: dichloromethane 9 / methanol 1) to give 400 mg of 17 as a colorless powder with a yield of 85%.

IR (diamond) υ (cm ⁴ ): 3434, 2972 (OH, NH); 1711 (C = O ester); 1655 and 1514 (C = O and

CONH); 1175 (C-OH).

Mass

(ESI): m / z: 587.5 ([M + H], 100); 588.4 (5).

HRMS (ESI) calcd for C ₃₅ H ₅₉ N ₂ O ₅ m / z = 587.4424; found: 587.4417. • Compound 18: (20S) -16α-pivalyl-3-isobutyrylamino-9,19-cyclo-4α-formyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregnan-11-one 18

Appearance: colorless powder Molecular Weight: 584.83

To a solution of 74 mg (0.12 mmol, 1.0 eq) of 16-O-pivalyl-N-3-isobutyrylcycloxobuxidine-F7 in 5 ml of dichloromethane is added 72 mg (0.16 mmol, 1%). 3 eq.) Of Dess-Martin periodinane. The solution becomes cloudy and becomes pink.

After stirring for 16 hours at ambient temperature, the mixture is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The residue thus obtained is purified by flash chromatography on silica gel (eluent: dichloromethane 95 / methanol 5) to give 44 mg of i8 as a colorless powder with a yield of 62%.

IR (diamond) υ (cm ⁴ ): 2966 (NH, CHO); 1720 (C = O ester); 1665 and 1528 (C = O and CONH).

Mass

(ESI): m / z: 585.4 ([M + H], 100); 586.4 (45).

HRMS (ESI) calcd for C ₃₅ H ₅₇ N ₂ O ₅ m / z = 585.4267; found: 585.4281. Compound 19: (20S) -16α-pivalyl-3-isobutyrylamino-9,19-cyclo-4α-benzyliminomethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregnan-11-one 19

C ₄₂ H ₆₃ N ₃ O ₄

Appearance: colorless powder

Molecular weight: 673.97

Under argon, to a suspension of 113 mg (0.19 mmol, 1.0 eq) of aldehyde 18 in 3 ml of dichloromethane is added 94 mg of anhydrous magnesium sulphate and 21 μl (0.19 mmol, 1, 0 eq.) Of benzylamine. After stirring for 24 hours at room temperature, the mixture is filtered and evaporated in vacuo to give 119 mg of i9 as a colorless powder with a yield of 92%.

IR (diamond) υ (cm ⁴ ): 2966 (NH); 1720 (C = O ester); 1662 and 1532 (C = O and CONH); 1156 (C = Q. Mass

(ESI): m / z: 674.4 ([M + H], 100); 675.5 (10).

HRMS (ESI) calculated for C ₄₂ H ₆₄ N ₃ O ₄ m / z = 674.4897; found: 674.4885. Compound 20: (20S) -16α-Pivalyl-3-isobutyrylamino-9,19-cyclo-4α-pivalylmethyl-4, 14α-dimethyl-20-dimethylamino-5α, 9 -pregnan-11-one

C ₄₀ H ₆₆ N ₂ O ₆

Appearance: colorless powder

Molecular weight: 670.96

To a solution of 400 mg (0.80 mmol, 1.0 eq.) Of N-3-isobutyrylcycloxobuxidine-F 2 in 2.0 ml of pyridine is added, dropwise, 0.3 ml (2.40 mmol, 3.0 eq.) of pivalyl chloride at room temperature. The reaction is exothermic. The solution becomes cloudy and becomes pale yellow. The formed precipitate is redissolved in 30 minutes. After stirring for 1 hour at ambient temperature, the mixture is co-evaporated in the presence of 1,2-dichloroethane.

The residue thus obtained is purified by flash chromatography on silica gel (eluent: dichloromethane 9 / methanol 1) to provide 240.5 mg of 20 as a colorless powder with a yield of 45%.

IR (diamond) υ (cm ⁴ ): 3440, 2974 (OH, NH); 1715 (C = O ester); 1668 and 1507 (C = O and CONH); 1171 (C-OH). Mass

(ESI): m / z: 671.5 ([M + H], 100); 672.5 (5).

HRMS (ESI) calcd for C ₄₀ H ₆₇ N ₂ O ₆ m / z = 671.4999; found: 671.4985 • Compound 21: (20S) -16α-acetyl-3-isobutyrylamino-9,19-cyclo-4α-hydroxymethyl-4, 14α-dimethyl-20-dimethylhydrogenoamino-5α, 9-pregnan-11-Tosylate -one 21

C ₃₉ H ₆₀ N ₂ O ₅ S

Appearance: colorless powder

Molecular weight: 716.97

To a solution of 20 mg (0.04 mmol, 1.0 eq.) Of 16-O-acetyl-N-3-isobutyrylcycloxobuxidine-F 2 in 2.0 ml of methanol is added 7 mg (0.04 mmol, 1.0 eq.) Of p-toluenesulphonic acid, in the presence of an anhydrous sodium sulfate spatula tip, at room temperature. After stirring for 30 minutes at room temperature, the suspension is filtered and evaporated under reduced pressure, to give 26 mg of 2i in the form of a colorless powder with a yield of 99%. IR (diamond) υ (cm ⁴ ): 3492, 2931 (OH, NH); 1732 (C = O); 1642 and 1546 (CONH); 1120 (C-OH); 1381 and 1170 (S = O); 1032 (CO); 816 (SO). Mass

(ESI): m / z: 545.4 ([M + H], 100); 546.4 (5); 503.4 (50); 413.3 (10). HRMS (ESI) calcd for C ₃₂ H ₅₃ N ₂ O ₅ + m / z = 545.3954; found: 545.3939. Compound 22: (20S) -16α-pivalyl-3-isobutyrylamino-9,19-cyclo-4α-tosylmethyl-4,4a-dimethyl-20-dimethylamino-5α, 9 -pregnan-1-one 22

C ₄₂ H ₆₄ N ₂ O ₇ S

Appearance: yellow powder

Molecular weight: 741.03

To a solution of 100 mg (0.17 mmol, 1.0 eq) of 16-O-pivalyl-N-3-isobutyrylcycloxobuxidine-17 and 32 mg (0.17 mmol, 1.0 eq. p-toluenesulfonic acid in 3 ml of methanol is added an anhydrous sodium sulfate spatula. The suspension is stirred for 30 minutes, then is filtered and evaporated under vacuum.

To a solution of the salt previously obtained in 3 ml of pyridine are added

99 mg (0.52 mmol, 3.0 eq) of tosyl chloride. The solution is colored lemon yellow.

After stirring for 5 hours at 90 ° C., the solution is evaporated under vacuum in the presence of 1,2-dichloroethane. The residue is taken up with 30 ml of dichloromethane and then washed with 30 ml of 10% sodium hydrogen carbonate solution (pH = 8) and extracted with 3 × 30 ml. dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on a silica plate preparative chromatography (eluent: dichloromethane 9 / methanol 1) to afford 55 mg of 22 _^ in the form of a yellow powder with a yield of 44%.

23: (20S) -16α-acetyl-3-isobutyrylamino-9,19-cyclo-4α-hydroxytosylmethyl-4,4a-dimethyl-20-dimethylamino-5α, 9-pregnan-1-one 23

C ₃₉ H ₅₈ N ₂ O ₇ S

Appearance: yellow powder

Molecular weight: 698.95

To a solution of 100 mg (0.18 mmol, 1.0 eq.) Of 16-O-acetyl-N-3-isobutyrylcycloxobuxidine-F 13 and 35 mg (0.18 mmol, 1.0 eq.) D p-toluenesulfonic acid in 1.5 ml of methanol is added an anhydrous sodium sulfate spatula. The suspension is stirred for 30 minutes, then filtered and evaporated under vacuum.

To a solution of the previously obtained salt in 2.5 ml of pyridine is added 91 mg (0.48 mmol, 2.6 eq.) Of tosyl chloride. The solution is colored lemon yellow. After stirring for 5 hours at 100 ° C., the solution is evaporated under vacuum in the presence of 1,2-dichloroethane. The residue is taken up with 20 ml of dichloromethane and then washed with 30 ml of a solution of 10% sodium hydrogen carbonate (pH = 8) and extracted with 3x20 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is purified on 0.75 g of celite then 0.75 g of florysil (magnesium trisilicate). Finally, the residue is purified by flash chromatography on silica gel (eluent: 9 dichloromethane / methanol 1) to provide 64 mg of 23 as a yellow powder with a yield of 50%. IR (diamond) υ (cm ⁴ ): 2932 (NH); 1729 (C = O ester); 1667 (CO, CONH and C = Q, 1526 (CONH), 1244, (C = C), 1357 and 1174 (S = O), 1095 (CO), 835 (SO).

(ESI): m / z: 699.2 ([M + H], 100); 700.3 (30); 657.3 (45); 587.3 (30). HRMS (ESI) calcd for C ₃₉ H ₅₉ N ₂ O ₇ S m / z = 699.4043; found: 639.4039. Compound 27: (20S) -3-isobutyrylamino-9,19-cyclo-4-benzylhydroxymethyl-4, 14α-dimethyl-20-dimethylamino-29-tosyl-5α, 9-pregnan-16α-ol-11-one 27

C ₃₇ H ₅₆ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 592.85 Under argon, to a solution at 0 ° C. of 300 mg (0.59 mmol, 1.0 eq.) Of N-3-isobutyrylcycloxobuxidine-F 2 in 2 ml of dimethylformamide is added 0.22 ml (1.80 mmol). , 3.0 eq.) Of benzyl bromide. The solution is stirred for 10 minutes at 0 ° C. Then 60 mg of sodium hydride (1.5 mmol, 2.5 eq) are added in several times. After 24 hours stirring at room temperature, the excess of sodium hydride is destroyed with methanol and the solution is concentrated in the presence of toluene.

The residue is taken up with 20 ml of dichloromethane and then washed with 30 ml of a solution of 10% sodium hydrogen carbonate (pH = 8) and extracted with 3x20 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is purified by flash chromatography on silica gel (eluent: dichloromethane 9 / methanol 1) to provide 131 mg of 27 in the form of a colorless powder with a yield of 37%.

IR (diamond) υ (cm ⁴ ): 3321, 2932 (OH, NH); 1649 (C = O and C = Q, 1649 and 1531 (CONH), 1225 (C = C), 1092 (C-OH).

(ESI): m / z: 593.4 ([M + H], 100); 594.5 (10). HRMS (ESI) calculated for C ₃₇ H ₅₇ N ₂ O ₄ m / z = 593.4318; found: 593.4311.

Compound 28: (20S) -3-amino-9,19-cyclo-4α-hydroxymethyl-4,4-dimethyl-20-dimethylamino-5α, 9 -pregnan-16α, 11-diol-11-one

C ₂₆ H ₄₆ N ₂ O ₃

Appearance: colorless powder

Molecular weight: 434.66

Under argon, a solution of 300 mg (0.69 mmol, 1.0 eq) of amine 5 in 25 ml of 1,4-dioxane is added 353 mg (9.01 mmol, 13.0 eq.) of lithium aluminum hydride. After stirring for 12 hours at room temperature, the mixture is hydrolyzed with 0.35 ml of water, then 0.35 ml of 6N sodium hydroxide and 1.05 ml of water. The gray suspension decolors and is filtered and evaporated in vacuo to provide 190 mg of 28 as a colorless powder after trituration in diethyl ether in 63% yield. IR (CHCl ₃ ) υ (cm ⁴ ): 3382 (OH, NH); 1037 (C-OH).

Mass

(ESI): m / z: 435.4 ([M + H], 100); 436.4 (5); 418.4 (10).

HRMS (ESI) calcd for C ₂₆ H ₄₇ N ₂ O ₃ m / z = 435.3587; found: 435.3581. 29: (20S) -3-isobutyrylamino-9,19-cyclo-4-hydroxymethyl-4, 14α-dimethyl-20-dimethylazinoyl-5α, 9 -pregnan-16α, 11 -ol-11-one 29

C ₃₀ H ₅₀ N ₂ O ₅

Appearance: colorless powder

Molecular weight: 518.73

To a solution of 202 mg (0.40 mmol, 1.0 eq.) Of N-3-isobutyrylcycloxobuxidine-F 2 in 6 ml of dichloromethane is added 95 mg (0.55 mmol, 1.4 eq.) Of m-chloroperbenzoic acid. After stirring for 30 minutes at room temperature, the mixture is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is triturated in diethyl ether to give 165 mg of 29 as a colorless powder in 79% yield.

IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1655 (C = O); 1655 and 1513 (CONH); 1049 (C-OH).

Mass

(ESI): m / z: 519.3 ([M + H], 100); 520.3 (10); 480.3 (20); 440.3 (30); 370.3 (20); 353.2 (10); 341.2 (25); 323.2 (25).

HRMS (ESI) calcd for C ₃₀ H ₅₁ N ₂ O ₅ m / z = 519.3798; found: 519.3770.

• Compound 30: (20S) -3-isobutyrylamino-9,19-cyclo-4-hydroxymethyl-4, 14α-dimethyl-20-methylamino-5α, 9 -pregnan-1α-ol-11-one

Appearance: colorless powder Molecular Weight: 488.70

To a solution of 29.5 mg (0.06 mmol, 1.0 eq) of N-oxide 29 in 3 ml of methanol is added 32 mg (0.11 mmol, 2.0 eq) of iron sulfate. II heptahydrate and 15 mg (0.06 mmol, 1.0 eq) of iron chloride III hexahydrate. The solution is orange. After stirring for 1 hour and 30 minutes at room temperature, the mixture is evaporated under vacuum. The residue is basified with 10 ml of a 10% sodium carbonate solution. A greenish precipitate forms and is filtered on celite. The filtrate is rinsed with water and then with dichloromethane. The filtered solution is acidified with 30 ml of a 1.0 M acetic acid / sodium acetate buffer solution (pH = 4.8). After stirring for 15 minutes, the solution is basified with 30 ml of a 10% ammonic solution (pH = 10) and extracted with 5 × 40 ml of dichloromethane. The combined organic phases are successively washed with 20 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum.

The residue is triturated in diethyl ether to provide 21 mg of 30 as a colorless powder with a yield of 76%. IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1655 (C = O); 1655 and 1514 (CONH); 1093 (C-OH). Mass

(ESI): m / z: 489.3 ([M + H], 100); 503.4 (40). HRMS (ESI) calcd for C ₂₉ H ₄₉ N ₂ O ₄ m / z = 489.3692; found: 489.3688. Compound 31: (20S) -9 (10-> 19) abeo-4? -Droxymethyl-3-isobutyrylamino-4,4a-dimethyl-20-dimethylamino-5a, 9-pregn-1 (10) -en-16a ol- 11-one 31

C ₃₀ H ₅₀ N ₂ O ₄

Appearance: colorless powder

Molecular weight: 502.73

Under argon, to a solution of 400 mg (0.80 mmol, 1.0 eq.) Of N-3-isobutyrylcycloxobuxidine-F 2 in 30 ml of dichloromethane is added, dropwise, 2.6 ml (24, 0 mmol, 30.0 eq.) Of titanium chloride at -78 ° C. The solution becomes yellow. After stirring for 30 minutes at -78 ° C., the solution is stirred at room temperature. The mixture is colored in dark green.

After stirring for 2 hours at room temperature, the mixture is alkalized with

100 ml of a 10% ammonia solution (pH = 10) and extracted with 3x75 ml of dichloromethane. The combined organic phases are successively washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated under vacuum.

The residue thus obtained is purified by chromatography on alumina (eluent: 99.7 dichloromethane / 0.3 methanol) to provide 185 mg of 3J in the form of a colorless powder with a yield of 46%. PF (° C): 312

Elemental analysis: for C ₃₀ H ₅₀ N ₂ O ₄ Calculated for C ₃₀ H ₅₀ N ₂ O ₄ .0.5H ₂ O% C 70.41 H 10.05 N

5.47

Found% C 70.84 H 9.71 N

5.21 IR (CHCl ₃ ) υ (cm ⁴ ): 3434 (OH, NH); 1675 (C = O); 1651 (C = C and CONH); 1514 (CONH); 1040 (C-OH).

Mass

(ESI): m / z: 503.3 ([M + H], 100); 504.4 (90). HRMS (ESI) calcd for C ₃₀ H ₅₁ N ₂ O ₄ m / z = 503.3849; found: 503.3843.

Compound 32: (20S) -9 (10-> 19) abeo-4,14a-dimethyl-20-dimethylamino- (2'-isopropyl-4 ', 4'-dihydro [3', r] oxazine) -5a, 9-pregn-1 (10) -en-16-ol-11-one 32

Appearance: light yellow solid

Molecular weight: 484.71

To a solution of 100 mg (0.20 mmol, 1.0 eq) of 3M amide in 2 ml of dichloromethane is added 586 mg (1.00 mmol, 5.0 eq) of a hydroxide solution. 25% tetraethylammonium in methanol. After evaporation in vacuo, the red residue heated at 300 ° C. under 0.03 mmHg for 4 hours gives 60 mg of 32 as a non-sublimed light yellow solid with a yield of 62%. Elemental analysis: for C ₃₀ H ₄₈ N ₂ O ₃

Calculated for C ₃₀ H ₄₈ N ₂ O ₃ .0,5H ₂ O 72.98% C lO H ₅ OO N

5.67

Found% C 72.61 H 9.65 N 5.64

Mass

(ESI): m / z: 485.4 ([M + H], 100); 486.4 (10); 503.4 (20).

HRMS (ESI) calculated for C ₃₀ H ₄₂ N ₂ O ₃ m / z = 485.3743; found: 485.3702.

Example 6: Biological Results The antiacetylcholinesterase (AChE isolated from E / ectrvphocus ekctήcus) and anti-butyrylcholinesterase (BChE isolated from human serum) activities were determined using the Ellman spectroscopic method (Ellman, GL et al, Biochem Pharmacol, 1961). , 7, 88-95). The results are summarized in Table 1.

The values given for galanthamine, tacrine and eserine serve as reference (360 and 74 for anti-AchE activity, and 18600, 58 and 800 for anti-BchE activity).

Table 1. In vitro inhibition of acetylcholinesterase (AChE) isolated from Electrophorus ekctήcus and human serum butyrylcholinesterase (BChE).

compound AChE BChE compound AChE BChE

^IC 50 ^IC 50

(nM) (nM)

1 31> 1000 8th 13> 1000

2> 10000> 10000 8f 225> 10000

3 9380 7407 8g 4205> 10000

5> 5000> 30000 8h 27 1535

6b> 10000 2215 8i 102 380

6d> 10000> 5000 9 2377> 10000

6g> 5000 30000 11 1498> 10000

6h> 100000 121 12 823> 10000

7b> 10000 1878 13> 10000> 1000

7d> 1000 4022 14> 1000> 1000

7c>1000> 10000 19> 1000 1277 7th 105> 10000 23 4368> 100,000

7f 4832> 1000 27 16768 5197

7g> 1000> 10000 28> 1000 2446

7h 120 1926 29 1418> 1000

7i 3270> 10000 32 112 1444

8a 676> 10000

8b 7648> 10000

8c 607> 10000

8d 403 375 galanthamine 360 18 600 tacrine 74 58 eserine 800

Example 7 Study of Compound 8e at the Skeletal Neuromuscular Junction of Vertebrates

Compound 8e has been found to possess a potent inhibitory effect of acetylcholinesterase in vitro, as previously detailed (Table 1). To verify the efficacy and specificity of compound 8e at a cholinergic synapse model the inventors tested these effects at the level of neuromuscular preparations isolated from vertebrates (frog and mouse) maintained in survival. To do this, they used conventional techniques of cellular electrophysiology. Compound 8e at doses between 1-25 μM produces an extension of the half-decay time of synaptic responses (motor plaque potentials caused by nerve stimulation, and spontaneous miniature motorplate potentials). This prolongation of synaptic potentials is observed when mouse neuromuscular preparations are placed in a normal survival medium (Krebs-Ringer) containing (mM: NaCl, 151; KCl, 5; MgCl ₂ , 1; CaCl ₂ , 2; glucose, 11 and HEPES-NaOH, (pH 7.4), and when the survival medium contains low concentrations of CaCl ₂ (0.4-1 mM) and high concentrations MgCl ₂ (4-8 mM) to reduce release of acetylcholine The prolongation of synaptic potentials at the neuromuscular junction reflects the average life span of the acetylcholine-open synaptic channels in their interactions with nicotinic receptors in skeletal muscle.The inhibition of acetylcholinesterase increases the acetylcholine concentration at the synaptic cleft, which allows for repetitive acetylcholine at these receptors, thereby prolonging the duration of synaptic responses. The electrophysiological results obtained confirm that compound 8e does have an anticholinesterase effect at the level of neuromuscular preparations isolated from mice. Similar effects have been observed on neuromuscular frog junctions. At concentrations that prolong the duration of synaptic potentials, and even at higher concentrations (160-200 μM) compound 8e has no significant effect on the resting potential of muscle fibers. Thus the inhibition of acetylcholinesterase by this compound is not accompanied by a depolarization of the muscle membrane.

From a pharmacological point of view, the inventors first tested the ability of compound 8e to modify axonal nerve conduction. The results obtained indicate that this molecule, at doses of between 1 and 300 μM, does not visibly modify nerve conduction in the neuromuscular preparations of mice.

In a second step, the inventors have determined, by electrophysiology, the ability of compound 8e to interact with muscle nicotinic receptors with acetylcholine. The results obtained show that compound 8e, at a concentration of 80 μM, causes a decrease in the amplitude and a blockage of the miniature motorplate potentials (which reflect the release of a quantum of acetylcholine). In addition, synaptic responses (motor plaque potentials), recorded in response to motor nerve stimulation, and compounds of approximately 40 acetylcholine quanta, are also 80% blocked by 160 μM of compound 8e, both on neuromuscular junctions of frog than of mice. All of these results show that compound 8e produces a blockage of the interaction of acetylcholine with its muscle receptor sites. These results are not surprising, as most anticholinesterase agents also block muscle nicotine receptors with acetylcholine. However, it should be noted that the muscle nicotinic receptor blocking effect at acetylcholine occurs at concentrations well above those required to inhibit acetylcholinesterase from the skeletal neuromuscular junction, as has been observed for other inhibitors of acetylcholinesterase, such as galanthamine and tacrine. Compound 8e is active as an AChE inhibitor from 13 nM. It can therefore be used in a quantity that makes it possible to inhibit AchE while not blocking nicotinic muscle receptors with AChE. Therefore, the triterpene alkaloids according to the invention have no side effects when used at a dose to inhibit AChE.

Example 8 Synthesis of Compounds 33 to 76

17 R ₂ = COC ₄ H ₉ 18 R ₂ = COC ₄ H ₉ (62%) 43 R ₂ = COC ₄ H ₉ (22%)

Figure 11

3 steps over 2 steps

Figure 12

52

Figure 13

NaHCO ₃ ZNa ₂ CO ₃

Figure 14

76

Figure 15

10 Compound 33: (20S) -10 (9 → 1) abeo-20-methylamino-4α, 14α-dimethyl- (2'-isopropyl-3,29-dihydro-4H- [1,3] oxazine) -5 (x9 $ -pregn-1 (10) -en-16 (X-ol-11-one 33

100 mg (0.20 mmol, 1.0 eq) of IVor-IV-3-butyrylcycloxobuxidine-F are heated to 273 ° C under 0.09 mmHg in a bunker or sublimator. A solid sublimate is obtained in 3 hours. To a solution of the sublimate in 2 ml of dichloromethane is added 600 mg (1.02 mmol, 5.0 eq) of a solution of 25% tetraethylammonium hydroxide in methanol. After evaporation in vacuo, the red residue heated at 273 ° C under 0.09 mmHg for 3 hours gives 56 mg of 33 as a light yellow amorphous sublimate with a yield of 60%.

IR (CHCl ₃ ) υClN ¹ ): 3367 (OH, NH); 2964 (CH); 1697 (C = O); 1667 (C = N and C = C); 1074 (CO).

Compound 34: (20S) -20-dimethylamino-3β- (isobutyrylamino) -9,19-cyclo-4α-hydroxymethyl-4α, 14α-dimethyl-5α, 9β-pregnan-11α, 16α-diol- ll-one 34

To a solution of 127 mg (0.29 mmol, 1.0 eq) of amine 28 in 0.7 ml of dichloromethane and 0.3 ml of methanol are added 51 μl (0.30 mmol, 1.05 ml). eq.) of isobutyric anhydride. The solution is light yellow. After stirring for 6 hours at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is precipitated in diethyl ether to give 110 mg of 34 as a colorless powder in 75% yield.

Elemental analysis: for C ₃₀ H ₅₂ N ₂ O ₄ .0.5H ₂ O Calculated for C ₃₀ H ₅₂ N ₂ O ₄ -O ₅ SH ₂ O%: C 70.14 H 10.4ON 5.45 Measured%: C 74.21 H 10.19N 5.14 IR (diamond) O (Cm- ¹ ): 3275 (OH, NH); 2932 (CH, CH 2); 1633 and 1551 (CONH); 1039 (CO).

S. M. (S.I.I.): m / z: 50.5, 4 ([M + H], 100); 50 6, 4 (30). HRMS (ESI) calcd for C ₃₀ H ₅₃ N ₂ O ₄ m / z = 505.4005; measured: 505.3992.

Compound 35: (20S) -20-dimethylamino-3β - ((S) -2-methylbydyrylamino) -9,19-cyclo-4α-hydroxymethyl, 14α-dimethyl-5α, 9β-pregnan-11α, 16α -diol-ll-one 35

To a solution of 131 mg (0.30 mmol, 1.0 eq) of amine 28 in 0.7 ml of dichloromethane and 0.3 ml of methanol are added 67 μl (0.31 mmol, 1.05 g). eq.) of (S) -2-methylbutyric anhydride. The solution is light yellow. After stirring for 6 hours at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is precipitated in diethyl ether to give 124 mg of 35 as a colorless powder with a yield of 80%.

Elemental analysis: for C ₃ H ₅₄ N ₂ O ₄ · 0.5H ₂ O Calc'd for C ₃ H ₅₄ N ₂ O ₄ -O ₅ SH ₂ O%: C 70.55 H 10.50 N 5.31 Measured%: C 74.57 H 10.52N 4 , 77 LR. (diamond) O (Cm- ¹ ): 3305 (OH, NH); 2932 (CH, CH 2); 1641 and 1537 (CONH); 1038 (CO). MS (ESI): m / z: 519.4 ([M + H], 100); 520.4 (10); 603.5

(10). HRMS (ESI) calculated for C ₃ H ₅₅ N ₂ O ₄ m / z = 519.4162; measured: 519.4140.

• Compound 36: (20S) -3 $ -isobutyrylamino-20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl-4α-hydroxymethyl-16α-tosyl-5 (X, 9 $ -pregnan-11-one)

Under argon, to a solution of 52 mg (0.10 mmol, 1.0 eq) of N-3-zsobutyrylcycloxobuxidine-F 2 and 7 mg (0.07 mmol, 0.7 eq) of dimethylaminopyridine in 3 ml of pyridine is added 60 mg (0.30 mmol, 3.0 eq) of tosyl chloride. After stirring for 12 hours at room temperature, the solution is co-evaporated in the presence of 1,2-dichloroethane. The residue is taken up with 30 ml of dichloromethane and then washed with 30 ml of a solution of 10% sodium hydrogen carbonate (pH = 8) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on a preparative silica plate (eluent: dichloromethane 9 / methanol 1) to give 54 mg of 36 as a yellow powder with a yield of 80%.

IR (CHCl ₃ ) O (Cl- ¹ ): 3434 (OH, NH); 1662 (C = O); 1662 and 1511 (CONH); 1096 (C-OH);

1354 and 1173 (C-OTs).

S.M. (E.S.I.): m / z: 503.4 ([M + H], 100); 504.4 (10).

HRMS (ESI) calculated for C ₃₇ H ₅₇ N ₂ O ₆ S m / z = 657.3937; measured: 657.3954.

¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.53 (3H, s, H30); 0.72 (3H, d, J = 6.0 Hz, H21); 0.76 (3H, s, H18); 0.84 (1H, m, H6β); 1.04

(1H, d, J = 4.0 Hz, H19α); 1.12 and 1.14 (6H, 2d, J = 6.6Hz, H3 'and H4'); 1.16 (3H, s, H28);

1.24-1.67 (5H, m, H1a, H2β, H7α, H7β and H2β); 1.52 (1H, d, J = 4.0 Hz, H19β); 1.78 (6H, s,

NB-CH3); 1.89-2.03 (5H, m, H15α, H2α, H6α, H8β, and H5α); 2.14-2.19 (2H, m, H15β, and H17α); 2.27-2.50 (3H, m, H 2 ', H 2 O, H 1 B); 2.41 (3H, s, H37); 2.35 and 2.43 (4H, 2d, J = 17.3 Hz, H12α and H12β); 2.94 (1H, dd, J = 12.6 Hz and 13.4 Hz, H29a); 3.30 (1H, d, J = 12.6 Hz, H29b); 3.94 (1H, m, H3α); 4.76 (1H, m, OH); 4.90 (1H, m, H16β); 5.59 (1H, d, J = 8.9 Hz, NAH); 7.28 and 7.73 (4H, AB system, HAr = 32, 33, 35 and 36). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

9.9 (C21); 11.1 (C30); 17.7 (Cl 8); 18.3 (C6); 19.4 and 19.5 (C3 'and C4'); 20.1 (C28); 21.6 (C37); 24.3 (CT); 27.4 and 27.6 (C2 and Cl); 30.8 (Cl 9); 33.8 (C9); 35.6 (C2 '); 38.0 (ClO); 39.8 (NB-CH 3); 41.1 and 41.4 (C5 and C8); 42.6 (Cl 5); 44.1 (C4); 44.5 (C13); 47.4 (C14); 50.6 (C3); 51.6 (C12); 55.6 (Cl 7); 59.2 (C20); 63.9 (C29); 88.1 (Cl 6); 127.9 and 129.2 (CAr = 32, 33, 35 and 36); 135.0 and 143.9 (CAr = 31 and 34); 178.6 (Cl '); 210.8 (Cl 1).

37: 20S) -3-isobutyrylamino-20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl-4α-hydroxymethyl-6α-mesyl-5α, 9β-pregnan-11-one 37

To a solution of 52 mg (0.10 mmol, 1.0 eq) of iV-3-zj-obutyrylcycloxobuxidine-F 2 and 9 mg (0.07 mmol, 0.7 eq) of 4-dimethylaminopyridine in 3.0 ml of pytidine are added 24 μl (0.31 mmol, 3.0 eq.) Of mesyl chloride. The solution is colored yellow. After stirring for 16 hours at room temperature, the solution is co-evaporated with 1,2-dichloroethane. The residue is taken up in 20 ml of dichloromethane and then washed with 25 ml of deionized water and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is chromatographed on preparative silica plate (eluent: dichloromethane 9 / methanol 1) to give 50 mg of 37 as a colorless powder with a yield of 83%.

LR. (diamond) O (Cm- ¹ ): 2963 (CH, CH 2); 1654 (C = O); 1654 and 1512 (CONH); 1261 (C-OMs);

1351, 1169 (OMs); 1097 (C-O).

S.M. (E.S.I.): m / z: 581.3 ([M + H], 100); 582.3 (60); 583.4 (10).

HRMS (ESI) calcd for C ₃ H ₅₃ N ₂ O ₆ S m / z = 581.3624; measured: 581.3607.

¹ H NMR (300 MHz, CDCl ₃ / D ₂ O), δ ppm: 0.57 (3H, s, H ₃ O); 0.85 (3H, s, H18); 0.88 (3H, d, J = 6.9 Hz, H21); 0.95 (1H, m, H6β); 1.06 (1H, d, J = 3.0 Hz, H19β); 1.17 and 1.19 (6H, 2d, J = 6.4

Hz, H3 'and H4'); 1.21 (3H, s, H28); 1.26 (1H, m, H1a); 1.30-1.53 (3H, m, H7α, H15α and H7β);

1.58 (1H, d, J = 3.0 Hz, H19α); 1.54-1.75 (3H, m, H2β, H2α and H6α); 1.95-2.23 (3H, m, H8β,

H1 5β and H5α); 2.17 (6H, bs, NB-CH3); 2.29 (1H, dd, J = 5.5 Hz and 11.3 Hz, H17α); 2.40 (1H, dq, J = 6.4Hz, HZ); 2.39 (1H, d, J = 17.1Hz, H12β); 2.46 (1H, m, H, B); 2.51 (1H, m, H 2 O); 2.56 (1H, d, J = 17.1Hz, H12α); 2.96 (1H, d, 12.8 Hz, H29a); 3.02 (3H, s, H31); 3.34 (1H, d, J

= 12.8 Hz, H29b); 4.00 (1H, ddd, J = 4.5 Hz, 8.8 Hz and 10.6 Hz, H3α); 4.83 (1H, m, H16β);

5.35 (1H, d, J = 9.0 Hz, NAH).

¹³ C NMR (75.5 MHz, CDCl ₃ / D ₂ O), δppm: 10.0 (C21); 11.2 (C30); 17.6 (Cl 8); 18.4 (C6);

19.5 and 19.6 (C3 'and C4'); 20.2 (C28); 24.5 (Cl); 27.6 (C2); 27.7 (Cl); 31.1 (C19); 33.9 (C9); 35.8 (C2 '); 37.3 (C31); 38.2 (ClO); 41.2 (C5); 41.7 (C8); 44.1 (Cl 5); 44.5 (C13); 44.6 (C4); 47.4

(C14); 50.7 (C3); 51.6 (C12); 55.1 (C17); 59.9 (C20); 64.0 (C29); 88.5 (C16); 178.5 (Cl '); 210.8

(Eyelash).

Compound 38: (20S) -20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl-16α-pivalyl- (2'-isopropyl-329-dihydro-4H- [1,3] oxazine) -5a $ 9 -pregn-ll-one 38

Under argon, a solution of 412 mg (0.55 mmol, 1.0 eq) of tosylate 22 in 36 ml of DMF is added 65 mg (0.66 mmol, 1.2 eq) of sodium diformylamide. After stirring for 5 hours at 130 ^° C., the mixture is basified with 30 ml of 10% sodium bicarbonate solution (pH = 8) and extracted with 3 × 20 ml of diethyl ether. The combined organic phases are successively washed with 2 × 20 ml of 10% sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated in vacuo to afford 300 mg of 38 as a light yellow solid with a yield of 94%.

IR (CHCl ₃₎ υ ^(cm-i): 2965 (CH); 1730 (C = O ester); 1667 (C = N and C = C); 1157 (CO). S. M. (S.I.I.): m / z: 569.4 ([M + H], 100); 693.5 (25); 763, 5

(5). HRMS (ESI) calcd for C ₃₅ H ₅₇ N ₂ O ₄ m / z = 569.4318; measured: 569.4330.

¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.83 (3H, s, H18); 0.87 (3H, d, J = 6.4 Hz, H21); 0.92 (3H, s, H30); 1.06 and 1.07 (6H, 2d, J = 7.0 Hz, H3 'and H4'); 1.15 (1H, m, H6β); 1.21 (1H, d, J = 4.0 Hz, H19β); 1.23 (3H, s, H28); 1.35 (1H, m, H1a); 1.37-1.53 (3H, m, H7α, H15α and H7β); 1.56 (1H, d, J = 4.0 Hz, H19α); 1.53-1.58 (3H, m, H2β); 1.95-2.19 (3H, m, H6α, H8β, H15β, H17α and H5α); 2.24 (6H, bs, NB-CH3); 2.26 (1H, dq, J = 7.0Hz, HZ); 2.31 (1H, d, J = 17.1 Hz, H12β); 2.42 (1H, m, H1β); 2.52 (1H, d, J = 17.3 Hz, H12α); 2.62 (1H, dq, J = 6.4 Hz and 10.9 Hz, H 2 O); 4.09 (1H, ddd, J = 2.1 Hz, 7.3 Hz and 9.7 Hz, H16β); 4.31 (1H, ddd, J = 4.2 Hz, 8.9 Hz and 12.4 Hz, H3α); 5.29 (1H, d, J = 9.1 Hz, NAH); 9.40 (1H, s, H29).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 7.8 (C30); 10.1 (C21); 18.0 (Cl 8); 19.4 and 19.9 (C3 'and C4'); 20.8 (C28); 21.2 (C6); 24.1 (C7); 27.5 (C2); 27.6 (Cl); 29.6 (C19); 34.1 (C9); 35.7 (C2 '); 35.9 (ClO); 41.5 (C8); 41.9 (C5); 42.8 (Cl 5); 44.6 (C13); 47.2 (C14); 49.7 (C3); 51.5 (C12); 56.0 (C17); 57.0 (C4); 62.2 (C20); 78.3 (C 16); 176.4 (Cl '); 203.4 (C29); 210.9 (ClI).

Compound 39: (20S) -10 (9-> 1) abeo-20-dimethylamino-4β, 14α-dimethyl-16α-pivalyl- (2'-isopropyl-3,29-dihydro-4H- [1,3]] -oxazine) -5a, 9 $ -pregn-1 (10) -en-ll-one 39

Under argon, to a solution of 50 mg (0.10 mmol, 1.0 eq) of dihydro-4H- (1,3) -oxazine 1 in 1 ml of pyridine is added 13 μl (0.10 mmol, 1.0 eq) of pivalyl chloride. After stirring for 2 hours and 30 minutes at room temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pΗ = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulfate and evaporated under vacuum to provide 45 mg of 39 as a light yellow solid in 77% yield.

IR (CHCl ₃ ) υCcm ¹ ): 1720 (C = O ester); 1698 (C = O); 1671 (C = N and C = C); 1158 (CO). S. M. (S.I.I.): m / z: 569.4 ([M + H], 100); 570.4 (30); 485, 4

(5); 285, 2 (1 0).

HRMS (ESI) calcd for C ₃₅ H ₅₇ N ₂ O ₄ m / z = 569.4318; measured: 569.4301.

¹ H NMR (500 MHz, CDCl ₃ ), δppm: 0.65 (3H, s, H18); 0.68 (3H, s, H30); 0.78 (3H, d, J = 6.9 Hz, H21); 1.04 and 1.06 (6H, 2d, J = 6.9 Hz, H3 'and H4'); 1.19 (3H, s, H28); 1.23 to 1.29

(2H, m, H6β and H7α); 1.26 (1H, dd, J = 5.7 Hz and 14.7 Hz, H1 5α); 1.53 (1H, dd, J = 6.9 Hz and

12.0 Hz, H6α); 1.62 (1H, ddd, J = 3.8 Hz, 10.4 Hz and 10.7 Hz, H8β); 1.72 (1H, m, H2β);

1.79-1.83 (3H, m, H5α, H7β and H9α); 1.98 (1, m, H15β); 2.02 (1H, m, H19β); 2.06 (6H, s,

NB-CH3); 2.20 (1H, dd, J = 5.6 Hz and 11.4 Hz, H17α); 2.28 (1H, m, H2α); 2.34 (1H, dq, J = 6.9 Hz, H2 '); 2.36 (1H, d, J = 15.8 Hz, H12β); 2.38 (1H, m, H 2 O); 2.52 (1H, bd, J = 15.8 Hz,

H12α); 3.16 (1H, dd, J = 6.3 Hz and 11.7 Hz, H3α); 3.29 (1H, d, J = 15.8 Hz, H19α); 3.67

(1H, d, J = 10.1 Hz, H29); 3.99 (1H, d, J = 10.1 Hz, H29); 4.98 (1H, dd, J = 5.7 Hz and

13.2 Hz, H16β); 5.53 (1H, m, H1).

¹³ C NMR (125 MHz, CDCl ₃ ), δppm: 9.62 (C30); 10.03 (C21); 17.84 (C18); 19.77 (C3 'and C4'); 19.84 (C28); 24.61 (C6); 27.17 (C33, C34 and C35); 30.73 (C2); 33.20 (C4); 33.52

(C7); 34.31 (C2 '); 37.11 (C19); 38.54 (C32); 40.64 (NB-CH 3); 43.26 (C15); 46.41 (C14);

47.11 (C13); 49.56 (C5); 49.82 (C8); 50.31 (C12); 50.32 (C9); 54.07 (C17); 55.65 (C3);

59.61 (C20); 74.74 (C29); 78.94 (C16); 121.87 (Cl); 137.08 (ClO); 162.70 (Cl '); 177,63

(C31); 211.23 (CIl).

• Compound 40: (20S) -10 (9-> 1) abeo-16a, acetyl-20-dimethylamino-4,14a, dimethyl- (2'-isopropyl-3,29-dihydro-4H- [1,3] ] -oxazine) -5q9 $ -pregn-l (10) -en-ll-one 40

Under argon, to a solution of 50 mg (0.10 mmol, 1.0 eq) of dihydro-4H- (1,3) -oxazine 1 in 1 ml of pyridine is added 8 μl (0.11 mmol, 1.0 eq) of acetyl chloride. After stirring for 2 hours and 30 minutes at room temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pΗ = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulfate and evaporated in vacuo with 1,2-dichloroethane to provide 37 mg of 40 as a light yellow solid in 70% yield.

IR (CHCl ₃ ) 0 (Cm ¹ ): 2965 (CH); 1729 (C = O ester); 1696 (C = O); 1670 (C = N and C = C); 1027 (CO).

Compound 41: (20S) -3-notobutyrylamino-20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl-4α-acetylmethyl-5α, 9β-pregnan-16α-ol-11-one

To a solution cooled to 5 ° C. of 200 mg (0.39 mmol, 1.0 eq.) Of ΛT-3 / β-obutyrylcycloxobuxidine-F 2 in 25 ml of glacial acetic acid is added 5 ml (0, 31 mmol, 3.0 eq.) Of 35% hydrochloric acid. After stirring for 30 minutes at room temperature, the solution is evaporated under vacuum. The residue is basified with 40 ml of a 10% ammonia solution and extracted with 3x40 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.8 dichloromethane / 0.2 methanol) to give 168 mg of 41 in the form of a colorless powder with a yield of 77%. %.

Elemental analysis: for C32H52N2O5

Calculated for C ₃₂ H ₅₂ N ₂ O ₅ %: C 70.55 H 9.62 N 5.14

Measured%: C 70.01 H 9.44 N 4.83

LR. (CHCl ₃ ) (cm- ¹ ): 3439 (OH, NH); 2966 (CH 2 CH 2) 1724 (C = O ester); 1667 and 1507 (C = O and CONH); 1095 (CO).

MS (ESI): m / z: 545.5 ([M + H], 100); 546.5 (10); 624.5 (20). HRMS (ESI) calcd for C ₃₂ H ₅₂ N ₂ O ₅ m / z = 545.3954; measured: 545.3607. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.67 (3H, s, H30); 0.78 (3H, s, H18); 0.81 (3H, d, J = 6.4 Hz, H21); 0.90 (1H, m, H6β); 0.97 (1H, d, J = 3.4 Hz, H19β); 1.05 and 1.06 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 1.16 (3H, s, H28); 1.20 (1H, m, Hlα); 1.25-1.52 (4H, m, H7α, H15α, H7β and H2β); 1.49 (1H, d, J = 3.4 Hz, H19α); 1.66 (1H, m, H2α); 1.89-2.01 (5H, m, H6α, H8β, H15β, H5α and H17α); 2.05 (3H, s, H32); 2.18 (6H, bs, NB-CH3); 2.22 (1H, dq, J = 6.8 Hz, H2 '); 2.23 (1H, d, J = 17.2 Hz, H12β); 2.31 (1H, m, H1β); 2.46 (1H, d, J = 17.2 Hz, H12α); 2.55 (1H, dq, J = 6.4 Hz and 11.8 Hz, H 2 O); 3.65 (1H, d, 11.7 Hz, H29a); 3.71 (1H, d, J = 11.7 Hz, H29b); 4.04 (1H, ddd, J = 2.6 Hz, 7.2 Hz and 9.2 Hz, H16β); 4.11 (1H, ddd, J = 4.1Hz, 8.1Hz and 10.6Hz, H3α); 5.24 (1H, d, J = 10.0 Hz, NAH).

NMR C C (75.5 MHz, CDCl ₃ ), δppm: 9.9 (C21); 11.3 (C30); 17.8 (C18); 18.7 (C6); 19.4 and 19.9 (C3 'and C4'); 20.7 (C28); 21.0 (C32); 24.4 (C7); 27.5 (C2); 28.1 (Cl); 30.5 (C19); 34.2 (C9); 35.9 (C2 '); 37.3 (ClO); 41.6 (C4); 42.5 (C8); 42.6 (C5); 42.7 (Cl 5); 44.3 (C13); 47.0 (C14); 49.5 (C3); 51.4 (C12); 55.7 (C17); 61.9 (C20); 65.3 (C29); 78.2 (C16); 171.3 (C31); 176.3 (Cl '); 211.3 (Cl).

42: (20S) -16α-acetyl-3β-isobutyrylamino-20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl-4α-acetylmethyl-5α, 9β-pregnan-11-one 42

To a solution of 200 mg (0.39 mmol, 1.0 eq) of JV-3-zjobutyrylcycloxobuxidine-F 2 in 1 ml of pytidine is added 0.11 ml (1.19 mmol, 3.0 eq.) of acetic anhydride. After stirring for 48 hours at room temperature, the solution is evaporated under vacuum in the presence of 1,2-dichloroethane.

The residue thus obtained is chromatographed on a column of Merck alumina of activity II-III (eluent: dichloromethane 99 / methanol 1) to give 212 mg of 42 in the form of a colorless powder with a yield of 91%.

IR (CHCl ₃₎ υ ^(cm-i): 2965 (CH CH2); 2359 (CH); 1729 (C = O ester); 1666 and 1527 (C = O and CONH); 1229 and 1034 (CO).

S.M. (E.S.I.): m / z: 587.4 ([M + H], 100); 588.4 (5); 545.4 (20).

HRMS (ESI) calculated for C ₃₄ H ₅₅ N ₂ O ₆ m / z = 587.4060; measured: 587.4063.

¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.74 (3H, s, H30); 0.82 (3H, d, J = 6.4 Hz, H21); 0.85

(3H, s, H18); 0.98 (1H, m, H6β); 1.05 (1H, d, J = 3.8 Hz, H19β); 1.13 and 1.14 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 1.18 (3H, s, H28); 1.26 (1H, m, H1, α); 1.26-1.52 (5H, m, H6α, H7α, H15α, H7β and H2β); 1.58 (1H, d, J = 3.8 Hz, H19α); 1.71-1.78 (2H, m, H2α, H8β); 2.00 (3H, s, H34); 2,02- 2.07 (2H, m, H5α and H1 5β); 2.11 (3H, s, H32); 2.14 (6H, bs, NB-CH3); 2.23 (1H, dd, J = 5.8 Hz and 11.2 Hz, H17α); 2.31 (1H, dq, J = 6.8 Hz, HZ); 2.36 (1H, m, H1β); 2.39 (1H, d, J = 17.1Hz, H12β); 2.47 (1H, dq, J = 6.4 Hz and 11.2 Hz, H 2 O); 2.56 (1H, d, J = 17.1Hz, H12α); 3.72 (1H, d, 11.7 Hz, H29a); 3.78 (1H, d, J = 11.7 Hz, H29b); 4.18 (1H, ddd, J = 4.1Hz, 10.1Hz and 12.1Hz, H3α); 5.12 (1H, dd, J = 5.8 Hz and 7.9 Hz, H16β); 5.18 (1H, d, J = 10.4 Hz, NAH).

NMR C C (75.5 MHz, CDCl ₃ ), δppm: 9.8 (C21); 11.4 (C30); 17.9 (C18); 18.8 (C6); 19.5 (C3 'and C4'); 20.0 (C28); 21.0 (C32); 21.2 (C34); 24.5 (C7); 27.5 (C2); 28.2 (Cl); 30.5 (C19); 33.8 (C9); 36.0 (CZ); 37.5 (ClO); 40.3 (NB-CH3); 41.5 (C8); 42.6 (C5 and C4); 43.0 (Cl 5); 44.5 (C13); 47.4 (Cl 4); 49.6 (C3); 51.9 (C12); 55.1 (ClI); 59.5 (C20); 65.4 (C29); 78.9 (Cl 6); 170.7 (C33); 171.3 (C31); 176.3 (Cl '); 211.0 (ClI).

Compound 43: (20S) -3-isobutyrylamino-20-methylamino-9,19-cyclo-4H, 14 (k-dimethyl-4-formyl-16as-pivafyl-5a) -pregnan-11-one 43

To a solution of 500 mg (0.85 mmol, 1.0 eq) of 16-O-pivalyl-N-3-isobutyrylcycloxobuxidine-F 17 in 32 ml of dichloromethane is added 486 mg (1.11 mmol, 1, 3 eq.) Of Dess-Martin periodinane under inert atmosphere. The solution becomes cloudy and becomes pink. After stirring for 16 hours at ambient temperature, the mixture is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is purified by flash chromatography on silica gel (eluent: dichloromethane 90 / methanol 10) to give 130 mg of 43 as a colorless powder with a yield of 22%.

¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.83 (3H, s, H18); 0.86 (3H, s, H30); 1.00 (3H, d, J = 6.6Hz, H21); 1.01 (1H, m, H6β); 1.01 and 1.02 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 1.09 (1H, m, H19α); 1.11 (3H, s, H28); 1.13 (9H, s, H33 H34 and H35); 1.22-1.51 (5H, m, Hlα, H7α, H15α, H7β and H2β); 1.53 (1H, d, J = 4.1 Hz, H19β); 1.71-1.77 (2H, m, H2, H6α); 1.96-2.14 (3H, m, H8β, H15β and H5α); 2.18 (1H, dq, J = 6.8 Hz, H2 '); 2.28 (3H, s, NB-CH3); 2.43 (1H, d, J = 17.3 Hz, H12β); 2.34-2.51 (3H, m, H20, H17α and Hlβ); 2.53 (1H, d, J = 17.3 Hz, H12α); 4.25 (1H, ddd, J = 4.2 Hz, 8.7 Hz and

12.2 Hz, H3α); 5.97 (1H, dd, J = 6.0 Hz, 7.5 Hz, H16β); 5.20 (1H, d, J = 9.0 Hz, NAH); 9.33

(1H, s, H29).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

7.6 (C30); 18.0 (C18); 18.5 (C21); 19.2 and 19.3 (C3 'and C4'); 19.8 (C28); 21.0 (C6); 24.0

(Cf); 27.0 (C33, C34 and C35); 27.2 (C2); 27.3 (Cl); 29.4 (C19); 33.2 (NB-CH3); 33.5 (C9);

35.6 (CT); 35.9 (ClO); 38.5 (C32); 40.9 (C5); 41.8 (C8); 43.6 (C15); 45.4 (C13); 47.0

(C14); 49.5 (C3); 51.6 (C12); 56.3 (Cl 7); 56.7 (C4); 56.9 (C20); 78.9 (C16); 176.3 (C31);

178.1 (Cl '); 198.9 (C29); 203.3 (ClI).

Compound 44: (20S) -3β-isobutylamino-20-dimethylamino-9,19-cyclo-4β, 14α-dimethyl-4α-formyl-5α, 9β-pregnan-16α-ol-11-one 44

To a solution of 1000 mg (1.84 mmol, 1.0 eq) of aldehyde 14 in 23.0 ml of methanol is added a solution of 1953 mg (18.42 mmol, 10.0 eq.) Of carbonate. of sodium and 2321 mg (27.63 mmol, 15.0 eq) of sodium hydrogencarbonate in 25.0 ml of water. A precipitate is formed. After stirring for 3 hours at room temperature, the solution is diluted with 50 ml of water and extracted with 3 × 45 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is triturated in ethyl acetate to give 567 mg of 44 as an ocher powder in 61% yield.

LR. (diamond) O (Cm- ¹ ): 3284 (OH, NH); 2936 (CH, CH 2); 2791 (CH = O); 1716 (C = O aldehyde); 1661, 1636 and 1549 (C = O and CONH); 1095 (CO).

S.M. (E.S.I.): m / z: 501.4 ([M + H], 100); 502.4 (15).

HRMS (ESI) calcd for C ₃₀ H ₄₉ N ₂ O ₄ m / z = 501.3692; measured: 501.3678.

¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.83 (3H, s, H18); 0.87 (3H, d, J = 6.4 Hz, H21); 0.92 (3H, s, H30); 1.06 and 1.07 (6H, 2d, J = 7.0 Hz, H3 'and H4'); 1.15 (1H, m, H6β); 1.21 (1H, d, J =

4.0 Hz, H19β); 1.23 (3H, s, H28); 1.35 (1H, m, H1, α); 1.37-1.53 (3H, m, H7α, H15α and H7β);

1.56 (1H, d, J = 4.0 Hz, H19α); 1.53-1.58 (3H, m, H2β); 1.95-2.19 (3H, m, H6α, H8β, H15β,

H17α and H5α); 2.24 (6H, bs, NB-CH3); 2.26 (1H, dq, J = 7.0 Hz, H2 '); 2.31 (1H, d, J = 17.1 Hz, H12β); 2.42 (1H, m, H1β); 2.52 (1H, d, J = 17.3 Hz, H12α); 2.62 (1H, dq, J = 6.4 Hz and 10.9 Hz, H 2 O); 4.09 (1H, ddd, J = 2.1 Hz, 7.3 Hz and 9.7 Hz, H16β); 4.31 (1H, ddd, J = 4.2 Hz, 8.9 Hz and 12.4 Hz, H3α); 5.29 (1H, d, J = 9.1 Hz, NAH); 9.40 (1H, s, H29).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 7.8 (C30); 10.1 (C21); 18.0 (Cl 8); 19.4 and 19.9 (C3 'and C4'); 20.8 (C28); 21.2 (C6); 24.1 (C7); 27.5 (C2); 27.6 (Cl); 29.6 (C19); 34.1 (C9); 35.7 (C2 '); 35.9 (ClO); 41.5 (C8); 41.9 (C5); 42.8 (Cl 5); 44.6 (C13); 47.2 (C14); 49.7 (C3); 51.5 (C12); 56.0 (C17); 57.0 (C4); 62.2 (C20); 78.3 (C 16); 176.4 (Cl '); 203.4 (C29); 210.9 (ClI).

Compound 45: (20S) -20-Dimethylamino-3β- (isobutyrylamino) -9,19-cyclo-4α-benzyliminomethyl-4α, 14α-dimethyl-5α, 9β-pregnan-16α-ol-11-one45

To a solution of 0.89 g (1.78 mmol, 1.0 eq) of aldehyde 44 and 900 mg of anhydrous magnesium sulfate in 10 ml of dichloromethane are added 253 μl (2.31 mmol, 1, 3 eq.) Of benzylamine. After stirring for 17 hours at 55 ° C, the solution was filtered through celite and evaporated in vacuo to afford 1.05 g of 45 as a yellow foam in quantitative yield.

IR (diamond) O (Cl- ¹ ): 3386 (OH, NH); 2958 (CH, CH 2); 1649 (C = O, C = N); 1649 and 1529 (CONH); 1451 (C = C Ar); 1227 and 1091 (C-OH).

S. M. (S.I.I.): m / z: 590.4 ([M + H], 100); 59 1, 4 (1 0). HRMS (ESI) calcd. For C ₃₇ H ₅₆ N ₃ O ₃ m / z = 590.4322; measured: 590.4304. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.77 (3H, s, H18); 0.81 (3H, d, J = 6.6Hz, H21); 0.93 (1H, m, H6β); 0.93 and 0.96 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 0.97 (3H, s, H30); 1.02 (1H, d, J = 4.0 Hz, H19α); 1.16 (3H, s, H28); 1.21-1.44 (5H, m, H1, H2β, H7β, H7α and H15α); 1.50 (1H, m, H6α); 1.53 (1H, d, J = 4.0 Hz, H19β); 1.76 (1H, m, H 2); 1.82-2.07 (4H, m, H15β, H17α, H5α and H8β); 2.10 (1H, dq, J = 6.8Hz, HZ); 2.19 (6H, s, NB-CH 3); 2.25 (1H, d, J = 17.3 Hz, H12β); 2.31 (1H, ddd, J = 3.3 Hz, 3.6 Hz and 13.4 Hz, Hlβ); 2.45 (1H, d, J = 17.3 Hz, H12α); 2.55 (1H, dd, J = 6.8 Hz and 10.8 Hz, H 2 O); 4.03 (2H, m, H3α and H16β); 4.45 and 4.49 (2H, 2d AB system, 15.2 Hz, H31); 5.26 (1H, d, J = 9.2 Hz, NAH); 7.14-7.27 (5H, m, HAr = 33-37); 7.49 (1H, s, H29). NMR C (75.5 MHz, CDCl ₃ ), δppm:

10.0 (C21); 10.2 (C30); 17.9 (C6 and C18); 19.3 and 19.6 (C3 'and C4'); 20.7 (C28); 24.2 (C7); 27.6 (C2); 27.7 (Cl); 29.8 (C 19); 34.3 (C9); 35.7 (C2 '); 36.7 (ClO); 41.3 (C8); 42.7 (Cl 5); 44.5 (C13); 44.8 (C5); 47.2 (C14); 50.0 (C4); 51.4 (Cl 2); 52.0 (C3); 55.9 (Cl 7); 62.1 (C20); 64.7 (C31); 78.2 (Cl 6); 126.7 (C35); 127.7 and 128.3 (C34-36 and C33-37); 139.5 (C32); 170.7 (C29); 176.0 (Cl '); 210.9 (Cl).

• Compound 46: (20S) -20-dimethylamino-3β- (isobutyrylamino) -9,19-cyclo-4α-benzylaminomethyl-4α, 14α-dimethyl-5α,% -pregnan-16α-ol-11-one46

To a suspension of 2.98 g (5.05 mmol, 1.0 eq) of imine 45 in 30 ml of methanol are successively added 381 mg (6.06 mmol, 1.2 eq) of sodium cyanoborohydride. and 289 μl (5.05 mmol, 1.05 eq) of glacial acetic acid. After stirring for 3 hours at room temperature, the mixture is basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 50 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on silica gel (eluent: 97.5 dichloromethane / 0.5 methanol / 2 ammonia) to provide 2.64 g of 46 as a yellow powder with a yield of 88% over two steps.

Elemental analysis: for C37Hs7N3O3.0.5H2θ

Calculated for C ₃₇ H ₅₇ N ₃ O ₃ ASH ₂ O%: C 73.96 H 9.73 N 6.99 O 9.32

Measured%: C 74.14 H 9.63 N 7.13 O

9.11 IR (diamond) O (Cl- ¹ ): 3312 (OH, NH); 2933 (CH, CH 2); 1660 (C = O); 1660 and 1534 (CONH); 1452 (C = C Ar); 1226 and 1095 (C-OH). MS (ESI): m / z: 592.5 ([M + H], 100); 593.5 (10); 296.7

(5).

HRMS (ESI) calculated for C ₃₇ H ₅₈ N ₃ O ₃ m / z = 592.4478; measured: 592.4451. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.51 (3H, s, H30); 0.65 (1H, m, H6β); 0.76 (3H, s, H18); 0.80 (3H, d, J = 6.6Hz, H21); 1.07 (6H, 2d, J = 7.0Hz, H3 'and H4'); 0.92 (1H, d, J = 3.4 Hz, H19α); 1.17 (3H, s, H28); 1.22-1.48 (4H, m, H1, H7, H2β and H15α); 1.45 (1H, d, J = 3.4 Hz, H19β); 1.60 (1H, m, H2α); 1.87-2.15 (5H, m, H15β, H17α, H6α, H5α and H8β); 2.02 (1H, d, J = 13.0 Hz, H29); 2.19 (6H, s, NBCH3); 2.14 (1H, d, J = 13.0 Hz, H29); 2.22 (1H, d, J = 17.1Hz, H12β); 2.24 (1H, dq, J = 7.0 Hz, H2 '); 2.32 (1H, m, H1β); 2.44 (1H, d, J = 17.1Hz, H12α); 2.55 (1H, dd, J = 6.6 Hz and 10.8 Hz, H 2 O); 3.56 and 3.71 (2H, 2d AB system, 13.8 Hz, H31); 4.00 (1H, m, H3α); 4.03 (1H, m, H16β); 5.10 (1H, d, J = 10.0 Hz, NAH); 7.19-7.28 (5H, m, Hrr = 33-37). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 9.9 (C21); 13.7 (C30); 17.8 (C18); 18.5 (C6); 19.5 and 20.2 (C3 'and C4'); 21.0 (C28); 24.5 (C7); 27.6 (C2); 28.4 (Cl); 31.0 (C19); 34.6 (C9); 36.0 (C2 '); 38.2 (ClO); 41.7 (C8); 42.1 (C5); 42.9 (Cl 5); 43.2 (C13); 44.5 (C4); 47.2 (C 14); 50.3 (C3); 51.5 (C 12); 52.9 (C29); 54.5 (C31); 55.8 (C17); 62.1 (C20); 78.4 (Cl 6); 126.5 (C35); 128.0 and 128.4 (C34-36 and C33-37); 141.2 (C32); 176.6 (Cl '); 211.6 (Cl).

• Compound 47: (20S) -3 $ -isobutyrylamino-20-dimethylamino-9,19-cyclo-4α-benzylaminomethyl-4α, 14α-dimethyl-16α-pivalyl-5αβ-pregnan-11-one 47

To a solution of 100 mg (0.15 mmol, 1.0 eq) of imine 19 in 0.5 ml of methanol is added 12 mg (0.18 mmol, 1.2 eq) of sodium cyanoborohydride and 9 μl (0.16 mmol, 1.05 eq.) Of glacial acetic acid. After stirring for 1 hour at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 20 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on Merck alumina column of activity II-III (eluent: 99.9 dichloromethane / 40% aqueous ammonia) to give 58 mg of 47 in the form of a colorless powder with a yield of 58%.

IR (diamond) O (Cm- ¹ ): 2964 (NH); 1720 (C = O ester); 1664 and 1530 (C = O and CONH); 1453

1365 1287 1229 1159 (C = CAr C-N C-O).

S.M. (E.S.I.): m / z: 676.5 ([M + H], 100); 586.5 (5); 339.3 (25); 338.8 (100).

HRMS (ESI) calcd for C ₄₂ H ₆₆ N ₃ O ₄ m / z = 676.5053; measured: 676.5053. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: NCH is not seen: No correlation is visible between this proton and the H36 protons on the COZY spectrum.

0.58 (3H, s, H30); 0.82 (3H, s, H18); 0.82 (1H, m, H6β); 0.84 (3H, d, J = 6.4 Hz, H21); 1.14 and 1.20 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 1.19 (3H, s, H28); 1.21 (9H, s, H33, H34 and H35); 1.13 (1H, m, H19α); 1.24-1.56 (5H, m, Hlα, H7α, H15α, H7β and H2β); 1.55 (1H, d, J = 3.8

Hz, H19β); 1.72-1.85 (2H, m, H2α, H6α); 2.14 (6H, s, NB-CH3); 2.08 and 2.16 (2H, 2d, J =

12.4 Hz, H29); 1.90-2.20 (3H, m, H8β, H1 5β and H5α); 2.37 (1H, m, H 2 '); 2.20-2.49 (4H, m,

H17α, H20, Hlβ and H12β); 2.56 (1H, d, J = 17.3 Hz, H12α); 3.63 (2H, AB system, H36);

3.97 (1H, ddd, J = 4.5 Hz, 11.1 Hz and 12.7 Hz, H3α); 4.96 (1H, dd, J = 5.6 Hz and 7.5 Hz, H16β); 5.08 (1H, d, J = 9.8 Hz, NAH); 7.10-7.25 (5H, m, HAr = 38, 39, 40, 41 and 42).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

13.7 (C30); 17.8 (C18); 18.4 (C6); 19.5 (C21); 19.5 and 19.7 (C3 'and C4'); 20.2 (C28); 24.5

(C7); 27.2 (C33-35); 27.6 (C2); 28.4 (Cl); 30.9 (C19); 34.1 (C9); 36.0 (C2 '); 36.8 (ClO);

38.6 (C32); 40.6 (NB-CH3); 41.3 (C8); 42.1 (C5); 43.2 (C13); 43.6 (C15); 44.7 (C14); 47.4 (C4); 50.3 (C3); 52.0 (C29); 52.9 (C12); 54.6 (C36); 54.9 (C17); 59.5 (C20); 79.2

(C16); 126.6 (CAr = 40); 127.7 and 128.0 (CAr = 38, 39, 40 and 41); 139.5 (C37); 170.7 (C31);

176.0 (Cl '); 211.4 (Cl).

• Compound 48: (20S) -3 $ -isobutyrylamino-20-methylamino-9,19-cyclo-4α-benzylaminomethyl-4α, 14α-dimethyl-16β-pivala-5aβ-pregnan-11-one 48

To a solution of 100 mg (0.15 mmol, 1.0 eq) of imine 19 in 0.5 ml of methanol is added 12 mg (0.18 mmol, 1.2 eq) of sodium cyanoborohydride and 9 μl (0.16 mmol, 1.05 eq.) Of glacial acetic acid. After stirring for 1 hour at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 20 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 99/40% aqueous ammonia) to give 35 mg of 48 in the form of a colorless powder with a yield of 35%.

IR (diamond) O (Cm- ¹ ): 3316 (NH and NH-CH 3), 1721 (C = O ester), 1662 and 1532 (C = O and

CONH); 1453 (C = C Ar); 1159-1029 (C-O).

S.M. (E.S.I.): m / z: 676.5 ([M + H], 100); 586.5 (5); 339.3 (25); 338.8 (100).

HRMS (ESI) calcd for C ₄₂ H ₆₆ N ₃ O ₄ m / z = 676.5053; measured: 676.5053. Compound 49: (20S) -20-Dimethylamino-3β- (isobutyrylamino) -9,19-cyclo-4α-aminomethyl-4α, 14α-dimethyl-5α, 9β-pregnan-16α-ol-11-one

To a suspension of 817 mg (1.38 mmol, 1.0 eq.) Of N-benzyl amine 46 in 30 ml of anhydrous methanol degassed with argon is added successively 408 mg (50% by weight relative to X) of 30% palladium on carbon and 435 mg (6.90 mmol, 5.0 eq) of ammonium formate. After stirring for 3 hours at 40 ^° C., the mixture is filtered on celite and evaporated under vacuum. The residue obtained is basified with 40 ml of a 10% sodium carbonate solution (pH = 8) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on a silica column (eluent: dichloromethane 96 / methanol 2 / ammonia 2) to provide 588 mg of 49 as a colorless powder in 85% yield over two steps.

PF ( ⁰ C): 232 ° C

LR. (diamond) O (Cm- ¹ ): 3313 (OH, NH); 2934 (CH, CH 2); 1650 (C = O); 1650 and 1536 (CONH); 1226 and 1094 (C-OH). MS (ESI): m / z: 502.4 ([M + H], 100); 503.4 (10); 296.7

(15); 251.7 ([M + 2H] / 2.10). HRMS (ESI) calcd for C ₃₀ H ₅₂ N ₃ O ₃ m / z = 502.4009; measured: 502.4008. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.56 (3H, s, H30); 0.78 (3H, s, H18); 0.80 (3H, d, J = 6.6Hz, H21); 0.87 (1H, m, H6β); 0.97 (1H, d, J = 3.8 Hz, H19α); 1.08 and 1.10 (6H, 2d, J = 6.6Hz, H3 'and H4'); 1.15 (3H, s, H28); 1.21- 1.48 (4H, m, H1, H7, H2β and H15α); 1.49 (1H, d, J = 3.8 Hz, H19β); 1.62 (1H, m, H 2); 1.88-2.00 (5H, m, H15β, H17α, H6α, H5α and H8β); 2.18 (6H, s, NB-CH3); 2.24 (1H, d, J = 17.1Hz, H12β); 2.26 (1H, d, J = 13.9 Hz, H29a); 2.28 (1H, dq, J = 6.6Hz, HZ); 2.38 (1H, d, J = 13.9 Hz, H29b); 2.39 (1H, m, H, B); 2.44 (1H, d, J = 17.1Hz, H12α); 2.55 (1H, dd, J = 6.6 Hz and 10.9 Hz, H 2 O); 3.99 (1H, m, H3α); 4.03 (1H, m, H16β); 5.13 (1H, d, J = 9.8 Hz, NAH). NMR C C (75.5 MHz, CDCl ₃ ), δppm: 9.9 (C21); 13.7 (C30); 17.8 (C18); 18.5 (C6); 19.5 and 20.1 (C3 'and C4'); 21.0 (C28); 24.6 (C7); 27.7 (C2); 28.4 (Cl); 31.2 (C19); 34.4 (C9); 35.9 (C2 '); 38.1 (ClO); 41.7 (C8); 42.0 (C5); 42.9 (C15); 43.7 (C13); 44.5 (C4); 46.2 (C29); 47.1 (C14); 49.5 (C3); 51.5 (Cl 2); 55.8 (C17); 62.0 (C20); 78.3 (C 16); 176.8 (Cl '); 211.5 (ClI).

Compound 50: (20S) -3β-isobutylamino-20-cliniethylamino-9,19-cyclo-4α-aminomethyl-4β, 14α-dimethyl-16α-pivalyl-5α, β-pregnan-11-one 50

The method: Benzylamine pathway, deprotection under hydrogen pressure

To a solution of 82 mg (0.12 mmol, 1.0 eq) of benzylamine 47 in 2 ml of methanol is added successively 40 mg (50% by weight) of palladium hydroxide on charcoal. The pH of the solution is adjusted to 3 with glacial acetic acid. After stirring for 48 hours at room temperature under a pressure of 2 bar of dihydrogen in a Parr apparatus, the mixture is filtered on celite and the solvents are evaporated under vacuum. The residue is basified with 20 ml of a 10% ammonia solution (pH = 10) and extracted with 3x20 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on Merck alumina column of activity II-III (eluent: 99.9 dichloromethane / 40% aqueous ammonia) to give 23 mg of 50 in the form of a colorless powder with a yield of 32%.

2 ^nd method: Benzylamine pathway, deprotection under ammonium formate

Under argon, to a solution of 227 mg (0.33 mmol, 1.0 eq) of benzylamine 47 in 5 ml of methanol are successively added 113 mg (50% by weight) of palladium on carbon at 30% and 109 mg. (1.73 mmol, 5.0 eq.) Of ammonium formate. After stirring for 5 hours at 65 ° C., the mixture is filtered on celite and the solvents are evaporated under vacuum. The residue is basified with 20 ml of 10% sodium hydrogencarbonate solution (pH = 8) and extracted with 3 × 20 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on Merck alumina column of activity II-III (eluent: 99.9 dichloromethane / 40% aqueous ammonia) to give 24 mg of 50 in the form of a colorless powder with a yield of 12%.

3rd method: bis (trimethylsilyl) methylamine

Under argon, to a solution of 65 mg (0.08 mmol, 1.0 eq.) Of amine 56 in 4 ml of methanol is successively added 371 mg (0.67 mmol, 8.0 eq.) Of cerium IV ammoniacal. The solution is red. After stirring for 4 days at room temperature, the solution became insolor and the mixture was basified with 20 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 25 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on a column of Merck alumina of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to give 37 mg of 50 in the form of a colorless powder with a yield of 55.degree. %.

LR. (diamond) O (Cm- ¹ ): 3320 (NH); 1720 (C = O ester); 1665 and 1530 (C = O and CONH); 1455

(C-H alkyl groups); 1377 (CH); 1159 (C-O). S.M. (E.S.I.): m / z: 586.4 ([M + H], 100); 591.4 (40); 559.4 (40); 394.6 (40).

HRMS (ESI) calculated for C ₃₅ H ₆₀ N ₃ O ₄ m / z = 586.4584; measured: 586.4579.

¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.66 (3H, s, H30); 0.82 (3H, d, J = 6.4 Hz, H21); 0.85 (3H, s, H18); 1.03 (1H, d, J = 3.6 Hz,

H19a); 1.06 (1H, m, H6b); 1.14 and 1.15 (6H, 2d, J = 6.8 Hz, H3 'and H4 ⁵ ); 1.17 (3H, s, H28); 1.19 (9H, s, H33, H34 and H35); 1.24 (1H, m, HIa); 1.35 (1H, bd, J = 14.3 Hz, H15a); 1.36 (1H, m, H7a); 1.43 (1H, m, H7b); 1.49 (1H, m, H2b); 1.55 (1H, d, J = 3.6 Hz, H19b); 1.68 (1H, m,

H2a); 1.77 (1H, m, H, 6a); 1.98 (1H, m, H15b); 2.02 (1H, m, H5a); 2.05 (1H, m, H8b); 2.13

(6H, s, NB-CH3); 2.24 (1H, d, J = 12.3 Hz, H29a); 2.25 (1H, dd, J = 5.3 Hz and 11.2 Hz, H17a);

2.28 (1H, d, 12.3 Hz, H29b); 2.38 (1H, d, J = 17.0 Hz, H12b); 2.38 (1H, m, HIb); 2.42 (1H, dq, J = 6.8 Hz, H2 ⁵ ); 2.44 (1H, dd, J = 6.2 Hz and 11.2 Hz, H 2 O); 2.54 (1H, d, J = 17.0 Hz, H12a);

3.98 (1H, ddd, J = 4.0 Hz, 10.3 Hz and 10.8 Hz, H3a); 5.05 (1H, dd, J = 5.3 Hz and 7.8 Hz, H16b);

5.24 (1H, d, J = 8.9 Hz, NAH).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 9.9 (C21); 13.9 (C30); 17.8 (C18); 18.6 (C6); 19.5 and 19.8 (C3 'and C4 ⁵ ); 20.2 (C28); 24.7 (C7); 27.2 (C33-35); 27.6 (CZ); 28.4 (Cl); 31.5 (Cl 9); 34.0 (C9); 36.0 (C2 ^5); 38.0 (ClO); 38.6 (C32); 40.6 (NB-CH3); 41.4 (C8); 41.8 (C5); 43.6 (C15); 43.7 (C13); 44.7 (C14); 44.9 (C29); 47.4 (C4); 50.4 (C3); 52.0 (C12); 54.9 (C17); 59.5 (C20); 79.2 (C16); 170.7 (C31); 177.9 (Cl-) 211.5 (Cl).

Compound 51: (20S) -20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl- (2-isopropyl-5α-methyl-1,4,5,6-tetrahydro-pyrimidin-5-yl) -5a, $ 9 -pregnan-16a-ol-ll-one51

To a solution of 537 mg (1.07 mmol, 1.0 eq) of amine 49 in 50 ml of n-butanol is added 299 μl (2.14 mmol, 2.0 eq) of triethylamine. After stirring for 16 hours at 120 ^° C., the mixture is evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 95 / methanol 5) to provide 331 mg of 51 as a yellow solid in 64% yield.

PF ( ⁰ C): 255 ° C

LR. (diamond) O (Cm- ¹ ): 3375-3143 (OH, NH); 2932 (CH, CH 2); 1662 (C = O); 1629 and 1530 (C-N, C = N); 1039 (C-OH).

S.M. (E.S.I.): m / z: 484.4 ([M + H], 100); 485.4 (5); 439.3

(5); 242.7 ([M + 2H / 2], 30), 243.2 (5).

HRMS (ESI) calcd for C ₃₀ H ₅₀ N ₃ O ₂ m / z = 484.3903; measured: 484.3904. ¹ H NMR (500 MHz, CDCl ₃ ), δppm: 0.67 (3H, s, H30); 0.77 (3H, s, H18); 0.80 (3H, d, J = 6.3 Hz, H21); 1.00 (1H, m, H6β); 1.01 (1H, d, J = 3.8 Hz, H19α); 1.06 and 1.07 (6H, 2d, J = 6.9 Hz, H3 'and H4'); 1.15 (3H, s, H28); 1,16- 1.37 (3H, m, H1 and H7); 1.42 (1H, dd, J = 3.2 Hz and 14.2 Hz, H15α); 1.49 (1H, m, H2β); 1.49 (1H, d, J = 3.8 Hz, H19β); 1.62 (2H, m, H6α and H2α); 1.89-1.99 (3H, m, H15β, H17α and H5α); 2.03 (1H, m, H8β); 2.18 (6H, s, NB-CH3); 2.25 (1H, d, J = 17.0 Hz, H12β); 2.30 (1H, dq, J = 6.6Hz, HZ); 2.31 (1H, m, H1β); 2.42 (1H, d, J = 17.0 Hz, H12α); 2.55 (1H, dd, J = 6.3 Hz and 10.8 Hz, H 2 O); 2.92 (1H, d, J = 13.0 Hz, H29a); 3.10 (1H, d, J = 13.0 Hz, H29b); 3.11 (1H, m, H3α); 4.02 (1H, ddd, J = 2.3 Hz, 7.6 Hz and 14.2 Hz, H16β); 4.23 (1H, bs, NcH / NAH in exchange).

¹³ C NMR (125.8 MHz, CDCl ₃ ), δppm:

9.9 (C21); 11.6 (C30); 17.8 (Cl 8); 18.2 (C6); 20.5 (C3 'and C4'); 20.6 (C28); 24.2 (C7); 27.4 (C2 and Cl); 30.3 (C19); 34.3 (C5); 34.8 (C2 '); 34.9 (C9); 38.0 (ClO); 41.0 (C8); 42.7 (C 15); 44.6 (C 13); 47.2 (C14); 47.3 (C4); 51.5 (C 12); 54.2 (low integration mass C3); 55.9 (C 17); 58.3 (low integration mass C29); 62.0 (C20); 78.3 (Cl 6); 160.6 (Cl '); 210.9 (ClI).

Compound 52: (20S) -20-Climethylamino-9,19-cyclo-4β, 14α-dimethyl-16α-pivalyl- (2'-isopfopyl-1 '/ 3', 3'-9-tetfahydfopyfimidine) -5α, β- pregnan-11-one 52

Method: ammonium formate

Under argon, to a solution of 66 mg (0.10 mmol, 1.0 eq) of benzylamine 47 in 2 ml of methanol is added successively 66 mg (100% by weight) of palladium on carbon to

30% and 62 mg (1.00 mmol, 10.0 eq) of ammonium formate. After stirring for 16 hours at 70 ^° C., the mixture is filtered on celite and the solvents are evaporated under vacuum. The residue is basified with 20 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is chromatographed on Merck alumina column of activity II-III (eluent: 93.9 dichloromethane / 40% aqueous ammonia 0.1 / MeOH 6) to give 18 mg of 52 in the form of a colorless powder. with a yield of 33%.

2nd method: in solution in n-butanol

To a solution of 50 mg (0.08 mmol, 1.0 eq) of amine 50 in 2 ml of n-butanol is added 24 ml (0.17 mmol, 2.0 eq) of triethylamine. After stirring for 16 hours at 120 ^° C., the mixture is evaporated under vacuum.

The residue is chromatographed on a Merck alumina column of activity II-III (eluent: 95 dichloromethane / methanol 5) to give 29.5 mg of 52 as a yellow solid with a yield of 61%. PF ( ⁰ C): 146

LR. (diamond) O (Cm- ¹ ): 2932-2967 (CH); 1716 (C = O ester); 1663 and 1631 (C = O and C = N); 1459 (CH alkyl groups); 1366 (CH ₃ ); 1160 (CO). MS (ESI): m / z: 568.4 ([M + H], 100); 569.4 (10); 484.4 (5). HRMS (ESI) calculated for C ₃₅ H ₅₈ N ₃ O ₃ m / z = 568.4478; measured: 568.4507.

Note: Tetahydro-pyrimidines are in equilibrium with each of their tautomeric form. Indeed, the study of the ¹³ C NMR spectra shows that the C-3, C-4 and C-29 carbons resonate in the form of masses of very low intensity. However, the chemical shift of these carbons is determined by their correlations with methyl protons at position 30 on the HMBC spectrum.

¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.74 (3H, s, H30); 0.83 (3H, d, J = 6.4 Hz, H21); 0.86 (3H, s, H18); 1.05 (1H, m, H6b); 1.13 and 1.14 (6H, 2d, J = 7.0Hz, H3 'and H4 ⁵ ); 1.16 (3H, s, H28); 1.18 (9H, s, H33, H34 and H35); 1.13 (1H, m, H19a); 1.25 (1H, m, HIa); 1.28 (1H, m, H7a); 1.31 (1H, m, H7b); 1.37 (1H, bd, J = 14.5 Hz, H15a); 1.45 (1H, m, H2b); 1.50 (1H, m, H2a); 1.65 (1H, d, J = 4.0 Hz, H19b); 1.67 (1H, m, H, 6a); 1.99 (1H, m, H5a); 2.02 (1H, m, H15b); 2.10 (1H, m, H8b); 2.14 (6H, s, NBCH3); 2.25 (1H, dd, J = 5.6 Hz and 11.2 Hz, H17a); 2.37 (1H, dq, J = 7.0Hz, H2 ⁵ ); 2.38 (1H, m, HIb); 2.43 (1H, J = 16.9 Hz, H12b); 2.47 (1H, dd, J = 6.4 Hz and 11.2 Hz, H 2 O); 2.53 (1H, d, J = 16.9 Hz, H12a); 2.97 (1H, d, J = 13.0 Hz, H29a); 2.95 (1H, m, H3a); 3.16 (1H, d, J = 13.0 Hz, H29b); 5.06 (1H, dd, J = 5.6 Hz and 7.7 Hz, H16b). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

9.9 (C21); 11.6 (C30); 17.8 (C18); 18.2 (C6); 19.4 and 20.5 (C3 'and C4 ⁵ ); 20.6 (C28); 24.2 (C7); 27.2 (C33-35); 27.3 (CZ); 27.3 (Cl); 30.2 (C19); 33.9 (C5); 33.9 (C9); 35.0 (C2 ⁵ ); 38.1 (ClO); 38.6 (C32); 40.6 (NB-CH3); 40.7 (C8); 43.4 (Cl 5); 44.8 (Cl 4); 47.3 (Cl 3); 47.4 (C4); 51.9 (Cl 2); 54.2 (C3); 55.0 (Cl 7); 58.3 (C29); 59.5 (C20); 79.1 (Cl 6); 160.5 (Cl ¹ ); 177.8 (C31); 210.7 (Cl).

Compound 54: (20S) -3-yl 4-butyricamino-20-dimethylamino-9,19-cyclo-4β, 14α-dimethyl-4α- (Bis- (trimethylsilanyl) methylimino) methyl-16α-pivalyl-5a, pregnan-11-one 54

To a solution of 123 mg (0.21 mmol, 1.0 eq) of aldehyde 18 in 0.7 ml of dichloromethane is added 101 mg of activated 4A molecular sieves (83% by weight relative to the starting material). and 53 mg (0.28 mmol, 1.3 eq) of bis (trimethylsilyl) methylamine. After stirring for 24 hours at 65 ° C., the solution is filtered through celite and evaporated under vacuum to give 151 mg of 54 as a yellow powder with a yield of 97%.

IR (diamond) O (Cm- ¹ ): 2959 (CH, CH 2); 1720 (C = O ester); 1668 and 1526 (C = O, C = N and

CONH); 1030 (C-O); 836 (Si-C). S.M. (E.S.I.): m / z: 742.5 ([M + H], 100); 743.5 (40); 744.5 (5); 371.8 ([M + 2H] / 2.80); 372.3

(35); 372.8 (10).

HRMS (ESI) calcd for C ₄₂ H ₇₆ N ₃ O ₄ Si ₂ m / z = 742.5374; measured: 742.5353.

¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.00 (18H, s, H37-42); 0.75 (3H, d, J = 6.4 Hz, H21);

0.76 (3H, s, H, 8); 0.91 (3H, s, H30); 0.92 (1H, m, H6β); 0.98 (1H, m, H19β); 0.99 and 1.02 (6H, 2d, J = 7.0Hz, H3 'and H4'); 1.07 (3H, s, H28); 1.11 (9H, s, H33-35); 1.16-1.40 (5H, m, Hl, H7α, H15α, H7β and H2β); 1.51 (1H, d, J = 3.8 Hz, H19α); 1.59 (1H, s, H36); 1.68 (1H, m, H 2); 1.86-2.02 (4H, m, H6α, H8β, H1 5β and H5α); 2.05 (6H, bs, NB-CH3); 2.08-2.20 (2H, m, H 2 and H 1a); 2.32 (1H, d, J = 17.0 Hz, H12β); 2.33 (1H, m, H1β); 2.38 (1H, dq, J = 6.4 Hz and 11.8 Hz, H 2 O); 2.48 (1H, d, J = 17.0 Hz, H12α); 3.89 (1H, ddd, J = 3.4 Hz, 9.8 Hz and 9.8 Hz, H3α); 4.96 (1H, dd, J = 5.3 Hz, 7.7 Hz, H16β); 5.29 (1H, d, J = 8.3 Hz, NAH); 7.19 (1H, s, H29).

NMR δ (75.5 MHz, CDCl ₃ ), δ ppm: -1.1 and -0.9 (C37-42); 10.1 (C21); 11.3 (C30); 17.9 (Cl 8); 18.9 and 19.5 (C3 'and C4'); 20.2 (C6); 20.5 (C28); 24.4 (C7); 27.3 (C33-35); 27.4 (C2); 27.8 (Cl); 29.7 (C19); 31.7 (C36); 34.2 (C9); 35.8 (C2 '); 37.7 (ClO); 38.7 (C32); 40.8 (NB-CH3); 41.1 (C8); 43.5 (C15); 44.9 (C13); 45.5 (C5); 47.5 (C14); 48.4 (C4); 52.1 (C12); 53.9 (C3); 55.1 (C17); 59.7 (C20); 79.3 (C16); 164.7 (C29); 176.3 (C31); 178.0 (Cl '); 210.8 (ClI).

• Compound 55: (20S) -3β-isobutylamino-20-dimethylamino-9,19-cyclo-4β, 14α-climethyl-4α- (Bis- (trimethylsilanyl) methylamino) methyl-5α, 9β-pfegnan-16α-ol- 11-one 55

Under argon, to a solution of 500 mg (0.92 mmol, 1.0 eq.) Of 16-0-acetylated aldehyde 14 in 0.5 ml of dichloromethane is added 415 mg of 4A activated molecular sieve (83% by mass relative to the starting material) and 210 mg (1.20 mmol, 1.3 eq) of bis (trimethylsilyl) methylamine. After stirring for 3 days at 65 ° C., the solution is filtered and evaporated under vacuum. To a solution of the residue obtained in 8 ml of methanol are added 138 mg (2.08 mmol, 2.3 eq.) Of sodium cyanoborohydride and 150 μl (2.62 mmol, 2.8 eq.) Of acid. glacial acetic. After stirring for 16 hours at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10), which saponifies the acetyl group at 16 and is extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 95 / methanol 5) to give 137 mg of 55 as an ocher powder in 25% yield over three steps. LR. (diamond) O (Cm- ¹ ): 3310 (OH, NH); 2948 (CH, CH 2); 1660 and 1535 (C = O and CONH); 1094 (CO); 837 (Si-C).

MS (ESI): m / z: 660.5 ([M + H], 40); 661.5 (10); 330.7 ([M + 2H] / 2, 100); 331.3 (35); 331.8 (5). HRMS (ESI) calculated for C ₃₇ H ₇₀ N ₃ O ₃ Si ₂ m / z = 660.4956; measured: 660.4974.

¹ H NMR (500 MHz, CDCl ₃ ), δppm: 0.04 and 0.06 (18H, 2s, H37-42); 0.59 (3H, s, H30); 0.80 (3H, d, J = 6.4 Hz, H21); 0.82 (3H, s, H18); 0.88 (1H, m, H6β); 1.00 (1H, d, J = 3.8 Hz, H19β); 1.13 and 1.14 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 1.21 (3H, s, H28); 1.24 (1H, s, H36); 1.26 (1H, m, H1a); 1.40-1.53 (4H, m, H7α, H15α, H7β and H2β); 1.54 (1H, d, J = 3.8 Hz, H19α); 1.67 (1H, m, H2α); 1.98-2.06 (3H, m, H6α, H15β and H17α); 2.05 (1H, d, 12.9Hz, H29a); 2.13 (6H, bs, NB-CH3); 2.22-2.34 (3H, m, H8β, H5α and Hlβ); 2.28 (1H, d, J = 17.0 Hz, H12β); 2.31 (1H, dq, J = 6.8 Hz and 11.2 Hz, H2 '); 2.50 (1H, d, J = 17.0 Hz, H1 2α); 2.64 (1H, m, H 2 O); 2.68 (1H, d, J = 12.9 Hz, H29b); 4.00 (1H, ddd, J = 4.1 Hz, 10.2 Hz and 11.0 Hz, H3α); 4.12 (1H, m, H16β); 5.13 (1H, d, J = 9.8 Hz, NAH). ¹³ C NMR (125.8 MHz, CDCl ₃ ), δppm: -0.2 and 0.7 (C37-42); 10.2 (C21); 13.8 (C30); 18.0 (Cl 8); 19.0 (C6); 20.0 (C3 'and C4'); 20.8 (C28); 24.1 (Cl); 27.8 (Cl); 28.7 (C2); 30.3 (Cl 9); 34.9 (C9); 36.1 (C2 '); 38.4 (ClO); 41.2 (C8); 41.7 (C5); 41.9 (C36); 43.1 (C4); 44.0 (Cl 5); 44.8 (C13); 47.5 (C 14); 50.5 (C3); 51.7 (C 12); 56.1 (C 17); 58.5 (C29); 59.7 (C20); 79.1 (C 16); 176.3 (Cl '); 211.5 (Cl).

Compound 56: (20S) -3- (4S) -butylamino-20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl-4α- (Bis- (trimethylsilyl) methylamino) methyl-16α-pivalyl-5α,% - pregnan -11-one 56

To a solution of 150 mg (0.20 mmol, 1.0 eq) of imine 54 in 0.7 ml of methanol is added 41 mg (0.61 mmol, 3.1 eq) of sodium cyanoborohydride and 35 μl (0.60 mmol, 3.0 eq) of glacial acetic acid. After stirring for 44 hours at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 25 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: 99.7 dichloromethane / 0.3 methanol) to give 84 mg of 56 in the form of an ocher powder with a yield of 54% over two hours. steps.

LR. (diamond) O (Cm- ¹ ): 3307 (NH), 2959 (CH, CH2); 1722 (C = O ester); 1658 and 1528 (C = O and CONH); 1095 (CO); 838 (Si-C).

MS (ESI): m / z: 744.6 ([M + H], 70); 745.6 (30); 746.6 (5); 372.8 ([M + 2H] / 2, 100); 373.3 (70); 373.8 (15). HRMS (ESI) calcd for C ₄₂ H ₇₈ N ₃ O ₄ Si ₂ m / z = 744.5531; measured: 744.5562. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.04 and 0.05 (18H, 2s, H37-42); 0.60 (3H, s, H30); 0.83 (3H, d, J = 6.4 Hz, H21); 0.85 (3H, s, H18); 0.90 (1H, m, H6β); 1.02 (1H, d, J = 3.8 Hz, H19β); 1.13 and 1.14 (6H, 2d, J = 6.8 Hz, H3 'and H4'); 1.15 (3H, s, H28); 1.19 (9H, s, H33-35); 1.24 (1H, s, H36); 1.22-1.52 (5H, m, H1, H7α, H15α, H7β and H2β); 1.57 (1H, d, J = 3.8 Hz, H19α); 1.67 (1H, m, H2α); 1.98-2.08 (4H, m, H6α, H8β, H15β and H5α); 2.01 (1H, d, 12.8 Hz, H29a); 2.13 (6H, bs, NB-CH3); 2.22-2.34 (3H, m, H 2 ', H 1 and H 17α); 2.38 (1H, d, J = 17.2 Hz, H12β); 2.46 (1H, dq, J = 6.4 Hz and 11.0 Hz, H 2 O); 2.55 (1H, d, J = 17.2 Hz, H12α); 2.69 (1H, d, J = 12.8 Hz, H29b); 4.01 (1H, ddd, J = 4.0 Hz, 10.9 Hz and 11.0 Hz, H3α); 5.05 (1H, dd, J = 5.5 Hz, 7.7 Hz, H16β); 5.12 (1H, d, J = 10.0 Hz, NAH).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: -0.3 and 0.7 (C37-42); 10.1 (C21); 13.7 (C30); 17.9 (C18); 18.9 (C6); 19.6 and 20.0 (C3 'and C4'); 20.0 (C28); 24.1 (C7); 27.3 (C33-35); 27.8 (Cl); 28.7 (C2); 30.0 (C19); 34.4 (C9); 36.1 (C2 '); 38.3 (ClO); 38.7 (C32); 40.8 (C36 and NB-CH3); 41.6 (C8); 41.9 (C5); 43.6 (C15); 44.0 (C4); 45.0 (C13); 47.6 (C14); 50.5 (C3); 52.2 (C12); 55.1 (C17); 58.5 (C29); 59.7 (C20); 79.4 (Cl 6); 176.3 (Cl '); 178.0 (C31); 211.3 (ClI).

Compound 57: (20S) -3 '-> isobutyrylamino-20-dimethylamino-9,19-cyclo-4', 14α-dimethyl-4α- (Bis- (trimethylsilanyl) methylamino) methyl-16a- (tert-Butyl) dimethylsilanyloxy) -5a, 9 $ -pregnan-ll-one 57

Under argon, to a solution of 93 mg (0.14 mmol, 1.0 eq) of amine 55 in 2.0 ml of tetrahydrofuran is added 276 mg (0.39 mmol, 2.8 eq.) Of imidazole and 36 mg (0.23 mmol, 1.7 eq) of β-butyldimethylsilyl chloride. After stirring for 16 hours at room temperature, the mixture is basified with 40 ml of a solution of 10% sodium hydrogen carbonate (pH = 8) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: 99.9 dichloromethane / 0.1 methanol) to give 84 mg of 57 as a colorless powder with a yield of 77%.

LR. (diamond) O (Cm- ¹ ): 3391 and 3112 (NH); 1666, 1653 and 1521 (C = O and CONH); 1093 (CO); 1028 (Si-OC); 833 (Si-C, Si-O).

MS (ESI): m / z: 774.6 ([M + H], 10); 387.8 ([M + 2H] / 2, 100); 388.3 (50); 388.8 (15). HRMS (ESI) calcd for C ₄₃ H ₈₄ N ₃ O ₃ Si ₃ m / z = 774.5821; measured: 774.5862. ¹ H NMR (500 MHz, CDCl ₃ ), δppm: 0.01 and 0.02 (6H, 2s, H31-32); 0.05 and 0.07 (18H, 2s, H38-

43); 0.60 (3H, s, H30); 0.79 (3H, s, H18); 0.80 (3H, d, J = 6.3 Hz, H21); 0.88 (9H, s, H34-36);

0.90 (1H, m, H6β); 0.98 (1H, d, J = 3.8 Hz, H19β); 1.15 and 1.16 (6H, 2d, J = 6.9 Hz, H3 'and H4');

1.20 (3H, s, H28); 1.25 (1H, s, H37); 1, 27 (1H, m, H1a); 1.39 (1H, m, H15α); 1.43-1.48 (3H, m, H7α, H7β and H2β); 1.56 (1H, d, J = 3.8 Hz, H19α); 1.67 (1H, m, H2α); 1.81 (1H, dd, J = 7.6

Hz and 13.6 Hz; Hl 5β); 2.01 (1H, dd, J = 9.5 Hz and 8.8 Hz, H8β); 2.06 (1H, m, H5α, H17α);

2.08 (1H, d, 12.9 Hz, H29a); 2.13 (6H, bs, NB-CH3); 2.19-2.22 (2H, m, H1 β and H6α); 2.31 (1H, dq, J = 6.9 Hz, H2 '); 2.34 (1H, d, J = 17.0 Hz, H 21); 2.41 (1H, dq, J = 6.3 Hz and 12.0 Hz,

H20); 2.52 (1H, d, J = 17.0 Hz, H12α); 2.69 (1H, d, J = 12.9 Hz, H29b); 4.01 (1H, ddd, J = 4.1Hz, 10.1Hz and 12.2Hz, H3α); 4.14 (1H, dd, J = 4.7 Hz, 7.6 Hz, H16β); 5.10 (1H, d, J = 9.8 Hz,

NAH).

NMR C (125.7 MHz, CDCl ₃ ), δppm: -0.2 and 0.7 (C37-42); 10.3 (C21); 13.8 (C30); 17.9

(Cl 8); 19.0 (C6); 19.6 (C28); 20.0 (C3 'and C4'); 24.1 (C7); 26.1 (C34-36); 27.8 (Cl); 28.7 (C2);

29.4 (C19); 34.6 (C9); 36.1 (C2 '); 37.9 (ClO); 40.8 (C4 and NB-CH3); 41.4 (C37 and C5); 41.9 (C8); 44.0 (C13); 45.3 (C14); 46.0 (C15); 50.6 (C3); 52.5 (Cl 2); 58.5 (C29); 59.5 (Cl 7); 60.2

(C20); 76.9 (C16); 176.3 (Cl '); 212.1 (ClI).

• Compound 59: (20S) -16α-acetyl-3β - ((S) -2-methylbutylamino) -20-dimethylamino-9,19-cyclo-4α-formyl-4β, 14α-dimethyl-5α, 9β-pregnan -11-one 59

To a solution of 496 mg (0.96 mmol, 1.0 eq) of amide 6e in a mixture of 48 ml of dichloromethane and 14 ml of pyridine are added 136 μl (1.44 mmol, 1.5 eq. .) acetic anhydride. After stirring for 16 hours at room temperature, the mixture is co-evaporated with 1,2-dichloroethane. The residue is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3x30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

To a solution of 519 mg (0.93 mmol, 1.0 eq.) Of the residue previously obtained in 30 ml of dichloromethane is added 511 mg (1.21 mmol, 1.3 eq) of Dess-Martin periodinane. After stirring for 1 hour at ambient temperature, the mixture is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: 95 dichloromethane / methanol 5) to give 500 mg of 59 in the form of a colorless powder after trituration in acetone and with a yield of 91%. %, on two steps.

PF ( ⁰ C): 265 ° C LR. (diamond) O (Cm- ¹ ): 3254 (OH, NH); 2926 (CH, CH 2); 2856 (CH = O); 1718 (C = O ester); 1666 (C = O); 1638 and 1538 (CONH); 1255, 1017 (C-OH). MS (ESI): m / z: 557.4 ([M + H], 100); 558.4 (15); 515.4

(20). HRMS (ESI) calcd for C ₃₃ H ₅₃ N ₂ O ₅ m / z = 557.3954; measured: 557.3948. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.81 (3H, d, J = 6.4 Hz, H21); 0.83 (3H, s, H18); 0.84 (3H, t, J = 7.3 Hz, H4 '); 0.92 (3H, s, H30); 1.06 (1H, m, H6β); 1.06 (3H, d, J = 6.8 Hz, H5 '); 1.07 (1H, d, J = 3.6 Hz, H19α); 1.18 (3H, s, H28); 1.24-1.59 (5H, m, H1, H2β, H7β, H7α and H15α); 1.58 (1H, d, J = 4.2 Hz, H19β) 1.73-1.82 (3H, m, H3 'and H2α); 1.99 (3H, s, H32); 2.04 (1H, m, H15β); 2.13 (6H, s, NB-CH3); 1.95-2.16 (4H, m, H2 ', H6α, H5α and H8β); 2.22 (1H, dd, J = 6.2 Hz and 10.0 Hz, H17α); 2.38 (1H, d, J = 17.0 Hz, H12β); 2.45 (2H, m, H 2 O and H 1 B); 2.56 (1H, d, J = 17.1Hz, H12α); 4.34 (1H, ddd, J = 4.1 Hz, 8.9 Hz and 12.4 Hz, H3α); 5.11 (1H, dd, J = 6.2 Hz and 8.0 Hz, H16β); 5.28 (1H, d, J = 9.1 Hz, NAH); 9.41 (1H, s, H29). NMR C (75.5 MHz, CDCl ₃ ), δppm:

7.8 (C30); 10.0 (C21); 11.8 (C4 '); 17.4 (C5 '); 18.0 (C18); 19.5 (C28); 21.1 (C6); 21.2 (C31); 24.2 (C7); 27.0 (C2); 27.5 (C3 '); 29.6 (Cl); 29.6 (C19); 33.7 (C9); 36.0 (ClO); 40.4 (NB-CH3); 41.3 (C2 '); 41.8 (C5); 43.0 (C15); 43.4 (C8); 44.6 (C13); 47.5 (CH); 50.0 (C3); 51.9 (C12); 55.3 (C17); 56.9 (C4); 59.6 (C20); 78.9 (C 16); 170.7 (C31); 175.9 (Cl '); 203.5 (C29); 211.6 (ClI).

Compound 60: (20S) -20-Dimethylamino-3β - ((S) -2-methylbutyrylamino) -9,19-cyclo-4α-formyl-4α, 14α-dimethyl-5α, 9β-pregnan-16α ol-l l-one60

To a solution of 1127 mg (2.02 mmol, 1.0 eq) of amide 59 in 26 ml of methanol preheated to 40 ^° C. for complete dissolution, a solution of 2542 mg (30.30 mmol) is added. 15.0 eq.) Of sodium hydrogencarbonate and 2138 mg (20.20 mmol, 10.0 eq) of sodium carbonate in 28 ml of deionized water. A precipitate is formed. After stirring for 6 hours at 60 ^° C., the mixture is diluted with 50 ml of water and extracted with 3.times.50 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 98 / methanol 2) to provide 710 mg of 60 as a colorless powder in 68% yield over two steps.

PF ( ⁰ C): 265 ° C

Elemental analysis: for C33H52N2O5

Calcd for C33H52N2O5%: C 71.19 H 9.41 N 5.03 O 14.37 Found%: C H N O

IR (diamond) O (Cm- ¹ ): 3287 (OH, NH); 2935 (CH, CH 2); 2709 (CH = O); 1717 (C = O aldehyde); 1659 (C = O); 1640 and 1548 (CONH); 1229 and 1093 (C-OH).

MS (ESI): m / z: 515.4 ([M + H], 100); 516.4 (5). HRMS (ESI) calcd for C31H51N2O4 m / z = 515.3849; measured: 515.3831. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.74 (3H, s, H18); 0.77 (3H, t, J = 7.5 Hz, H4 '); 0.81 (3H, d, J = 6.4 Hz, H21); 0.87 (3H, s, H30); 0.98 (1H, m, H6β); 1.00 (3H, d, J = 6.8 Hz, H5 '); 1.01 (1H, m, H19α); 1.18 (3H, s, H28); 1.24-1.59 (7H, m, H1a, H2β, H3 ', H7β, H7α and H15α); 1.50 (1H, d, J = 4.1 Hz, H19β); 1.69-1.78 (2H, m, H8β and H2α); 1.90 (1H, dd, J = 7.4 Hz and 10.8 Hz, H1 7α); 1.95-2.16 (4H, m, H2 ', H6α, H5α and H1 5β); 2.18 (6H, s, NB-CH3); 2.25 (1H, d, J = 17.3 Hz, H 21); 2.36 (1H, ddd, J = 3.0 Hz, 4.7 Hz and 12.6 Hz, H1β); 2.47 (1H, d, J = 17.3 Hz, H12α); 2.55 (1H, dd, J = 6.8 Hz and 10.8 Hz, H 2 O); 4.03 (1H, ddd, J = 2.8 Hz, 7.4 Hz and 10.0 Hz, H16β); 4.28 (1H, ddd, J = 4.2 Hz, 8.7 Hz and 12.4 Hz, H3α); 5.28 (1H, d, J = 9.1 Hz, NAH); 9.36 (1H, s, H29). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

7.7 (C30); 10.0 (C21); 11.7 (C4 '); 17.3 (C5 '); 17.9 (C18); 20.7 (C28); 21.0 (C6); 24.0 (Cl); 27.3 (Cl); 27.5 (C3 'and C2); 29.6 (C19); 34.0 (C9); 35.8 (ClO); 41.3 (C5); 41.7 (C8); 41.8 (NB-CH3); 42.6 (C15); 43.2 (C2 '); 44.4 (C13); 47.1 (Cl 4); 49.8 (C3); 51.4 (C12); 55.8 (C17); 56.8 (C4); 62.0 (C20); 78.2 (C16); 175.8 (Cl '); 203.4 (C29); 210.9 (ClI).

Compound 61: (20S) -20-dimethylamino-3β - ((S) -2-methylbutyrylamino) -9,19-cyclo-4α-benzyliminomethyl-4β, 14α-dimethyl-Sa, 9β-pregnan-16α-ol- ll-one 61

Under argon, to a suspension of 650 mg (1.26 mmol, 1.0 eq.) Of aldehyde 60 and 540 mg of anhydrous magnesium sulphate in 5 ml of dichloromethane are added 179 μl (1.63 mmol, 1 g). 3 eq.) Of benzylamine. After stirring for 10 hours at 55 ° C, the solution is filtered through celite and evaporated in vacuo to provide 793 mg of 61 as a colorless powder in quantitative yield.

IR (diamond) O (Cl- ¹ ): 3386 (OH, NH); 2958 (CH, CH 2); 1649 (C = O, C = N); 1649 and 1529

(CONH); 1451 (C = C Ar); 1227 and 1091 (C-OH).

S. M. (S.I.I.): m / z: 604.4 ([M + H], 100); 605, 4 (55); 90, 4 (30).

HRMS (ESI) calculated for C ₃₈ H ₅₈ N ₃ O ₃ m / z = 604.4478; measured: 604.4468.

¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.73 (3H, t, J = 7.5 Hz, H4 '); 0.77 (3H, s, H18); 0.81 (3H, d, J = 6.6Hz, H21); 0.93 (1H, m,

H6β); 0.95 (3H, d, J = 6.8 Hz, H5 '); 0.98 (3H, s, H30); 1.01 (1H, d, J = 4.3 Hz, H19α); 1.16 (3H, s, H28); 1.24-1.59 (7H, m, H1, H2β, H3 ', H7β, H7α and H15α); 1.52 (1H, d, J = 4.3 Hz, H19β);

1.75 (1H, m, H2α); 1.82-2.07 (6H, m, H1 5β, H17α, H2 ', H6α, H5α and H8β); 2.19 (6H, s, NB- CH3); 2.24 (1H, d, J = 17.3 Hz, H12β); 2.31 (1H, ddd, J = 3.2 Hz, 3.3 Hz and 13.2 Hz, H1β); 2.46 (1H, d, J = 17.3 Hz, H12α); 2.56 (1H, dd, J = 6.6Hz and 12.0Hz, H2O); 4.03 (2H, m, H3α and H16β); 4.43 and 4.50 (2H, 2d AB system, 14.1 Hz, H31); 5.25 (1H, d, J = 9.2 Hz, NAH); 7.14-7.25 (5H, m, HAr = 33-37); 7.50 (1H, s, H29). NMR C (75.5 MHz, CDCl ₃ ), δppm:

10.0 (C30); 10.3 (C21); 11.8 (C4 '); 17.1 (C5 '); 17.9 (C18); 20.6 (C6); 20.7 (C28); 24.2 (C7); 27.2 (C3 '); 27.5 (Cl); 27.7 (C2); 29.8 (C19); 34.3 (C9); 36.7 (ClO); 41.3 (C8); 42.7 (C15); 43.3 (C2 '); 44.5 (C13); 44.7 (C5); 47.1 (CH); 49.9 (C4); 51.4 (C12); 52.2 (C3); 55.8 (C17); 62.1 (C20); 64.7 (C31); 78.2 (C 16); 126.7 (C35); 127.7 and 128.3 (C34-36 and C33-37); 139.5 (C32); 170.9 (C29); 175.6 (Cl '); 211.0 (Cl).

Compound 62: (20S) -20-Dimethylamino-3β - ((S) -2-methylbutyrylamino) -9,19-cyclo-4α-benzylaminomethyl-4β, 14α-dimethyl-6α, 9β-pregnan-16α-ol- ll-one 62

To a suspension of 770 mg (1.26 mmol, 1.0 eq) of imine 61 in 7 ml of methanol are successively added 102 mg (1.54 mmol, 1.2 eq) of sodium cyanoborohydride and μl (1.27 mmol, 1.05 eq) of glacial acetic acid. After stirring for 3 hours at room temperature, the mixture is basified with 50 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 50 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 98 / methanol 1) to provide 618 mg of 62 as a colorless powder in 81% yield over two steps.

LR. (diamond) O (Cm- ¹ ): 3314 (OH, NH); 2932 (CH, CH 2); 1660 (C = O); 1660 and 1529 (CONH); 1452 (C = C Ar); 1226 and 1094 (C-OH).

S. M. (S.I.I.): m / z: 606.5 ([M + H], 100); 60, 7.5 (1 0). HRMS (ESI) calcd for C ₃₈ H ₆₀ N ₃ O ₃ m / z = 606.4635; measured: 606.4634. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.59 (3H, s, H18); 0.83 (3H, s, H30); 0.88 (3H, d, J = 6.6Hz, H21); 0.90 (3H, t, J = 7.3 Hz, H4 '); 0.95 (1H, m, H6β); 1.09 (1H, d, J = 3.4 Hz, H19α); 1.13 (3H, d, J = 6.8 Hz, H5 '); 1.25 (3H, s, H28); 1.25-1.50 (5H, m, H1, H3a ', H7, H2β and H15α); 1.52 (1H, d, J = 3.4 Hz, H19β); 1.58-1.75 (2H, m, H3b 'and H2α); 1.94-2.19 (6H, m, H15β, H17α, H2 ', H6α, H5α and H8β); 2.12 (1H, d, J = 12.2 Hz, H29); 2.25 (6H, s, NB-CH3); 2.27 (1H, d, J = 12.2 Hz, H29); 2.29 (1H, d, J = 17.1Hz, H12β); 2.36 (1H, m, H1β); 2.52 (1H, d, J = 17.1Hz, H12α); 2.62 (1H, dd, J = 6.6 Hz and 10.8 Hz, H 2 O); 3.62 and 3.81 (2H, 2d AB system, 13.7 Hz, H31); 4.07 (1H, m, H3α); 4.11 (1H, m, H16β); 5.19 (1H, d, J = 9.8 Hz, NAH); 7.18-7.35 (5H, m, HAr = 33-37). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 9.9 (C21); 12.1 (C4 '); 13.7 (C30); 17.7 (C5 '); 17.8 (C18); 18.4 (C6); 21.0 (C28); 24.4 (Cl); 27.5 (C3 '); 27.6 (Cl); 28.5 (C2); 31.0 (C19); 34.6 (C9); 38.2 (ClO); 41.6 (C8); 42.0 (C5); 42.9 (C15); 43.1 (C4); 43.7 (C2 '); 44.5 (Cl 3); 47.1 (CH); 50.5 (C3); 51.5 (C12); 52.9 (C29); 54.5 (C31); 55.8 (C17); 62.0 (C20); 78.4 (C16); 126.5 (C35); 128.0 and 128.4 (C34-36 and C33-37); 141.3 (C32); 176.1 (Cl '); 211.6 (Cl).

Compound 63: (20S) -20-dimethylamino-3β - ((S) -2-methylbutyrylamino) -9,19-cyclo-4α-aminomethyl-4α, 14α-dimethyl-5α, 9β-pregnan-16α ol-ll-one 63

Under argon, to a suspension of 580 mg (0.96 mmol, 1.0 eq.) Of N-benzyl amine 62 in 20 ml of anhydrous methanol degassed with argon is added successively 290 mg (50% by weight compared to 62) of 30% palladium on carbon and 311 mg (4.79 mmol, 5.0 eq.) of ammonium formate. After stirring for 3 hours at 40 ^° C., the mixture is filtered on celite and evaporated under vacuum. The residue obtained is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3x30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on a silica column (eluent: dichloromethane 98 / methanol 1.9 / 0.1 ammonia) to provide 414 mg of 63 as a colorless powder in 84% yield over two steps.

IR (diamond) O (Cl- ¹ ): 3314 (OH, NH); 2932 (CH, CH 2); 1660 (C = O); 1660 and 1529 (CONH); 1452 (C = C Ar); 1226 and 1094 (C-OH).

S. M. (S.I.I.): m / z: 606.5 ([M + H], 100); 60, 7.5 (10), HRMS (ESI) calculated for C ₃₈ H ₆₀ N ₃ O ₃ m / z = 606.4635; measured: 606.4634. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.63 (3H, s, H30); 0.84 (3H, s, H18); 0.87 (3H, d, J = 6.6Hz, H21); 0.92 (3H, t, J = 7.4 Hz, H4 '); 0.93 (1H, m, H6β); 1.04 (1H, d, J = 3.8 Hz, H19α); 1.13 (3H, d, J = 6.8 Hz, H5 '); 1.22 (3H, s, H28); 1.26-1.57 (5H, m, H1, H3a ', H7, H2β and H15α); 1.56 (1H, d, J = 3.8 Hz, H19β); 1.59-1.74 (2H, m, H3b 'and H2α); 1.95-2.13 (6H, m, H15β, H17α, H2 ', H6α, H5α and H8β); 2.24 (6H, s, NB-CH3); 2.31 (1H, d, J = 17.5 Hz, H12β); 2.36 (1H, d, J = 13.9 Hz, H29a); 2.41 (1H, m, H1β); 2.46 (1H, d, J = 13.9 Hz, H29b); 2.51 (1H, d, J = 17.5 Hz, H12α); 2.61 (1H, dd, J = 6.6 Hz and 10.9 Hz, H 2 O); 4.06 (1H, m, H3α); 4.10 (1H, m, H16β); 5.24 (1H, d, J = 9.8 Hz, NAH).

¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 9.9 (C21); 12.1 (C4 '); 13.7 (C30); 17.6 (C5 '); 17.8 (C18); 18.5 (C6); 21.0 (C28); 24.6 (Cl); 27.5 (C3 '); 27.7 (Cl); 28.4 (C2); 31.2 (C19); 34.4 (C9); 38.1 (ClO); 41.7 (C8); 41.9 (C5); 42.9 (C15); 43.6 (CT and C4); 44.4 (C13); 46.2 (C29); 47.1 (C14); 49.7 (C3); 51.5 (Cl 2); 55.8 (Cl 7); 62.0 (C20); 78.3 (C16); 176.3 (Cl '); 211.5 (ClI).

Compound 64: (20S) -20-dimethylamino-9,19-cyclo-4α, 14α-dimethyl- (2- (S) -sec-butyl-5-methyl-1,5,5,6-tetrahydropyrimidin). 5-yl) -5α, 9β-pregnan-16α-ol-11-one 64

To a solution of 300 mg (0.58 mmol, 1.0 eq) of amine 63 in 30 ml of n-butanol is added 162 μl (1.15 mmol, 2.0 eq) of triethylamine. After stirring for 16 hours at 120 ^° C., the mixture is evaporated under vacuum. The residue obtained is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 95 / methanol 5) to give 210 mg of 64 as a light yellow foam with a yield of 73%.

IR (diamond) O (Cm- ¹ ): 3312 (OH, NH); 2932 (CH, CH 2); 1665 (C = O); 1625 and 1518 (CN,

C = N); 1039 (C-OH).

S. M. (S.I.I.): m / z: 498.4 ([M + H], 100); 49 9, 4 (1 0).

HRMS (ESI) calcd for C31H52N3O2 m / z = 498.4060; measured: 498.4049. Note: This is a mixture of two tautomeric forms. Nitrogen NA and Nc exchange a proton. In ¹³ C NMR, the C3 and C29 carbons give weak integration masses. ¹ H NMR (500 MHz, CDCl ₃ ), δppm:

0.69 (3H, s, H30); 0.77 (3H, s, H18); 0.80 (3H, d, J = 6.6Hz, H21); 0.85 (3H, t, J = 7.6 Hz, H4 '); 1.01 (1H, m, H6β); 1.04 (3H, d, J = 6.8 Hz, H5 '); 1.07 (1H, d, J = 3.8 Hz, H19α); 1.14 (3H, s, H28); 1.16-1.43 (6H, m, H1a, H3a ', H7, H2β and H15α); 1.50 (1H, m, H3a '); 1.55 (1H, d, J = 3.8 Hz, H19β); 1.61 (1H, m, H 2); 1.98-2.02 (2H, m, H6α and H8β); 1.90 (1H, dd, J = 7.6 Hz and 10.7 Hz, H17α); 1.96 (1H, dd, J = 10.4 Hz and 14.0 Hz, H15β); 2.01-2.05 (2H, m, H5α and H2 '); 2.18 (6H, s, NB-CH3); 2.25 (1H, d, J = 17.7 Hz, H12β); 2.40 (1H, m, H1β); 2.42 (1H, d, J = 17.7 Hz, H12α); 2.55 (1H, dd, J = 6.6 Hz and 10.7 Hz, H 2 O); 2.92 (1H, d, J = 13.9 Hz, H29a); 3.09 (1H, m, H3α); 3.11 (1H, d, J = 13.9 Hz, H29b); 4.02 (1H, m, H16β); 4.23 (1H, bs, NAH or NCH).

¹³ C NMR (125.8 MHz, CDCl ₃ ), δppm:

9.9 (C21); 11.8 (C30); 12.2 (C4 '); 17.9 (C18); 18.2 (C6); 18.4 (C5 '); 20.6 (C28); 24.2 (C7); 27.5 (C3 '); 28.1 (Cl and C2); 30.3 (C19); 34.4 (C5 and C9); 38.0 (ClO); 41.0 (C8); 42.4 (C2 '); 42.7 (C15); 44.6 (C13); 47.2 (C4); 47.3 (C14); 51.5 (Cl 2); 55.5 (C3); 55.9 (C17); 58.1 (C29); 62.1 (C20); 78.3 (Cl 6); 159.8 (Cl '); 211.0 (ClI).

Compound 65: (20S) -10 (9-> 1) abeo-16α-triacetyl-3 - ((S)) - 2-methylbuylamino) -20-dimethylamino-4β, 14α-dimethyl-4α-hydroxymethyl-5α9β-pregnate -l (10) -en-ll-one 65

To a solution of 735.5 mg (1.42 mmol, 1.0 eq) of amide 7e in 71 ml of dichloromethane and 21 ml of pyridine are added 202 μl (2.13 mmol, 1.5 eq. ) of acetic anhydride. The solution is light yellow. After stirring for 16 hours at room temperature, the mixture is co-evaporated in the presence of 1,2-dichloroethane. The residue is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3x20 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue thus obtained is crystallized from acetone to give 169 mg of 65 as colorless crystals. The mother liquors are evaporated under vacuum and the residue is chromatographed on a column of Merck alumina of activity II-III (eluent: dichloromethane 9 / methanol 1) to give 378 mg of 65 in the form of a colorless powder after recrystallization from the reaction medium. acetone with a total yield of 90%.

PF ( ⁰ C): MISSING

Elemental analysis: for C ₃₃ H ₅₄ N ₂ O ₅

Calculated for C ₃₃ H ₅₄ N ₂ O ₅ %: C 70.93H 9.74 N 5.01 O 14.32

Measured%: C 70.82H 10.05 N 4.95 0 14.16 IR (diamond) "(cm ¹ ): 3238 (OH, NH); 1731 (C = O ester) and 1698 (C = O); 1632 and 1552 (CONH); 1454 1377 1243 1034 (C-OH). MS (ESI): m / z: 559.4 ([M + H], 100); 560.4 (15).

HRMS (ESI) calcd for C ₃₃ H ₅₅ N ₂ O ₅ m / z = 559.4111; measured: 559.4150. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.47 (3H, s, H30); 0.70 (3H, s, H18); 0.82 (3H, d, J = 6.2 Hz, H21); 0.92 (1H, m, H6β); 0.95 (3H, t, J = 7.5 Hz, H4 '); 1.16 (3H, d, J = 6.8 Hz, H5 '); 1.22 (3H, s, H28); 1.40-1.96 (7H, m, H2β, H2 ', H3', H7β, H7α and H15α); 1.90 (1H, m, H19β); 2.01 (6H, s, NB-CH3); 2.35 - 2.45 (6H, m, H2α, H6α, H17α, H5α, H8β, H9α and H15β); 2.13 (3H, s, H32); 2.41 (1H, d, J = 15.6 Hz, H12β); 2.45 (1H, m, H 2 O); 2.61 (1H, d, J = 15.6 Hz, H12α); 3.16 (1H, dd, J = 4.5 Hz and 12.4 Hz, H29a); 3.36 (1H, d, J = 14.3 Hz, H19α); 3.40 (1H, d, J = 10.9 Hz and 12.4 Hz, H29b);

4.08 (1H, ddd, J = 6.1 Hz, 9.0 Hz and 10.9 Hz, H3α); 4.66 (1H, dd, J = 4.5 Hz and 10.9 Hz, OH); 5.12 (1H, dd, J = 6.1 Hz and 8.0 Hz, H16β); 5.39 (1H, d, J = 8.9 Hz, NAH); 5.48 (1H, s, H1). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

9.9 (C30); 10.0 (C21); 12.1 (C4 '); 17.6 (C5 '); 17.9 (Cl 8); 18.0 (C28); 21.2 (C32); 25.0 (C6); 27.5 (C3 '); 30.1 (C2); 33.3 (CJ); 37.5 (C19); 40.1 (NB-CH3); 42.0 (C4); 42.7 (C15); 43.3 (C2 '); 43.5 (C5); 46.2 (C13); 47.3 (C14); 48.0 (C3); 49.7 (C8); 49.9 (C9); 50.3 (C12); 54.2 (C17); 59.6 (C20); 63.8 (C29); 78.7 (Cl 6); 117.9 (Cl); 139.9 (ClO); 170.6 (C31); 178.4 (Cl '); 211.6 (ClI).

Compound 66: (20S) -10 (9-> 1) abeo-16α-acetyl-3β - ((S) -2-methylbutyrylamino) -20-dimethylamino-4α-formyl-4β, 14α-dimethyl-Sa, 9β -pregn-l (10) -en-ll-one 66

To a solution of 159.5 mg (0.28 mmol, 1.0 eq) of amide 65 in 3 ml of dichloromethane is added 162 mg (0.37 mmol, 1.3 eq) of Martin. After stirring for 1 hour at ambient temperature, the mixture is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 25 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on a silica column with solid deposition (eluent: dichloromethane 95 / methanol 5) to give 122 mg of 66 in the form of a colorless powder after recrystallization from acetone and with a yield of 77%.

PF ( ⁰ C): 215 ° C

Elemental analysis: for C ₃₃ H ₅₂ N ₂ O ₅ .0.5 H2O

Calculated for C ₃₃ H ₅₂ N ₂ O ₅ -O ₅ SH ₂ O%: C 70.05 H 9.44 N 4.95

Found%: C 70.06 H 9.61 N 4.55 LR. (diamond) O (Cm- ¹ ): 3374 (OH, NH); 2965 (CH, CH 2); 2790 (CH = O); 1726 (C = O ester); 1697 (C = O); 1666 and 1529 (C = C and CONH); 1245, 1030 (C-OH). MS (ESI): m / z: 557.4 ([M + H], 100); 558.4 (15); 515.4 (15); 501.4 (5). HRMS (ESI) calcd for C ₃₃ H ₅₃ N ₂ O ₅ m / z = 557.3954; measured: 557.3957. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.68 (3H, s, H18); 0.81 (3H, d, J = 6.4 Hz, H21); 0.82 (3H, t, J = 7.3 Hz, H4 '); 0.83 (3H, s, H30); 1.06 (3H, d, J = 6.9 Hz, H5 '); 1.21 (3H, s, H28); 1.26-1.42 (3H, m, H6β, H7α and H15α); 1.51-1.65 (4H, m, H3 ', H8β and H6α); 1.77-1.90 (3H, m, H7β, H5α and H2β); 1.99 (3H, s, H32); 2.12 (6H, s, NB-CH3); 1.95-2.16 (3H, m, H19β, H15β and H9β); 2.24 (1H, dd, J = 5.8 Hz and 10.8 Hz, H1 7α); 2.41 (1H, d, J = 15.1 Hz, H 21); 2.33-2.48 (3H, m, H2 ', H2O and H2α); 2.60 (1H, d, J = 15.1 Hz, H12α); 3.40 (1H, d, J = 14.3 Hz, H19α); 4.47 (1H, ddd, J = 6.4 Hz, 9.3 Hz and 10.0 Hz, H3α); 5.10 (1H, dd, J = 6.2 Hz and 7.9 Hz, H16β); 5.27 (1H, d, J = 8.5 Hz, NAH); 5.54 (1H, s, H1); 9.47 (1H, s, H29). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

6.9 (C30); 10.1 (C21); 11.9 (C4 '); 17.4 (C5 '); 18.0 (C18 and C28); 21.3 (C31); 27.1 (C6); 27.4 (C3 '); 29.3 (C2); 33.2 (C7); 36.9 (Cl 9); 40.4 (NB-CH3); 42.8 (Cl 5); 43.3 (C2 '); 44.7 (C5); 46.4 (C14); 47.0 (C9); 47.4 (C14); 49.6 (C3); 50.0 (C8); 50.4 (C12); 54.4 (C17); 55.5 (C4); 59.7 (C20); 78.7 (C16); 120.1 (Cl); 136.9 (ClO); 170.6 (C31); 176.2 (Cl '); 204.5 (C29); 211.0 (ClI).

• Compound 67: (20S) -10 (9-> 1) -abeo-20-dimethylamino-3 $ - ((S) -2-methylbtaytlamino) -4α-formyl-4β, 14α-dimethyl-Sa, 9β-pregnane 1 (10) -en-16α-ol-11-one 67

To a solution of 304 mg (0.54 mmol, 1.0 eq) of amide 66 in 7 ml of methanol preheated to 40 ^° C. for complete dissolution, a solution of 688 mg (8.18 mmol) is added. 15.0 eq.) Of sodium hydrogencarbonate and 579 mg (5.46 mmol, 10.0 eq.) Of sodium carbonate in 11.5 ml of deionized water. A precipitate is formed. After stirring for 7 hours at 55 ° C., the mixture is diluted with 40 ml of water and extracted with 3.times.40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 98 / methanol 2) to give 237 mg of 67 as a colorless powder in 84% yield over two steps.

PF ( ⁰ C): 265 ° C

Elemental analysis: for C33H52N2O5 Calcd for C ₃₃ H ₅₂ N ₂ O ₅ %: C 71.19 H 9.41 N 5.03 O 14.37

Found%: C H N O

IR (diamond) O (Cm- ¹ ): 3319 (OH, NH); 2931 (CH, CH 2); 2787 (CH = O); 1722 (C = O aldehyde); 1695 (C = O); 1649 and 1528 (CONH); 1214 and 1016 (C-OH). S. M. (E, S.I.): m / z: 51.5, 3 ([M + H], 100); 6, 4 (45); 501, 4

(5).

HRMS (ESI) calcd for C31H51N2O4 m / z = 515.3849; measured: 515.3844. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.62 (3H, s, H18); 0.76 (3H, s, H30); 0.78 (3H, t, J = 7.4 Hz, H4 '); 0.81 (3H, d, J = 6.4 Hz, H21); 1.00 (3H, d, J = 6.8 Hz, H5 '); 1.20 (3H, s, H28); 1.22-1.60 (6H, m, H3 ', H6α, H6β, H7β, and H1 5α); 1.69-1.83 (4H, m, H2β, H7β, H8β and H5α); 1.84-2.01 (5H, m, H2 ', H9α, H1 9β, H1 5β and H7α); 2.17 (6H, s, NB-CH3); 2.29 (1H, d, J = 15.8 Hz, H12β); 2.36 (1H, m, H2α); 2.52 (1H, d, J = 15.8 Hz, H12α); 2.55 (1H, m, H 2 O); 3.34 (1H, d, J = 14.3 Hz, H19α); 4.01 (1H, ddd, J = 2.5 Hz, 8.4 Hz and 8.5 Hz, H16β); 4.40 (1H, ddd, J = 6.4 Hz, 7.1 Hz and 12.1 Hz, H3α); 5.22 (1H, d, J = 10.0 Hz, NAH); 5.48 (1H, s, H1); 9.42 (1H, s, H29). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

6.8 (C30); 10.0 (C21); 11.8 (C4 '); 17.3 (C5 '); 17.8 (C18); 18.8 (C28); 27.1 (C6); 27.3 (C3 '); 29.2 (C2); 33.2 (C7); 37.0 (C19); 42.4 (C15); 43.2 (C2 '); 44.6 (C8); 46.2 (C13); 46.8 (C5); 47.0 (C14); 49.6 (C3); 50.0 (C12); 50.3 (C9); 55.4 (C17 and C4); 62.0 (C20); 78.3 (C16); 119.9 (Cl); 136.8 (ClO); 176.1 (Cl '); 204.5 (C29); 211.4 (ClI).

Compound 68: (20S) -10 (9 - 1) -abeo-20-dimethylamino-3 - ((S) -2-methylbutyrylamino) -4α-benzyliminomethyl-4α, 14α-dimethyl-5α, 9 ^> - pregn-l (10) - en-16a-ol-ll-one 68

Under argon, to a suspension of 200 mg (0.39 mmol, 1.0 eq) of aldehyde 67 and 160 mg of anhydrous magnesium sulfate in 2 ml of dichloromethane are added 55 μl (0.50 mmol, 1 3 eq.) Of benzylamine. After stirring for 7 hours at 55 ° C, the solution was filtered through celite and evaporated in vacuo to provide 272 mg of 68 as a yellow powder in quantitative yield.

IR (diamond) O (Cl- ¹ ): 3309 (OH, NH); 2929 (CH, CH 2); 1728 (C = O); 1695 (C = N); 1649 and

1532 (C = C, CONH); 1451 (C = C Ar); 1227 and 1091 (C-OH). S.M. (E.S.I.): m / z: 604.4 ([M + H], 100); 605.4 (10); 646.5

(5).

HRMS (ESI) calculated for C ₃₈ H ₅₈ N ₃ O ₃ m / z = 604.4478; measured: 604.4460.

¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.61 (3H, s, H18); 0.75 (3H, t, J = 7.4 Hz, H4 '); 0.80 (3H, d, J = 6.4 Hz, H21); 0.86 (3H, s, H30); 0.96 (3H, d, J = 7.0Hz, H5 '); 1.19 (3H, s, H28); 1.21-1.62 (6H, m, H3 ', H6α, H6β, H7β, and

H15α); 1.67-1.83 (4H, m, H2β, H7β, H8β and H5α); 1.86-1.97 (4H, m, H2 ', H9α, H15β and H7α); 2.01 (1H, m, H19β); 2.06 (6H, s, NB-CH3); 2.28 (1H, d, J = 16.0 Hz, H12β); 2.33 (1H, m, H2α); 2.51 (1H, d, J = 16.0 Hz, H12α); 2.54 (1H, m, H 2 O); 3.30 (1H, d, J = 14.5 Hz, H19α);

4.02 (1H, ddd, J = 2.0Hz, 7.5Hz and 7.9Hz, H16β); 4.19 (1H, ddd, J = 6.2 Hz, 7.0 Hz and 13.0 Hz, H3α); 4.44 and 4.56 (2H, 2d AB system, J = 13.4 Hz, H31); 5.22 (1H, d, J = 9.0 Hz, NAH); 5.47 (1H, s, H1); 7.15-7.28 (5H, m, HAr = 33-37); 7.56 (1H, s, H29).

NMR C (75.5 MHz, CDCl ₃ ), δppm:

Compound 69: (20S) -10 (9-> 1) abeo-20-dimethylamino-3 ', - ((S) -2-methylbutyrylamino) -4α-benzylaminomethyl-4α, 14α-dimethyl-5α, 9 ^> - pregn-l (10) - en-16a-ol-ll-one 69

To a suspension of 272 mg (0.39 mmol, 1.0 eq) of imine 68 in 2 ml of methanol are successively added 36 mg (0.54 mmol, 1.4 eq) of sodium cyanoborohydride and 26 ml of sodium cyanoborohydride. μl (0.45 mmol, 1.15 eq) of glacial acetic acid. After stirring for 3 hours at ambient temperature, the mixture is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 98 / methanol 1) to provide 173 mg of 69 as a colorless powder in 73% yield over two steps.

IR (diamond) O (Cm- ¹ ): 3313 (OH, NH); 2961 (CH, CH 2); 1695 (C = O); 1644 and 1530 (CONH); 1452 (C = C Ar); 1237 and 1095 (C-OH).

S. M. (S.I.I.): m / z: 606.4 ([M + H], 100); 607.5 (20), HRMS (ESI) calculated for C ₃₈ H ₆₀ N ₃ O ₃ m / z = 606.4635; measured: 606.4636. ¹ H NMR (300 MHz, CDCl ₃ ), δppm: 0.45 (3H, s, H30); 0.61 (3H, s, H18); 0.80 (3H, d, J = 6.4 Hz, H21); 0.86 (3H, t, J = 7.4 Hz, H4 '); 1.06 (3H, d, J = 6.8 Hz, H5 '); 1.24 (3H, s, H28); 1.28-1.62 (6H, m, H3 ', H6α, H6β, H7β, and H15α); 1.67-1.76 (4H, m, H2β, H7β, H8β and H5α); 1.82 (1H, m, H19β); 1.88-2.08 (4H, m, H2 ', H9α, H1 5β and H7α); 2.17 (6H, s, NB-CH3); 2.20 (1H, d, J = 12.5 Hz, H29); 2.27 (1H, d, J = 15.6 Hz, H12β); 2.32 (1H, d, J = 12.5 Hz, H29); 2.33 (1H, m, H2α); 2.52 (1H, d, J = 15.6 Hz, H12α); 2.62 (1H, m, H 2 O); 3.23 (1H, d, J = 14.1 Hz, H19α); 3.48 and 3.78 (2H, 2d AB system, J = 13.6 Hz, H31); 4.02 (2H, m, H16β and H3α); 5.23 (1H, d, J = 9.6 Hz, NAH); 5.37 (1H, s, H1); 7.12-7.27 (5H, m, HAr = 33-37). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm: 10.0 (C21); 12.0 (C4 '); 12.4 (C30); 17.6 (Cl 8); 17.7 (C5 '); 19.0 (C28); 25.2 (C6); 27.4 (C3 ');

30.7 (C2); 33.3 (C7); 37.5 (Cl 9); 40.5 (C4); 42.5 (Cl 5); 43.7 (C2 '); 44.7 (C5); 46.3 (Cl 3); 47.1 (CH); 48.0 (C3); 49.7 (C8); 50.1 (C12); 50.3 (C9); 52.6 (C29); 54.3 (C31); 55.4 (C17); 62.1 (C20); 78.4 (C16); 118.3 (Cl); 126.6 (C35); 128.0 and 128.4 (C34-36 and C33-37); 139.8 (ClO); 141.2 (C32); 176.4 (Cl '); 212.0 (ClI).

• Compound 70: (20S) -10 (9-> 1) -abeo-20-dimethylamino-3α - ((S) -2-methylbutyrylamino) -4α-aminomethyl-4α, 14α-dimethyl-5α, 9 -pregn-1 (10) -en-16α-ol-11-one 70

Under argon, to a suspension of 296 mg (0.49 mmol, 1.0 eq.) Of N-benzyl amine 69 in 10 ml of anhydrous methanol degassed with argon, are added successively 148 mg (50% by weight compared to 69) of 30% palladium on carbon and 159 mg (2.43 mmol, 5.0 eq) of ammonium formate. After stirring for 3 hours at 40 ^° C., the mixture is filtered on celite and evaporated under vacuum. The residue obtained is basified with 40 ml of a 10% ammonia solution (pH = 10) and extracted with 3x30 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is chromatographed on a silica column (eluent: dichloromethane 90 / methanol 9.9 / 0.1 ammonia) to provide 90 mg of 70 as a colorless powder in 36% yield over two steps.

LR. (diamond) O (Cm- ¹ ): 3314 (OH, NH); 2932 (CH, CH 2); 1660 (C = O); 1660 and 1529 (CONH); 1452 (C = C Ar); 1226 and 1094 (C-OH).

S. M. (S.I.I.): m / z: 606.5 ([M + H], 100); 60, 7.5 (10), HRMS (ESI) calculated for C ₃₈ H ₆₀ N ₃ O ₃ m / z = 606.4635; measured: 606.4634. ¹ H NMR (300 MHz, CDCl ₃ ), δppm:

0.50 (3H, s, H30); 0.62 (3H, s, H18); 0.81 (3H, d, J = 6.6Hz, H21); 0.86 (3H, t, J = 7.4 Hz, H4 '); 1.05 (3H, d, J = 6.8 Hz, H5 '); 1.21 (3H, s, H28); 1.17-1.25 (2H, m, H6); 1.26-1.64 (4H, m, H3 ', H7β); 1.45 (1H, dd, J = 1.7 Hz and 13.8 Hz, H15α); 1.65-1.81 (3H, m, H2β, H8β and H5α); 1.82 (1H, m, H19β); 1.82-2.11 (3H, m, H9α, H170C, H15β and H7α); 2.04 (1H, m, HZ); 2.19 (6H, s, NB-CH 3); 2.28 (1H, d, J = 15.3 Hz, H12β); 2.27 (1H, m, H2α); 2.46 (1H, d, J = 12.5 Hz, H29a); 2.50 (1H, d, J = 15.3 Hz, H12α); 2.56 (1H, d, J = 13.0 Hz, H29b); 2.57 (1H, m, H 2 O); 3.27 (1H, d, J = 13.8 Hz, H19α); 4.04 (1H, m, H16β); 4.06 (1H, m, H3α); 5.30 (1H, d, J = 9.6 Hz, NAH); 5.41 (1H, s, H1). ¹³ C NMR (75.5 MHz, CDCl ₃ ), δppm:

10.0 (C21); 12.0 (C4 '); 12.4 (C30); 17.6 (C5 '); 17.8 (Cl8); 19.0 (C28); 25.0 (C6); 27.4 (C3 '); 30.7 (C2); 33.4 (C7); 37.5 (C19); 41.1 (C4); 42.5 (Cl5); 43.6 (C2 '); 43.9 (C5); 45.6 (C29); 46.3 (C13); 47.1 (C14); 47.2 (C3); 49.8 (C12); 50.0 (C8); 50.2 (C9); 55.3 (C17); 62.1 (C20); 78.2 (C16); 118.8 (Cl); 139.2 (ClO); 176.8 (Cl '); 211.8 (ClI).

Compound 71: (20S) -10 (9-> 1) -abeo-20-dimethylamino-4α, 14α-dimethyl-2- (S) -s-butyl-5α-methyl-1,5,5, 6-Tetrahydro-pyrimidin-5-yl) -5a,% -pregnan-1 (10) -en-16α-ol-11-one 71

To a solution of 61 mg (0.12 mmol, 1.0 eq) of amine 70 in 30 ml of n-butanol is added 37 μl (0.26 mmol, 2.0 eq) of triethylamine. After stirring for 16 hours at 120 ^° C., the mixture is evaporated under vacuum. The residue obtained is basified with 30 ml of a 10% ammonia solution (pH = 10) and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue is chromatographed on Merck alumina column of activity II-III (eluent: dichloromethane 95 / methanol 5) to give 29 mg of 71 as a light yellow foam with a yield of 49%.

PF ( ⁰ C): 225 ° C

IR (diamond) O (Cl- ¹ ): 3315 (OH, NH); 2930 (CH, CH 2); 1694 (C = O); 1627 and 1518 (C = C,

C-N); 1039 (C-OH).

S. M. (E, S.I.): m / z: 498.4 ([M + H], 100); 499, 4 (1 0). HRMS (ESI) calcd for C31H52N3O4 m / z = 498.4060; measured: 498.4043. Note: This is a mixture of two tautomeric forms. Nitrogen NA and Nc exchange a proton. In ¹³ C NMR, the C3 and C29 carbons give weak integration masses.

¹ H NMR (500 MHz, CDCl ₃₎ δppm: 0.63 (3H, s, H 8); 0.67 (3H, s, H30); 0.80 (3H, d, J = 6.3 Hz, H21); 0.85 (3H, t, J = 7.5 Hz,

H4 '); 1.04 (3H, d, J = 6.9 Hz, H5 '); 1.17 (3H, s, H28); 1.19-1.36 (3H, m, H3a 'and H6); 1.48 to 1.62

(3H, m, H3b ', H7); 1.44 (1H, dd, J = 1.9 Hz and 13.9 Hz, H15α); 1.67-1.75 (2H, m, H2); 1,83-

1.93 (3H, m, H9α, H170C and H15β); 1.97-2.04 (4H, m, H2 ', H5α, H8β and H19β); 2.19 (7H, s, NB-

CH3 and H2α); 2.28 (1H, d, J = 15.8 Hz, HI 2β); 2.48 (1H, d, J = 15.8 Hz, H1 2α); 2.57 (1H, dd, J = 6.3 Hz and 10.7 Hz, H 2 O); 2.95 (1H, d, J = 12.9 Hz, H29a); 3.24 (1H, d, J = 15.8 Hz, H19α);

3.25 (1H, d, J = 12.9 Hz, H29b); 4.04 (1H, dd, J = 6.9 Hz and 7.3 Hz, H16β); 4.17 (1H, bs, NAH or NCH); 5.47 (1H, s, H1).

¹³ C NMR (128.5 MHz, CDCl ₃ ), δppm:

10.0 (C21); 10.9 (C30); 12.2 (C4 '); 17.8 (Cl 8); 18.6 (C5 '); 18.8 (C28); 25.0 (C6); 28.2 (C3 '); 29.7 (C2); 33.1 (C4); 33.8 (C7); 37.5 (C19); 42.4 (C2 '); 42.5 (C15); 46.2 (C13); 47.1 (C14); 49.8

(C5); 50.1 (Cl 2); 50.4 (C9); 50.8 (C3); 51.0 (C8); 54.2 (C29); 55.5 (Cl 7); 62.0 (C20); 78.4

(C16); 120.1 (Cl); 138.5 (ClO); 159.9 (Cl '); 211.9 (ClI).

Compound 75: (20S) -20-aminoethylamino-16α-acetyl-3β-isobutylamino-9,19-cyclo- 4α-methylethanethioate-4β, 14α-dimethyl-5α, 9β-pregnan-11-one 75

To a solution of 100 mg (1.78 mmol, 1.0 eq) of potassium hydroxide in 1.5 mL of ethanol is added 126.8 μL (1.78 mmol, 1.0 eq.) D thiolacetic acid. After stirring for 20 minutes at room temperature, the reaction medium is evaporated and the yellow powder obtained is washed with tetrahydrofuran to provide 203 mg of potassium thioacetate as a light yellow powder.

• 166.8 mg (1.46 mmol, 7.0 eq) of potassium thioacetate thus prepared are added to 145.8 mg (0.21 mmol, 1.0 eq.) Of (20S) -16θC-acetyl -3β-isobutyrylamino-9,19-cyclo-4α-hydroxytosyl] -ethyl-4β, 14α-dimethyl-20-dimethylamino-5α, 9β-pregnan-1-one dissolved in 5 ml of 1,3-dimethyl-3, Anhydrous 4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU). After stirring for 5 hours at 100 ^° C., the reaction mixture is basified with 20 ml of a solution of 10% sodium hydrogen carbonate (pH = 8) and extracted with 3 × 20 ml of ether. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum. The residue obtained is purified by flash chromatography on silica gel (eluent: 9.8 dichloromethane / 0.2 methanol) to give 70.1 mg of 75 as a light yellow powder with a yield of 56%. LR. (diamond) O (Cm- ¹ ): 2930 (NH); 1730 (C = O); 1666 and 1529 (C = O ester, CONH and COS). S. M. (S.I.I.): m / z: 603.4 ([M + H].

• Compound 76: (20S) -20-climethylamino-16α-acetyl-3β-isobutylamino-9,19-cyclo-4α-mefcaptomethyl-4β, 14α-dimethyl-5α, 9β-pregnan-11-one 76

C ₃₀ H ₅₀ N ₂ O ₃ S

Appearance: white solid

Molar weight: 518.79

To a solution of 318.2 mg (0.53 mmol, 1.0 eq.) (20S) -20-dimethylamino-16α-acetyl-3β-isobutyrylamino-9,19-cyclo-4α-methylethanethioate-4β, 14α -dimethyl-5α, 9β-pregnan-11-one in 6 ml of methanol is added a solution of 559.4 mg (5.27 mmol, 10.0 eq) of sodium carbonate and 665.1 mg (7 92 mmol, 15.0 eq.) Of sodium hydrogencarbonate in 6 ml of deionized water preheated to 40 ⁰ C for complete dissolution. A precipitate is formed. After stirring for 6 hours at 65 ° C., the mixture is diluted with 40 ml of water and extracted with 3 × 40 ml of dichloromethane. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue obtained is purified by flash chromatography on silica gel (eluent: dichloromethane 9 / methanol 1) to provide 229.9 mg of (20S) -20-dimethylamino-16α-acetyl-3β-isobutyrylamino-9,19-cyclohexane. 4α-mercaptomethyl-4β, 14α-dimethyl-5α, 9β-pregnan-11-one in the form of a white powder with a yield of 84%. LR. (diamond) O (Cm- ¹ ): 3317 (OH); 2932 (NH); 2359 (SH); 1659 (C = O); 1659 and 1531 (CONH); 1039 (C-OH).

S.M. (E.S.I.): m / z: 519.4 ([M + H].

Example 9: sulfur molecule

Figure 14

(20S) -20-climéthylamino-16α-acetyl-3β-acetylamino-9,19-cyclo-4α-thioacétylméthyl-

4β, 14α-dimethyl-5α, 9β-pregnan-11-one

To a solution of 100 mg (1.78 mmol, 1.0 eq) of potassium hydroxide in 1.5 ml of ethanol is added 126.8 μl (1.78 mmol, 1.0 eq.) D thiolacetic acid. After stirring for 20 minutes at room temperature, the reaction medium is evaporated and the yellow powder obtained is washed with tetrahydrofuran to provide 203 mg of potassium thioacetate as a light yellow powder.

166.8 mg (1.46 mmol, 7.0 eq) of potassium thioacetate thus prepared are added to 145.8 mg (0.21 mmol, 1.0 eq.) Of ?? dissolved in 5 mL of anhydrous 1,3,6-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU). After stirring for 5 hours at 100 ^° C., the reaction mixture is basified with 20 ml of a solution of 10% sodium hydrogen carbonate (pH = 8) and extracted with 3 × 20 ml of ether. The combined organic phases are successively dried over anhydrous sodium sulphate and evaporated under vacuum.

The residue obtained is purified by flash chromatography on silica gel (eluent: 9.8 dichloromethane / 0.2 methanol) to provide 70.1 mg of the product in the form of a light yellow powder with a yield of 56%.

IR (diamond) O (Cm- ¹ ): 2930 (NH); 1730 (C = O); 1666 and 1529 (C = O ester, CONH and COS). S. M. (S.I.I.): m / z: 603.4 ([M + H].

Example 10: Complementary biological results (see Example 6 for details)

Table 2: AChE compound ^composed AChE

IC ₅₀ (nM) IC ₅₀ (nM)

33 ^{"""""" """"""""} 54 ^{"""""""" """"""} TTδooδδ ^"

34> 100000 55> 100,000

35> 100000 56> 100000

36> 100000 57> 100000

37 100000 59> 100000

38 181 60> 100,000

39,198 61> 100,000

40,112 62 100,000 41> 100000 63 637

42> 100000 64 14

43> 100000 65 7937

44> 100000 66> 100,000

45> 100000 67> 100000

46 33873 68 780

47 20057 69> 100,000

48 17522 70 368

49 1342 71 28

50 1330 1 32

51 18 tacrine 74

52 29

76 43000

Claims

1. Triterpenic alkaloids of general formula (I) below

wherein one of the three dashed lines present in cycles a and b and only one represents a bond;

R ₁ represents -CH ₂ X ₁ R ₇ , -CH = NR ₈ or -CH = O wherein X ₁ represents O, NH or S;

R ₇ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀ ) - bisftrialkyl (C ₁ -C ₁₀ ) silyl] or SO ₂ R ₉ , wherein R ₉ is C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkylphenyl, with the proviso that R ₇ does not represent SO ₂ R ₉ when X ₁ represents S;

R ₈ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ - bisftrialkyl (C ₁ -C ₁₀₎ alkylsilyl], or SO ₂ R _9, R ₉ representing an alkyl C ₁ -C ₁₀ alkyl or a (C ₁ -C ₁₀₎ phenyl;

R ₂ and R ₃ represent independently of each other a hydrogen atom or

II ² ~ -C-R ₁₀

wherein X ₂ is O, NH or S and R ₁₀ is hydrogen, C ₁ -C ₁₀ alkyl, phenyl, C ₃ -C ₁₀ cycloalkyl, or alkyl (C ₁ -C ₁₀ ) phenyl, with the proviso that at least one and only one of R ₂ or R ₃ represents a hydrogen atom, or R ₂ is absent, R ₁ represents -CH ₂ X ₁ R ₇ and -NR ₃ and -X ₁ R ₇ taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, or R ₂ represents an atom of hydrogen, R ₁ represents -CH ₂ X ₁ R ₇ and -NHR ₃ and -X ₁ R ₇ taken together represent

/ ^xr

~ HN - CH \ ^{R i 1} wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C ₁₀ alkyl or a (C ₁ -C ₁₀₎ phenyl, or R ₂ represents a hydrogen atom, R ₁ represents - CH ₂ = NR ₈ and -NHR ₃ and taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, a phenyl, a C ₃ -C ₁₀ cycloalkyl or a C ₁ -C ₁₀ alkyl phenyl; R ₄ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl or a radical -X ₃ R ₁₂ in which X ₃ represents O, NH or S, advantageously O and R ₁₂ represents a hydrogen atom, an alkyl (C ₁ -C ₁₀ ) carbonyl, a (C ₁ -C ₁₀ ) alkyl phenyl, an alkyl

(C ₁ to C ₁₀ ) sulfonyl, a C ₁ to C ₁₀ alkylphenylsulphonyl or a C ₁ to C ₁₀ alkylsidyl (C ₁ to C ₁₀ ) silyl, advantageously an atom of hydrogen; R ₅ represents the N-oxide group N ⁺ OCH ₃ R ₁₃ or the group NCH ₃ R ₁₃ in which R ₁₃ represents a hydrogen atom, a cycloalkyl C ₃ -C ₁₀ alkyl, C ₁ -C _10, phenyl or a phthalimide, preferably -CH _3, and

- - [^

⁶ is = O, or -OR ₁₄ wherein R ₁₄ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁

C ₁₀ ) phenyl or (C ₁ -C ₁₀ ) alkylsulfonyl; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof, with the exception of compounds of the following formulas:

2. Triterpene alkaloid according to claim 1, characterized in that R ₁ represents -CH ₂ X ₁ R ₇

3. Triterpene alkaloid according to claim 1 or 2, characterized in that X ₁ represents O.

4. Triterpene alkaloid according to any one of claims 1 to 3, characterized in that it is represented by the following general formula (II): wherein one of the three dashed lines present in cycles a and b and only one represents a bond;

- - [^

R ₄ , R ₅ , R ₁₁ and ⁶ are as defined in claim 1 and X ₁ is as defined in claims 1 or 3 or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof .

Triterpene alkaloids according to any one of claims 1 to 4,

- R characterizes in this represents = O.

6. Triterpene alkaloids according to any one of claims 1 to 3 or 5, characterized in that it is represented by the following general formula (III):

wherein one of the two dashed lines present in cycles a and b and only one represents a bond; R ₄ , R ₅ and R ₁₁ are as defined in the claim 1, X ₁ is as defined in claims 1 or 3, and ⁶ is as defined in claims 1 or 5; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof.

7. Triterpene alkaloid according to claim 1 or 5, characterized in that it is represented by the following general formula (VIII):

wherein one of the three dashed lines present in cycles a and b and only one represents a bond; R ₄ , R ₅ and R ₁₁ are as defined in claim 1, and

- 1_ ^

⁶ is as defined in claims 1 or 5; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof.

8. Triterpenic alkaloids according to any one of claims 1 to 3 or 5, characterized in that it is represented by the following general formula (TV):

wherein one of the two dashed lines present in rings a and b and only one is a bond, R ₄ , R ₅ , R ₇ , X ₂ and R ₁₀ are as defined in claim 1, X ₁ is such that defined in claims 1 or 3, and ⁶ is as defined in claims 1 or 5; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof.

9. Triterpenic alkaloids according to any one of claims 1 to 6 and 8, characterized in that X ₂ represents O.

10. Triterpene alkaloid according to any one of the preceding claims, characterized in that R ₁₀ or R ₁₁ represent, independently of each other, a C ₁ to C ₁₀ alkyl, advantageously branched.

11. Triterpene alkaloid according to any one of the preceding claims, characterized in that it is chosen from one of the compounds of the following formulas:

6h 7th

7h 8a

8c 8d

8th 8f

32 33

38 39

40 51

52 63

64 68

70 71

12. Process for producing the compound of general formula (TVb) below:

- R ^~ wherein R _4, R _5, R _7, R _10, X ₁ and ⁶ are as defined in claim

8 and X ₂ represent, by reaction, the following compound of formula (Vb):

^Wherein R ₄ , R ₅ , R ₇ , X ₁ and ⁶ are as defined in claim 8 with the anhydride of the formula R ₁₀ (CO) ₂ O wherein R ₁₀ is as defined in the claim 8, advantageously in methanol.

13. Process according to claim 12, characterized in that the compound of formula (Vb) is obtained by acid hydrolysis, advantageously in MeOH with H ₂ SO ₄ , of the compound of formula (VI) below

- R ^~ wherein R _4, R _5, R _7, X ₁ and ⁶ are as defined in claim 8.

14. The method of claim 13 characterized in that the compound of general formula (VI) has the following formula (2)

15. Process for producing the compound of formula (2) comprising the following successive stages: a) alkalinization of the crushed and dried leaves of Buxus balearica WiId, b) extraction and maceration in a CH ₂ Cl ₂ / EtOH mixture to obtain a solid extract c) extraction in dichloromethane at a pH of between 5.8 and 6 to obtain a crude extract of the compound of formula (2), d) purifying the compound of formula (2), advantageously by recrystallization from acetone.

16. Process for producing the compounds of general formula (IIa) below

wherein R ₄ , R ₅ , R ₁₁ , X ₁ and ⁶ are as defined in claim 4 comprising the following successive steps: a) pyrolysis of the compound of formula (TVb) wherein R ₁₀ = R ₁₁ and R ₄ , R ₅ , R ₁₁ , X ₁ and

⁶ are as defined in claim 4, and R ₇ and X ₂ are as defined in claim 8, preferably at a pressure of 0.03 mm Hg, with a temperature between 235 and 270 ° C for 3 hours, b) thermolysis of the mixture obtained in step (a), advantageously at a pressure of 0.03 mmHg, with a temperature of between 235 and 270 ° C. and in the presence of tetraalkylammonium hydroxide, advantageously tetraethylammonium hydroxide; .

17. A process for producing the compound of general formula (IIa) in which R ₅ represents -CH ₃ , R ₄ represents -OH, ⁶ represents = O, X ₁ represents O, R ₁₁ represents -CH (CH ₃ ) ₂ comprising the successive successive steps: a) pyrolysis of the compound of formula (2) at a pressure of 0.03 mm Hg, with a temperature of 240 ° C, b) thermolysis of the mixture obtained in step (a), at a pressure of 0.05 mm Hg with a temperature of 240 ° C in the presence of tetraalkylammonium hydroxide, preferably tetraethylammonium hydroxide.

18. Process for producing the compound of general formula (IIa) in which R ₅ represents -CH ₃ , R ₄ represents -OH, ⁶ represents = O, X ₁ represents O, R ₁₁ represents -CH (CH ₃ ) ₂ by heating at 210 ° C of the compound of formula (2) in ethylene glycol in the presence of NaOH.

19. Process for producing the compounds of general formula (TVa) below

- ^~ R wherein R _4, R _5, R _7, R _10, X _1, X ₂ and ⁶ are as defined in claim 8 comprising the following successive steps: a) pyrolyzing the compound of formula (IVb) wherein R ₄ , R ₅ , R ₇ , R ₁₀ , X ₁ , X ₂ and

⁶ are as defined in claim 8, preferably at a pressure of 0.03 mm Hg, with a temperature between 235 and 270 ° C for 3 hours b) chromatography on alumina of the mixture obtained in step (a).

20. Process for producing the compounds of the following general formula (HIa)

wherein R ₄ , R ₅ , R ₁₁ , X ₁ and ⁶ are as defined in claim 6 comprising the following successive steps: a) acid hydrolysis in methanol, preferably with H ₂ SO ₄ at 90 ° C for 2 hours then, after evaporation of the methanol at ambient temperature, at 80 ° C. for

1 hour, the compound of general formula (TVa) wherein R ₄ , R ₅ , X ₁ and ⁶ are as defined in claim 6 and R ₇ , R ₁₀ and X ₂ are as defined in claim 8, for obtain the compound of formula (Va) below:

in which R ₄ , R ₅ , X ₁ and ⁶ are as defined in claim 6 and R ₇ is as defined in claim 8; b) condensation, advantageously at 50 ° C, of the compound of formula (Va) with the compound of formula R ₁₅ CHO wherein R ₁₅ CH represents R ₁₁ and R ₁₁ is as defined in claim 6.

21. Process for producing the compound of general formula (IHb) below

- R ^~ wherein R _4, R _5, R _11, X ₁ and ⁶ are as defined in claim 6 by condensation, preferably at 50 ° C, the compound of formula (Vb) in ^Wherein R ₄ , R ₅ , X ₁ and ⁶ are as defined in claim 6, and R ₇ is as defined in claim 8 with the compound of the formula R ₁₅ CHO wherein R ₁₅ CH is R ₁₁ and R ₁₁ is as defined in claim 6.

22. Process for manufacturing the compound of formula QJb) below

- R ^~ wherein R _4, R _5, R _11, X ₁ and ⁶ are as defined in claim 4 by heating at 300 ° C in the presence of tetraethylammonium hydroxide the compound of formula (VII)

- R ^~ wherein R ₁₀ = R ₁₁ and R _4, R _5, R _11, X ₁ and ⁶ are as defined in claim 4 and R ₇ and X ₂ are as defined in claim 8.

23. The method of claim 22 characterized in that the compound of formula (VLT) is obtained by reaction in the presence of a Lewis acid, preferably TiCl ₄ in dichloromethane, of the compound of formula (TVb) wherein R ₁₀ = R ₁₁ , R ₄ , R ₅ , - ^~ R

R ₁₁ , X ₁ and ⁶ are as defined in claim 4 and R ₇ and X ₂ are as defined in claim 7.

24. Process for producing the compound of general formula (TVb) below

wherein R ₅ , R ₁₀ and ⁶ are as defined in claim 8, R ₄ is -OR ₁₂ wherein R ₁₂ is as defined in claim 1, X ₁ is NH, R ₇ is H and X ₂ is O comprising the following successive steps:

reaction of the compound of general formula (TX) below:

in which R ₅ , R ₁₀ , R ₁₂ and ⁶ are as defined in the general formula

(TVb) above with benzylamine in the presence of anhydrous magnesium sulfate in dichloromethane to obtain the compound of formula (X) below:

- R ^~ wherein R _5, R _10, R ₁₂ and ⁶ are as defined in general formula

(IX) above;

reaction of the compound of formula (X) with sodium cyanoborohydride and glacial acetic acid in methanol to obtain a compound of formula

(XI) following:

- R ^~ wherein R _5, R _10, R ₁₂ and ⁶ are as defined in general formula

(X) above;

reaction of the compound of formula (XI) in the presence of the 30% Pd / C catalyst in methanol with ammonium formate or under hydrogen pressure with glacial acetic acid at pH 3 followed by alkalisation with ammonia solution to obtain the compound of formula (Wb).

25. Process according to claim 24, characterized in that the compound of formula (IX) in which R ₁₂ does not represent a hydrogen atom is obtained by the process comprising the following successive stages: protection of the hydroxyl group of the compound of formula General (TVb) following:

wherein R ₅ , R ₁₀ , and ⁶ are as defined in claim 8, R ₇ is H, and X ₁ and X ₂ are O by reaction with the compound of formula (R ₁₂ ) ₂ O wherein R ₁₂ is as defined in claim 8 but does not represent a hydrogen atom in a pyridine / dichloromethane mixture to obtain the compound of general formula (TVb) below:

in which, R ₅ , R ₁₀ , and ⁶ are as defined in claim 8, R ₇ is H, R ₁₂ is as defined in claim 1, but does not represent a hydrogen atom and X ₁ and X ₂ represent O; reaction of the compound of formula (TVb) as defined above with Dess-Martin periodinane in dichloromethane to obtain the compound of formula (IX) in which R ₁₂ does not represent a hydrogen atom.

26. Process according to claim 25, characterized in that the compound of formula (IX) in which R ₁₂ represents a hydrogen atom is obtained by the deprotection reaction of the compound of formula (IX) in which R ₁₂ does not represent a hydrogen atom.

27. Process for producing the compound of formula (II) below:

in which R ₅ , R ₁₁ , and ⁶ are as defined in claim 4, X ₁ represents NH, R ₄ represents -OR ₁₂ and R ₁₂ is as defined in claim 1 by reaction of the compound of general formula (Wb ) next :

in which R ₁₀ = R ₁₁ , R ₅ and ⁶ are as defined in claim 4,

R ₄ represents -OR ₁₂ in which R ₁₂ is as defined in claim 1, X ₁ represents NH, R ₇ represents H and X ₂ represents O with triethylamine in butanol

28. A process for producing a compound of formula (VIII) below:

in which R ₅ , R ₁₁ and ⁶ are as defined in claim 7, R ₄ represents -OR ₁₂ and R ₁₂ is as defined in claim 1 by reaction of the compound of the following general formula (TVb):

in which R ₁₀ = R ₁₁ , R ₅ and ⁶ are as defined in claim 7,

R ₄ represents -OR ₁₂ in which R ₁₂ is as defined in claim 1, X ₁ represents NH, R ₇ represents H and X ₂ represents O with ammonium formate in the presence of the 30% Pd / C catalyst in methanol.

29. Triterpenic alkaloids of general formula (I) below:

wherein one of the three dashed lines present in cycles a and b and only one represents a bond;

R ₁ represents -CH ₂ X ₁ R ₇ , -CH = NR ₈ or -CH = O in which X ₁ represents O, NH or S,

R ₇ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀ ) - bisftrialkyl (C ₁ -C ₁₀ ) silyl] or SO ₂ R ₉ , wherein R ₉ is C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkylphenyl, with the proviso that R ₇ does not represent SO ₂ R ₉ when X ₁ represents S;

R ₈ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ - bisftrialkyl (C ₁ -C ₁₀₎ alkylsilyl], or SO ₂ R _9, R ₉ representing an alkyl C ₁ -C ₁₀ alkyl or a (C ₁ -C ₁₀₎ phenyl;

R ₂ and R ₃ represent independently of each other a hydrogen atom or

II ² ~ -C-R ₁₀

wherein X ₂ is O, NH or S and R ₁₀ is hydrogen, C ₁ -C ₁₀ alkyl, phenyl, C ₃ -C ₁₀ cycloalkyl, or C ₁ -C ₁₀ alkyl, C ₁₀ ) phenyl, with the proviso that at least one and only one of R ₂ or R ₃ represents a hydrogen atom, or R ₂ is absent, R ₁ represents -CH ₂ X ₁ R ₇ and -NR ₃ and -X ₁ R ₇ taken together represent wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, or R2 represents a hydrogen atom hydrogen, R ₁ represents -CH ₂ X ₁ R ₇ and -NHR ₃ and - X ₁ R ₇ taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C _10, phenyl, cycloalkyl C ₃ -C _10, alkyl (C ₁ -C ₁₀₎ phenyl, or R ₂ represents an atom of hydrogen, R ₁ represents - CH ₂ = NR ₈ and -NHR ₃ and taken together represent

wherein R ₁₁ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl, a phenyl, a C ₃ -C ₁₀ cycloalkyl or a C ₁ -C ₁₀ alkyl phenyl;

R ₄ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl or a radical -X ₃ R ₁₂ in which X ₃ represents O, NH or S, advantageously O and R ₁₂ represents a hydrogen atom, an alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ phenyl, alkyl (C ₁ -C ₁₀₎ alkylsulfonyl, alkyl (C ₁ -C ₁₀₎ phenyl sulfonyl or alkyl ( C ₁ -C ₁₀ ) dialkyl (C ₁ -C ₁₀ ) silyl, preferably a hydrogen atom; R ₅ represents the group N ⁺ R ₁₃ OCH ₃ or NCH ₃ R ₁₃ wherein R ₁₃ represents a hydrogen atom, a cycloalkyl C ₃ -C ₁₀ alkyl C ₁

C ₁₀ , phenyl or phthalimide, advantageously -CH ₃ and

- 1_ ^

⁶ is = O, or -OR ₁₄ wherein R ₁₄ represents a hydrogen atom, a C ₁ -C _10, alkyl (C ₁ -C ₁₀ alkyl) carbonyl, alkyl (C ₁ -C ₁₀₎ phenyl or (C ₁ -C ₁₀ ) alkylsulfonyl; or its pharmaceutically acceptable addition salts, isomers, enantiomers, diastereoisomers, and mixtures thereof, as a medicament.

30. Triterpenic alkaloid as a medicament according to claim 29, characterized in that it is chosen from one of the compounds of the following formulas:

6h 7th

7h 8a

8c 8d

8th 8f

12 32

33 38

63 64

68 70

71

31. Triterpene alkaloid according to claim 29 or 30, characterized in that the medicament is for treating a subject suffering from a disease of the central or peripheral nervous system.

32. Triterpene alkaloid according to claim 31, characterized in that the disease of the central or peripheral nervous system is selected from the group consisting of Alzheimer's disease, memory disorders associated with aging or Alzheimer's disease, disorders associated with trisomy 21, Lewy body dementia, Parkinson's dementia, vascular dementia, delirium, traumatic brain injury, myasthenia of congenital or autoimmune origin to reverse neuromuscular blocking agents acting at level of postsynaptic muscle receptors and any cholinergic syndrome in which there is a decrease in the amount of acetylcholinesterase released.