The present invention relates to analogs of squalamine for use in the treatment of bacterial, fungal, viral or parasitic infections in humans or animals, as well as pharmaceutical or veterinary compositions comprising them.
In 1993, squalamine, a natural steroid, predominantly isolated tissues of a small shark Squalus acanthias, has proved to be a very active compound essentially having antiangiogenic activity against cells and viral and anti antibacterial activity.

Squalamine

Chemically, squalamine is an original molecule of amphiphilic character. It thus comprises a central portion apolar (a cholestane-type skeleton) and two pole ends (a polyamine chain and a sulfate group).

Initially, this water-soluble polyaminostérol aroused interest for its antiangiogenic and antimicrobial properties on a variety of gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa), fungi (Candia albicans, Candida tropicalis) and protozoa.

The natural source of squalamine is limited, have been sought like synthetic derivatives aminostéroïdiens squalamine. Have been described including derivatives or analogues comprising a polyamino chain in position 3 or 7 cycles 10, 13 Dimethyl, 17 octane cholestane or cholestene, optionally hydroxylated at the 7 position or respectively 3. In particular, derivatives of formula IIa - IIb - Ile - IId and II- 1 below were described as having a similar antibacterial activity to squalamine vis-à-vis various Gram positive and Gram negative multiresistant.

more particularly it has been suggested the application of these derivatives for curative treatment of pulmonary infections by aerosol route. However, the Applicant has observed that these compounds exhibited a significant cytotoxicity and that the compounds of formula IIc and IId exhibited weak activity against certain gram-negative bacteria such as E. coli.

Are known in particular WO 2011/067501 derivatives antibacterial aminostéroïdiens type polyamino cholestane or cholestene for locally topical application for the rapid mucocutaneous decolonization of Staphylococcus aureus, particularly in the form of ointment or cream.

U.S. Patent 5,856,535 also describes esters aminosterols, some of which exhibit inter alia inhibitory of angiogenesis activities, antiproliferative or antibacterial activities. However none of the compounds described herein are especially amides.

Also known Wen-Hua Chen et al document "A Bioconjugate approach mimics Toward squalamine: insight into the mechanism of the biological action," Bioconjugate Chemistry, vol. 17, no. 6, 1582-1591 and AM Bellini et al "Antimicrobial activity of basic share cholan derivatives IX" Archiv des Pharmazie, vol. 323, no. 4, 201-205. However, these documents describe not only structurally remote compounds of the compounds of the present invention but having no interesting antimicrobial activities.

It has now been discovered similar compounds squalamine, with good antibacterial activity against gram-positive and gram-negative, while advantageously less cytotoxic than squalamine. This new family of molecules, thanks to its chemical structure, has better chemical stability than the compounds described in US 5,856,535.

These compounds have an interesting activity to prevent and / or inhibit and / or treat bacterial, fungal, viral or parasitic infections in humans and animals. These compounds are also compounds of choice as substitutes for antibiotics. According to a particular embodiment of the invention, it is intended for domestic mammals such as ruminants, horses, pigs, dogs and cats and wildlife. According to one embodiment even more special it is for pets, more specifically to dogs and cats, or rodents, and more specifically for dogs and cats.

The compounds of the invention provide excellent activity against bacteria, while preventing the emergence of resistance, which is a major asset as the problem of the emergence of resistance to conventional antibiotics has become a public health problem. By their mechanism of action, different from that of antibiotics, the compounds of the invention are therefore as excellent substitutes for antibiotics.

Thus, in a first aspect, the present invention relates to a compound of formula

in which

RI and R2 independently represent a hydrogen atom, a group

SO3H or hydroxy,

R 'is - (CR a R b) NX (CRcRd) m- [Y- (CReRf) o] t-NR9Rio,

Pa, Rb, Rc, Pd, Pe and Rf independently represent a hydrogen atom or a (Ci-Cs) alkyl or a (C 6 -Cio) aryl,

X and Y independently represent an -NR 1 group, 1-, -O- or a divalent heterocyclic group comprising at least one nitrogen atom, a 5 or 6-membered,

R9 and RIO independently represent a hydrogen atom or a (Ci-Cs) alkyl group or form together with the nitrogen atom which carries them, a heterocyclic group with 5 or 6 members, optionally substituted by one or two group (s) = 0 or = s,

Rl l represents a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2 ) S -NH 2 ,

RI and RI 5 6 independently represent a hydrogen atom or a (Ci-Cs) alkyl or a (C 6 -Cio) aryl,

n, m, o and s independently represent an integer between 1 and 5,

t is 0, 1, 2 or 3,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

In the context of the present invention:

- The "alkyl" radicals are saturated hydrocarbon radicals, straight or branched chain of 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. These include, when linear, methyl, ethyl, propyl, butyl, pentyl, hexyl. These include, when branched, the isopropyl, tert-butyl, 2-methylbutyl, 2-methylpentyl and 1-methylpentyl.

- By "aryl" is meant within the meaning of the present application, an aromatic hydrocarbon system, mono or bicyclic 6 to 10 carbon atoms. Among the aryl radicals, there may be mentioned phenyl or naphthyl, and more particularly the phenyl radical.

- For group "hétérocyclyclique" is meant within the meaning of the present application, a hydrocarbon system mono- or bicyclic saturated, unsaturated or aromatic comprising one or more heteroatoms such as O, N or S. The heterocyclic groups include the heteroaryl or heterocycloalkyl groups.

- Groups "heteroaryl" refers to mono or bicyclic aromatic ring systems, and having from 5 to 7 members (ring atoms), including 5 to 6 members, including one or more heteroatoms selected from nitrogen, oxygen or sulfur. Among the heteroaryl radicals include imidazolyl, pyrazinyl, thienyl, oxazolyl, pyrrolyl and furazanyl.

- Radicals "heterocycloalkyl" refer to mono- or bicyclic ring systems, saturated 5 to 7 members (ring atoms), including 5 to 6 members, including one or more heteroatoms selected from N, O or S. Among the heterocycloalkyls, there may be mentioned pyrazolidine, piperidine, morpholine and piperazine.

- As used herein, the term "pharmaceutically acceptable" refers to compounds, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the cells humans and lower animals without undue toxicity, irritation, undue allergic response and the like and are commensurate with a reasonable benefit / risk.

- The term "pharmaceutically acceptable salts" refers to the addition salts of inorganic and organic acids, pharmaceutically acceptable, and the addition salts of pharmaceutically acceptable bases of compounds of the present invention. These salts include acid addition salts, that is to say, organic acid salts or mineral of a compound having a basic function such as an amine, or basic addition salts is -to say, alkali or organic salts of a compound having an acidic function such as a carboxylic acid. These salts can be prepared in situ during the final isolation and / or purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound with an organic or inorganic acid and isolating the salt thus formed. Examples of acid addition salts there are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphthoates, gentisic acid, isethionates, di-p-

toluoyltartrates, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonates, cyclohexyl sulfamates and quinateslaurylsulfonate, and the like. (See for example SM Berge et al, "Pharmaceutical Salts," J. Pharm Sci., 66:. P.1-19 (1977)).

- Basic addition salts may also be prepared by separately reacting the purified compound in its acid form with an organic or inorganic base and isolating the salt thus formed. Examples of base addition salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Sodium and potassium salts are preferred. Basic addition salts can in particular be prepared from hydrides or hydroxides of alkaline or earthy alkaline metal which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, hydroxide lithium, magnesium hydroxide, zinc hydroxide.

Among the compounds of general formula (I), a first subgroup of compounds consists of compounds wherein RI and R2 independently represent a hydrogen atom or hydroxy,

Among compounds of general formula (I), a second subgroup of compounds consists of compounds in which RI and RI 5 6 independently represent a hydrogen atom or a (Ci-C4) alkyl,

Among the compounds of general formula (I), a third subgroup of compounds consists of compounds for which X is a group -NH- or a group 1, 4-piperydinyle,

Among the compounds of general formula (I), a fourth subgroup of compounds consists of compounds wherein R9 and RIO represent a hydrogen atom.

Among the compounds of general formula (I), a fifth subgroup of compounds consists of the compounds for which Ra, Rb, R c , Rd, Re and Rf represents a hydrogen atom.

Among the compounds of general formula (I), a sixth subgroup of compounds consists of compounds for which Y is -NR11- group, with R l denoting a hydrogen atom or a (Ci-C4) alkyl or a group - (CH 2 ) s NH 2 wherein s is 1, 2 or 3.

Among the compounds of general formula (I), a seventh subgroup of compounds consists of compounds for which m is equal to 2, 3, 4, or 5, more preferably 2 or 3.

Among the compounds of general formula (I), an eighth subgroup of compounds consists of compounds for which n is 2, 3, 4 or 5, more preferably 2, 3 or 4, and even more preferably 2 or 3.

Among the compounds of general formula (I), a ninth subgroup of compounds consists of compounds for which m is other than 4.

Among the compounds of general formula (I), a tenth subgroup of compounds consists of compounds for which o is 2 or 3.

Among the compounds of general formula (I), an eleventh subgroup of compounds consists of compounds wherein the group -NHR 'is selected from:

According to a preferred variant, the compounds of formula (I) are synthesized from the following bile acids:

The subgroups defined above, taken alone or in combination, are also part of the invention.

Accordingly, the present invention relates to a compound as defined above, characterized in that it is defined by at least one of the following subgroups:

- first subgroup of compounds of formula (I) wherein RI and R2 independently represent a hydrogen atom or hydroxy,

- second subgroup of compounds of formula (I) wherein RI and RI 5 6 independently represent a hydrogen atom or a (Ci-C4) alkyl,

- third subgroup of compounds of formula (I) wherein X is an -NH- group, a heterocyclic 6-membered having one or two nitrogen atoms, preferably a group 1, 4-piperazinylene or 1 , 4-piperidinylene,

- fourth subgroup of compounds of formula (I) wherein R9 and RIO represent a hydrogen atom,

- fifth subgroup of compounds of formula (I) for which Ra, Rb, Rc, Rd, Re and Rf represent a hydrogen atom,

- sixth subgroup of compounds of formula (I) wherein Y is -NR11- group, with R 1 representing a hydrogen atom or a (Ci-C4) alkyl or a group - (CH 2 ) s- NH 2 wherein s is 1, 2 or 3,

- seventh subgroup of compounds of formula (I) wherein m is 2, 3, 4 or 5, more preferably 2 or 3,

- eighth subgroup of compounds of formula (I) wherein n is 2, 3, 4 or 5, more preferably 2, 3 or 4,

- ninth subgroup of compounds of formula (I) wherein m is different from 4,

- tenth subgroup of compounds of formula (I) wherein o is 2 or 3,

- eleventh subgroup of compounds of formula (I) wherein the group -NHR 'is selected from:

or

- or by the combination of the subgroups as defined above.

According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that it represents (Γ)

in which

RI and R2 are as defined in claim 1 or 2,

RI and RI 5 6 independently represent a hydrogen atom or a (Ci-C 8 ) alkyl,

n represents the integer 2, 3 or 4,

m represents the integer 2, 3 or 4,

X is -NR11- group or a divalent heterocyclic group comprising one or two nitrogen atoms, a 5 or 6 membered ring, such as 1, 4-piperazinylene or 1, 4-piperidinylene,

R 4 and R s independently represent a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2 ) s NH 2 ,

R5 represents a hydrogen atom, a group - (CH 2 ) P -NH 2 , a group - (CH 2 ) p -NH- (CH 2 ) q -NH 2 or - (CH 2 ) p-NH- (CH 2) q -NH- (CH 2 ) r-NH2, p, q, r and s independently represent an integer which can vary between

1 and 5,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

Among the compounds of formula (I) and (Γ) are preferred compounds for which n and m are equal to 3.

According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that RI RI 5 and 6 represent independently a hydrogen atom or a (Ci-C4) alkyl such as methyl or isoproyle.

According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that n is 2 and m is 3, n is 2 and m is 2, n is equal to 3 and m is 4 or n is 3 and m is equal to 3.

According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that X represents -NR11- group, or a 1, 4-piperazinylene and Rl and R4 independently representing a hydrogen atom, hydrogen, methyl or a group - (CH 2 ) s NH 2 wherein s is 2 or 3.

According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that R5 represents a hydrogen atom, a group - (CH 2 ) P -NH 2 , a group - (CH 2 ) p-NH- (CH 2 ) q NH 2 or a group - (CH 2 ) p-NH- (CH2) q-NH- (CH 2 ) r -NH 2, where p is 2 or 3, q is equal to 2 and r is 2.

According to a particular embodiment n is equal to m.

The present invention also relates to a compound of formula (Ia)

(Ia) wherein

R15, R16, RI and R2 are as defined above,

X is -NH- or a group 1, 4-piperazinylene,

R5 represents a hydrogen atom or a group - (CH 2 ) P -NH 2 , where p is 2 or 3,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

According to a preferred embodiment, the present invention relates to compounds of formula (Ia) in which RI 5 is hydrogen and RI 6 is methyl or isopropyl or RI RI 5 and 6 are both an ethyl group .

The present invention also relates to a compound of formula (Ib)

in which

R15, R16, RI and R2 are as defined above,

u is 0, 1, 2 or 3, preferably 1, 2 or 3,

R6 and R7 independently represent a hydrogen atom or a (Ci-C8) alkyl, preferably a hydrogen atom or a (Ci-C 4 ) alkyl,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

The present invention also relates to a compound of formula (Ic)

in which

R15, R16, RI, R2, n and m are as defined above, and

R8 is (Ci-C8) alkyl, preferably methyl, or a group - (CH 2 ) s NH 2 , with s being an integer which can vary between 1 and 5, preferably equal to 2 or 3 ,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

According to a preferred embodiment, the present invention is directed to compounds of formula (Ic) in which when R8 represents - (CH 2 ) S NH 2 , then n = m = s.

According to a preferred embodiment, the present invention is directed to compounds of formula (Ic) in which when R8 is methyl, then n is equal to m.

The present invention also relates to a compound of formula (Id)

in which

R15, R16, RI and R2 are as defined above,

R5 represents a group - (CH 2 ) P -NH 2 , where p is 2 or 3, and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

The present invention also relates to a compound of formula (Ic)

in which

R15, R16, RI and R2 are as defined above,

R5 represents a group - (CH 2 ) P -NH 2 , where p is 2 or 3, and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

According to a particularly preferred embodiment, the present invention relates to a compound of formula (Ia) and formula (Ic) as defined above. We may mention in particular compounds as representatives of this particular embodiment of the compounds (5) and (15) as defined below.

According to a preferred embodiment of the present invention, a compound of formula (I) is selected from:

- (1) 3P-norspermino-N-isopropyl-désoxycholamide,

- (2) 3P-norspermidino-N-isopropyl-désoxycholamide,

- (3) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide,

- (4) 3P-norspermino-N-isopropyl-cholamide,

- (5) 3P-norspermidino-N-isopropyl-cholamide,

- (6) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide,

- (7) 3 β-norspermino-N-isopropyl-chénodésoxycho lamide,

- (8) 3P-norspermidino-N-isopropyl-chénodésoxycholamide,

- (9) 3P- (l, 4-Bis (3-aminopropyl) piperazine) -N-isopropyl-chénodésoxycho lamide,

- (10) 3 P-norspermino-N-methyl-chénodésoxycholamide,

- (11) 3 β-norspermidino-N-méthyl chénodésoxycho lamide,

- (12) 3P- (l, 4-Bis (3-aminopropyl) piperazine) -N-methyl-chénodésoxycho lamide,

- (13) 3 P-norspermidino- N, N-diethyl-chénodésoxycholamide,

- (14) 3P-norspermino-N-isopropyl-ursodésoxycholamide,

- (15) 3P-norspermidino-N-isopropyl-ursodésoxycholamide,

- (16) 3P- (l, 4-Bis (3-aminopropyl) piperazine) -N-isopropyl-ursodésoxycho lamide,

- (17) 3P-norspermino-N-isopropyl-lithocholamide,

- (18) 3P-norspermidino-N-isopropyl-lithocholamide,

- (19) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-lithocho lamide,

- (20) 3 P- (pentaethylenehexamine) -N-isopropyl-désoxycho lamide,

- (21) 3P- (pentaethylenehexamine) -N-isopropyl-cholamide,

- (22) 3 P- (pentaethylenehexamine) -N-isopropyl-chénodésoxycho lamide,

- (23) 3 P- (pentaethylenehexamine) -N-isopropyl-ursodésoxycho lamide,

- (24) N-isopropyl-3P-pentaethylenehexamine désoxycho-lamide,

- (25) 3 β-( 1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycho lamide,

- (26) 3 P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-cho lamide, - (27) 3P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-chénodésoxycho lamide,

- (28) 3P-(Bis(3-aminopropyl)méthylamine)-N-isopropyl-ursodésoxycho lamide,

- (29) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-lithocho lamide, - (30) 3 β-spermino-N-isopropyl-désoxycho lamide,

- (31) 3P-spermino-N-isopropyl-cholamide,

- (32) 3P-spermino-N-isopropyl-chénodésoxycholamide,

- (33) 3 β-spermino-N-méthyl désoxycho lamide,

- (34) 3 P-spermino-N, N-diethyl-chénodésoxycholamide,

- (35) 3 β-spermino-N-isopropyl-ursodésoxycho lamide,

- (36) 3P-spermino-N-isopropyl-lithocholamide,

- (37) 3P-norspermidino-N-diisopropyl-chénodésoxycholamide,

- (38) 3P-norspermidino-N-cyclohexyl-chénodésoxycholamide,

- (39) 3 P-norspermino-N, N-diethyl-chénodésoxycholamide,

- (40) 3P-norspermino-N,N- diisopropyl-chénodésoxycholamide,

- (42) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-désoxycho lamide,

- (43) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-cho lamide,

- (44) 3 P- (Tris (3-aminopropyl) amine) -N, N-diethyl-chénodésoxycho lamide,

- (45) 3 P-(Tris(2-amino éthyl)amine)-N-isopropyl-chénodésoxycho lamide, - (46) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-chénodésoxycho lamide,

- (47) 3P-(Tris(3-aminopropyl)amine)-N-cyclohexyl-chénodésoxycho lamide,

- (48) 3P-(Tris(3-aminopropyl)amine)-N-isopropyl-ursodésoxycholamide,

- (49) 3 P-(Tris(3 -aminopropyl)amine)-N-isopropyl-lithocho lamide,

- (50) 3P-spermino-N,N-diisopropyl-chénodésoxycholamide,

- (51) 3P-spermino-N-cyclohexyl-chénodésoxycholamide,

- (52) 3P-spermidino-N-isopropyl-chénodésoxycholamide,

- (53) 3P- (Bis (3-aminopropyl) ethylenediamine) -N, N-Diethyl-cho chénodésoxy lamide,

- (54) 3P- (Bis (3-aminopropyl) ethylenediamine) -N, N-diisopropyl-cho chénodésoxy lamide,

- (55) Mélange 50/50 de 3P-spermidino-N-isopropyl-chénodésoxycholamide et de 3P-N-[4'N-(3'-aminopropyl)aminobutyl]amino-N-isopropyl-chénodésoxycho lamide,

- (56) 3P-(Tris(3-aminopropyl)amine)-N,N- diisopropyl-chénodésoxy cho lamide,

or a pharmaceutically acceptable salt thereof.

The compounds of the invention may exist in the form of free bases or of addition salts with pharmaceutically acceptable acids.

According to a particular embodiment of the invention, such addition salts of pharmaceutically acceptable acids include the hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, maleate, mesylate , formate, acetate, fumarate, particularly hydrochloride.

The compounds of formula (I), (F), (Ia), (Ib), (Ic), (Id) and (Ie) as well as compounds (1) to (56) may be in the form of solvates such as hydrates. The invention includes such solvates.

A compound of formula (I), (Γ), (Ia), (Ib), (Ic), (Id) or (Ic) may comprise one or more asymmetric carbon atoms. They can exist as enantioselective mothers or diastereoisomers. These mothers enantioselective, diastereoisomers, and mixtures thereof, including racemic mixtures, are included within the scope of the present invention. Generally, in the context of the present invention, when a bond is represented by the symbol ~ ~ ΛΛΛ / , it means that the common group

considered by the carbon may be behind or in front of the molecule imaging plane. Thus, the resulting stereochemistry of the carbon bearing this group can be S or R.

According to another aspect, the present invention relates to a compound of formula (I), (F), (Ia), (Ib), (Ic), (Id) or (Ic) or a compound (1) to (56 ) or a pharmaceutically acceptable salt thereof, for use as a medicament.

According to another aspect, the present invention relates to a compound of formula (I), (Γ), (Ia), (Ib), (Ic), (Id) or (Ie) for use in preventing and / or inhibiting and / or treat bacterial, fungal, viral or parasitic infections in humans and animals.

According to the present invention, the term "prevent" or "prevention" means to reduce the risk of onset or slow the onset of a given phenomenon, namely a bacterial, fungal, viral or parasitic.

The compounds of the present invention may be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction scheme described below is a useful general method for preparing the compounds of the present invention and is not intended to limit its scope or usefulness.

Thus, the compounds of the invention may be prepared by application or adaptation of any method known per se and / or within the skill in the art, especially those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989 or by application or adaptation of methods described in the examples which follow.

According to a particular embodiment, the compounds of the invention may be prepared according to the synthetic scheme 1 below.

diagram 1

(II)

According to Scheme 1, a compound of formula (IV), wherein RI and R2 are as defined above, is reacted, in a solvent such as CH2Cl2, THF, dioxane, for example in the presence of coupling agent such as HOBT / DCC, BOP, methyl chloroformate with a compound of the formula R15R16NH wherein R15 and RI 6 are as hereinbefore defined, for example at a temperature between -20 ° C and 20 ° C, to obtain a compound of formula (III).

According to this scheme 1, the compound of formula (III) thus obtained is subjected to oxidation in the presence of a ligand, for example tri-tert-butoxide, aluminum tri-isopropoxide or Ag2C0 3 , in a solvent such as for example benzene, toluene, cyclohexane or trifluorotoluene, for example at a temperature between 20 ° C and 100 ° C, to obtain a compound of formula (II).

According to this scheme 1, the compound of formula (II) thus obtained is subjected to reductive amination by reaction with a compound of the formula R'NH 2 wherein R 'is as defined above in the presence of a reducing agent such as titanium tetraisopropoxide, zirconium tetraisopropoxide, NaBH 3 CN, NaBH 4 , or a mixture thereof, preferably the titanium tetraisopropoxide torque / NaBH 4 , for example at a temperature between -120 ° C and -10 ° C, preferably -80 ° C and -10 ° C, to obtain the compound of formula (I).

Optionally the method may also comprise the step of isolating the product obtained.

The compound thus prepared may be recovered from the reaction mixture by conventional means. For example, the compounds may be recovered by distilling the solvent from the reaction mixture or, if necessary after distilling off the solvent of the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in water, and distilling the solvent from the extract. In addition, the product can, if desired, be further purified by various techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.

The starting compound of formula (IV) is available or can be prepared according to methods known to those skilled in the art and / or can be prepared by the application of methods as described in the Examples or their obvious chemical equivalents .

According to a preferred variant, the compounds of formula (I) are synthesized from compounds of formula (IV) as defined above or the following bile acids:

lithocholic acid

Thus, according to another object, the present invention also concerns the method for preparing the compounds of formula (I) described above, comprising a reductive amination step the compound of formula (II)

wherein R15, R16, RI and R2 are as hereinbefore defined with an amine of formula R'NH 2 wherein R 'is as defined above, in the presence of a reducing agent may be chosen from titanium tetraisopropoxide, zirconium tetraisopropoxide, NaBH 3 CN, NaBH 4 , or a mixture thereof, preferably the titanium tetraisopropoxide torque / NaBH 4 , to obtain said compound of formula (I).

The chemical structures and spectroscopic data of some compounds of formula (I) of the invention are respectively illustrated in Table I and Table II below.

Table I

The invention also covers a 50/50 mixture of 3P-spermidino-N- isopropyl-chénodésoxycholamide and 3P-N- [4'N- (3'-aminopropyl) aminobutyl] amino-N- isopropyl-chénodésoxycholamide named compound (55 ) in the following description

Tableau II

The synthesized chemical structures were all verified by proton NMR analysis ( ? H) and / or carbon ( 13 C) in deuterated chloroform or methanol CDCl3 deuterated CD3OD on a Bruker AC-type apparatus 300. Chemical shifts δ are expressed in ppm. Records frequencies of nuclei and references used are as follows:

Du Ή NMR: 300 MHz, (CH 3 ) 4

RMN to 13 C, 75 MHz, Si (CH 3 ) 4

The abbreviations used for the writing of the spectrum J H are the following:

- s = singulet

- d = doublet

- 1 = triplet

- q = quadruplet

- m = mass

ex Characterization

1 RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 2H), 2.71-2.59 (m, 13H), 2.21-0.70 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.19, 59.07, 49.31, 49.00, 48.24, 47.74, 45.85, 44.08, 42.41, 40.78, 37.59, 37.12, 37.01, 35.95, 35.92, 34.94, 34.58, 34.36, 33.56, 30.50, 30.30, 29.98, 28.84, 28.64, 28.27, 27.64, 25.04, 24.08, 22.82, 22.76, 17.85, 13.35

2 RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.89 (m, 2H), 2.72-2.51 (m, 9H), 2.25-0.70 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.55, 72.85, 59.06, 49.33, 49.06, 48.42, 48.25, 47.76, 45.84, 44.06, 42.41, 40.75, 37.58, 37.10, 37.01, 35.91, 34.95, 34.47, 34.37, 33.55, 33.34, 30.33, 29.98, 28.84, 28.62, 28.19, 27.64, 25.04, 24.07, 22.82, 22.76, 17.84, 13.35

3 RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.89 (m, 2H), 2.69-2.38 (m, 17H), 2.27-0.70 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 74.13, 59.06, 58.03, 57.50, 54.10, 54.03, 49.30, 48.21, 47.75, 46.29, 44.04, 42.38, 41.16, 37.58, 37.01, 35.92, 34.92, 34.64, 34.35, 33.53, 30.55, 30.00, 28.85, 28.65, 28.34, 27.65, 27.42, 25.06, 24.12, 22.85, 22.79, 17.87, 13.38

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.96-3.95 (m, 2H), 3.80(m, 1H), 2.76-2.69 (m, 13H), 2.54-0.72 (m, 53H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 74.01, 69.00, 59.32, 57.39, 54.01, 48.21, 47.64, 45.53, 43.55, 43.13, 42.39, 41.16, 41.00, 40.54, 37.07, 36.92, 36.73, 36.38, 35.98, 34.43, 33.56, 32.12, 29.65, 28.89, 28.02, 27.45, 24.38, 23.44, 22.84, 22.78, 17.93, 13.16

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.97-3.94 (m, 2H), 3.80 (m, 1H), 2.90-2.59 (m, 9H), 2.29-0.71 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.91, 74.00, 68.98, 59.23, 49.00, 48.22, 47.62, 45.64, 43.42, 43.19, 42.40, 41.15, 40.42, 37.07, 36.74, 36.30, 35.89, 34.43, 33.56, 31.66, 29.69, 28.87, 28.32, 28.05, 27.14, 24.34, 23.36, 22.82, 22.76, 17.90, 13.15

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 2H), 3.79(m, 1H), 2.76-2.39 (m, 23H), 2.28-0.71 (m, 43H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.03, 69.03, 59.34, 57.97, 57.44, 54.10, 54.02, 47.66, 46.24, 46.08, 43.65, 43.14, 42.41, 41.21, 41.09, 37.28, 37.07, 36.42, 36.02, 34.43, 33.56, 30.11, 29.74, 28.87, 28.06, 27.92, 26.67, 24.38, 23.48, 22.83, 22.76, 17.91, 13.16

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.92-2.74 (m, 13H), 2.20-0.69 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 68.97, 59.31, 57.60, 51.74, 48.54, 45.26, 43.83, 43.42, 42.43, 41.21, 40.91, 40.32, 37.06, 36.65, 36.06, 35.88, 34.40, 34.21, 33.56, 30.84, 29.44, 29.04, 27.99, 27.01, 24.74, 23.55, 22.81, 22.73, 21.91, 19.07, 12.33

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.95 (m, 1H), 3.80 (m, 1H), 2.75-2.63 (m, 9H), 2.27-0.70 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.82, 69.03, 59.40, 57.51, 51.69, 48.94, 48.28, 45.64, 43.82, 43.61, 42.41, 41.20, 40.94, 40.63, 37.05, 36.76, 36.03, 34.36, 34.19, 33.55, 32.81, 29.57, 29.45, 28.01, 24.77, 23.72, 22.83, 22.76, 21.91, 19.11, 12.37

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.81 (m, 1H), 3.09-2.82 (m, 17H), 2.20-0.70 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 68.81, 59.37, 57.67, 55.76, 52.43, 52.27, 52.16, 52.09, 51.82, 51.99, 43.83, 43.09, 42.44, 41.24, 40.90, 40.75, 37.07, 36.67, 36.46, 34.43, 34.24, 34.16, 33.56, 30.91, 30.89, 29.46, 25.36, 24.74, 23.55, 22.80, 22.73, 19.08, 12.33

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.73-2.61 (m, 13H), 2.24-0.69 (m, 48H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.40, 69.03, 59.45, 57.44, 52.18, 51.67, 48.95, 48.43, 45.73, 43.81, 43.69, 41.20, 40.96, 40.72, 37.57, 37.21, 36.80, 36.10, 34.18, 33.21, 32.39, 31.97, 30.13, 30.02, 29.41, 28.29, 24.79, 23.79, 21.95, 19.00, 12.42

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.72-2.63 (m, 9H), 2.44-0.69 (m, 45H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.38, 68.95, 59.31, 57.34, 52.02, 51.57, 48.86, 48.19, 45.55, 43.70, 43.54, 41.10, 40.85, 40.55, 37.00, 36.79, 36.67, 35.93, 34.09, 32.77, 32.28, 31.87, 29.57, 29.29, 27.97, 24.67, 23.63, 21.83, 18.87, 12.28

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.71-0.42 (m, 17H), 2.32-0.70 (m, 44H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.46, 69.03, 59.36, 58.05, 57.47, 54.13, 53.99, 52.18, 51.69, 46.18, 43.82, 43.66, 41.22, 41.12, 40.97, 37.58, 37.18, 37.18, 36.90, 36.79, 36.07, 34.21, 32.39, 31.97, 30.35, 29.40, 28.36, 26.93, 24.77, 23.75, 21.93, 18.98, 12.40

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.72-2.59 (m, 8H), 2.38-0.70 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.42, 69.07, 59.48, 57.47, 51.66, 49.08, 48.42, 45.79, 43.83, 43.74, 41.62, 41.21, 40.98, 40.79, 37.86, 37.30, 37.18, 36.83, 36.11, 34.18, 33.58, 33.23, 31.15, 30.41, 29.48, 28.54, 24.80, 23.82, 21.94, 19.25, 14.84, 13.47, 12.42

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.46 (m, 1H), 2.89-2.65 (m, 13H), 2.54-0.71 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 72.04, 58.88, 57.64, 56.75, 48.31, 46.72, 45.74, 44.94, 44.66, 44.46, 42.42, 41.70, 40.80, 40.56, 38.82, 36.97, 36.68, 35.85, 35.75, 34.97, 34.40, 33.60, 32.19, 29.84, 29.71, 29.66, 28.10, 24.25, 22.81, 22.76, 22.54, 19.22, 12.80

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.85-2.49 (m, 9H), 2.24-0.71 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 72.06, 58.89, 57.65, 56.74, 48.94, 48.39, 45.85, 44.95, 44.67, 44.50, 42.42, 41.72, 40.81, 40.70, 38.87, 36.97, 36.75, 35.86, 35.78, 35.25, 34.39, 33.60, 33.06, 30.26, 29.84, 28.10, 24.28, 22.81, 22.76, 22.54, 19.23, 12.80

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.70-2.38 (m, 17H), 2.20-0.71 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.74, 72.01, 58.86, 58.05, 57.67, 56.74, 54.13, 54.03, 46.41, 44.94, 44.65,

44.48, 44.39, 42.38, 41.73, 41.16, 40.81, 38.93, 36.97, 36.80, 35.89, 35.78,

35.49, 34.39, 33.59, 30.51, 29.87, 28.33, 28.11, 27.37, 24.37, 22.87, 22.81, 22.56, 19.29, 12.87

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.96-2.77 (m, 13H), 2.52-0.69 (m, 55H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.89, 59.07, 58.00, 57.69, 47.93, 44.06, 42.44, 41.91, 41.59, 39.96, 37.29, 36.99, 36.03, 34.40, 33.53, 29.42, 29.01, 28.75, 28.24, 26.01, 25.37, 23.96, 23.93, 22.79, 22.73, 22.07, 19.03, 12.61

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.74-2.62 (m, 9H), 2.25-0.69 (m, 52H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.86, 59.04, 58.06, 57.63, 48.92, 48.37, 45.83, 44.07, 43.92, 42.43, 41.97, 41.67, 40.67, 37.37, 37.05, 36.98, 36.26, 34.35, 33.52, 32.90, 30.02, 29.44, 28.55, 28.11, 27.80, 25.42, 24.28, 22.81, 22.75, 22.11, 19.06, 12.65

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.72-2.39 (m, 15H), 2.23-0.96 (m, 53H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 59.01, 58.12, 58.02, 57.66, 57.50, 54.14, 54.02, 46.36, 44.09, 43.90, 42.43, 42.00, 41.69, 41.09, 37.37, 37.06, 36.99, 36.27, 34.40, 34.35, 33.53, 30.17, 29.44, 28.55, 28.28, 27.83, 27.12, 25.42, 24.28, 22.81, 22.75, 22.11, 19.05, 12.65

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.89 (m, 2H), 2.85-2.54 (m, 21H), 2.27-0.70 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 74.06, 59.10, 57.27, 55.25, 55.05, 54.99, 54.27, 54.18, 49.31, 48.23, 47.74,

46.97, 46.32, 46.18, 43.95, 42.38, 37.55, 36.99, 35.84, 34.94, 34.39, 33.52,

29.98, 28.84, 28.55, 27.60, 25.02, 24.02, 22.84, 22.78, 22.27, 17.86, 13.37

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.96-3.91 (m, 2H), 3.79 (m, 1H), 2.85-2.46 (m, 24H), 2.24-0.93 (m, 43H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.95, 74.10, 69.11, 59.54, 55.35, 54.48, 54.27, 54.07, 49.68, 48.19, 47.66, 47.07, 46.21, 43.73, 43.11, 42.41, 41.89, 41.21, 39.08, 37.77, 37.14, 37.06, 36.48, 36.06, 34.40, 33.55, 29.70, 28.87, 28.34, 28.04, 24.38, 23.52, 22.82, 22.76, 17.91, 13.15

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.85-2.43 (m, 23H), 2.37-0.69 (m, 48H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 69.10, 59.59, 58.60, 57.52, 55.37, 54.48, 54.28, 54.08, 51.70, 43.84, 42.42, 41.92, 41.23, 40.97, 39.11, 37.23, 37.05, 36.82, 36.10, 34.37, 34.21, 33.56, 29.44, 28.64, 28.59, 24.78, 23.76, 22.83, 22.76, 21.94, 19.10, 12.36

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.84-2.46 (m, 22H), 2.26-0.71 (m, 49H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.81, 72.04, 57.68, 56.74, 54.29, 54.26, 49.93, 47.10, 46.93, 46.37, 46.23, 44.94, 44.66, 44.50, 42.41, 41.93, 41.73, 40.83, 39.12, 38.90, 36.97, 36.77, 35.78, 34.39, 33.59, 29.85, 28.41, 28.10, 24.33, 22.84, 22.78, 22.54, 19.25, 12.83

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.95 (m, 1H), 2.84-2.53 (m, 22H), 2.27-0.69 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.80, 58.07, 57.63, 54.28, 52.23, 44.06, 43.91, 42.41, 41.99, 41.81, 41.67, 37.37, 36.97, 36.27, 34.39, 34.34, 33.51, 29.43, 28.58, 28.42, 28.32, 27.83, 25.44, 24.33, 22.84, 22.78, 22.11, 19.09, 12.69

RMN ¾ (250 MHz, CD3OD) : d (ppm) = 3.99-3.91 (m, 2H), 2.68-0.70 (m, 62H). RMN 13 C (63 MHz, CD3 OD): d (ppm) = 175.84, 74.13, 59.10, 57.14, 56.62, 56.57, 49.29, 47.69, 46.19, 44.06, 42.47, 42.37, 41.13, 37.58, 36.99,

35.91, 34.92, 34.66, 34.33, 33.53, 31.06, 30.98, 29.98, 28.84, 28.65, 28.33,

27.92, 27.65, 25.06, 24.14, 22.86, 22.80, 17.87, 13.39

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94-3.89 (m, 2H), 2.75-2.40 (m, 14H), 2.24-0.85 (m, 45H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.98, 74.08, 69.06, 59.99, 57.30, 56.64, 56.60, 50.72, 48.22, 47.67, 42.43, 41.05, 37.09, 37.03, 36.43, 36.00, 34.43, 34.37, 33.56, 30.61, 30.52, 28.89, 27.61, 24.36, 23.46, 22.81, 22.74, 17.89, 13.15

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.70-

0.69 (m, 51H). RMN 13C (62 MHz, CD3OD) : δ (ppm) = 175.80, 69.04, 59.50, 57.50, 57.13, 56.55, 51.69, 46.04, 43.82, 43.69, 42.43, 42.39, 41.21, 41.05, 40.96, 37.60, 37.21, 37.04, 36.80, 36.08, 34.35, 34.19, 33.54, 30.69, 29.45, 28.35, 27.52, 24.78, 23.77, 22.84, 22.77, 21.93, 19.12, 12.39

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.75-2.32 (m, 12H), 2.24-0.71 (m, 50H). RMN 13C (62 MHz, CD3OD) : δ (ppm) = 175.84, 72.05, 58.94, 57.64, 57.01, 56.73, 56.57, 46.17, 44.93, 44.82, 44.66, 44.48, 42.41, 41.70, 41.05, 40.80, 36.95, 35.77, 34.41, 34.39, 33.59, 30.54, 30.42, 29.84, 28.09, 27.74, 24.30, 22.83, 22.76, 19.24, 12.82

RMN ¾ (250 MHz, CD3OD) : δ (ppm) =3.94 (m, 1H), 2.75-2.37 (m, 10H), 2.24-0.69 (m, 53H). RMN 13C (62 MHz, CD3OD) : δ (ppm) = 175.81, 58.05, 57.59, 56.57, 46.26, 44.06, 43.98, 42.49, 42.41, 41.97, 41.66, 41.14, 37.39, 37.22, 36.97, 36.31, 34.37, 33.51, 31.09, 31.04, 29.43, 27.82, 25.44, 24.36, 22.83, 22.77, 22.11, 19.08, 12.69

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94-3.91 (m, 2H), 2.83-2.53 (m, 13H), 2.26-0.70 (m, 56H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.12, 59.03, 49.98, 49.30, 48.27, 47.76, 45.42, 43.93, 42.41, 40.37, 37.56, 37.01, 35.81, 34.94, 34.41, 33.55, 31.13, 29.98, 28.84, 28.74, 28.51, 27.61, 27.43, 25.03, 23.91, 22.82, 22.76, 17.86, 13.34

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.96-3.94 (m, 2H), 3.79 (m, 1H), 2.85-2.68 (m, 13H), 2.54-0.71 (m, 55H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.91, 74.02, 69.02, 59.34, 50.08, 48.66, 48.21, 47.64, 45.47, 43.52, 43.12, 42.40, 41.16, 40.48, 37.08, 36.87, 36.65, 36.49, 36.35, 35.95, 34.44, 33.56, 31.65, 29.68, 28.87, 28.64, 28.02, 27.84, 27.78, 27.36, 24.36, 23.41, 22.82, 22.76, 17.91, 13.14

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.89 (m, 1H), 3.74 (m, 1H), 2.70-2.41 (m, 13H), 2.17-0.64 (m, 56H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.82, 69.03, 59.40, 57.55, 51.70, 50.44, 50.33, 48.27, 45.61, 43.83, 43.63, 42.41, 41.22, 40.95, 40.63, 37.06, 36.76, 36.04, 34.37, 34.21, 33.56, 32.53, 29.46, 29.37, 28.10, 27.98, 24.78, 23.71, 22.83, 22.76, 21.94, 19.11, 12.37

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.75-2.64 (m, 13H), 2.27-0.69 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.47, 69.04, 59.40, 57.46, 52.17, 51.69, 50.46, 50.36, 48.27, 45.62, 43.81, 43.63, 41.20, 40.95, 40.63, 37.27, 37.11, 36.90, 36.76, 36.03, 34.19, 32.61, 32.39, 31.97, 29.46, 29.40, 28.11, 28.04, 24.77, 23.72, 21.93, 18.96, 12.37

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.73-2.62 (m, 13H), 2.40-0.70 (m, 55H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.43, 69.05, 59.44, 57.50, 51.67, 50.57, 50.49, 48.89, 48.34, 45.69, 43.83, 43.75, 43.68, 41.62, 41.20, 40.97, 40.70, 37.54, 37.18, 36.79, 36.07, 34.18, 33.23, 33.07, 31.17, 29.89, 29.48, 28.25, 24.79, 23.76, 21.94, 19.23, 14.83, 13.45, 12.40

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.98-2.52 (m, 15H), 2.33-0.71 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.86, 72.04, 58.87, 57.65, 56.76, 55.13, 50.29, 45.73, 45.66, 44.94, 44.66, 44.44, 42.42, 41.69, 40.80, 40.56, 38.81, 36.97, 36.65, 35.74, 34.42, 33.60, 32.03, 29.83, 29.56, 28.02, 24.32, 22.82, 22.76, 22.54, 19.23, 12.80

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.98-2.69 (m, 13H), 2.20-0.69 (m, 57H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.85, 59.05, 57.98, 57.65, 49.71, 49.65, 47.94, 45.00, 44.05, 43.58, 42.43, 41.88, 41.59, 39.91, 37.28, 36.98, 36.29, 36.03, 34.38, 33.53, 29.43, 28.88, 27.39, 27.33, 25.38, 24.51, 24.00, 22.81, 22.74, 22.06, 19.04, 12.63

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.05 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.79-2.63 (m, 8H), 2.52-0.95 (m, 54H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.27, 69.02, 59.41, 57.49, 51.69, 50.64, 48.95, 48.27, 47.11, 45.69, 43.84, 43.59, 41.19, 40.95, 40.65, 37.25, 37.10, 37.04, 36.74, 36.00, 34.21, 33.54, 33.38, 32.80, 29.54, 29.37, 27.89, 24.78, 23.70, 21.93, 21.30, 21.12, 19.23, 12.39.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.87-2.61 (m, 9H), 2.47-0.95 (m, 52H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.86, 69.08, 59.44, 57.54, 51.70, 49.75, 48.34, 45.71, 43.84, 43.66, 41.21, 40.95, 40.70, 37.41, 37.14, 37.06, 36.79, 36.05, 34.37, 34.21, 34.02, 33.94, 33.61, 33.11, 29.80, 29.47, 28.15, 26.81, 26.35, 24.78, 23.73, 21.93, 19.11, 12.37

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.83-2.60 (m, 13H), 2.46-0.95 (m, 50H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.42, 69.06, 59.47, 57.48, 51.66, 48.99, 48.93, 45.76, 43.83, 43.74, 41.62, 41.20, 40.97, 40.76, 37.74, 37.19, 36.82, 36.10, 34.18, 33.48, 33.23, 31.14, 30.25, 29.89, 29.49, 28.43, 24.80, 23.79, 21.94, 19.23, 14.83, 13.46, 12.40

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.06 (m, 1H), 3.79 (m, 1H), 3.53 (m, 1H), 2.88-2.61 (m, 12H), 2.49-0.95 (m, 57H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.31, 69.06, 59.45, 57.51, 51.71, 50.68, 48.95, 48.43, 47.13, 45.71, 43.85, 43.67, 41.21, 40.97, 40.72, 37.39, 37.28, 37.13, 36.79, 36.04, 34.21, 33.56, 33.40, 33.16, 31.12, 30.12, 29.78, 29.57, 28.13, 24.79, 23.71, 21.93, 21.28, 21.10, 19.21, 12.36

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.97-3.91 (m, 2H), 2.78-2.49 (m, 13H), 2.25-0.95 (m, 51H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.13, 59.15, 53.41, 52.83, 49.35, 48.25, 47.75, 46.14, 43.96, 42.41, 41.01, 37.55, 37.01, 35.85, 34.95, 34.38, 34.14, 33.53, 30.11, 30.05, 29.98, 28.84, 28.55, 27.91, 27.61, 27.24, 25.02, 24.02, 22.82, 22.76, 17.85, 13.35.

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.97-3.91 (m, 2H), 3.79 (m, 1H), 2.83-2.39 (m, 15H), 2.27-0.94 (m, 48H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.05, 69.04, 59.40, 53.67, 52.87, 52.77, 48.19, 47.64, 46.02, 43.61, 43.15, 42.41, 41.18, 41.01, 37.08, 36.41, 36.00, 34.41, 33.57, 30.20, 29.71, 28.89, 28.05, 27.83, 26.91, 24.36, 23.46, 22.82, 22.76, 17.90, 13.15.

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.80 (m, 1H), 3.41-3.35 (m, 4H), 2.80-2.53 (m, 13H), 2.43-0.96 (m, 50H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.41, 68.97, 59.41, 57.50, 53.29, 52.77, 51.69, 45.66, 43.82, 43.75, 43.46, 41.62, 41.18, 40.91, 40.74, 37.17, 36.68, 35.93, 34.19, 33.23, 31.19, 29.46, 29.21, 27.40, 26.48, 24.77, 23.66, 21.93, 19.24, 14.84, 13.47, 12.41.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.83-2.57 (m, 13H), 2.27-0.93 (m, 45H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.89, 69.06, 59.41, 57.64, 57.53, 57.49, 56.98, 54.03, 51.77, 44.82, 43.85, 43.53, 42.43, 41.24, 41.20, 40.95, 39.99, 37.05, 36.71, 35.95, 34.41, 34.27, 33.56, 29.45, 27.67, 24.74, 23.60, 22.80, 22.73, 21.90, 19.07, 12.34.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.83-2.37 (m, 15H), 2.24-0.95 (m, 49H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.77, 69.01, 59.56, 57.47, 53.55, 52.83, 51.68, 46.23, 43.81, 43.68, 42.38, 41.13, 40.94, 37.67, 37.22, 37.03, 36.81, 36.11, 34.33, 34.19, 33.54, 30.61, 29.46, 28.40, 27.38, 24.78, 23.80, 22.86, 22.79, 21.94, 19.13.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.80-2.47 (m, 13H), 2.21-0.95 (m, 57H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 69.09, 59.57, 57.54, 53.56, 52.85, 51.71 , 49.76, 46.22, 43.84, 43.71, 41.13, 40.97, 37.19, 37.05, 36.82, 36.07, 34.37, 34.22, 34.02, 33.94, 33.60, 30.60, 29.47, 28.36, 27.34, 26.81, 26.34, 24.77, 23.73, 21.94, 19.10, 12.36

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.89-2.52 (m, 13H), 2.37-0.96 (m, 50H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 72.05, 59.99, 57.67, 56.71, 53.38, 52.84, 46.23, 44.94, 44.66, 44.42, 42.43, 40.96, 40.82, 38.80, 36.98, 35.75, 34.40, 33.60, 29.84, 28.10, 24.25, 22.81, 22.75, 19.21, 12.79

RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.97-2.50 (m, 12H), 2.25-0.86 (m, 53H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 59.16, 58.08, 57.63, 53.52, 53.31, 52.85, 46.12, 44.07, 43.92, 43.84, 42.43, 41.99, 41.66, 40.89, 37.36, 37.20, 36.98, 36.33, 36.23, 34.37, 33.90, 33.52, 29.62, 29.43, 27.79, 27.10, 25.41, 24.22, 22.81, 22.75, 22.10, 19.05, 12.66

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.05 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.80-2.61 (m, 13H), 2.45-0.95 (m, 58H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.28, 69.07, 59.45, 57.47, 51.67, 50.62, 50.52, 48.89, 48.35, 47.11, 45.71, 43.84, 43.68, 41.19, 40.96, 40.72, 37.56, 37.25, 36.85, 36.79, 36.09, 35.83, 34.19, 33.54, 33.38, 33.21, 29.96, 29.54, 28.30, 24.79, 23.75, 21.93, 21.30, 21.12, 19.23, 12.39

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.76-2.62 (m, 13H), 2.49-0.95 (m, 57H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.83, 69.04, 59.43, 57.56, 51.70, 50.55, 50.44, 49.74, 48.32, 45.69, 43.83, 43.63, 41.21, 40.95, 40.69, 37.30, 37.05, 36.76, 36.05, 34.39, 34.21, 34.00, 33.92, 33.60, 32.93, 29.56, 29.46, 28.26, 28.06, 26.80, 26.34, 24.77, 23.71, 21.92, 19.12, 12.38.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.82-2.60 (m, 9H), 2.42-0.96 (m, 50H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.90, 69.00, 59.37, 57.63, 51.76, 50.06, 48.65, 45.53, 43.84, 43.45, 42.44, 41.84, 41.73, 41.23, 40.91, 40.60, 37.09, 36.67, 36.35, 34.42, 34.24, 33.57, 30.03, 29.46, 28.25, 27.70, 27.21, 24.74, 23.55, 22.80, 22.73, 21.89, 19.07, 12.33

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.71-2.60 (m, 13H), 2.46-0.95 (m, 48H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.50, 69.12, 59.49, 57.50, 51.67, 49.87, 45.69, 43.84, 43.76, 41.64, 41.21, 40.97, 40.73, 37.79, 37.25, 37.20, 36.83, 36.08, 34.19, 33.66, 33.24, 31.16, 30.49, 29.49, 28.48, 24.79, 23.76, 21.93, 19.20, 14.80, 13.42, 12.36.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.05 (m, 1H), 3.79 (m, 1H), 3.53 (m, 1H), 2.82-2.61 (m, 13H), 2.47-0.95 (m, 54H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.15, 69.00, 59.49, 57.41, 51.63, 50.63, 50.60, 50.17, 48.44, 47.07, 45.72, 43.82, 43.73, 41.18, 40.97, 40.73, 37.79, 37.25, 36.82, 36.12, 34.16, 33.62, 33.50, 33.35, 30.52, 29.57, 28.50, 24.82, 23.86, 21.96, 21.34, 21.17, 19.28, 12.46.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.81-2.48 (m, 9H), 2.40-0.86 (m, 50H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.79, 69.06, 59.48, 59.45, 57.50, 51.68, 50.69, 50.66, 49.01, 48.40, 47.42, 45.77, 43.83, 43.76, 42.56, 42.39, 41.22, 40.97, 40.79, 37.87, 37.30, 37.06, 36.84, 36.12, 34.35, 34.19, 33.59, 33.56, 31.74, 30.46, 29.46, 28.57, 28.47, 27.97, 24.79, 23.82, 22.86, 22.78, 21.95, 19.13, 12.40.

RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.06 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.80-2.47 (m, 13H), 2.39-0.95 (m, 56H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.29, 69.07, 59.58, 57.47, 53.58, 52.86, 51.70, 50.68, 47.12, 46.26, 43.84, 43.71, 41.16, 40.98, 40.75, 37.26, 36.08, 34.21, 33.53, 33.38, 30.69, 29.56, 28.43, 27.42, 24.79, 23.76, 21.92, 21.29, 21.11, 19.22, 12.38

Among said compounds of formula (I), the compounds (1), (2), (5), (13), (15), (33) and (34) or a pharmaceutically acceptable salts, especially their hydrochlorides, are particularly interesting.

The following examples illustrate in detail the preparation of the compounds according to the invention. The structures of the products were confirmed at least by NMR spectra.

EXAMPLES

All syntheses were performed using solvents purified by conventional methods. Commercial reagents are used directly without purification.

"Yield" means yield.

Example 1: preparation of compounds of formula (III) as defined above

Exemple 1.1 N-isopropyl-désoxycholamide 1

In a two-necked flask equipped with a magnetic stir bar, is placed 2 g (5.1 mmol) of deoxycholic acid dissolved in 20 mL of THF. Is added following 1.7 equivalents of HOBT (1.36 g, 8.8 mmol) and 1 equivalent of DCC (1.04 g, 5.1mmol). It also adds 600 isopropyl lamine (13 mmol) and placed under stirring for 24 h at room temperature. After evaporation of THF and taken up in 40 mL of CH2C12 was filtered and the precipitate which was washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (eluent: ethyl acetate / methanol (9/1)). The desired product 1 was obtained as a white solid (1.9 g).

RMN JH (250 MHz, CDC13) : δ (ppm) = 4.17 (m, 2H), 2.39-0.63 (m, 45H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.39 ; 73.17 ; 71.59 ; 50.36 ; 48.93 ; 48.06 ; 46.76 ; 42.09 ; 41.23 ; 36.26 ; 35.96 ; 35.35 ; 34.14 ; 33.68 ; 33.68 ; 33.51 ; 33.44 ; 31.68 ; 30.65 ; 28.47 ; 27.60 ; 27.17 ; 26.19 ; 25.62 ; 24.95 ; 23.75 ; 23.10 ; 22.68 ; 17.31 ; 12.69. Rdt : 79%. C27H47NO3

Compounds 2-7 were prepared according to the procedure by considering the appropriate bile acid starting.

Exemple 1.2 N-isopropy -chénodésoxycholamide 2

RMN JH (250 MHz, CDCI3) : δ (ppm) = 3.96 (m, 2H), 3.69 (m, 1H), 3.31 (m, 1H), 2.30-0.75 (m, 41H), 0.50 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 172.88, 72.02, 68.53, 60.46, 55.80, 50.45, 42.69, 41.49, 41.28, 39.83, 39.64, 39.41, 35.47, 35.33, 35.06, 34.60, 33.75, 32.83, 31.82, 30.64, 28.23, 23.71, 22.83, 20.59, 18.42, 14.22, 11.78. Rdt : 67%. C27H47NO3

Example 1.3 N-methyl-3 chénodésoxycholamide

0

RMN *H (250 MHz, CDC13) : δ (ppm) = 3.78 (m, 1H), 3.60 (s, 3H), 3.39 (m, 1H), 2.35-2.06 (m, 3H), 1.98-0.73 (m, 31H), 0.59 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 189.68, 174.82, 71.99, 66.51, 55.78, 51.54, 50.46, 42.69, 41.49, 39.86, 39.64, 39.41, 35.39, 35.08, 34.62, 32.84, 31.02, 30.67, 28.17, 23.71, 22.80, 20.59, 18.28, 11.78. Rdt : 57%. C25H42NO3

-isopropyl-lithocholamide 4

RMN ^ (250 MHz, CDCb) : δ (ppm) = 4.1 1-3.40 (m, 3H), 2.1 1-0.55 (m, 44H). RMN 13C (63 MHz, CDCb) : δ (ppm) = 171.71 , 71.87, 58.53, 56.01 , 42.76, 42.09, 41.21 , 40.43, 40.20, 36.45, 35.88, 35.50, 35.38, 34.58, 34.00, 33.84, 31.81 , 30.55, 28.29, 27.20, 26.43, 24.98, 24.22, 23.40, 22.88, 20.84, 18.43, 12.05. Rdt : 92%. C27H47NO2

Exemple 1.5 N-isopro

RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.19-385 (m, 3H), 3.42 (m, 1H), 2.22-0.87 (m, 40H), 0.66 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.88, 73.24, 71.86, 68.50, 60.46, 49.07, 46.27, 41.50, 41.33, 39.33, 35.35, 34.78, 34.86, 33.81, 33.06, 31.78, 30.18, 28.01, 27.57, 26.22, 24.91, 23.26, 22.63, 22.39, 21.09, 17.41, 14.20, 12.40 Rdt : 83%. C27H47NO4

Exemple 1.6 N-isopropyl-ursodésoxycholamide 6

RMN ^ (250 MHz, CDC13) : δ (ppm) = 4.01-3.92 (m, 1H), 3.59-3.33 (m, 2H), 2.20-0.79 (m, 41H), 0.52 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.72, 71.38, 71.35, 55.69, 54.78, 43.68, 43.51, 42.14, 41.51, 40.09, 39.24, 37.14, 36.91, 35.42, 34.93, 34.01, 33.69, 31.97, 30.15, 28.66, 26.87, 25.51, 24.84, 23.38, 22.67, 21.16, 18.45, 12.07. Rdt : 70%. C27H47NO3

Example 1.7 N, N-diethyl-7 chénodésoxycholamide

RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.03 (m, 1H), 3.76-3.57 (m, 2H), 3.37-3.22 (m, 5H), 2.31-0.83 (m, 38H), 0.59 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.38, 72.36, 68.85, 67.57, 60.94, 56.44, 50.94, 43.16, 42.55, 42.07, 40.58, 40.21, 39.93, 36.13, 35.92, 35.56, 35.20, 33.33,32.08, 31.13, 30.47, 28.75, 24.19, 23.35, 21.57, 21.13, 19.07, 14.96, 14.71, 13.61, 12.30.

Example 2 Preparation of compounds of formula (II) as defined above

Exemple 2.1 3-oxo-N-isopropyl-désoxycholamide 8

In a two-necked flask equipped with a magnetic stirring bar and topped with a Dean-Stark trap was placed 2 g (5 mmol) of N-isopropyl-désoxycholamide 1 dissolved in 40 mL of toluene and 30 mL of acetone. Is added following 2.2 equivalents of tri-feri-butoxide (2.7 g, 11 mmol). The mixture is refluxed toluene for 8 hours. After cooling, the mixture was washed three times with 30 mL of 2N sulfuric acid and then with 30 mL of water. After drying over anhydrous sodium sulfate and filtration, the filtrate is evaporated in vacuo. The crude product thus obtained is purified by chromatography on silica gel (eluent: ethyl acetate). The desired product 8 was obtained as a white solid. NMR J H (250 MHz, CD CL): δ (ppm) = 4.09-4.01 (m, 2H), 2.78-0.68 (m, 43H). NMR 13 C (63 MHz, CDC1 3 ): δ (ppm) = 213.51, 172.55, 72.85, 48.06, 47.24, 46.52, 44.23, 42.28, 41.16, 37.08, 36.82, 35.63, 35.12, 34.34, 33.74, 33.69, 31.61, 28.87, 27.44, 26.48, 25.41, 23.52, 22.78, 22.75, 22.32, 17.42, 12.72. Yield: 49%. C27H45NO3

Compounds 9-12 were all produced according to the same procedure as that developed for the synthesis of compound 8 described above by considering the appropriate starting diol (2.5-7 compounds) previously prepared.

RMN JH (250 MHz, CDCL) : δ (ppm) = 4.07 (m, 1H), 3.91 (m, 1H), 2.44-0.64 (m, 43H). RMN 13C (63 MHz, CDCL) : δ (ppm) = 213.40, 172.57, 68.28, 55.79, 50.25, 45.59, 43.19, 42.65, 41.15, 39.46, 39.29, 36.93, 36.77, 35.41, 35.25, 33.82, 33.69, 33.16, 31.69, 23.60, 22.79, 22.76, 21.88, 20.91, 18.34, 11.73. Rdt : 58%. C27H45NO3

2.3 Example 3-oxo-N-Hyssop

RMN *H (250 MHz, CDC13) : δ (ppm) = 3.99-3.86 (m, 3H), 2.41-0.62 (m, 42H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.74, 173.30, 72.97, 68.97, 46.55, 46.39, 45.37, 43.01, 41.55, 41.08, 39.11, 36.68, 36.54, 35.35, 34.82, 33.93, 32.99, 31.41, 28.29, 27.51, 26.70, 23.14, 22.54, 21.38, 17.20, 12.34. Rdt : 58%. C27H45NO4

2:43 Example-oxo-N-Hyssop

RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.07 (m, 1H), 3.58 (m, 1H), 2.56-0.67 (m, 43H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 212.12, 172.65, 70.58, 55.61, 54.87, 44.31, 43.64, 43.20, 43.04, 41.13, 39.90, 39.27, 36.93, 36.28, 36.15, 35.27, 34.30, 33.67, 31.71, 28.53, 26.72, 22.69, 22.66, 22.57, 21.54, 18.40, 12.04. Rdt : 67%. C27H45NO3

Example 2.5 3-oxo-N, N-diethyl-12 chénodésoxycholamide

RMN JH (250 MHz, CDCI3) : δ (ppm) = 3.89 (m, 1H), 3.29 (m, 4H), 2.43-0.67 (m, 42H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.48, 172.63, 68.08, 55.85, 50.21, 45.59, 43.25, 42.57, 41.90, 39.97, 39.43, 39.29, 36.90, 36.77, 35.52, 35.22, 33.83, 33.10, 31.42, 29.82, 28.14, 23.57, 21.86, 20.90, 18.43, 14.34, 13.01, 11.71. Rdt : 65%. C28H47NO3

Compounds 13 and 14 were produced from N-methyl-3 chénodésoxycholamide and N-isopropyl-lithocholamide 4 respectively according to the same procedure as that used for the synthesis of compound 8 described above, with the exception of chromatography purification conditions on silica gel of the crude products which have been modified (eluent: ethyl acetate / petroleum ether (1/1)).

Example 2.6 3-oxo-N-methyl-chénodésoxycholamide 13

RMN JH (250 MHz, CDC13) : δ (ppm) = 3.79 (m, 1H), 3.54 (s, 3H), 2.34-0.58 (m, 37H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.33, 174.42, 67.69, 55.44, 51.18, 49.90, 45.30, 42.99, 42.28, 39.17, 39.02, 36.60, 36.52, 35.00, 34.96, 33.63, 32.83, 30.61, 27.84, 23.26, 21.61, 20.65, 17.95, 11.45. Rdt : 42%. C25H41NO3

Exemple 2.7 3-oxo-N-isopro l-lithocholamide 14

RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.06 (m, 1H), 2.67-0.65 (m, 44H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.44, 172.55, 56.32, 55.93, 44.23, 42.66, 42.26, 41.06, 40.58, 39.94, 37.12, 36.90, 35.38, 34.77, 33.70, 31.69, 28.11, 26.50, 25.65, 24.05, 22.74, 22.71, 22.55, 21.08, 18.30, 11.96. Rdt : 37%. C27H45NO2

EXAMPLE 3 Preparation of compounds of formula (I)

The compounds of the invention were all prepared by reductive amination of the ketone precursor prepared above in Example 2 (compounds 8-14) in the presence of suitable polyamine chain.

Example 3.1 Preparation of Compound (1)

In a three-necked flask equipped with a magnetic stirrer, 100 mg of 3-oxo-N-isopropyl-désoxycholamide 8 (0.23 mmol) were dissolved in 7 mL of methanol. Is added following 3 equivalents of titanium tetraisopropoxide (205 μί, 0.7 mmol) followed by 2 equivalents of norspermine (95 μί, 0.46 mmol). After stirring for 12h at room temperature, the flask was placed in an ice bath and added with stirring 4 equivalents of sodium borohydride (35 mg, 0.92 mmol). After stirring for 2 h and cooling to room temperature, 300 of water was added to terminate the reaction. After lh of additional stirring, the mixture was filtered through Celite, rinsed with ammonia and then with methanol and evaporated in vacuo. The crude product thus obtained is purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia (7/3/1)). The compound (1) is obtained as a yellow oil. Yield: 40%.

Example 3.2 Preparation of compounds (2), (25), (3), (20) and (30)

The compounds (2), (25), (3), (20) and (30) were prepared according to the same procedure developed for the synthesis of compound (1) used as the starting precursor 3-oxo-N désoxycholamide isopropyl-8 and considering the appropriate polyamine chain.

The compound (2) is obtained with a yield of 36%. (C33H62N4O2). compounds

(25), (3), (20) and (30) are obtained with respective yields of 70% (C34H64N4O2), 58% (C37H69N5O2), 43% (C37H73N7O2) and 38% (C37H71N5O2).

Example 3.3 Preparation of compounds (31), (4), (5), (26), (6) and (21)

The compounds (31), (4), (5), (26), (6) and (21) were prepared according to the same procedure developed for the synthesis of compound (1) used as the starting precursor 3 oxo-N-isopropyl-cholamide 10 and considering the appropriate polyamine chain.

The compound (31) was obtained in a yield of 37% (C37H71N5O3). The compounds (31), (4), (5), (26), (6) and (21) are obtained with the respective yields of 38% (C36H69N5O3), 47% (C33H62N4O3), 24% (C34H64N4O3) 40% (C37H69N5O3) and 32%. C37H73N7O3.

Example 3.4 Preparation of compounds (32), (7), (8), (27), (9) and (22)

The compounds (32), (7), (8), (27), (9) and (22) were prepared according to the same procedure developed for the synthesis of compound (1) used as the starting precursor 3 oxo-N-isopropyl-chénodésoxycholamide 9 and considering the appropriate polyamine chain.

The compound (32) was obtained in a yield of 51% (C37H71N5O2). The compounds (7), (8), (27), (9) and (22) are obtained with the respective yields of 20% (C36H69N5O2), 55% (C33H62N4O2), 65% (C34H64N4O2), 15% (C37H69N5O2 ) and 26% (C37H73N7O2).

Example 3.5 Preparation of compounds (33), (10), (11) and (12)

The compounds (33), (10), (11) and (12) were prepared according to the same procedure developed for the synthesis of compound (1) used as the starting precursor 3-oxo-N-methyl-chénodésoxycholamide 13 and considering the appropriate polyamine chain.

Compound (33) is obtained with a yield of 36% (C35H67N5O2). The compounds (10), (11) and (12) are obtained with the respective yields of 58% (C34H65N5O2), 51% (C31H58N4O2) and 48% (C35H65N5O2).

CLAIMS
1. A compound of formula (I)

in which

RI and R2 independently represent a hydrogen atom, a SO3H group or a hydroxy group,

R 'is - (CR a R b) NX (CRcRd) m- [Y- (CReRf) o] t-NR9Rio,

Ra, Rb, Rc, Rd, Re and Rf independently represent a hydrogen atom or a (Ci-Cs) alkyl or a (C 6 -Cio) aryl,

X and Y independently represent an -NR 1 group, 1-, -O- or a divalent heterocyclic group comprising at least one nitrogen atom, a 5 or 6-membered,

R9 and RIO independently represent a hydrogen atom or a (Ci-Cs) alkyl group or form together with the nitrogen atom which carries them, a heterocyclic group with 5 or 6 members, optionally substituted by one or two group (s) = 0 or = s,

Rl l represents a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2 ) S -NH 2 ,

RI and RI 5 6 independently represent a hydrogen atom or a (Ci-Cs) alkyl or a (C 6 -Cio) aryl,

n, m, o and s independently represent an integer between 1 and 5,

t is 0, 1, 2 or 3,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, characterized in that it is defined by at least one of the following subgroups:

- first subgroup of compounds of formula (I) wherein RI and R2 independently represent a hydrogen atom or hydroxy,

- second subgroup of compounds of formula (I) wherein RI and RI 5 6 independently represent a hydrogen atom or a (Ci-C4) alkyl,

- third subgroup of compounds of formula (I) wherein X is an -NH- group, a heterocyclic 6-membered having one or two nitrogen atoms, preferably a group 1, 4-piperazinylene or 1 , 4-piperidinylene,

- fourth subgroup of compounds of formula (I) wherein R9 and RIO represent a hydrogen atom,

- fifth subgroup of compounds of formula (I) for which Ra, Rb, Rc,

Rd, Re and Rf represent a hydrogen atom,

- sixth subgroup of compounds of formula (I) wherein Y is -NR11- group, with R 1 representing a hydrogen atom or a (Ci-C4) alkyl or a group - (CH 2 ) s- NH 2 wherein s is 1, 2 or 3,

- seventh subgroup of compounds of formula (I) wherein m is

2, 3, 4 or 5, more preferably 2 or 3,

- eighth subgroup of compounds of formula (I) for which n is equal to 2,

3, 4 or 5, more preferably 2, 3 or 4,

- ninth subgroup of compounds of formula (I) wherein m is different from 4,

- tenth subgroup of compounds of formula (I) wherein o is 2 or 3,

- eleventh subgroup of compounds of formula (I) wherein the group -NHR 'is selected from:

in which

RI and R2 are as defined in claim 1 or 2,

RI and RI 5 6 independently represent a hydrogen atom or a (Ci-C 8 ) alkyl,

n represents the integer 2, 3 or 4,

m represents the integer 2, 3 or 4,

X is -NRl l- group or a divalent heterocyclic group comprising one or two nitrogen atoms, a 5 or 6 membered ring, such as 1, 4-piperazinylene or 1, 4-piperidinylene,

R 4 and R s independently represent a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2 ) s NH 2 ,

R5 represents a hydrogen atom, a group - (CH 2 ) P -NH 2 , a group - (CH 2 ) p -NH- (CH 2 ) q -NH 2 or - (CH 2 ) p-NH- (CH 2) q -NH- (CH 2 ) r-NH2, p, q, r and s independently represent an integer which can vary between 1 and 5,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

4. A compound according to any one of claims 1 to 3, characterized in that RI RI 5 and 6 represent independently a hydrogen atom or a (Ci-C4) alkyl such as methyl or isoproyle.

5. A compound according to any one of claims 1 to 4, characterized in that n is 2 and m is 3, n is 2 and m is 2, n is 3 and m is equal to 4 or n is 3 and m is equal to 3.

6. A compound according to any one of claims 3 to 5, characterized in that X represents a group -NRl l- or 1, 4-piperazinylene and Rl and R4 independently representing a hydrogen atom, a methyl group or a group - (CH 2 ) s -NH 2 , wherein s is 2 or 3.

7. A compound according to any one of claims 3 to 5, characterized in that R5 represents a hydrogen atom, a group - (CH 2 ) P -NH 2 , a group - (CH 2 ) p -NH- ( CH 2 ) q -NH 2 or - (CH 2 ) p -NH- (CH 2) q -NH- (CH 2 ) r -NH 2, where p is 2 or 3, q is 2 and r is equal to 2.

8. A compound according to any one of the preceding claims, characterized in that it is alternately

- formula (Ia)

in which

5 RI, RI 6, RI and R2 are as defined in any one of claims 3 to 5,

X is -NH- or a group 1, 4-piperazinylene,

R5 represents a hydrogen atom or a group - (CH 2 ) P -NH 2 , where p is 2 or 3,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof,

- the Formule (Ib)

(Ib) wherein

5 RI, RI 6, RI and R2 are as defined in any one of claims 3 to 5,

u is 0, 1, 2 or 3, preferably 1, 2 or 3,

R6 and R7 independently represent a hydrogen atom or a (Ci-C8) alkyl, preferably a hydrogen atom or a (Ci-C 4 ) alkyl,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof,

- the formula (Ic)

in which

RI 5, 6 RI, RI, R2, n and m are as defined in any one of claims 3 to 5, and

R8 is (Ci-C8) alkyl, preferably methyl, or a group - (CH 2 ) s NH 2 , with s being an integer which can vary between 1 and 5, preferably equal to 2 or 3 ,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof,

- formula (Id)

in which

5 RI, RI 6, RI and R2 are as defined in any one of claims 3 to 5,

R5 represents a group - (CH 2 ) P -NH 2 , where p is 2 or 3,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof, or

- the formula (Ic)

in which

R15, R16, RI and R2 are as defined according to any one of claims 3 to 5,

R5 represents a group - (CH 2 ) p NH 2 , where p is 2 or 3, and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof.

9. A compound of formula (I) as defined in claim 1 selected from the following compounds:

- (1) 3P-norspermino-N-isopropyl-désoxycholamide,

- (2) 3P-norspermidino-N-isopropyl-désoxycholamide,

- (3) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide,

- (4) 3P-norspermino-N-isopropyl-cholamide,

- (5) 3P-norspermidino-N-isopropyl-cholamide,

- (6) 3P- (l, 4-Bis (3-aminopropyl) piperazine) -N-isopropyl-désoxycholamide,

- (7) 3P-norspermino-N-isopropyl-chénodésoxycholamide,

- (8) 3P-norspermidino-N-isopropyl-chénodésoxycholamide,

- (9) 3β- (1, 4-Bis (3-aminopropyl) piperazine) -N-isopropyl-chénodésoxy cholamide,

- (10) 3 P-norspermino-N-methyl-chénodésoxycholamide,

- (11) 3 P-norspermidino-N-methyl-chénodésoxycholamide,

- (12) 3β- (1, 4-Bis (3-aminopropyl) piperazine) -N-methyl-chénodésoxy cholamide,

- (13) 3 P-norspermidino- N, N-diethyl-chénodésoxycholamide,

- (14) 3P-norspermino-N-isopropyl-ursodésoxycholamide,

- (15) 3P-norspermidino-N-isopropyl-ursodésoxycholamide,

- (16) 3β- (1, 4-Bis (3-aminopropyl) piperazine) -N-isopropyl-ursodésoxy

for lamide,

- (17) 3P-norspermino-N-isopropyl-lithocholamide,

- (18) 3P-norspermidino-N-isopropyl-lithocholamide,

- (19) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-lithocho lamide,

- (20) 3 P- (pentaethylenehexamine) -N-isopropyl-deoxy cho lamide,

- (21) 3P- (pentaethylenehexamine) -N-isopropyl-cholamide,

- (22) 3 P- (pentaethylenehexamine) -N-isopropyl-chénodésoxycho lamide,

- (23) 3 P- (pentaethylenehexamine) -N-isopropyl-ursodésoxycho lamide,

- (24) N-isopropyl-3P-pentaethylenehexamine désoxycho-lamide,

- (25) 3-β- (1, 4-Bis (3-aminopropyl) piperazine) -N-isopropyl-deoxy cho lamide,

- (26) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-cho lamide,

- (27) 3P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-cho chénodésoxy lamide,

- (28) 3 P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-cho ursodésoxy lamide,

- (29) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-lithocho lamide,

- (30) 3 β-spermino-N-isopropyl-désoxycho lamide,

- (31) 3P-spermino-N-isopropyl-cholamide,

- (32) 3P-spermino-N-isopropyl-chénodésoxycholamide,

- (33) 3 β-spermino-N-méthyl désoxycho lamide,

- (34) 3 P-spermino-N, N-diethyl-chénodésoxycholamide,

- (35) 3 β-spermino-N-isopropyl-ursodésoxycho lamide,

- (36) 3P-spermino-N-isopropyl-lithocholamide,

- (37) 3P-norspermidino-N-diisopropyl-chénodésoxycholamide,

- (38) 3P-norspermidino-N-cyclohexyl-chénodésoxycholamide,

- (39) 3 P-norspermino-N, N-diethyl-chénodésoxycholamide,

- (40) 3P-norspermino-N,N- diisopropyl-chénodésoxycholamide,

- (42) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-désoxycho lamide,

- (43) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-cho lamide,

- (44) 3 P- (Tris (3-aminopropyl) amine) -N, N-diethyl-chénodésoxycho lamide,

- (45) 3 P-(Tris(2-amino éthyl)amine)-N-isopropyl-chénodésoxycho lamide,

- (46) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-chénodésoxycho lamide, - (47) 3P-(Tris(3-aminopropyl)amine)-N-cyclohexyl-chénodésoxycholamide,

- (48) 3P-(Tris(3-aminopropyl)amine)-N-isopropyl-ursodésoxycholamide,

- (49) 3 P-(Tris(3 -aminopropyl)amine)-N-isopropyl-lithocho lamide,

- (50) 3P-spermino-N,N-diisopropyl-chénodésoxycholamide,

- (51) 3P-spermino-N-cyclohexyl-chénodésoxycholamide,

- (52) 3 β-spermidino-N-isopropyl-chénodésoxycho lamide,

- (53) 3P- (Bis (3-aminopropyl) ethylenediamine) -N, N-Diethyl-cho chénodésoxy lamide,

- (54) 3P- (Bis (3-aminopropyl) ethylenediamine) -N, N-diisopropyl-cho chénodésoxy lamide,

- (55) Mélange 50/50 de 3P-spermidino-N-isopropyl-chénodésoxycholamide et de 3P-N-[4'N-(3'-aminopropyl)aminobutyl]amino-N-isopropyl-chénodésoxycho lamide,

- (56) 3P-(Tris(3-aminopropyl)amine)-N,N- diisopropyl-chénodésoxy cho lamide,

or a pharmaceutically acceptable salt thereof, more particularly chosen from the compounds (1), (2), (5), (13), (15), (33) and (34).

10. A compound of formula (I) according to any preceding claim, for use as a medicament.

11. A pharmaceutical or veterinary composition comprising a compound of formula (I) as defined in any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

12. Pharmaceutical or veterinary compositions comprising at least one compound of formula (I) as defined in any one of claims 1 to 9 and at least one antibiotic, other than such a compound of formula (I), more preferably betalactam, aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitroimidazole, derivatives nitrofurans, derivatives of benzyl-pyrimidine ring, tetracyclines or phenicol, such as doxycycline or chloramphenicol, penicillin, ampicillin , amoxicillin, cloxacillin, dicloxacillin, oxacillin, nafcillin, cephalexin, cephapirin, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, the thimaphénicol, f florfenicol, Terramycin, erythromycin , spiramycin, tylosin, josamycin, the tilmicosin, tulathromycin, gamithromycin, tildipirosin, the clyndamycine, the lyncomycine, the pirlimycin, tiamulin the , Valnemulin, oxo Unique acid, flumequine, enrofloxacin, danofloxacin, Pibafloxacine, marbofloxacin, difloxacin, the obifloxacine, pradofloxacin, rifampicin, rifaximin, the Sulfamethizol, the sulfathiazole, sulfamethazine, the sulfamethoxazole, sulfadiazine, sulfadiméthoxine the sulphamethoxypyridazine, trimethoprim, baquiloprime, metronidazole, dimetridazole the ronidazole, nitrofurantoin, furazolidone or furaltadone, and more particularly doxycycline, ampicillin, erythromycin or chloramphenicol.

13. A compound according to any one of claims 1 to 9 for use for preventing and / or inhibiting and or treat bacterial, fungal, viral or parasitic infections in humans or animals.

14. Use of a compound according to any one of claims 1 to 9, for potentiating the antibiotic activity of antibiotic compounds may be chosen from the antibiotic compounds as described in claim 12.

15. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 9, comprising a reductive amination step the compound of formula (II)

wherein R15, R16, RI and R2 are as defined in one of claims 1, 2 or 3,

with an amine of formula R'NH 2 wherein R 'is as defined in claim 1 in the presence of a reducing agent may be chosen from titanium tetraisopropoxide, zirconium tetraisopropoxide, NaBH 3 CN, NaBH 4 , or a mixture thereof, preferably the pair of titanium tetraisopropoxide / NaBH 4 , to obtain said compound of formula (I).