ESTERS DERIVATIVES OF SQUALAMINE FOR THE TREATMENT OF INFECTIONS

专利摘要:
The present invention relates to a compound of formula (I) wherein R 'represents a group - (CRaRb) nX- (CRcRd) m- [Y- (CReRf) o] t-NR9R10 and X and Y independently represent a group -NR11-, a -O- group or a divalent heterocyclic group comprising at least one nitrogen atom, 5 or 6 membered, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical or veterinary compositions containing them and their use as a medicament, and more particularly in the treatment of bacterial, fungal, viral or parasitic infections. Finally, it relates to pharmaceutical or veterinary compositions comprising such a compound of formula (I) in combination with an antibiotic different from such a compound of formula (I).
公开号:FR3055801A1
申请号:FR1658649
申请日:2016-09-15
公开日:2018-03-16
发明作者:Jean-Michel Brunel；Marine BLANCHET；Jean-Pascal MARC
申请人:Virbac SA；
IPC主号:

专利说明:

© Publication number: 3,055,801 (use only for reproduction orders)
©) National registration number: 16 58649 ® FRENCH REPUBLIC
NATIONAL INSTITUTE OF INDUSTRIAL PROPERTY
COURBEVOIE
©) Int Cl ⁸ : A 61 K 31/567 (2017.01), A 61 K 31/568, C 07 J 9/00
A1 PATENT APPLICATION
©) Date of filing: 15.09.16. ©) Applicant (s): VIRBAC Société anonyme - FR. (30) Priority: ©) Inventor (s): BRUNEL JEAN-MICHEL, BLANCHET MARINE and MARC JEAN-PASCAL. (43) Date of public availability of the request: 16.03.18 Bulletin 18/11. (56) List of documents cited in the report preliminary research: Refer to end of present booklet @) References to other national documents ©) Holder (s): VIRBAC Société anonyme. related: ©) Extension request (s): @) Agent (s): CABINET NONY.
ESQUER DERIVATIVES OF SQUALAMINE FOR THE TREATMENT OF INFECTIONS.
(g /) The present invention relates to a compound of formula (I)
FR 3 055 801 - A1
rement in the treatment of bacterial, fungal, viral or parasitic infections.
Finally, it relates to pharmaceutical or veterinary compositions comprising such a compound of formula (I) in combination with an antibiotic different from such a compound of formula (I).
in which K 'represents a group - (CR _a R _b ) _n -X (CRcRjjm-IY-iCReRfjJt-NRgR ^ and X and Y independently represent a group -NR11-, a group -O- or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
The present invention also relates to the pharmaceutical or veterinary compositions containing them as well as their use as a medicament, and more particularly
i
The present invention relates to squalamine analogues for their 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, mostly isolated from the tissues of a small shark Squalus acanthias, was found to be a very active substance with mainly antiangiogenic activity against cells and anti viral and antibacterial activity.
NH.
OH
OSO-H
Squalamine
Chemically, squalamine is an original molecule with an amphiphilic nature. It thus comprises a central apolar part (a cholestane-type skeleton) and two polar ends (a polyamine chain and a sulphate group).
Initially, this water-soluble polyaminosterol had aroused interest in its antiangiogenic and antimicrobial properties on a variety of Gram positive (Staphylococcus aureus, Enterococcus faecalis) and Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa), fungi (Candia albicans, Candida tropicalis) and protozoa.
The natural source of squalamine being limited, we looked for synthetic aminosteroid analogues of squalamine. In particular, derivatives or analogues have been described comprising a polyamine chain in position 3 or 7 of rings 10, 13 dimethyl, 17 octane cholestane or cholestene, optionally hydroxylated in position 7 or respectively 3. In particular, derivatives of formula Ha - Ilb - Ile - Ild and II-1 below have been described as having squalamine-like antibacterial activity against a variety of multidrug-resistant Gram-positive and Gram-negative bacteria.

More particularly, an application of these derivatives has been suggested for the curative treatment of pulmonary infections by aerosol route. However, the Applicant has observed that these compounds exhibit significant cytotoxicity and that the compounds of formula Ile and Ild exhibit weak activity against certain gram-negative bacteria such as E. coli.
WO 2011/067501 is known in particular of aminosteroid antibacterial derivatives of the polyamino cholestane or cholestene type for application by local topical route, for rapid cutaneous-mucosal decolonization of Staphylococcus aureus, in particular in the form of ointment or cream.
US Patent 5,856,535 also describes aminosterol esters, some of which have, among other activities, inhibition of angiogenesis, antiproliferative activities or even antibacterial activities.
Squalamine analogues have now been discovered which exhibit good antibacterial activity against gram-positive and gram-negative bacteria, while being advantageously less cytotoxic than squalamine. These compounds have an interesting activity for preventing and / or inhibiting and / or treating bacterial, fungal, viral or parasitic infections in humans or animals.
According to a particular embodiment of the invention, it is intended for domestic mammals such as ruminants, horses, pigs, dogs and cats and for wild animals. According to an even more particular embodiment, it is intended for pets, even more specifically dogs and cats, or even rodents, and is more particularly intended for dogs and cats.
Thus, according to a first aspect, the present invention relates to a compound
in which
R represents a (C | -Cx) alkyl group,
RI and R2 independently represent a hydrogen atom, a group
SO3H or a hydroxy group,
R 'represents a group - (CRaRb) nX- (CR _c Rd) m- [Y- (CR _c Rfjo] t-NR9Rio,
R _a , Rb, Rc, Rd, Re and Rf independently represent a hydrogen atom, a (Ci-C6alkyl) group or a (Ce-Cio) aryl group,
X and Y independently represent a group -NR11-, a group -O- or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members,
R9 and RIO independently represent a hydrogen atom, a group (Ci-Cgjalkyle 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,
RI 1 represents a hydrogen atom, a group (Ci-Cgjalkyle or a group (CH ₂ ) _s -NH ₂ , n, m, o and s independently represent an integer between 1 and
5, t is equal to 0, 1, 2 or 3, with the exception of the compounds for which t is equal to 1 and m + n + o is equal to 10, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
In the context of the present invention:
- The “alkyl” radicals represent saturated hydrocarbon radicals, in a straight or branched chain, from 1 to 8 carbon atoms, in particular from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Mention may in particular be made, when they are linear, of the methyl, ethyl, propyl, butyl, pentyl and hexyl radicals. Mention may especially be made, when branched, of the isopropyl, tert-butyl, 2methylbutyl, 2-methylpentyl and 1-methylpentyl radicals.
- By “aryl” group is meant, within the meaning of the present application, a hydrocarbon, mono or bicyclic aromatic system of 6 to 10 carbon atoms. Among the aryl radicals, mention may in particular be made of the phenyl or naphthyl radical, and even more particularly the phenyl radical.
- By “heterocyclyclic” group is meant, within the meaning of the present application, a mono-, or bicyclic, saturated, unsaturated or aromatic hydrocarbon system comprising one or more heteroatoms such as O, N or S. The heterocyclic groups include in particular the heteroaryl or heterocycloalkyl groups.
- “Heteroaryl” groups denote mono or bicyclic aromatic systems, and having 5 to 7 members (ring atoms), in particular 5 to 6 members, comprising one or more heteroatoms chosen from nitrogen, oxygen or sulfur. Among the heteroaryl radicals, there may be mentioned imidazolyl, pyrazinyl, thienyl, oxazolyl, furazanyl and pyrrolyl.
- The “heterocycloalkyl” radicals denote mono or bicyclic systems, saturated with 5 to 7 members (ring atoms), in particular with 5 to 6 members, comprising one or more heteroatoms chosen from N, O or S. Among the heterocycloalkyls, may especially cite pyrazolidine, piperidine, morpholine and piperazine.
- As used here, the term "pharmaceutically acceptable" refers to compounds, compositions and / or dosage forms which are, within the scope of valid medical judgment, suitable for use in contact with cells humans and lower animals without toxicity, irritation, undue allergic response and the like, and are proportionate to a reasonable benefit / risk ratio.
- 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 the compounds of the present invention. These salts include acid addition salts, that is to say organic or mineral acid salts of a compound comprising a basic function such as an amine, or basic addition salts, it is that is to say alkaline or organic salts of a compound comprising an acid 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, the acid addition salts can be prepared by separately reacting the purified compound with an organic or inorganic acid and by isolating the salt thus formed. Examples of acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate salts. , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphtoates, gentisic acid, isethionates, di-ptoluoyltartrates, methanesulfonates, methanesulfonates cyclohexyl sulfamates and quinateslaurylsulfonate, and the like. (See for example S.M. Berge et al. "Pharmaceutical Salts" J. Pharm. Sci, 66: p. 1-19 (1977)).
- The basic addition salts can also be prepared by reacting the purified compound separately in its acid form with an organic or inorganic base and by isolating the salt thus formed. Examples of basic addition salts include the sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Sodium and potassium salts are preferred. The basic addition salts can in particular be prepared from hydrides or hydroxides of alkali or alkaline-earth metal which comprise 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 the compounds for which RI and R2 independently represent a hydrogen atom or a hydroxy group,
Among the compounds of general formula (I), a second subgroup of compounds consists of the compounds for which R is a (C 1 -C 4) alkyl group, in particular a methyl or isopropyl group.
Among the compounds of general formula (I), a third subgroup of compounds consists of the compounds for which X is a group -NH-.
Among the compounds of general formula (I), a fourth subgroup of compounds consists of the compounds for which 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 R _a , Rb, R _c , Ra, Re and Rf represents a hydrogen atom.
Among the compounds of general formula (I), a sixth subgroup of compounds consists of the compounds for which Y is a group -NR11-, with R11 representing a hydrogen atom, a (Ci-C4) alkyl group or a group - (CH ₂ ) _S -NH ₂ where s is 1, 2 or 3.
Among the compounds of general formula (I), a seventh subgroup of compounds consists of the 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 the compounds for which n is equal to 2, 3, 4 or 5, more preferably to 2 or 3.
Among the compounds of general formula (I), a ninth subgroup of compounds consists of the compounds for which m is different from 4.
Among the compounds of general formula (I), a tenth subgroup of compounds consists of the compounds for which o is equal to 2 or 3.
Among the compounds of general formula (I), an eleventh subgroup of compounds consists of the compounds for which the group -NHR ’is chosen from:
According to a particular embodiment of this eleventh subgroup of compounds, the group -NHR ’is chosen from:
The subgroups defined above, taken individually or in combination, also form part of the invention.
Therefore, 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) which RI and R2 independently represent a hydrogen atom or a hydroxy group,
- second subgroup of compounds of formula (I) for which R is a (Ci-C4) alkyl group, in particular a methyl or isopropyl group,
- third subgroup of compounds of formula (I) for which X is a group -NH-,
- fourth subgroup of compounds of formula (I) for which R9 and RIO represent a hydrogen atom,
fifth subgroup of compounds of formula (I) for which R _a , Rb, Rc, Rd, Re and Rf represent a hydrogen atom,
- sixth subgroup of compounds of formula (I) for which Y is a group -NR11-, with RI 1 representing a hydrogen atom, a (Ci-C4) alkyl group or a group - (CH ₂ ) _S - NH ₂ where s is 1, 2 or 3,
- seventh subgroup of compounds of formula (I) for which m is equal to
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 or 3,
- ninth subgroup of compounds of formula (I) for which m is different from 4,
- tenth subgroup of compounds of formula (I) for which o is equal to 2 or 3,
- eleventh subgroup of compounds of formula (I) for which the NHR ’group is chosen 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 the formula (Γ)
OR ^R5 ^
I I n
R4 R3 in which
R, RI and R2 are as defined above, n and m independently represent the integer 2 or 3,
R3 and R4 independently represent a hydrogen atom, a (C1-C6alkyl) group or a group - (CH ₂ ) _S -NH ₂ , and
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 - (CH ₂ ) _q -NH- (CH ₂ ) _r NH ₂ , p, q, r and s independently represent an integer which can vary between 1 and 5.
ίο as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that R represents a group (C 1 -C 4 alkyl and preferably a methyl or an isoproyl.
According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that n is equal to 2 and m is equal to 3, n is equal to 2 and m is equal to 2 or else n is equal to 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 R3 and R4 independently represent a hydrogen atom, a methyl group or a group - (CH ₂ ) _S -NH ₂ , where s is 2 or 3.
According to yet another 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- (CH ₂ ) _q -NH- (CH ₂ ) _r -NH ₂ , with p is equal to 2 or 3, q is 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 (la)
in which
R, RI and R2 are as defined above, and
R5 represents a hydrogen atom or a group - (CH ₂ ) _P -NH ₂ , with p is equal to 2 or 3, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
According to a preferred embodiment, the present invention relates to the compounds of formula (la) for which R is a methyl group or an isopropyl group.
The present invention also relates to a compound of formula (Ib)
in which
R, RI and R2 are as defined above, u is equal to 0, 1, 2 or 3, preferably to 1, 2 or 3,
R6 and R7 independently represent a hydrogen atom or a (Ci-Cgjalkyle, preferably a hydrogen atom or a (Ci-C ₄₎ alkyl, and stereoisomers, mixtures of stereoisomers and / or pharmaceutically salts acceptable from it.
The present invention also relates to a compound of formula (Ie)
in which
R, RI, R2, n and m are as defined above, and
R8 represents a group (Ci-Cgalkyl, preferably a methyl group, 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, thus as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
According to a preferred embodiment, the present invention relates to the 5 compounds of formula (Ic) for which when R8 represents a group - (CH ₂ ) _S NH ₂ , then n = m = s.
According to a preferred embodiment, the present invention relates to the compounds of formula (Ic) for which when R8 represents a methyl group, then n is equal to m.
According to a preferred embodiment of the present invention, a compound of formula (I) is chosen from:
- (1) isopropyl 33-norspermino-deoxycholate,
- (2) 33-norspermidino-isopropyl deoxycholate,
- (3) methyl 33-norspermino-deoxycholate,
- (4) methyl 33-norspermidino-deoxycholate,
- (5) methyl 33-norspermidino-cholate,
- (6) 33-norspermino-isopropyl cholate,
- (7) 33-norspermidino-isopropyl cholate,
- (8) methyl 33-norspermino-chenodeoxycholate,
- (9) methyl 33-norspermidino-chenodeoxycholate,
- (10) 33-norspermino-chenodeoxycholate isopropyl,
- (11) 33-norspermidino-chenodeoxycholate isopropyl,
- (12) methyl 33-norspermino-ursodeoxycholate,
- (13) methyl 33-norspermidino-ursodeoxycholate,
- (14) 33-norspermidino-ursodeoxycholate, isopropyl,
- (15) 33-norspermino-isopropyl lithocholate,
- (16) 33-norspermidino-isopropyl lithocholate,
- (17) methyl 33-norspermino-lithocholate,
- (18) methyl 33-norspermidino-lithocholate,
- (19) 33- (methyl tetraethylenepentamine) deoxycholate,
- (20) 33- (pentaethylenehexamine) -methyl deoxycholate,
- (21) 33- (pentaethylenehexamine) -isopropylcholate,
- (22) 33- (pentaethylene hexamine) -methyl chenodeoxycholate,
- (23) 33- (pentaethylenehexamine) -isopropyl chenodeoxycholate,
- (24) 33- (pentaethylene hexamine) -isopropyl ursodeoxycholate,
- (25) 33- (pentaethylenehexamine) -lithocholate,
- (26) 33- (pentaethylenehexamine) -isopropyllithocholate,
- (27) 33- (pentaethylenehexamine) -isopropyl deoxycholate,
- (28) 33- (Tris (3-aminopropyl) amine) -isopropyl deoxycholate,
- (29) 33- (Tris (2-aminoethyl) amine) -isopropyl deoxycholate,
- (30) 33- (Bis (3-aminopropyl) methylamine) isopropyl deoxycholate,
- (31) 33- (Bis (3-aminopropyl) methylamine) -methyl deoxycholate,
- (32) 33- (Tris (3-aminopropyl) amine) -methyl deoxycholate,
- (33) 33- (Bis (3-aminopropyl) methylamine) -methyl chlorate,
- (34) 33- (Tris (3-aminopropyl) amine) -isopropylcholate,
- (35) 33- (Tris (2-aminoethyl) amine) -isopropylcholate,
- (36) 33- (Bis (3-aminopropyl) methylamine) -isopropylcholate,
- (37) 33- (Bis (3-aminopropyl) methylamine) -methyl chenodeoxycholate,
- (38) 33- (Tris (3-aminopropyl) amine) -methyl chenodeoxycholate,
- (39) 33- (Tris (3-aminopropyl) amine) -isopropyl chenodeoxycholate,
- (40) 33- (Tris (2-aminoethyl) amine) -isopropyl chenodeoxycholate,
- (41) 33- (Bis (3-aminopropyl) methylamine) -isopropyl chenodeoxycholate,
- (42) 33- (Tris (3-aminopropyl) amine) -isopropyl ursodeoxycholate,
- (43) 33- (Tris (2-aminoethyl) amine) -isopropyl ursodeoxycholate,
- (44) 33- (Bis (3-aminopropyl) methylamine) -isopropyl ursodeoxycholate,
- (45) 33- (Bis (3-aminopropyl) methylamine) -methyllithocholate,
- (46) 33- (Methyl tris (3-aminopropyl) amine) -lithocholate,
- (47) 33- (Tris (3-aminopropyl) amine) -isopropyllithocholate,
- (48) 33- (Tris (2-aminoethyl) amine) -isopropyllithocholate,
- (49) 33- (Bis (3-aminopropyl) methylamine) isopropyl lithocholate, 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 pharmaceutically acceptable acid addition salts include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, maleate, mesylate , formate, acetate and fumarate, and more particularly the hydrochloride.
The compounds of formula (I), (Γ), (la), (Ib) and (le), as well as compounds (1) to (49) can be in the form of solvates such as hydrates. The invention includes these solvates.
A compound of formula (I), (Γ), (la), (Ib) or (le) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, are included within the scope of the present invention. In general, in the context of the present invention, when a bond is represented by the symbol ~ ^vVVV , this means that the group carried by the carbon considered may be behind or in front of the plane of representation of the molecule . Thus, the resulting stereochemistry of carbon carrying this group can be S or R.
According to another aspect, the present invention relates to a compound of formula (I), (Γ), (la), (Ib) or (le) or also a compound (1) to (49) or one of its salts pharmaceutically acceptable, for use as a medicament.
According to another aspect, the present invention relates to a compound of formula (I), (Γ), (la), (Ib) or (le) for its use for preventing and / or inhibiting and / or treating bacterial, fungal infections , viral or parasitic in humans or animals.
According to the present invention, the term "prevent" or "prevention" means that in order to reduce the risk of the appearance or to slow down the appearance of a given phenomenon, namely a bacterial, fungal, viral or parasitic infection.
The compounds of the present invention can be prepared by conventional methods of organic synthesis carried out by a person skilled in the art. The general reaction scheme described below represents a general method useful for preparing the compounds of the present invention and is not intended to limit its scope or usefulness.
Thus, the compounds of the invention can be prepared by application or adaptation of any method known per se from and / or within the reach of those skilled in the art, in particular those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989 , or by application or adaptation of the methods described in the examples which follow.
According to a particular embodiment, the compounds of the invention can be prepared according to the synthetic scheme 1 below.
Diagram 1
(i) (II)
According to this scheme 1, a compound of formula (IV), in which RI and R2 are as defined above, is reacted, in a solvent, for example dichloromethane in the presence of an acid such as paratoluenesulfonic acid with a compound of formula ROH, in which R is as defined above, for example at a temperature between 20 ° C and 100 ° C, to obtain a compound of formula (III).
Still according to this scheme 1, the compound of formula (III) thus obtained is subjected to oxidation in the presence of a ligand, for example aluminum tri-fe / 7-butylate, aluminum tri-isopropylate or Ag ₂ CO3, 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).
Still according to this scheme 1, the compound of formula (II) thus obtained is subjected to a reductive amination by reaction with a compound of formula R'NH ₂ , in which R 'is as defined above, in the presence of a reducing agent such as titanium tetraisopropylate, zirconium tetraisopropylate, NaBH ₃ CN, NaBH ₄ , or a mixture of them, preferably the couple titanium tetraisopropylate / NaBH ₄ , for example at a temperature between −120 ° C. and 10 ° C, preferably -80 ° C and 10 ° C.
Optionally, said process can also include the step of isolating the product obtained.
The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or if necessary after distillation of the solvent from the solution mixture, by pouring the remainder into water followed by extraction with an organic solvent immiscible in l 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 various chromatography techniques, including column chromatography or preparative thin layer chromatography.
The starting compound of formula (IV) is available or can be prepared according to methods known to a person skilled in the art and / or can be prepared by applying the methods as described in the Examples or their obvious chemical equivalents .
According to a preferred variant, the compounds of formula (I) are synthesized from the compounds of formula (IV), as defined above or following bile acids:
deoxycholic acid
cholic acid
chenodeoxycholic acid
ursodeoxycholic acid
lithocholic acid
Thus, according to another object, the present invention also relates to the process for the preparation of the compounds of formula (I) previously described, comprising a step of reductive amination of the compound of formula (II)
(Π) in which R, RI and R2 are as defined above, with an amine of formula R'NH ₂ , in which R 'is as defined above, in the presence of a reducing agent such as titanium tetraisopropylate, zirconium tetraisopropylate, NaBH ₃ CN, NaBH ₄ , or a mixture of these, preferably the titanium tetraisopropylate / NaBH ₄ pair, to obtain said compound of formula (I).
The chemical structures and the spectroscopic data of some compounds of formula (I) of the invention are illustrated respectively in table I and table II below.

31 NH,yH O 32 NH, NH,7<^ Ν * ΤλH O OH 'A ---- ^ OMe OH 7> Me 33 NH, OH ^Z < O 34 nh ₂ nh, OH A.— ΛΛ VS 'OMe 7 7 ---not'H H A) H H 7v _oh35 ⁰ 1 oh .JL JL -. f— 36 nh ₉ Oh 'ta- _s Yes vs NH,J 7 <4h ₂ n ~ ⁿ · ' ^Ζ ΟΗ 7 _n * 7 7'oh H H 37 nh ₂ O 38 NH, NH ₂ ·>. 0_ JL 7 here V _r sixCb ^^ OMe --- N ¹ 7 'OH kx-AH 77 H 39 AT 7⁰ 1 7 _o 7 40 ^ H AÇÎ5 ⁰ 1 - ~ “· <Α H - 7 a.m. z .N.x AH --- I '' oh 41 nh ₂'' y- ° 1 42 NH ₂ nh, 7 <4 S—- ⁰ 1 aA 7 7 7 75 7-7 ^, 77 ' ^χ4 * ΟΗ H H 43 nh ₂ here 44) / 7 τ7 ⁰ 1 ~ aA r plA L A <4 ζΤγχΤ ^ / h ₂ n ^ - ^{, N} ' k.— Sh <- _n 77 —7> h H H
Table II
The chemical structures synthesized were all verified by NMR analysis of the proton ( ¹ H) and / or carbon ( ¹³ C) in deuterated chloroform CDCI3 or deuterated methanol CD ₃ OD on a Bruker AC 300 type device. δ chemicals are expressed in ppm. The recording frequencies of the nuclei as well as of the references used are the following:
³ H NMR: 300 MHz, Si (CH3) 4 ¹³ C NMR: 75 MHz, Si (CH3) ₄
The abbreviations used to write the 'H spectrum are as follows:
- s = singlet
- d = doublet -1 = triplet
- q = quadruplet
- m = massive
Ex Characterization 1 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 5.01 (m, 1H), 4.00 (m, 1H), 2.84-0.76 (m, 66H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.76, 74.10, 69.00, 59.10, 48.95, 48.42, 47.86, 45.85, 44.04, 40.75, 37.63, 36.95, 36.79, 36.74, 35.83, 35.10, 32.88, 32.49 , 32.29, 30.04, 29.70, 29.27, 28.72, 28.51, 27.56, 24.96, 23.90, 22.22, 17.79, 13.35. 2 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.95 (m, 1H), 2.81-2.67 (m, 9H), 2.39-0.71 (m, 50H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.77, 74.10, 69.01, 59.04, 47.86, 45.83, 45.79, 45.72, 43.96, 40.70, 37.60, 36.84, 36.79, 36.74, 35.79, 35.09, 32.88, 32.48 , 30.03, 28.72, 28.48, 28.45, 27.53, 24.95, 23.84, 22.21, 17.78, 13.33. 3 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.94 (m, 1H), 3.65 (s, 3H), 2.75-2.63 (m, 9H), 2.27-0.71 (m, 51H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.62, 74.08, 59.15, 52.16, 49.36, 48.30, 48.24, 47.75, 43.93, 37.55, 36.87, 35.80, 34.98, 32.38, 32.01, 29.97, 28.80 , 28.49, 27.57, 24.99, 23.93, 22.23, 17.70, 13.31. 4 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.94 (m, 1H), 3.65 (s, 3H), 2.81-2.21 (m, 11H), 1.9-0.71 (m, 42H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.59, 74.11, 59.04, 52.16, 49.35, 48.92, 48.31, 47.74, 45.74, 43.99, 40.61, 37.55, 36.86, 35.84, 34.95, 32.64, 32.36 , 32.00, 29.97, 28.79, 28.56, 27.59, 25.01, 23.98, 13.71, 13.31. 5 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.94 (m, 1H), 3.88 (m, 1H), 3.82 (m, 1H), 3.13-0.72 (m, 54H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 173.10, 73.30, 68.41, 62.84, 51.90, 54.04, 47.42, 47.36, 43.37, 41.22, 41.12, 36.59, 36.31, 36.02, 35.80, 32.90, 32.50 , 28.74, 28.23, 28.12, 26.01, 24.28, 19.10, 13.52, 12.64. 6 'H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.98 (m, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 3.13-2.81 (m, 13H), 2.59-0.72 (m, 52H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.80, 73.96, 69.03, 68.96, 59.44, 54.04, 48.38, 47.75, 47.73, 43.37, 41.25, 41.22, 36.79, 36.21, 35.85, 35.80, 32.90 , 32.51, 39.78, 28.75, 28.23, 28.19, 26.16, 24.28, 23.16, 22.20, 17.83, 13.13. 7 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.95 (m, 1H), 3.91 (m, 3H), 3.75 (m, 1H), 2.92-0.65 (m, 56H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.82, 73.99,
69.05, 48.30, 48.24, 48.19, 47.70, 43.30, 43.25, 43.21, 43.16, 41.16, 36.71, 36.17,32.85, 32.45, 32.14, 29.70, 28.68, 28.12, 24.25, 23.18, 22.20, 17.82, 13.13. 8 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.78-0.70 (m, 60H). ¹³ C NMR (63 MHz CD ₃ OD): δ (ppm) = 176.53, 69.12, 59.55, 57.58, 52.07, 51.74, 49.60, 48.95, 43.91, 41.26, 41.09, 41.02, 40.85, 36.83, 34.34, 34.29, 33.31, 32.45, 32.14, 30.33, 29.34, 29.30, 24.75, 23.69, 22.22, 21.98, 18.99, 12.39. 9 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.84 (m, 1H), 3.68 (s, 3H), 2.99-0.73 (m, 53H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.58, 69.02, 59.42, 57.65, 52.07, 51.82, 45.70, 45.69, 43.44, 43.90, 43.41, 41.26, 41.24, 41.04, 36.82, 36.60, 35.89 , 35.84, 34.43, 34.37, 32.44, 32.14, 29.26, 24.70, 21.93, 18.96, 12.34. 10 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.79 (m, 1H), 2.70-2.59 (m, 13H), 2.33-0.69 (m, 53H). ¹³ C NMR (63 MHz CD3OD): δ (ppm) = 175.62, 69.16, 68.98, 59.58, 57.61, 51.74, 48.54, 45.93, 43.92, 41.27, 41.13, 40.94, 38.24, 37.43, 36.88, 36.77, 36.24, 34.32, 33.91, 32.85, 32.53, 30.82, 30.56, 29.32, 28.91, 24.77, 23.78, 22.25, 21.98, 19.03, 12.43. 11 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.79 (m, 1H), 2.72-2.60 (m, 9H), 2.42-0.70 (m, 50H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.67, 69.16, 69.00, 59.53, 57.65, 51.74, 45.93, 45.86, 43.93, 43.85, 41.27, 41.11, 40.89, 37.32, 36.84, 36.78, 36.17 , 34.34, 33.63, 32.84, 32.53, 30.38, 29.31, 28.67, 24.76, 23.72, 22.23, 21.97, 19.00, 12.40. 12 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.64 (s, 3H), 3.46 (m, 1H), 2.72-2.48 (m, 13H), 2.23-0.7 (m, 47H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.53, 72.06, 58.91, 57.62, 56.69, 52.16, 48.95, 44.93, 44.68, 44.51, 41.70, 40.80, 40.72, 38.87, 36.82, 35.78, 35.35 , 35.30, 33.18, 32.43, 33.65, 33.63, 32.02, 30.36, 30.19, 29.79, 28.18, 28.08, 24.28, 22.54, 19.07, 12.80. 13 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.68 (s, 3H), 3.51 (m, 1H), 2.83-2.67 (m, 7H), 2.43-0.75 (m, 46H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 176.51, 72.05, 58.94, 57.68, 56.82, 52.07, 48.89, 48.30, 45.00, 44.85, 44.51, 41.75, 41.69, 40.87, 38.74, 36.73, 35.75, 32.47 , 32.17, 29.79, 29.65, 28.03, 24.16, 22.57, 19.12, 12.82. 14 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.39 (m, 1H), 2.79-2.66 (m, 9H), 2.41-0.71 (m, 50H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.72,
72.04, 69.03, 57.84, 57.71, 57.60, 56.71, 53.81, 48.29, 45.67, 44.93, 44.82, 44.67,40.51, 36.76, 36.73, 35.72, 32.72, 32.49, 31.92, 30.92, 30.63, 29.79, 28.70, 28.06,22.22, 19.03, 12.77. 15 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.98 (m, 1H), 2.76-2.63 (m, 13H), 2.320.69 (m, 54H). ¹³ C NMR (63 MHz CD ₃ OD): δ (ppm) = 175.58, 68.98, 59.04, 58.01, 57.62, 52.18, 48.88, 48.37, 44.06, 43.90, 41.94, 41.65, 40.63, 37.36, 37.03, 36.84, 36.79, 36.35, 36.25, 32.68, 32.63, 32.43, 32.36, 31.98, 29.92, 29.42, 28.54, 27.80, 25.43, 24.29, 22.67, 22.27, 22.11, 18.94, 12.69. 16 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 2.99-2.64 (m, 8H), 2.430.69 (m, 52H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.58, 68.98, 59.08, 58.03, 57.63, 52.16, 48.96, 47.96, 44.07, 43.94, 41.96, 41.67, 40.71, 38.20, 37.38, 37.22, 37.03 , 36.78, 36.28, 34.37, 32.69, 32.45, 29.41, 28.57, 28.53, 25.44, 24.32, 22.27, 22.13, 18.96, 12.72. 17 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.65 (s, 3H), 2.78-2.62 (m, 12H), 2.370.69 (m, 49H). ¹³ C NMR (63 MHz CD ₃ OD): δ (ppm) = 176.86, 59.05, 58.05, 57.67, 54.32, 52.17, 48.97, 44.09, 41.97, 41.68, 40.72, 38.19, 37.39, 36.85, 36.30, 34.41, 33.57, 33.24, 32.37, 31.99, 31.49, 30.38, 29.41, 28.62, 28.27, 27.86, 25.48, 24.36, 22.34, 22.13, 19.09, 12.77. 18 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.65 (s, 3H), 2.71-2.56 (m, 7H), 2.230.93 (m, 44H), 0.69 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.45, 59.07, 58.02, 57.58, 52.17, 49.04, 45.93, 44.06, 41.97, 41.67, 40.79, 38.23, 37.40, 37.24, 37.19, 36.84, 36.31 , 34.59, 33.56, 32.37, 32.01, 30.54, 29.41, 28.62, 28.43, 27.84, 25.45, 24.36, 22.13, 18.95. 19 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.94 (m, 1H), 3.65 (s, 3H), 2.91-0.71 (m, 59H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.56, 74.05, 59.12, 54.25, 54.15, 52.18, 49.68, 49.33, 48.18, 47.74, 46.51, 43.95, 41.59, 37.55, 36.97, 36.85, 35.84 , 34.96, 32.36, 32.01, 29.99, 28.79, 28.56, 27.61, 25.02, 24.01, 22.26, 17.71, 13.35. 20 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.95 (m, 1H), 3.65 (s, 3H), 2.84-2.54 (m, 24H), 2.38-0.71 (m, 40H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.61, 74.06, 59.08, 54.26, 54.15, 52.16, 49.34, 48.19, 47.74, 46.28, 43.95, 41.46, 37.55,
36.85, 35.82, 34.97, 32.36, 32.01, 29.97, 28.78, 28.51, 27.63, 27.59, 25.01, 23.96,22.23, 17.70, 13.31. 21 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.94 (m, 1H), 3.80 (m, 1H), 3.01-2.54 (m, 22H), 2.40-0.71 (m , 48H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.69, 74.05, 69.10, 68.95, 59.50, 58.61, 55.36, 55.19, 54.26, 54.23, 48.16, 47.66, 46.21, 43.74, 43.09, 41.21, 39.09, 37.87 , 37.84, 37.18, 36.84, 36.48, 36.06, 32.72, 32.46, 29.71, 28.84, 28.40, 28.36, 28.02, 24.37, 23.54, 22.27, 17.76, 13.18. 22 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.84-0.95 (m, 61H), 0.70 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.54, 69.14, 59.66, 57.60, 57.53, 54.56, 54.34, 52.07, 51.74, 49.91, 46.40, 43.90, 41.27, 41.10, 37.33, 36.84, 36.21 , 34.34, 32.45, 32.14, 29.29, 24.76, 23.72, 21.97, 18.99, 12.38. 23 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.79 (m, 1H), 2.84-2.14 (m, 24H), 2.02-0.69 (m, 46H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.60, 69.06, 68.96, 59.59, 58.62, 57.50, 55.39, 55.20, 54.29, 51.68, 43.84, 43.76, 41.21, 40.98, 38.02, 37.28, 36.84 , 36.12, 34.21, 32.69, 32.47, 29.42, 28.70, 24.77, 23.80, 22.27, 21.94, 18.98, 12.40. 24 'H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.47 (m, 1H), 3.00-2.45 (m, 23H), 2.39-0.94 (m, 44H), 0.71 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.55, 72.01, 68.95, 61.54, 58.88, 58.63, 57.63, 56.73, 55.22, 54.27, 47.10, 46.92, 46.38, 46.23, 44.94, 44.66, 44.50 , 42.20, 41.95, 41.71, 40.81, 39.13, 38.90, 37.76, 35.79, 35.57, 32.71, 32.50, 29.83, 28.40, 28.09, 24.34, 22.54, 22.28, 19.10, 12.85. 25 MB223 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.65 (m, 1H), 2.84-2.47 (m, 22H), 2.31-0.69 (s, 43H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.42, 59.03, 58.05, 57.57, 55.35, 55.18, 54.30, 54.07, 52.17, 44.06, 43.93, 41.93, 41.67, 39.05, 37.37, 37.11, 36.84 , 36.29, 32.36, 31.98, 29.41, 28.59, 27.83, 25.44, 24.33, 22.33, 22.11, 18.93, 12.69. 26 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 2.77-2.45 (m, 24H), 2.300.93 (m, 44H), 0.69 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.59, 68.98, 59.10, 58.64, 58.07, 57.64, 55.38, 55.22, 54.50, 54.09, 46.38, 46.23, 44.07,
43.95, 42.00, 41.95, 41.67, 39.11, 37.39, 37.24, 37.13, 36.78, 36.30, 34.68, 32.69,32.44, 29.41, 28.59, 27.83, 25.42, 24.32, 22.26, 22.11, 18.92, 12.69. 27 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.94 (m, 1H), 2.84-2.47 (m, 22H), 2.33-0.71 (m, 48H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.74, 74.12, 68.98, 59.13, 58.59, 55.32, 55.14, 54.50, 54.29, 54.05, 49.63, 49.34, 48.29, 47.77, 44.04, 37.58, 37.03, 36.81 , 35.88, 34.97, 32.79, 32.74, 32.45, 29.99, 28.82, 28.59, 28.22, 27.62, 25.01, 24.86, 24.03, 22.24, 17.68, 13.34. 28 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.95 (m, 1H), 2.77-2.21 (m, 15H), 1.94-0.71 (m, 51H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.74, 74.08, 68.99, 59.14, 53.30, 52.86, 52.77, 49.38, 48.28, 47.75, 45.94, 43.90, 40.85, 37.53, 36.81, 35.80, 34.97, 32.73 , 32.44, 29.98, 29.55, 29.46, 28.81, 28.48, 27.58, 26.89, 24.99, 24.48, 23.94, 22.24, 17.68, 13.33. 29 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.95 (m, 1H), 2.85-2.51 (m, 13H), 2.37-0.71 (m, 47H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.77, 74.12, 69.00, 59.17, 57.74, 54.93, 48.28, 47.76, 45.19, 44.03, 40.22, 37.58, 37.51, 37.04, 36.82, 35.87, 34.99 , 34.46, 32.73, 32.45, 29.98, 28.82, 27.64, 25.01, 24.01, 22.24, 17.68, 13.33. 30 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.94 (m, 1H), 2.90-2.29 (m, 13H), 2.24-0.71 (m, 48H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.74, 74.17, 68.98, 59.10, 57.12, 56.62, 49.34, 48.28, 47.77, 46.12, 44.06, 42.47, 42.42, 41.10, 37.58, 37.10, 36.81 , 35.91, 34.96, 34.53, 32.72, 32.45, 30.84, 29.98, 28.82, 28.62, 28.24, 27.78, 27.63, 25.02, 24.26, 22.24, 17.68, 13.34. 31 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.93 (m, 1H), 3.65 (s, 3H), 2.74-2.32 (m, 12H), 2.24-0.71 (m, 43H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.53, 74.13, 59.12, 57.28, 56.74, 52.03, 49.40, 48.35, 47.86, 46.22, 44.19, 42.50, 41.23, 37.67, 37.43, 37.22, 36.76 , 35.94, 35.11, 32.42, 32.18, 31.12, 30.06, 28.67, 28.13, 27.61, 24.99, 24.03, 17.83, 13.38. 32 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.95 (m, 1H), 3.65 (s, 3H), 2.89-2.54 (m, 13H), 2.38-0.71 (m, 47H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.59, 74.05, 59.16, 53.54, 53.41, 53.05, 52.92, 52.07, 49.40, 48.35, 47.84, 45.74, 43.91, 43.87, 40.83, 40.76, 37.58 , 37.39, 36.79, 35.75, 35.04, 32.40, 32.15, 30.02, 28.69, 28.40,
27.53, 24.96, 23.82, 22.22, 17.79, 13.34. 33 ³ H NMR (250 MHz, CD3OD): δ (ppm) = 4.92 (m, 1H), 3.84 (m, 1H), 3.82 (m, 1H), 3.13-0.78 (m, 56H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 173.14, 73.28, 68.37, 62.91, 51.90, 54.04, 47.42, 47.36, 47.21, 43.37, 41.22, 41.12, 36.59, 36.29, 36.02, 35.48, 32.65, 31.50 , 28.34, 28.13, 28.01, 26.11, 24.48, 19.0, 13.42, 12.64. 34 ³ N NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.95 (m, 1H), 3.80 (m, 1H), 2.71-2.50 (m, 13H), 2.38-0.71 (m , 52H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.69, 74.02, 69.08, 68.95, 59.42, 53.72, 52.86, 48.17, 47.65, 46.12, 43.71, 43.11, 41.20, 41.12, 37.54, 37.14, 36.84, 36.45 , 36.05, 32.72, 32.46, 30.57, 29.71, 28.84, 28.17, 28.03, 27.30, 24.36, 23.52, 22.27, 17.76, 13.17. 35 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.95 (m, 1H), 3.80 (m, 1H), 2.86-2.53 (m, 13H), 2.46-0.94 (m, 43H), 0.71 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.71, 74.02, 69.11, 68.95, 59.45, 57.91, 55.17, 54.98, 51.72, 47.67, 46.35, 44.95, 43.72, 43.11, 41.24, 40.28, 37.75 , 37.17, 36.68, 36.46, 36.00, 32.72, 32.46, 29.71, 28.85, 28.05, 24.36, 23.52, 22.25, 17.74, 13.16. 36 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.96 (m, 1H), 3.80 (m, 1H), 2.81-2.41 (m, 12H), 2.34-0.71 (m, 48H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.77, 74.00, 69.00, 59.37, 57.27, 56.59, 52.31, 47.65, 43.57, 43.22, 43.13, 42.36, 41.03, 40.97, 40.91, 36.86, 36.37 , 35.92, 32.72, 32.46, 30.24, 28.86, 28.06, 24.32, 23.41, 22.24, 17.72, 13.14. 37 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.79 (m, 1H), 3.64 (s, 3H), 2.76-0.68 (m, 55H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.53, 89.36, 69.08, 57.59, 57.33, 56.99, 56.74, 52.06, 51.75, 51.71, 43.90, 43.66, 42.38, 41.22, 41.10, 37.03, 36.82 , 36.06, 34.33, 34.28, 32.43, 32.14, 30.39, 29.23, 24.72, 23.60, 22.00, 21.95, 18.99, 12.39. 38 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.80 (m, 1H), 3.65 (s, 3H), 2.80-0.94 (m, 57H), 0.70 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.82, 69.08, 59.57, 57.48, 54.24, 53.87, 53.56, 52.91, 52.85, 51.71, 45.69, 43.83, 41.15, 38.93, 37.61, 37.10, 36.82 , 34.22, 33.62, 32.39, 31.97, 30.58, 29.52, 27.81, 27.10, 24.82, 23.73, 21.94, 19.20, 18.94, 12.35. 39 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.80 (m, 1H), 2.73-2.51
(m, 13H), 2.32-0.69 (m, 53H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.63, 69.06, 68.98, 59.51, 57.52, 53.52, 52.87, 51.71, 46.03, 43.84, 43.63, 41.21, 41.02, 40.97, 37.27, 37.10, 36.84 , 36.77, 36.03, 34.22, 32.69, 32.47, 30.17, 29.41, 28.08, 27.10, 24.76, 23.72, 22.26, 21.93, 18.96, 12.38. 40 ³ N NMR (250 MHz, CD3OD): δ (ppm) = 4.96 (m, 1H), 3.80 (m, 1H), 2.84-2.54 (m, 13H), 2.46-0.69 (m, 47H). ¹³ C NMR (63 MHz, CD3OD): δ (ppm) = 175.61, 69.08, 68.98, 59.48, 57.76, 57.50, 54.86, 51.68, 44.98, 43.82, 43.66, 41.19, 40.97, 40.21, 37.66, 37.20, 36.82, 36.79 , 36.04, 34.21, 32.69, 32.45, 29.41, 24.76, 23.76, 22.27, 21.92, 18.97, 12.41. 41 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.79 (m, 1H), 2.74-2.29 (m, 12H), 2.24-0.95 (m, 46H), 0.69 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.56, 69.08, 68.95, 59.53, 57.48, 57.17, 56.58, 51.66, 46.11, 43.63, 42.46, 41.21, 41.12, 40.97, 37.87, 37.30, 36.83 , 36.11, 34.18, 32.68, 32.46, 30.99, 29.42, 28.56, 27.78, 24.78, 23.81, 22.27, 21.94, 18.98, 12.41. 42 'H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.38 (m, 1H), 2.89-2.47 (m, 13H), 2.35-0.87 (m, 50H), 0.71 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.64, 72.07, 68.99, 59.02, 57.73, 57.63, 56.74, 56.72, 53.51, 52.96, 44.94, 44.84, 44.68, 41.23, 36.82, 36.76, 35.80 , 32.72, 32.49, 30.90, 30.82, 29.79, 28.08, 25.44, 24.31, 22.25, 19.08, 12.82. 43 'H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.45 (m, 1H), 2.82-2.50 (m, 13H), 2.32-0.94 (m, 44H), 0.71 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.63, 72.05, 68.98, 59.04, 58.08, 57.66, 56.74, 55.19, 45.37, 44.94, 44.68, 44.50, 41.72, 40.83, 40.40, 40.30, 38.87 , 36.76, 35.79, 35.56, 32.72, 32.50, 29.81, 28.39, 28.08, 24.30, 22.54, 22.25, 19.07, 12.82. 44 RMN 'H (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 3.46 (m, 1H), 2.91-2.20 (m, 14H), 2.07-0.88 (m, 44H), 0.72 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.71, 71.88, 69.03, 58.96, 57.56, 56.74, 56.61, 53.38, 44.93, 44.63, 44.16, 42.08, 41.63, 40.74, 40.38, 38.50, 36.75 , 35.57, 32.72, 32.48, 29.78, 28.94, 28.05, 27.17, 26.39, 26.00, 23.99, 22.51, 22.22, 19.02, 12.76. 45 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.65 (m, 3H), 2.70-2.18 (m, 15H), 2.030.70 (m, 41H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.31, 59.10, 58.00,
57.55, 57.09, 56.59, 52.18, 44.05, 43.93, 42.62, 42.48, 41.94, 41.64, 41.08, 37.37,37.21, 36.84, 36.30, 32.36, 31.98, 30.79, 29.43, 28.62, 28.35, 27.84, 25.47, 24.39,22.13, 19.01, 12.75. 46 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 3.65 (m, 3H), 2.70-2.47 (m, 13H), 2.230.69 (s, 48H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 176.51, 59.18, 58.09, 57.71, 52.96, 52.16, 44.08, 42.00, 41.69, 41.16, 38.90, 37.39, 37.05, 36.84, 36.31, 34.40, 33.59 , 32.39, 32.00, 30.61, 29.44, 27.90, 25.47, 24.47, 22.16, 19.15, 12.77. 47 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 2.89-2.47 (m, 13H), 2.380.93 (m, 51H), 0.69 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.44, 68.91, 59.16, 58.02, 57.60, 54.37, 53.50, 52.93, 46.41, 44.07, 43.92, 41.97, 41.65, 41.15, 37.38, 37.22, 36.77 , 36.36, 36.30, 34.51, 32.69, 30.60, 29.43, 28.62, 28.37, 27.84, 27.65, 25.45, 24.55, 24.40, 22.32, 22.14, 18.98, 12.78. 48 1 H NMR (250 MHz, CD ₃ OD): δ (ppm) = 4.96 (m, 1H), 2.83-2.56 (m, 12H), 2.380.90 (m, 46H), 0.69 (s, 3H). ¹³ C NMR (63 MHz, CD ₃ OD): δ (ppm) = 175.55, 68.95, 59.12, 58.05, 57.63, 57.25, 54.67, 45.17, 44.07, 43.88, 42.11, 41.99, 41.66, 40.07, 37.36, 37.20, 37.03 , 36.76, 36.36, 36.25, 34.20, 32.69, 32.43, 29.41, 27.82, 25.42, 24.28, 22.28, 22.11, 18.93, 12.71. 49 1 H NMR (250 MHz, X): δ (ppm) = 4.96 (m, 1H), 2.73-2.12 (m, 14H), 2.03-0.93 (m, 45H), 0.69 (s, 3H). ¹³ C NMR (63 MHz, X): δ (ppm) = 175.56, 68.98, 59.10, 58.02, 57.62, 57.03, 56.57, 46.17, 44.07, 43.91, 42.42, 41.97, 41.65, 41.00, 37.37, 37.09, 36.77, 36.27 , 34.30, 32.69, 32.43, 30.34, 29.42, 28.57, 28.17, 27.81, 27.61, 25.44, 24.33, 22.29, 22.13, 18.96, 12.73.
Among said compounds of formula (I), compounds (1), (10), (11), (18) and (20) or one of their pharmaceutically acceptable salts, in particular their hydrochlorides, are particularly advantageous.
The following examples illustrate in detail the preparation of the compounds according to the invention. The structures of the products obtained were confirmed at least by the NMR spectra.
EXAMPLES
All the syntheses were carried out with solvents purified according to the usual methods. Commercial reagents are used directly without prior purification.
"Yield" means yield.
Example 1: preparation of the compounds of formula (III) as defined above
Example 1.1 Methyl deoxycholate 1
In a 250 mL flask fitted with a magnetic bar, 8 g of deoxycholic acid (20.4 mmol) and 1.5 g of paratoluenesulfonic acid (9 mmol) are dissolved in 40 mL of methanol and 30 mL of dichloromethane. The reaction mixture is brought to reflux of dichloromethane. After 8 hours of stirring, the solvent is evaporated off and the residue is taken up in 100 ml of dichloromethane and washed with 3 × 50 ml of an aqueous solution of sodium hydrogen carbonate (10%). The aqueous phase is extracted with 2x50 mL of dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, filtered and then the solvent is evaporated in vacuo in order to obtain the desired product 1 in the form of a white solid. ¹ H NMR (250 MHz, CDCfi): δ (ppm) = 3.97 (m, 1H), 3.663.57 (m, 4H), 2.43-0.67 (m, 37H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 174.73, 73.11, 71.73, 51.49, 48.20, 47.24, 46.45, 42.02, 36.36, 35.98, 35.17, 35.10, 34.07, 33.59, 31.06, 30.85, 30.40, 28.59, 27.43, 27.08, 26.08, 23.61, 23.10, 17.25, 12.69. YId: 98%. C25H42O4.
EXAMPLE 1.2 Methyl Cholate 2 o
Purified product by column chromatography (eluent: petroleum ether / ethyl acetate: 1/1) 1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 3.88 (m, 1H), 3.66-3.53 (m, 4H), 2.45-0.68 (m, 37H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 174.87, 73.36, 72.87, 68.72, 51.53, 50.48, 46.96, 46.33.41.61, 41.29, 39.35, 38.38, 35.34, 35.12, 34.64, 34.13, 33.17,
30.94, 29.31, 27.97, 26.36, 23.13, 22.40, 17.24, 12.44. YId: 78%. C25H42O5
EXAMPLE 1.3 Methyl Chenodeoxycholate 3
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 3.76 (m, 1H), 3.59 (s, 3H), 3.36 (m, 1H), 2.280.59 (m, 37). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 174.53, 71.56, 68.04, 55.67, 51.29,
50.22, 42.39, 41.40, 39.53, 39.19, 35.25, 35.13, 34.84, 34.58, 32.67, 30.78, 30.74, 30.44,
27.98, 23.41, 22.65, 20.44, 18.10, 11.55. Yid: 90%. C25H42O4
EXAMPLES 1.4 Methyl ursodeoxycholate 4
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 3.63 (s, 3H), 3.54 (m, 2H), 2.37-0.64 (m, 37H).
¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 174.67, 71.13, 71.10, 55.71, 54.83, 51.44, 43.63,
43.55, 42.35, 40.05, 39.15, 37.21, 36.87, 35.19, 34.84, 33.95, 30.97, 30.90, 30.16, 28.52,
26.80, 23.32, 21.08, 18.27, 12.03. YId: 89%. C25H42O4
Example 1.5 Methyl lithocholate 5
³ H NMR (250 MHz, CDC13): δ (ppm) = 3.64-3.59 (m, 4H), 2.39-0.61 (m, 38H). ¹³ C NMR (63 MHz, CDC13): δ (ppm) = 174.51, 71.73, 56.56, 56.11, 51.23, 42.78, 42.22, 40.57, 40.24, 36.58, 35.93, 35.44, 35.31, 34.59, 31.09, 31.05, 30.62. 28.08, 27.23, 26.43, 24.17, 23.31, 20.86, 18.25, 12.01. YId: 91%. C25H ₄₂ O ₃
Compounds 6-10 were all prepared according to the same procedure, considering the appropriate starting bile acid.
Example 1.6 Isopropyl deoxycholate 6
10 g of deoxycholic acid (25.5 mmol) and 2.2 g of paratoluenesulfonic acid (13 mmol) which are dissolved in 70 ml of isopropanol and 30 ml of dichloromethane are introduced into a 250 ml flask fitted with a magnetic bar . The reaction mixture is brought to reflux of dichloromethane and left under magnetic stirring for 8 h. After evaporation of the solvent, the residue is taken up in 100 ml of dichloromethane and then washed with 3 × 50 ml of an aqueous solution of sodium hydrogencarbonate (10%). The aqueous phase is washed with 2x50 mL of dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, filtered and then the solvent is evaporated in vacuo in order to obtain the desired product 6 in the form of a white solid. 1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.94 (m, 1H), 3.92 (s, 1H), 3.53 (m, 1H), 2.310.61 (m, 43H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 173.68, 72.86, 71.37, 67.17, 47.99,
47.05, 46.32, 41.95, 36.23, 35.86, 35.17, 35.11, 33.97, 33.38, 31.61, 30.80, 30.20, 28.49,
27.42, 27.05, 26.01, 23.58, 22.99, 21.70, 17.06, 12.53. Yid: 90%. C ₂₇ H ₄₆ O ₄
Example 1.7 Isopropyl Cholate 7
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.92 (m, 1H), 4.05-3.78 (m, 2H), 3.36-3.18 (m, 4H), 2.26-0.81 (m, 36H), 0.60 (m, 3H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 173.98,
73.11, 71.88, 68.47, 67.38, 47.06, 46.44, 41.59, 39.50, 35.31, 34.81, 31.76, 30.97, 30.40,
28.15, 2755, 26.30, 25.85, 23.36, 22.47, 21.89, 17.34, 12.48. YId: 98%. C27H46O5
Example 1.8 Isopropyl Chenodeoxycholate 8
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.97 (m, 1H), 3.82 (m, 1H), 3.42 (m, 1H), 2.3410 0.64 (m, 43). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 173.63, 71.94, 68.44, 67.24, 56.02,
50.52, 42.74, 41.67, 39.97, 39.75, 39.59, 35.44, 35.28, 35.09, 34.76, 32.98, 31.69, 31.08, 30.76, 28.06, 23.67, 22.75, 21.79, 20.65, 18.28, 11.75. Yid: 72%. C27H46O4
Example 1.9 Isopropyl ursodeoxycholate 9
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.92 (m, 1H), 3.49 (m, 2H), 2.24-0.61 (m, 43H).
¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 173.64, 70.90, 70.87, 67.19, 55.74, 54.84, 43.55, 43.39, 42.33, 40.02, 39.15, 37.16, 36.92, 35.09, 34.79, 33.86, 31.50, 30.84, 30.04, 28.46, 26.72, 23.25, 21.64, 21.02, 18.18, 11.93. Yid: 40%. C27H46O4
Example 1.10 Isopropyl Lithocholate 10

1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.95 (m, 1H), 3.57 (m, 1H), 2.42-0.60 (m, 44H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 173.59, 71.62, 67.15, 56.52, 56.11, 42.74, 42.17,
40.52, 40.21, 36.49, 35.89, 35.41, 35.22, 34.55, 31.66, 31.02, 30.54, 28.04, 27.20, 26.40,
24.12, 23.28, 21.73, 20.81, 18.21, 11.96. YId: 85%. C27H ₄₆ O ₃
Compounds 11-18 were all produced according to the same procedure, considering the appropriate starting diol previously prepared as described above.
Example 2: preparation of the compounds of formula (II) as defined above
Example 2.1 Isopropyl 3-oxo-deoxycholate 11
2 g of diol 6 (4.6 mmol) dissolved in 40 mL of toluene and 30 mL of acetone are placed in a two-necked flask fitted with a magnetic stirrer and surmounted by a DeanStark. The following are added 2.2 equivalents of aluminum tri- / e / 7-butoxide (2.5 g, 10 mmol). The mixture is brought to toluene reflux for 8 h. After cooling, the mixture is with 3 × 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 residue thus obtained is purified by chromatography on silica gel (eluent: ethyl acetate / petroleum ether (1/1)). The desired ketone 11 is obtained in the form of a white solid. 1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 5.10 (m, 1H), 4.13 (m, 1H), 2.57-0.79 (m, 42H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 212.74, 173.57, 72.98, 67.34, 48.22, 47.59, 46.70, 44.30,
42.33, 37.04, 36.92, 35.87, 35.05, 34.45, 34.11, 31.76, 31.00, 29.06, 27.40, 26.64, 25.55, 23.58, 22.38, 21.81, 17.42, 12.75. YId: 70%. C27H44O4
Example 2.2 Methyl 3-oxo-deoxycholate 12
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 3.99 (m, 1H), 3.62 (s, 3H), 2.75-0.68 (m, 36H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 213.02, 174.10, 71.87, 50.83, 47.30, 46.25, 45.91, 43.66, 41.62, 36.41, 36.26, 35.06, 34.64, 33.75, 32.95, 30.33, 28.46, 26.94, 25.97, 24.91, 23.09, 21.73, 16.55, 12.10. YId: 62%. C2 ₅ H ₄ o0 ₄
EXAMPLE 2.3 Methyl 3-oxo-cholate 13
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 3.92 (m, 1H), 3.52-0.64 (m, 39H). ¹³ C NMR (63 MHz, CDCI3): δ (ppm) = 213.74, 174.84, 72.96, 68.26, 51.54, 47.21, 46.56, 45.53, 43.04, 41.63, 39.37, 36.75, 36.64, 35.31, 34.94, 34.93, 31.11, 30.62 , 28.62, 27.49, 26.89, 23.21, 21.58, 17.30, 12.51. Yid: 54%. C2 ₅ H ₄ o0 ₅
Example 2.4 Isopropyl 3-oxo-cholate 14
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.02 (m, 1H), 3.89-3.78 (m, 3H), 3.16-0.63 (m, 40H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 213.88, 174.00, 72.97, 68.25, 67.46, 58.24, 47.25, 46.57, 46.64, 45.53, 43.04, 41.68, 39.41, 36.79, 36.53, 35.28, 34.93, 34.77, 33.95,
31.71, 30.88, 28.63, 27.62, 27.00, 23.21, 21.82, 21.55, 17.31, 12.51. YId: 68%. C27H44O5
Example 2.5 Methyl 3-oxo-chenodeoxycholate 15
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.00 (m, 1H), 3.75 (s, 3H), 2.26-0.79 (m, 36H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 213.33, 174.63, 68.18, 55.68, 51.38, 50.17, 45.51,
43.12, 42.57, 39.40, 39.24, 36.83, 36.71, 35.23, 35.19, 33.80, 33.13, 30.85, 28.03, 23.53,
21.82, 20.86, 18.15, 11.67. Yid: 75%. C25H40O4
Example 2.6 Isopropyl 3-oxo-chenodeoxycholate 16
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.96 (m, 1H), 3.89 (m, 1H), 2.42-0.67 (m, 42H). 10 ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 212.65, 173.55, 68.30, 67.23, 56.02, 50.35, 45.59,
43.18, 42.76, 39.63, 39.53, 36.83, 35.30, 35.25, 34.01, 33.57, 31.66, 31.04, 28.02, 23.63, 21.87, 21.76, 21.02, 18.26, 11.75. YId: 66%. C27H44O4
Example 2.7 Methyl 3-oxo-ursodeoxycholate 17
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 3.62-3.51 (m, 4H), 2.54-0.67 (m, 36H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 211.62, 174.15, 69.93, 55.33, 54.49, 51.03, 44.03, 43.22, 42.76, 42.66, 39.56, 38.89, 36.54, 36.11, 35.96, 34.77, 33.94, 30.52, 28.12, 26.37, 22.22, 21.24, 17.96, 11.74. Yid: 37%. C25H40O4
Example 2.8 Isopropyl 18 3-oxo-ursodeoxycholate 18
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.86 (m, 1H), 3.47 (m, 1H), 2.47-0.59 (m, 42H). ¹³ C NMR (63 MHz, CDC1 ₃ ): δ (ppm) = 211.89, 173.45, 70.17, 67.05, 55.45, 54.64, 44.13,
43.37, 42.90, 42.78, 39.69, 39.05, 36.67, 36.12, 36.07, 34.86, 34.06, 31.28, 30.67, 28.23,
26.48, 22.32, 21.52, 21.35, 18.07, 11.84. Yid: 43%. C27H44O4.
Compounds 19 and 20 were prepared according to the same procedure as that used for the synthesis of compound 11 described above from the compounds isopropyl lithocholate 10 and methyl lithocholate 5, respectively. Only the conditions for purification by chromatography on silica gel have been modified (eluent: ethyl acetate / petroleum ether (1/4)).
Example 2.9 Isopropyl 3-oxo-lithocholate 19
1 H NMR (250 MHz, CDC1 ₃ ): δ (ppm) = 4.94 (m, 1H), 2.35-0.60 (m, 43H). ¹³ C NMR (63 15 MHz, CDC1 ₃ ): δ (ppm) = 212.41, 173.40, 67.11, 56.44, 56.11, 44.21, 42.76, 42.22, 40.91,
40.08, 37.01, 36.94, 35.57, 35.19, 34.83, 31.61, 30.99, 27.99, 26.62, 25.73, 24.07, 22.52, 21.72, 21.17, 18.21, 11.98. Yid: 65%. C27H ₄₄ O ₃
Example 2.10 Methyl 3-oxo-lithocholate 20
³ H NMR (250 MHz, CDC13): δ (ppm) = 3.65 (s, 3H), 2.41-0.67 (m, 37H). ¹³ C NMR (63 MHz, CDC13): δ (ppm) = 212.60, 174.47, 56.55, 56.17, 51.27, 44.31, 42.87, 42.35, 41.04, 40.18, 37.12, 37.04, 35.68, 35.33, 34.94, 31.12, 31.07, 28.08 , 26.70, 25.83, 24.16, 22.62, 21.27, 18.30, 12.07. Yid: 36%. C ₂ 5H4 ₀ O ₃
Example 3: preparation of the compounds of formula (I)
The derivatives according to the invention were all prepared by reductive amination of the ketone precursors prepared previously in Example 2 (compounds 11-20, 22, 24) in the presence of the appropriate polyamine chain.
Example 3.1 preparation of compound (1)
In a three-necked flask fitted with a magnetic stirrer, 100 mg of isopropyl 3-oxodeoxycholate 11 (0.23 mmol) are dissolved in 7 ml of methanol. 3 equivalents of titanium tetraisopropylate (205 pL, 0.7 mmol) are then added, followed by 2 equivalents of norspermine (95 pL, 0.46 mmol). After stirring for 12 h at room temperature, the flask is placed at -20 ° C and 4 equivalents of sodium borohydride (35 mg, 0.92 mmol) are added with stirring. After stirring for 2 h and return to ambient temperature, 300 μl of water are added to terminate the reaction. After 1 hour of additional stirring, the mixture is filtered through Celite, rinsed with ammonia then with methanol and evaporated under vacuum. The crude product thus obtained is chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia (7/3/1)). Compound (1) is obtained in the form of a yellow oil. Yid: 47%. C ₃ 6H ₆ 8N4O
Example 3.2 Synthesis of Compounds (2), (27), (28), (29) and (30)
Derivatives (2), (27), (28), (29) and (30) were prepared according to the same procedure as that developed for the synthesis of compound (1) described above by considering the appropriate polyamine chain.
Compound (2) is obtained with a yield of 37% (C ₃₃ H ₆ iN ₃ O ₃ ). Compounds (27), (28), (29) and (30) are obtained with respective yields of 24% (C ₃₇ H ₇₂ N ₆ O ₃ ), 26% (C ₃₆ H ₆₈ N ₄ O ₃ ), 24% (C ₃₃ H ₆₂ N ₄ O ₃ ) and 24% (C ₃₄ H ₆₃ N ₃ O ₃ ).
Example 3.3 Synthesis of Compounds (3), (4), (19), (20), (31) and (32)
The derivatives (3), (4), (19), (20), (31) and (32) were prepared according to the same procedure as that developed for the synthesis of the compound (1) described above using as a precursor starting with methyl 3-oxo-deoxycholate 12 and considering the appropriate polyamine chain.
Compound (3) is obtained with a yield of 40% (C34H64N4O3). Compounds (4), (19), (20), (31) and (32) are obtained with respective yields of 55/0 (Ε ₃ ιΗ57 · ^ ΐ ₃ ^^ 3) 60% (C33H63N5O3), 25% (C3 ₅ H ₆₈ N ₆ O3), 64% (C32H ₅₉ N ₃ O ₃ ) and 47% C34H64N4O3).
Example 3.4 Synthesis of Compounds (5) and (33)
The derivatives (5) and (33) were prepared according to the same operating procedure developed for the synthesis of the compound (1) described above using as starting precursor methyl 3-oxo-cholate 13 and considering the adequate polyamine chain .
Compound (5) is obtained with a yield of 39% (C31H57N3O4) and compound (33) is obtained with a yield of 39% (C32H59N3O4).
Example 3.5 Synthesis of Compounds (6), (7), (21), (34), (35) and (36)
Derivatives (6), (7), (21), (34), (35) and (36) were prepared according to the same procedure developed for the synthesis of compound (1) described above using as starting precursor isopropyl 14 3-oxo-cholate and considering the appropriate polyamine chain.
Compound (6) is obtained with a yield of 30% (C36H68N4O4). Compounds (7), (21), (34), (35) and (36) are obtained with respective yields of 45/0 ((333H6ikÎ3f ^ 4) 45% (C ₃₇ H ₇₂ N ₆ O ₄ ) , 40% (CseiLsMCh), 35% (C ^ H ^ CL) and 28% (C ₃ 4H ₆ 3N ₃ O4).
Example 3.6 Synthesis of Compounds (8), (9), (22), (37) and (38)
The derivatives (8), (9), (22), (37) and (38) were all prepared according to the same procedure developed for the synthesis of the compound (1) described previously using as starting precursor 3- methyl oxo-chenodeoxycholate and considering the appropriate polyamine chain.
Compound (8) is obtained with a yield of 59% (C34H64N4O3). Compounds (9), (22), (37) and (38) are obtained with respective yields of 27% (C3iH ₅₇ N ₃ O ₃ ), 46% (C3 ₅ H ₆₈ N ₆ O3), 40% ( C32H ₅₉ N ₃ O ₃ ) and 25% (C34H64N4O3).
Example 3.7 Synthesis of Compounds (10), (11), (23), (39), (40) and (41)
The derivatives (10), (11), (23), (39), (40) and (41) were all prepared according to the same procedure developed for the synthesis of the compound (1) described above using as precursor of starting with isopropyl 16-3-oxo-chenodeoxycholate and considering the appropriate polyamine chain.
Compound (10) is obtained with a yield of 40% (C36H68N4O3). Compounds (11), (23), (39), (40) and (41) are obtained with respective yields of 45% (C33H61N3O3), 30% (C3 ₇ H ₇₂ N ₆ O ₃ ), 37% ( C36H ₆₈ N ₄ O3), 40% (633 ^ 2 ^ 03) and 47% (C ₃ 4H ₆ 3N ₃ O3).
Example 3.8 Synthesis of Compounds (12) and (13)
The derivatives (12) and (13) were prepared according to the same procedure developed for the synthesis of the compound (1) described above using as starting precursor methyl 3-oxo-ursodeoxycholate 17 and considering the appropriate polyamine chain .
Compound (12) is obtained with a yield of 31% (C34H04N4O3) and compound (13) is obtained with a yield of 41% (C31H5-N3O3).
Example 3.9 Synthesis of Compounds (14), (42), (24), (43) and (44)
The derivatives (14), (42), (24), (43) and (44) were prepared according to the same procedure developed for the synthesis of the compound (1) described previously using as starting precursor 3-oxo -isopropyl 18 ursodeoxycholate and considering the appropriate polyamine chain.
Compound (14) is obtained with a yield of 15% (C33H61N3O3). Compounds (42), (24), (43) and (44) are obtained with respective yields of 26%. C36H ₆₈ N ₄ O3, 34% (C ₃₇ H ₇₂ N ₆ O ₃ ), 34% (633 ^ 2 ^ 03) and 12% (C34H63N3O3).
Example 3.10 Synthesis of Compounds (15), (16), (26), (47), (48) and (49)
The derivatives (15), (16), (26), (47), (48) and (49) were prepared according to the same procedure developed for the synthesis of the compound (1) described above using as starting precursor isopropyl 19 3-oxo-lithocholate and considering the appropriate polyamine chain.
Compound (15) is obtained with a yield of 36% (C36H68N4O2). Compounds (16), (26), (47), (48) and (49) are obtained with respective yields of 41% (C33H61N3O2), 24% (C ₃ 7H ₇ 2N ₆ O2), 41% (C ₃ 6H ₆₈ N ₄ O2), 38% (C33IU2N4O2) and 43% (C ₃ 4H ₆ 3N ₃ O2).
Example 3.11 Synthesis of Compounds (17), (18), (25), (45) and (46)
The derivatives (17), (18), (25), (45) and (46) were all prepared according to the same operating procedure developed for the synthesis of the compound (1) described above using as starting precursor 3- methyl oxo-lithocholate 20 and considering the appropriate polyamine chain.
Compound (17) is obtained with a yield of 36% (C34H64N4O2). Compounds (18), (25), (45), and (46) are obtained with respective yields of 28% (C31H57N3O2), 32% (C3 ₅ H ₆₈ N ₆ O2), 68% (C ₃ 2H ₅₉ N ₃ O2) and 41% (C34H64N4O2).
Example 4 Intrinsic Antibacterial Activities of the Compounds of Formula (I)
1) Preparation of the preculture
Two tubes were prepared:
A negative control (2 mL of sterile culture medium)
A positive control (1940 qL of culture medium + 40qL of DMSO + 20 qL of the bacterial suspension) from a thawed biological strain (The conservation of the biological strains is carried out at -80 ° C. in glycerol).
The tubes were incubated in an infors at 37 ° C for 24 hours at 100 rpm.
The germs were handled under a hood in the L2 type laboratory and before any manipulation a UV cycle was programmed and only sterile equipment was used. A solvent toxicity test (methanol, ethanol, DMSO) was carried out and the latter proved to be non-toxic at concentrations less than or equal to 2%. The chemical compounds to be tested were prepared in a mixture of DMSO / methanol (50/50) at a concentration of 5 mg / ml.
2) Preparation of the microplate for the determination of the minimum inhibition concentration (MIC)
After 24 hours of incubation, a measurement of the optical density was carried out using a spectrophotometer at 600 nm by taking 100 g of the bacterial suspension diluted in 900 g of the sterile culture medium. This test required the use of a 96-well plate and the necessary volume of the microbial suspension to be inoculated was calculated for an OD corresponding to a value equal to 0.01 in each well. In this plate, the first line corresponded to the negative control (195 gL of sterile culture medium in each well), the second line to the positive control (culture medium seeded and supplemented with 2% of DMSO), the third line was loaded twice in bacterial suspension, 8 gL of product to be tested were placed in each well. Subsequently, a half cascade dilution was made from this line.
The first column served as an inhibition control. A sterile filter was then placed on the microplate allowing the passage of gases but not of contaminants. The microplate was incubated at 37 ° C in a humid atmosphere for 24 hours.
NB: The medium used is the Mueller-Hinton (MH) medium for bacteria. All tests were carried out in duplicate.
3) Cytotoxicity
The WST1 test was used to measure the cytotoxic activity of the products. It is a colorimetric test that measures the viability and the rate of cell proliferation. It is based on the cleavage of colorless tetrazolium salts WST-1 (4- [3- (4iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolio] -l, 3-benzene disulfonate) by mitochondrial dehydrogenases yellow formazan derivative, quantifiable by spectrophotometry at 420-480 nm.
The WST1 test was carried out on Chinese hamster ovary cells. CHO-K1 cells (ATCC, USA) are maintained in culture in Mac Coy's 5A medium supplemented with 10% fetal calf serum, 2 mM L-glutamine and a mixture of penicillin streptomycin (100 U / ml : 10 pg / ml). Incubate at 37 ° C under an atmosphere enriched in CO ₂ (5%) and transplanted every other day.
The cells are transferred into 96-well plates (25,000 cells / ml) in complete Mc Coy's 5A medium, and maintained for 24 h at 37 ° C. under a humid atmosphere enriched in CO ₂ (5%). Increasing concentrations of test products are added to the wells in double tests and 8 growth controls containing the cells in the medium alone are included in each series of tests. After 24 hours at 37 ° C (5% CO ₂ ), the culture medium is eliminated, the cells are rinsed in phosphate buffer (PB S) and 50 μL of
PBS containing 10% of reagent WST1 are added to each well.
After 20 minutes of incubation at 37 ° C., the results are read by spectrophotometry at 450 nm.
Results are expressed as dose-response relationships, modeled by non-linear regression analysis using TableCurve software. The
Inhibitory Concentration 50% (IC50) represents the concentration of product capable of reducing cell viability by 50%.
4) Reading the results
After incubation, the filter was replaced by a transparent film, then an OD reading was carried out in an IEMS plate spectrophotometer at 620 nm. A calculation of the minimum inhibition concentration (MIC) was carried out.
The results are collated in Table III below.
Table III: Intrinsic antibacterial activities of the compounds of formula (I)
CMI(pg / mL) Clso(pg / mL) Gram positive bacteria E.faecalis Gram negative bacteria CHO S. aureus S.intermediariesus E. coli P. aeruginosa CompoundNo HumanATCC25923 Animal(340) Animal(1051997) HumanATCC29212 HumanATCC28922 Animal(1956) HumanATCC27853 Animal(1051575) (1) 4 2 2 8 8 10 8 2 50 (2) 3 3 3 14 14 28 14 14 60 (3) 2 4 1 2 29 14 2 2 6 (4) 2 3 1 3 3 13 3 3 20 (19) 4 7 7 7 7 29 15 7 40 (20) 4 6 1 16 8 14 8 8 90 (31) 7 7 3 13 26 13 26 13 55 (32) 4 7 7 14 7 30 14 7 30 (27) 16 > 130 16 32 32 65 65 65 - (28) 15 15 8 30 15 30 30 30 85 (29) 28 14 14 28 14 28 56 56 - (30) 28 28 14 56 28 56 56 56 - (5) 3 7 2 3 14 27 7 13 27 (33) 14 14 14 14 27 50 27 50 126 (6) 8 8 16 > 60 30 30 30 30 90 (7) 28 14 28 28 28 > 50 30 30 110 (21) 33 33 16 33 33 66 66 66 - (34) 15 15 7 30 30 30 30 30 - (35) 28 14 14 28 28 56 56 56 - (36) 29 29 14 58 58 58 58 58 - (8) 4 4 2 15 15 29 29 7 22 (9) 13 7 7 26 26 26 26 26 70
(22) 16 4 2 8 31 8 31 31 60 (37) 27 27 > 107 13 27 13 27 13 115 (38) 14 14 29 3.5 28 14 28 14 17 (10) 4 2 0.8 8 16 10 16 4 85 (11) 7 2 2 3.5 14 14 28 14 140 (23) 16 16 8 16 16 32 64 64 - (39) 7 7 3.5 14 14 28 28 28 - (40) 14 14 7 14 14 28 56 28 - (41) 14 14 7 28 56 28 28 28 4 (12) 7 4 1 30 4 60 30 7 20 (13) 27 14 7 28 55 55 28 55 70 (14) - 55 12.5 - - 110 - 110 - (42) - 30 15 - - 120 - 60 - (24) - 32 8 - - 65 - 130 - (43) - 28 7 - - 56 - 14 - (44) - 28 14 - - 56 - 28 - (15) 7 7 1 14 14 7 28 2 15 (16) 3.5 3.5 7 3.5 14 7 7 3.5 13 (17) 16 4 4 4 28 7 28 7 14 (18) 16 0.7 0.7 32 32 3 32 3 80 (25) 8 8 4 15 30 30 60 60 76 (45) 12 6 3 12 26 6 26 26 46 (46) 14 7 4 14 56 28 28 28 30 (26) - 18 8 - - 60 - 60 - (47) - 7 4 - - 60 - 30 - (48) - 14 7 - - 55 - 55 - (49) - 27 14 - - 27 - 27 -
Example 5 Antibacterial Activities of the Compounds of Formula (I) in Combination with Doxycycline
Preparation of the microplate for determining the minimum inhibition concentration (MIC) of the combination of a compound of formula (I) and doxycycline
This method requires the use of a 96-well plate, 100 μL of a liquid culture medium is deposited in each well and then inoculated with the microbial suspension previously prepared. The volume required for sowing is calculated for an OD of 0.01 which corresponds to approximately 5.10 ⁶ bacteria in each well. In this plate, the first line corresponds to a negative control (200 μL of sterile culture medium in each well), the second line to a positive control (100 μL of sterile culture medium + 100 μL of the bacterial suspension), the third line contains 192 μL of culture medium, 8 μL of compound of formula (I) to be tested are placed in each well. Thereafter, a cascade dilution is made from this line. Lines 3 to 8 μL of a doxycycline solution (1 mg dissolved in 20 ml) are then added to each well of lines to obtain a final antibiotic concentration of 2 μg / ml. 92 μL of bacterial suspension are then added to lines 3 to 8. The results are read (the determination of the MIC (2 μg / ml of doxyccyline) in the presence of X μg / ml of compound of formula (I)) is done. after 24 hours incubation at 37 ° in a humid atmosphere. After 24 hours of incubation at 37 ° C, 40 μL of nitro tetrazolium iodide are added to each well, allowing the presence of live bacteria to be revealed by coloring the medium in pink.
On the Gram-negative strain of P. aeruginosa (PAO1), doxycycline has an MIC of 40 pg / mL.
The results are reported in Table IV. They indicate the concentration of compounds of formula (I) necessary to restore the activity of doxycycline (2 pg / mL).
Table IV: Potentiation of the activity of doxycycline at 2pg / ml in the presence of the compounds of formula (I)
Compound No MIC - P. aeruginosa (1051575) (pg / mL) Content (in pg / ml_) of compound of formula (I) to restore the activity ofdoxycycycline (2 pg / ml) (1) 2 (2) 3 (3) 4 (4) 3 (19) 4 (20) 4 (31) 3 (32) 4 (27) 8 (28) 2 (29) 4 (30) 7 (6) 4 (7) 4 (34) 4 (35) 7 (36) 4 (8) 1 (9) 3 (22) 4 (37) 3 (38) 2 (10) 2 (11) 1
(23) 8 (39) 2 (40) 4 (41) 4 (12) 2 (13) 7 (42) 4 (15) 2 (16) 3 (18) 3
The use of small amounts of compounds of formula (I) makes it possible to restore (reduce) the concentration necessary in antibiotics to kill the strain considered. There is thus a very good synergy of certain compounds with doxycycline thus restoring the activity of this antibiotic at low concentrations of use (2 pg / ml).
In particular, compound (11) achieves remarkable synergy when administered with doxycycline at 2 pg / mL.
Thus, the compounds of the invention, of formula (I), (Γ), (la), (Ib) or (le), and more particularly compounds (1) to (49) or one of their salts pharmaceutically acceptable demonstrate antibacterial activity. These compounds are useful for the treatment of bacterial infections, in particular Gram positive bacterial infections such as Staphylococcus aureus, Staphylococcus intermedius or
Staphylococcus faecalis and / or Gram negative such as Escherichia Coli and Pseudonomas aeruginosa.
The compounds of formula (I), (Γ), (la), (Ib) or (le), and more particularly compounds (1) to (49) or one of their pharmaceutically acceptable salts according to the invention are especially useful for the antibiotic treatment of bacterial infections, in particular of strains of Gram-positive or Gram-negative bacteria, in humans or animals. By way of example, the compounds according to the invention are useful for the treatment of mastitis, metritis, dental infection, urinary infection, digestive disorder, pyoderma or otitis in humans or the animal. The compounds according to the invention are also useful as a coating preventing bacterial proliferation, for the manufacture of products intended to destroy biofilms or to prevent their formation. These compounds can be used in a medical device, for example: catheters, prostheses, implants, dialysis machines, surgical instruments, sutures or dressings.
Mastitis or mastitis is the inflammation of the udder in mammals, it is a common infection in dairy farming (cows, sheep, goats, buffaloes and camels). It is characterized by the presence in the milk of inflammatory cells (leukocytes) and possibly bacteria. This inflammation can have clinical consequences with a change in the appearance of milk, visible inflammation of the udder (swelling, pain, edema) and possibly damage to the general condition. Most often the disease remains subclinical with alteration of the composition of milk and reduction of production. Mastitis results from an infection of the udder by bacteria more or less adapted to this biotope. In specialized dairy farming, mastitis causes significant economic losses (milk not produced, unfit for use, deterioration in the quality of the milk) and constitutes a public health risk (pathogenic bacteria and antibiotic residues). Mastitis is caused by the penetration and then the development of a bacteria in the mammary gland. The entry of the germ is generally done by the end of the teat. Mastitis therefore does not generally affect all parts of the animal's udder. The main bacteria responsible for mastitis can be grouped into two sets, depending on their contamination reservoir. The germs found on the surface of the udder: Staphylococci, Streptococcus agalactiae, Streptococcus disgalactiae, Streptococcus uberis. These bacteria are mainly responsible for sub-clinical mastitis (not detectable with the naked eye) which is sometimes difficult to cure during lactation, the period of drying up is then used to treat the quarters infected with antibiotics. Germs found in the environment (litter): for example, Streptococcus uberis, Escherichia colt. These bacteria generally cause clinical mastitis, which can go as far as the rapid death of the animal in the absence of appropriate treatment. Mycoplasma mastitis is still a problem in goat herds, although it has now almost disappeared from cattle herds.
Metritis is an inflammation of the entire uterine wall. It can affect different species of domestic mammals (ruminants, horses, pigs, dogs, cats) and wild animals and humans. It is caused by a bacterial infection and is almost always seen after an abnormal parturition or a significant uterine infection. Its severity ranges from a subclinical infection to a disease declared with fever and reduced milk production. In cows, metritis can predispose to ketosis, abomasal displacement and other postpartum disorders. It can also lead to a decline in fertility, temporary or permanent, and even, in some cases, to the death of the animal. Metritis is often linked to contamination of the uterus by the bacteria Arcanobacterium pyogenes, either alone or in conjunction with other pathogenic microorganisms such as: Fusobacterium necrophorum, Bacteroides spp. or Escherichia coli. Right after calving, the uterus provides an ideal environment for bacterial growth. During the first week postpartum, up to 90% of cows are victims of a bacterial uterine infection.
Pyoderma is a purulent skin disease, which can be acute or chronic, local or diffuse. Pyoderma is etymologically an infection of the skin. It is of external origin, caused by a bacterium, generally staphylococcus or Streptococcus pyogenes. Line pyoderma can be circumscribed or generalized. This disease is common in dogs, but can affect all species with close pathogens, including humans. In dogs, pyotraumatic dermatitis is often observed. It is a skin lesion resulting from a compulsion to scratch, nibble and lick part of the body. As soon as the lesion is large enough, a secondary infection with opportunistic bacteria can occur, causing the animal to nibble or scratch more. Most of the animals often affected have allergies: particularly animals allergic to fleas. However, any skin irritation can cause pyotraumatic dermatitis.
Periodontal disease or dental infection is a disease that can affect all species, including humans. It is the leading cause of dental disease in dogs and is common in cats. Yet characterized by bad breath, it is often not identified by the owner. Its prevention requires regular care because it can lead to the loss of teeth or even serious infections. The presence of bacteria in the mouth is normal, but when they grow too quickly, they can lead to the formation of dental plaque. If the plaque builds up and is not removed, gingivitis (inflammation of the gums) may appear. At this stage, the treatment can be completely curative. However, in the absence of treatment, the disease progresses to periodontitis, which is characterized by greater inflammation of the gums, tartar deposits on the teeth and the disappearance of the bone and support structures surrounding the tooth. The violation can be managed but is irreversible. Periodontitis can lead to the loss of teeth and the spread of serious infections in the liver, heart or lungs.
Cystitis, or urinary tract infection, is a disease that can affect all species, including humans. This pathology is particularly frequent in cats but is also frequently encountered in dogs. It can be the result of local trauma such as urinary stones or infections of exogenous origin.
Digestive ailments, and more particularly those leading to diarrhea, are very frequent affections in humans and animals, in particular in dogs and cats. These conditions are often due to contamination and an increased proliferation of aerobic or anaerobic bacteria, or contamination by protozoa.
Otitis is an inflammation of the ear canal. Otitis can affect all animal species, as well as humans. It is an extremely common pathology in domestic carnivores, especially dogs. It can have many origins, some of which will be responsible for recurrent ear infections. Several types of bacteria (Staphylococci, Pseudomonas., 1) and yeast (Malassezia) can develop in the ear canal, causing the development of otitis. These ear infections are then associated with purulent secretions and a very unpleasant odor.
According to a particular aspect of the invention, the compounds of formula (I) are administered in combination with another antibiotic compound, in particular of the family of beta-lactams (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitro- imidazoles, nitrofuran derivatives, benzyl-pyrimidine nucleus derivatives, tetracyclines or phenicolins, such as doxycycline or chloramphenicol, penicillin, ampicillin, amoxicillin, cloxacillin, dicloxacillin, oxacillin, nafcillin cefalexin, cefapirine, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, thimaphenicol, florfenicol, terramycin, erythromycin, spiramycin, tylosin, josamycin, tycin tycin, tycin , tildipirosin, clyndamycin, lyncomycin, pirlymicin, tiamulin, valnemulin, oxolinic acid, flumequin, enrofloxacin, danofloxacin, ibaflox acine, marbofloxacin, difloxacin, obifloxacin, pradofloxacin, rifampicin, rifaximin, sulfamethizol, sulfathiazol, sulfadimidine, sulfamethoxazole, sulfadiazine, sulfadimethoxidin, sulfamethimyrazin, trimamid , dimetridazole, ronidazole, nitrofurantoin, furazolidone or furaltadone. In a particularly advantageous use of the compounds of the invention, a synergy is observed during the joint use of the compounds of the invention with antibiotics.
Indeed, it has been observed that when the compounds of formula (I) were combined with another antibiotic compound, for example doxycycline or chloramphenicol on a Gram-negative strain of Pseudonomas aentginosa, a synergy was observed, as illustrated in Example 5 above. This property makes it possible, for example, to effectively treat patients with a lower rate of antibiotics, which can reduce the appearance of resistance to antibiotics.
The present invention thus also relates to pharmaceutical or veterinary compositions comprising at least one compound chosen from the compounds of formulas (I), (la), (Ib) and (le) as defined above and the compounds (1) to (49) as defined above or a pharmaceutically acceptable salt thereof and at least one antibiotic different from an aforementioned compound, more particularly as defined above, and even more particularly doxycycline.
According to one aspect of the invention, the pharmaceutical or veterinary compositions further comprise a second antibiotic compound, in particular of the family of beta-lactam antibiotics (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitro-imidazoles, nitrofuran derivatives , derivatives of the benzyl-pyrimidine ring, tetracyclines or phenicolics.
The present invention further relates to the use of the compounds of formula (I), (Γ), (la), (Ib) or (le), or a compound of formula (1) to (49) or one of its pharmaceutically acceptable salts, to potentiate the antibiotic activity of antibiotic compounds which can be chosen from the antibiotic compounds mentioned above.
According to another aspect of the invention, the pharmaceutical or veterinary compositions also comprise a second antiparasitic compound, in particular antimalarial.
According to another aspect, the invention provides compounds of formula (I), (F), (la), (Ib) or (le), or a compound of formula (1) to (49) or one its pharmaceutically acceptable salts, for their use in the treatment of parasitic or viral infections, of the man or the animal, such as malaria, the feline immunodeficiency virus (FIV), the feline infectious peritonitis ( PIF), toxoplasmosis, leishmaniasis, echinococcosis, ehrlichiosis, Rubarth hepatitis, leptospirosis, distemper, dog parvovirus, piroplasmosis, kennel or whooping cough, heartworm disease, heartworm feline leukosis (FeLV), coryza, typhus or even feline panleucopenia. The compounds according to the invention can also be used as an antiviral agent.
According to a particular aspect, the compounds of formula (I) are administered in combination with another antimalarial compound. Advantageously, the compounds of formula (I) make it possible to potentiate the activity of antiparasitic compounds, in particular antimalarial.
The present invention further relates to a method of treating a human or animal suffering from bacterial, fungal, viral or parasitic infections, which comprises at least one step of administration of an effective amount of a compound according to any one of the formulas (I), (F), (la), (Ib) and (le) as defined above and (1) to (49) or one of its pharmaceutically acceptable salts.
The present invention also relates to pharmaceutical or veterinary compositions comprising at least one compound chosen from the compounds of formulas (I), (la), (Ib) and (le) as defined above and the compounds (1) to ( 49) as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
The pharmaceutical or veterinary compositions according to the invention can be presented in solid or liquid forms, intended for example for administration by parenteral (intravenous, intramuscular, subcutaneous), general, local, oral, transmucosal, percutaneous, cutaneous, pulmonary, ocular or topical.
They are therefore presented in the form of solutions or injectable suspensions or single-dose or multi-dose vials, in the form of naked or coated tablets, dragees, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules, granules or solutions.
Advantageously, the product according to the invention also comprises one or more additional ingredients well known to those skilled in the art such as in particular, binding agents, granulating agents, lubricants, dyes, fillers, emulsifiers, minerals, film-coating agents, salts, stabilizers, buffers or vitamins. Stabilizers include substances which tend to increase the shelf life of the composition such as preservatives, emulsifiers, thickeners, packaging gases, gelling agents, humectants, sequestrants, synergists or stabilizers.
For oral administration, suitable excipients may be cellulose or microcrystalline cellulose derivatives, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.
For injectable use, the formulation may comprise an aqueous solvent, an organic solvent or the mixture of the two or a vegetable oil, an organic solvent or the mixture of the two. Among the aqueous solvents, water, aqueous solutes, physiological saline, isotonic solutes are the most often used excipients. Among the vegetable oils, there may be mentioned for example palm oil, corn oil, cottonseed oil, sunflower oil, peanut oil, olive oil, soybean oil, safflower oil, coconut oil, sesame oil, or among the semi-synthetic vegetable oils obtained by fractionation and / or hydrolysis and / or total esterification of natural vegetable oils such as, for example, triglycerides d fatty acid derived from vegetable oils, such as the triglycerides of caprylic, capric, linoleic and succinic acids (sold under the trade names Miglyol® 810, 812, 818, 820, 829), the esters of propylene glycol and of fatty acid derived from vegetable oil such as propylene glycol esters and caprylic and capric acids (sold under the trade names Miglyol® 840), as well as their mixture, as well as esters including Triacetin (glyceryl triacetate), oleate ethyl, for example. Among the organic solvents, there may be mentioned, for example, benzyl alcohol, ethanol, N-methyl pyrrolidone, glycerol-formal, glycofurol, Diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol for example, PEG300, PEG 200 and PEG 400. The vehicle is selected so as to form liquid solutions, depending on its ability to dissolve the active substance at room temperature without changing its chemical structure and stability. The vehicle chosen must be biocompatible and suitable for the injectable route. The vehicle will be chosen from polar solvents, non-polar aprotic solvents or their mixture. The liquid injectable composition may also comprise at least one antioxidant chosen from butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), vitamin E and its derivatives, propylgallate and mixtures thereof.
For administration by the transmucosal route, in particular rectally, cocoa butter or polyethylene glycol stearates are the preferred excipients.
For percutaneous or cutaneous use, in particular on the skin, mucous membranes or the hair, in particular for pouring solutions of the “pour-on” or “spot-on” type in veterinary medicine, the usual excipients are aqueous solvents , alcoholic, polar or not, which favor the transcutaneous passage, such as water, benzyl alcohol, vegetable and mineral oils, resuspension agents, antioxidants, surfactants, in particular a mixture consisting of alcohol benzyl and / or labrasol and / or propylene glycol laurate, as a penetrating agent can be used.
For ocular use, the appropriate excipients may also be selected by the skilled person according to the specific requirements.
The dosage may vary within wide limits (0.05 mg to 1000 mg) depending on the therapeutic indication and the route of administration, as well as the subject's age and weight.
Other uses of the compounds of the invention are envisaged, for example as an agent for restricting contamination, such as the formulation in a nasal ointment.
The present invention also relates to the use of at least one compound chosen from a compound of any one of the formulas (I), (I '), (la), (lb) and (le) as defined above, and the compounds (1) to (49) as defined above, or a pharmaceutically acceptable salt thereof according to the present invention for the manufacture of a pharmaceutical or veterinary composition intended for the prevention and / or treatment of a bacterial infection , fungal, viral or parasitic.

权利要求:
Claims (17)
[1" id="c-fr-0001]
R'HN
1. Compound of formula (I) h ₃ c
O
R2
OR (I) in which
R represents a (Ci-Cs) alkyl group,
RI and R2 independently represent a hydrogen atom, an SO3H group or a hydroxy group,
R ’represents a group - (CRaRb) n-X- (CRcRd) m- [Y- (CReRf) o] t-NR9Rio,
Ra, Rb, Rc, Rd, Re and Rf independently represent a hydrogen atom, a (Ci-Cs) alkyl group or a (C6-Cio) aryl group,
X and Y independently represent a group -NR11-, a group -O- or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members,
R9 and RIO independently represent a hydrogen atom, a (Ci-Cs) alkyl group or together form, with the nitrogen atom which carries them, a 5 or 6-membered heterocyclic group, optionally substituted by one or two groups (s) = O or = S,
RI 1 represents a hydrogen atom, a (Ci-Cg) alkyl group or a (CH ₂ ) group s-NH ₂ , n, m, o and s independently represent an integer between 1 and 5, t is equal to 0, 1, 2 or 3, with the exception of the compounds for which t is equal to 1 and m + n + o is equal to 10, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof -this.
[2" id="c-fr-0002]
2. Compound according to claim 1, characterized in that it is defined by at least one of the following sub-groups:
- first subgroup of compounds of formula (I) which RI and R2 independently represent a hydrogen atom or a hydroxy group,
second subgroup of compounds of formula (I) for which R is a (Ci-C4) alkyl group, in particular a methyl or isopropyl group,
- third subgroup of compounds of formula (I) for which X is a group -NH-,
- fourth subgroup of compounds of formula (I) for which R9 and RIO represent a hydrogen atom,
- fifth subgroup of compounds of formula (I) for which Ra, Rb, Rc, Ra, Re and Rf represent a hydrogen atom,
- sixth subgroup of compounds of formula (I) for which Y is a group -NR11-, with RI 1 representing a hydrogen atom, a (Ci-C4) alkyl group or a group - (CKbjs-Nîfe where s is 1, 2 or 3,
- seventh subgroup of compounds of formula (I) for which m is equal to 2, 3, 4, or 5, more preferably to 2 or 3,
- eighth subgroup of compounds of formula (I) for which n is equal to 2, 3, 4 or 5, more preferably to 2 or 3,
- ninth subgroup of compounds of formula (I) for which m is different from 4,
- tenth subgroup of compounds of formula (I) for which o is equal to 2 or 3,
- eleventh subgroup of compounds of formula (I) for which the group -NHR ’is chosen from:
or
- or by the combination of the subgroups as defined above.
[3" id="c-fr-0003]
3. Compound according to claim 1 or 2, characterized in that it represents the formula (F) in which
R, RI and R2 are as defined in claim 1 or 2, n and m independently represent the integer 2 or 3,
R3 and R4 independently represent a hydrogen atom, a (Ci-Cs) alkyl group or a group - (CH2) _S -NH2, and
R5 represents a hydrogen atom, a group - (CH2) _P -NH2, a group - (CH ₂ ) _P -NH- (CH ₂ ) q-NH2 or a group - (CH2) _P -NH- (CH2) _q -NH- (CH2) rNH2, p, q, r and s independently represent an integer which can vary between 1 and 5, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
[4" id="c-fr-0004]
4. Compound according to any one of claims 1 to 3, characterized in that R represents a (Ci-C4) alkyl group and preferably a methyl or an isoproyl.
[5" id="c-fr-0005]
5. Compound according to any one of claims 1 to 4, characterized in that n is equal to 2 and m is equal to 3, n is equal to 2 and m is equal to 2 or else n is equal to 3 and m is equal to 3.
[6" id="c-fr-0006]
6. Compound according to any one of claims 3 to 5, characterized in that R3 and R4 independently represent a hydrogen atom, a methyl group or a group - (CH2) _S -NH2, in which s is equal to 2 or 3.
[7" id="c-fr-0007]
7. 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-NH2 or a group - (CH2) _P -NH- (CH2) _q -NH- (CH ₂ ) r-NH2, with p is equal to 2 or 3, q is equal to 2 and r is equal to 2.
[8" id="c-fr-0008]
8. Compound according to any one of the preceding claims, characterized in that it represents the formula (la)
GOLD
R5 _n © ch ₂ - ~ ^ _n I '3 H
H (la) in which
R, RI and R2 are as defined in any one of claims 3 to 5, and
R5 represents a hydrogen atom or a group - (CH2) _P -NH2, with p is equal to 2 or 3, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
[9" id="c-fr-0009]
9. Compound according to any one of claims 1 to 7, characterized in that it represents the formula (lb)
R6
R7 / N © ^ch 2TnH
2T ~ N 2
H
CH
OR (Ib) in which
R, RI and R2 are as defined in any one of claims 3 to 5, u is equal to 0, 1, 2 or 3, preferably to 1,2 or 3,
R6 and R7 independently represent a hydrogen atom or a (Ci-Cs) alkyl group, preferably a hydrogen atom or a (Ci-C ₄ ) alkyl group, as well as the stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
[10" id="c-fr-0010]
10. Compound according to any one of claims 1 to 7, characterized in
GOLD
R8 (le) in which
R, RI, R2, n and m are as defined in any one of claims 3 to 5, and
R8 represents a (Ci-Cg) alkyl group, preferably a methyl group, or a group - (CH2) s-NH2, with s being an integer which can vary between 1 and 5, preferably equal to 2 or 3, thus as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
[11" id="c-fr-0011]
11. Compound of formula (I) as defined in claim 1 chosen from the following compounds:
(1) isopropyl 3P-norspermino-deoxycholate, (2) isopropyl 3p-norspermidino-deoxycholate, (3) 3p-norspermino-methyl deoxycholate, (4) 3p-norspermidino-deoxycholate,
5 (5) methyl 3p-norspermidino-cholate, (6) 3h-isopropyl norspermino-cholate, (7) 3p-norspermid isopropyl-cholate, (8) 3p-norspermino-chenodeoxycholate, (9) Methyl 3p-norspermidino-chenodeoxycholate,
10 (10) Isopropyl 3p-norspermino-chenodeoxycholate, (11) Isopropyl 3p-norspermidino-chenodeoxycholate, (12) 3p-norspermino-ursodeoxycholate, (13) 3p-norspermidino-ursodeoxycholate (methyl) Isopropyl 3p-norspermidino-ursodeoxycholate,
15 (15) Methyl 3p-norspermino-lithocholate, (16) 3p-norspermidino-isopropyl lithocholate, (17) 3p-norspermino-methyl lithocholate, (18) 3p-norspermidino-lithocholate, (19) 3P- (tetraethylenepentamine) -methyl deoxycholate,
20 (20) 3p- (pentaethylenehexamine) -methyl deoxycholate, (21) 3p- (pentaethylenehexamine) -isopropylcholate, (22) 3P- (pentaethylenehexamine) -methyl chenodeoxycholate, (23) 3p- (pentaethylenehexamine) -isopropyl chenodeoxycholate, (24) 3p- (pentaethylenehexamine) -isopropyl ursodeoxycholate,
25 (25) 3p- (pentaethylenehexamine) -methyllithocholate, (26) 3p- (pentaethylenehexamine) -isopropyllithocholate, (27) 3p- (pentaethylenehexamine) -isopropyl deoxycholate, (28) 3p- (Tris ( 3-aminopropyl) amine) -isopropyl deoxycholate, (29) 3P- (Tris (2-aminoethyl) amine) -isopropyl deoxycholate,
30 (30) 3p- (Bis (3-aminopropyl) methylamine) -isopropyl deoxycholate, (31) 33- (Bis (3-aminopropyl) methylamine) -methyl deoxycholate, (32) 3p- (Tris (3- aminopropyl) amine) -methyl deoxycholate, (33) 3p- (Bis (3-aminopropyl) methylamine) -methyl chlorate, (34) 3p- (Tris (3-aminopropyl) amine) -isopropyl chlorate, (35 ) 3p- (Tris (2-aminoethyl) amine) -isopropÿlcholate, (36) 3p- (Bis (3-aminopropyl) methylamine) -isopropÿlcholate, (37) 3p- (Bis (3-aminopropyl) methyl methyl) -methyl chenodeoxycholate, (38) 3P- (Tris (3-aminopropyl) amine) -methyl chenodeoxycholate, (39) 3 p- (Tris (3-aminopropyl) amine)-isopropyl chenodeoxycho late, (40 ) 3p- (Tris (2-aminoethyl) amine) -isopropÿl chenodeoxycholate, (41) 3p- (Bis (3-aminopropyl) methylamine) -isopropÿl chenodeoxycholate, (42) 3p- (Tris (3-aminopropyl) amine) -isopropyl ursodeoxycholate, (43) 3 P- (Tris (2-aminoethyl) amine) -isopropyl ursodeoxycholate, (44) 3 P- (Bis (3-aminopropyl) methylamine) -isopropyl ursodeoxycholate , (45) 3p- (Bi s (3-aminopropyl) methylamine) -methyllithocholate, (46) 3p- (Tris (3-aminopropyl) amine) -methyllithocholate, (47) 3p- (Tris (3-aminopropyl) amine) -lithocholate isopropÿle, (48) 3p- (Tris (2-aminoethyl) amine) -isopropÿl lithocholate, (49) 3p- (Bis (3-aminopropyl) methylamine) -isopropÿl lithocholate, or a salt thereof acceptable, and more particularly chosen from compounds (1), (10), (11), (18) and (20).
[12" id="c-fr-0012]
12. Compound of formula (I) according to any one of the preceding claims, for its use as a medicament.
[13" id="c-fr-0013]
13. Pharmaceutical or veterinary composition comprising a compound of formula (I) as defined in any one of claims 1 to 11 and a pharmaceutically acceptable excipient.
[14" id="c-fr-0014]
14. Pharmaceutical or veterinary compositions comprising at least one compound of formula (I) as defined in any one of claims 1 to 11 and at least one antibiotic, different from such a compound of formula (I), more particularly of the family of beta-lactams, aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitro-imidazoles, nitrofuran derivatives, derivatives of the benzylpyrimidine nucleus, tetracyclines or phenicolines, such as doxycycline or chloramphenicol, penicillin, ampicillin, amic , cloxacillin, dicloxacillin, oxacillin, nafcillin, cefalexin, cefapirin, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, thimaphenicol, florfenicol, terramycin, terramycin , tylosin, josamycin, tilmicosin, tulathromycin, gamithromycin, tildipirosin, clyndamycin, lyncomycin, pirlymicin, tiamulin, valnemulin, oxo acid linic, flumequin, enrofloxacin, danofloxacin, ibafloxacin, marbofloxacin, difloxacin, obifloxacin, pradofloxacin, rifampicin, rifaximine, sulfamethizol, sulfathetholaz, sulfamethiazine sulfadimethoxine, sulfamethoxypyridazine, trimethoprim, baquiloprime, metronidazole, dimetridazole, ronidazole, nitrofurantoin, furazolidone or furaltadone, and even more particularly doxycycline.
[15" id="c-fr-0015]
15. Compound according to any one of claims 1 to 11 for its use for preventing and / or inhibiting and or treating bacterial, fungal, viral or parasitic infections in humans or animals.
[16" id="c-fr-0016]
16. Compound according to any one of claims 1 to 11, for its use for potentiating the antibiotic activity of antibiotic compounds which can be chosen from the antibiotic compounds as described in claim 14.
[17" id="c-fr-0017]
17. Process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 11, comprising a step of reductive amination of the compound of formula (II) in which R, RI and R2 are as defined in one of claims 1,
2 or 3, with an amine of formula R'Nth, in which R 'is as defined in claim 1, in the presence of a reducing agent such as titanium tetraisopropylate, zirconium tetraisopropylate, NaBfhCN, NaBFfi , or a mixture thereof, to obtain said compound of formula (I).

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优先权:

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申请号 | 申请日 | 专利标题

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FR1658649|2016-09-15|

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FR1658649A|FR3055801B1|2016-09-15|2016-09-15|SQUALAMINE ESTERS FOR THE TREATMENT OF INFECTIONS|FR1658649A| FR3055801B1|2016-09-15|2016-09-15|SQUALAMINE ESTERS FOR THE TREATMENT OF INFECTIONS|

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EP17768444.6A| EP3512865B1|2016-09-15|2017-09-15|Esters of 3-polyamine derivatives of bile acids for the treatment of infections|

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CN201780057129.8A| CN110023324A|2016-09-15|2017-09-15|For treating the squalamine ester derivant of infection|

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US16/333,451| US20190255073A1|2016-09-15|2017-09-15|Esters of 3-polyamine derivatives of bile acids for the treatment of infections|

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PCT/EP2017/073266| WO2018050814A1|2016-09-15|2017-09-15|Esters of 3-polyamine derivatives of bile acids for the treatment of infections|