The invention of squalamine analogs for use in the treatment of bacterial, fungal, viral, parasitic or in the treatment of cancer in humans or animals, as well as pharmaceutical or veterinary compositions comprising them.

In 1993, squalamine, a natural steroid, predominantly isolated tissues of a small shark Squalus has canihias, has been found to be a very active substance having essenti actually antiangiogenic activity against cells and viral and anti antibacterial activity.

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

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

The natural source of squalamine is limited, have been sought like synthetic derivatives aminostéroïdiens squalamine. Have been described including derivatives or analogues comprising a polyamino chain in position 3 or 7 cycles 1 0, 1 3-dimethyl, 1 7 cholestane octane or chol Estène optionally hydroxylated in position 7 or respectively 3. In particular, the derivatives of formula IIa - IIb - Ile - IId and II- 1 below have been disclosed as having antibacterial activity

similar to sqvtalamine vis-à-vis various Gram positive and Gram negative multidrug WO 201 1/067 501 and references 1 to 7).

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

It has now been discovered similar compounds squalamine, with good antibacterial activity against gram-positive and gram-negative, while advantageously less cytotoxic than squalamine.

Thus, according to a first object, the invention provides a compound of formula (I):

in which :

Ri is selected from H, SO3H, alkyl CVCg, aryl Ce-Cio, C (= 0) Rn,

R2 est -(CRîR4)m )p-(C 5R6)n (Y) -(CR7R8)o]q-NR9R10,

R 3 , R 4, R 5, R 6 , R-7, Rs are, at each occurrence, identical or different, each independently selected from H, Q-Cg alkyl, C 6 aryl -Cio and C (= 0) ORi 2 ;

R9, Rio, same or different are each independently selected from H, alkyl, Cs-Cg, a group
or together form a heterocyclyl group having 5 to 7 ring members optionally substituted by one to three groups R 14 ;

X, Y, are the same or different at each occurrence, each independently selected from NR] 3j O, or heterocyclyl nitrogen-containing 5 to 6 members,

Ru, Ru are each independently selected from alkyl, Q-Cg, an aryl group of C 6 -Cio,

R13 is H, C Î -C 6 alkyl, or a group - (CH 2 ) s ~ NH 2 ;

R14 is = 0 or = S;

m is an integer between 1 and 5;

n is an integer between 1 and 5,

o is an integer between 1 and 5,

p is 0 or 1,

q is 0, lou 2

r is an integer between 1 and 4,

s is an integer between 1 and 5;

provided that when p = l and q = l, then m + n + o ^ 7

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof, for use in treating bacterial, fungal, viral, parasitic or in the treatment of cancer in a human or the animal.

The inventio also provides a compound of formula (1):

in which

Ri is selected from H, SO 3 H, alkyl C₁-C₆, aryl C O -CJO, C (= 0) Rn,

R2 est -(CR3R4)m-(X)P-(CR5R6)n-[(Y) -(CR7R8)o]q-NR9Rî0,

R 3 , R 4, R 5 , Re, R 7 , Rg are, at each occurrence, identical or different, each independently selected from H, alkyl CRCS, aryl and C5-C10
;

R9, Rio, same or different are each independently selected from H, alkyl CpCg, a group - (CH 2 ) R - NH2, or together form a heterocyclyl group having 5 to 7 ring members optionally substituted by one to three groups R 14 ;

X, Y, are the same or different at each occurrence, each independently selected from NR i3 , O, or heterocyclyl nitrogen-containing 5 to 6 members,

Ru, R12 are each independently selected from alkyl, Ci-Cs, aryl Ce-Cio,

Rn is H, a C-C 6 alkyl, or a group - (CH2) s-NH 2 ;

R14 is = 0 or = S;

m is an integer between 1 and 5;

n is an integer between 1 and 5,

o is an integer between 1 and 5,

p is 0 or 1,

q is 0, lou 2

r is an integer between 1 and 4,

s is an integer between 1 and 5;

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof, for use in treating bacterial, fungal, viral, parasitic or in the treatment of cancer in humans or animals.

In a preferred aspect, the compound 3p- (norspermine) -7a-hydroxy ~ 5a-cholestane and the following compounds of formula are excluded:

SA-Z

According to a preferred aspect, the compounds for which p = q = 0, m = 3, n = 3 or 4, and X = NH are excluded.

In a preferred embodiment, it is understood that:

when p = l and q = 0, then m + n ≠ 6 and 7,

when p = 0 and q = l, then m + n + o ^ 6 and 7.

Preferably R [is H.

Preferably, X is NR ] 3 , more preferably NH.

Preferably, R 9 and / or R 10 are H.

Preferably, m is 2, 3, 4 or 5, more preferably 3.

Preferably, n is 2, 3, 4 or 5, more preferably 2 or 4.

In a preferred aspect, the invention includes compounds of formula (I) wherein the group -NHR 2 is selected from:

In a preferred aspect, the invention includes compounds of formula (I) wherein the group -NHR 2 is selected from:

According to a preferred variant, the compounds of formula (I) are chosen from:

3P-spermino-7a~hydroxy-5a-cholestane (SA-1)

3 -spermino-7-hydroxy-5.alpha.-cholestane (SA-2)

3p-Norspermidino-7p~hydroxy-5a-cholestane (SA-3)

3p~(l,3-diammopropane)-7p-hydroxy-5a-cholestane (SA-4)

3 -(l,4~diaminobutane)-7 -hydroxy-5a-cholestane (SA-5)

3p-(Tris(2aminoethyl)amine)-7p-hydroxy-5 -cholestane (SA-6) 3p-(l ,5-diaminopentane)-7a-hydroxy-5 -cholestane (SA-7)

3 ~(l,4-bis (3-aminopropyl)piperazine)-7 -hydroxy-5a-cholestane (SA- 8)

3p-(l,4-bis-(3-aminopropoxy)butane)-7 -hydroxy-5a-cholestane (SA- 9)

3 -(norspermine)-7a-hydroxy-5a-cholestane (SA- 10)

3 - (i- (3-aminopropyl) imidazole) -7a-hydroxy-5a-cholestane (SA-1 i) 3 β- (1 - (3 aminopropyl) morpholine) ~ 7a-hydroxy-5a-cholestane (SA- 12) According to another preferred variant, the compounds of formula (I) are chosen 3 -spermino-7p-hydroxy-5 -cholesiane (SA-2)

3 -(l,3-diaminopropane)-7p-hydroxy-5a-cholestane (SA-4)

3p-(norspermine)-7a-hydroxy-5a-cholestane (SA- 10)

According to another preferred embodiment, the invention includes compounds of formula (I) for the treatment of bacterial infections, particularly Gram-positive bacterial infections such as infections Sîaphyîococcus aureus, Sîaphyîococcus faecalis and / or Gram-negative such as Escherichia coli, Pseudomonas aeruginosa.

The compounds of formula (I) according to the invention are especially useful for antibiotic treatment of bacterial infections, in particular strains of Gram-positive bacteria or Gram -negative, in humans or animals. According to one embodiment, the compounds of formula (I) are used in animals, including dogs, cats or ruminants.

For example, compounds of the invention are useful for the treatment of mastitis, metritis, dental infections, pyoderma or ear infections especially in animals. The compounds according to the invention are also useful for the manufacture of products intended to destroy the biofilms.

According to a particular embodiment, the invention relates to the SA-10 compound, SA or SA-Y-Z for use in the treatment of mastitis, metritis, dental infections, ear infections, or pyoderma, including in animals. The SA-10 compound, or SA SA- Y-Z according to the invention is also useful for the manufacture of products intended to destroy the biofilms.

Mastitis or mastitis is inflammation of the udder in mammals is a common infection in breeding of dairy animals (cows, sheep, goats, buffaloes and camels). It is characterized by the presence in the milk of inflammatory cells (leukocytes) and optionally bacteria. This inflammation may have clinical implications with changing the appearance of milk, recognizable inflammation of the udder (swelling, pain, edema) and possibly impairment of general condition. Most often the disease remains with subclinical alteration of the composition of milk and decreased production. Mastitis resulting from infection of the udder by bacteria more or less adapted to this habitat. In specialized dairy farming, mastitis causing significant economic losses (not produced milk unfit for use, impaired quality of milk) and constitute a public health risk (pathogenic bacteria and antibiotic residues). Mastitis due to penetration and development

of bacteria in the mammary gland. The entry of the seed is usually done by the end of the teat. Mastitis therefore relates generally not all parts of the animal's udder. Main mastitis causing bacteria can be grouped into two sets, depending on their contamination tank: the germs on the surface of the breast: Staphylococci, Streptococcus agalactiae, Streptococcus disgalactiae, Streptococcus uberis. These bacteria are primarily responsible for subclinical mastitis (undetectable to the naked eye) it is sometimes difficult to cure during lactation, dry period is then utilized to treat infected quarters with antibiotics. Germs in the environment (litter): for example, Streptococcus uberis, Escherichia coli. These bacteria usually cause clinical mastitis, which can go up to the rapid death of the animal in the absence of appropriate treatment. Mycoplasma mastitis still cause problems in herds goats, although they have now almost disappeared cattle herds.

Metritis is an inflammation of the entire uterine wall. It is caused by a bacterial infection and is almost always observed after an abnormal calving or major uterine infection. Its severity ranges from subclinical infection to overt disease with fever and decreased milk production. Metritis may predispose cows to ketosis, displacement of the abomasum and other postpartum disorders. It can also lead to decreased fertility, temporary or permanent, and even, in some cases, death of the animal. Metritis is often linked to contamination of the uterus by the bacterium Arcanobacterium pyogenes, either alone or in conjunction with other pathogens such as Fusobacterium necrophorum, Bacteroides spp. or Escherichia coli. Immediately after calving, the uterus is an ideal environment for bacterial growth. During the first week postpartum, up to 90% of cows are victims of a uterine infection of bacterial origin.

Pyoderma is a purulent skin disease, which can be acute or chronic, local or diffuse. Pyoderma is etymologically a skin infection. It is of external origin, caused by bacteria, usually Staphylococcus or Streptococcus pyogenes. Pyoderma may be limited or widespread. In dogs, there is often a pyotraumatic dermatitis. This is a skin lesion resulting from a compulsion to scratching, biting and licking a body part. Once the lesion is large enough, a secondary infection by opportunistic bacteria can occur, causing the animal to bite or scratch is more. Most often affected animals have allergies: allergic animals particularly Flea. However, any skin irritation can cause pyotraumatic dermatitis.

Otitis media is an inflammation of the ear canal. This is an extremely common condition in pets, especially dogs. It can have many origins, some of which will be responsible for recurrent ear infections. Several types of bacteria {Staphylococcus, Pseudomonas ...) and yeast (M lassezià) may develop in the ear canal, causing the appearance of an ear infection. These ear infections are then associated with purulent secretions and a very unpleasant odor.

Periodontal disease or tooth infection is the main cause of dental disease in dogs. Yet characterized by bad breath, it is often not identified by the owner. Its prevention requires regular care because it can lead to tooth loss or serious infections. The presence of bacteria in the mouth is normal but when they grow too quickly, it can lead to plaque formation. If plaque builds up and is not removed, gingivitis (gum inflammation) may occur. At this stage, treatment can be completely curative. However, in the absence of treatment, the disease progresses to periodontitis characterized by a larger inflamed gums, tartar deposits on the teeth and loss of bone and supporting structures surrounding the tooth. The achievement can be supported, but is irreversible. Periodontitis can cause tooth loss and the spread of serious infections in the liver, heart or lungs.

According to a particular aspect of the invention, the compounds of formula (I) are administered in combination with another antibiotic compound, including the beta-lactam (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitro- imidazole, derivatives nitrofurans, derivatives of benzyl-pyrimidine ring, tetracyclines or phenicol, such as doxycycline or chloramphenicol, penicillin, ampicillin, amoxicillin, cloxacillin, dicloxacillin, oxacillin, nafcillin, cefalexin cephapirin, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, the thimaphénicol, florfenicol, Terramycin, erythromycin, spiramycin, tylosin, josamycin, the tilmicosin, tulathromycin, gamithromycin, the tildipirosin, the clyndamycine, the lyncomycine, the pirlimycin, the tiamulin, valnemulin, oxolinic acid, flumequine, Penrofloxacine, the has danofloxacin, ibafloxacin, marbofloxacin, the difîoxacine, Pobifloxacine, pradofloxacin, rifampicin, rifaximin, the Sulfamethizol, the sulfathiazole, sulfamethazine, sulfamethoxazole, sulfadiazine, sulfadimethoxine, the

sulfamethoxypyridazine, trimethoprim, baquiloprime, metronidazole, dimetridazole, ronidazole, nitrofurantoin, furazolidone or furaltadone. In a particularly advantageous use of the compounds of the invention, there is a synergy in the joint use of compounds of the invention with antibiotics. Indeed, it has been observed that when the compounds of formula (I) were associated with a different antibiotic compound, e.g., doxycycline or chloramphénicoî on a Gram-negative strain of Pseudomonas aeruginosa, synergy was observed. This property allows for example to effectively treat patients with a lower rate of antibiotic, which may decrease the occurrence of antibiotic resistance.

According to another aspect, the invention provides compounds of formula (I) for use in the treatment of parasitic or viral infections, human or animal, such as malaria, the feline immunodeficiency virus ( FIV), feline infectious peritonitis (FIP), the toxopîasmose, leishmaniasis, echinococcosis, ehrlichiosis, hepatitis Rubarth, leptospirosis, distemper, parvovirus dog, piroplasmosis, cough kennel or whooping cough, heartworm, feline leukemia (FeLV), coryza, typhus or feline panleukopenia. The compounds of the invention may also be used as an antiviral agent or as an nti-cancer.

According to one aspect, the invention relates to the compound SA-10, SA-SA-Y or Z for use in the treatment of parasitic or viral infections, human or animal, such as malaria, the feline immunodeficiency virus (FIV), feline infectious peritonitis (FIP), the toxopîasmose, leishmaniasis, Techinococcose, ehrlichiosis, hepatitis Rubarth, leptospirosis, distemper, parvovirus dog, piroplasmosis, kennel cough or pertussis, heartworm, feline leukemia (FeLV), coryza, typhus or feline panleukopenia. The SA-10 compound, SA or SA-Y-Z according to the invention can also be used as antiviral agent or as an anti-cancer.

In a particular aspect, the compounds of formula (I) are administered in combination with another anti-malarial compound. Advantageously, the compounds of formula (I) make it possible to potentiate the activity of antiparasitic compounds, particularly antimalarial.

A pharmaceutical composition

According to a second object, the invention provides a pharmaceutical or veterinary composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier:

in which :

Ri, are as defined above,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts of compounds of formula (I).

In a preferred aspect, the compound 3p- (norspermine) -7a-hydroxy-5a-cholestane and the following compounds of formula are excluded:

SA-Z

According to a preferred aspect, the compounds for which p = q = 0, m = 3, n = 3 or 4, and X = NH are excluded.

In a preferred embodiment, it is understood that:

when p = l and q = 0, then m + n ≠ 6 and 7,

when p = 0 and q = l, then m + n + o ≠ 6 and 7.

According to a particular embodiment, the invention relates to compounds of formula (I) as described previously with the exception of compounds of formula (I) wherein:

Ri is H, R 2 is NHR and R is selected from:

According to one aspect of the invention there is provided pharmaceutical compositions further comprising a second antibiotic compound, in particular the beta-lactam (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitroimidazole, derived from nitrofurans, derivatives benzyi-pyrimidine ring, tetracyclines or phenicol, or a second compound control, including antipaîudéen.

The pharmaceutical or veterinary compositions according to the invention may be presented in solid or liquid forms, intended for example for parenteral administration (intravenous, intramuscular, subcutaneous), oral or topical.

They will therefore be presented as solutions or suspensions for injection or bottles single-dose or muiti-doses in the form of uncoated or coated tablets, dragées, capsules, capsules, pills, cachets, powders, granules , suppositories or rectal capsules.

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, colorants, fillers, emulsifiers, minerals, coating agents, salts, stabilizers, buffers or vitamins. Stabilizers include substances that tend to increase the shelf life of the composition such as preservatives, emulsifiers, thickeners, packaging gases, gelling agents, humectants, sequestering agents, synergists or stabilizers.

For parenteral use, water, aqueous solutions, physiological serum, isotonic solutes are the most conveniently used vehicles.

For percutaneous use, especially to the skin, mucous membranes or the hair, in particular for solutions to pay type 'pour-on' or 'spot-on' in veterinary medicine, the excipients are aqueous solvents, alcoholic , polar or not, that promote the transcutaneous passage, such as water, alcohol benzyîique, vegetable and mineral oils, the resuspension agents, antioxidants, surfactants, in particular a mixture of alcohol and benzyîique / or labrasol and / or propylene glycol laurate, as a penetrant may be used.

The dosage can vary in wide limits (from 0.05 mg to 1000 mg) depending on the therapeutic indication and the route of administration and the age and weight of the subject.

Compounds of formula (I)

According to a third object, the invention relates to compounds of formula (I):

(0

in which :

R \ , R, are as defined above,

as well as stereo isomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts of compounds of formula (I).

In a preferred aspect, the compound 3- (norspermine) -7a-hydroxy-5 cholestane and the following compounds of formula are excluded:

SA-Z

According to a preferred aspect, the compounds for which p = q = 0, m = 3, n-3 or 4 and X = NH are excluded.

In a preferred embodiment, it is understood that:

- when p = l and q = 0, then m + n ≠ 6 and 7,

when p = 0 and q = l, then m + n + o ≠ 6 and 7,

Process for preparing the compounds of formula (I)

The compounds of general formula (1) may be prepared by application or adaptation of any method known per se and / or within the skill in the art, especially those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989 or by application or adaptation of methods described in the examples which follow.

According to another object, the present invention therefore also relates to the process for preparing the compounds of formula (I) described above, comprising a reductive amination step the compound of formula (II) in the presence of an amine R 2 NH 2 , whereby there is obtained the compound of formula (I):

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

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

It will be appreciated that compounds useful according to the present invention may contain several asymmetric centers. These asymmetric centers may independently be in the R or S configuration is to be understood that the present invention includes stereoisomers, including enantiomers or diastereomers, and mixtures thereof, including racemic mixtures, of compounds of formula (I) -above. These stereoisomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromato graphy techniques or recrystallisation techniques, or they are separately prepared from the appropriate intermediates of stereoisomers.

The basic products or the reagents used are commercially available and / or can be prepared by the application or adaptation of known methods, for example methods as described in the Examples or their obvious chemical equivalents.

Definitions

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

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

By group "heterocyclyl" is meant within the meaning of the present application, a hydrocarbon system mono- or bicyclic saturated, unsaturated or aromatic comprising one or

more heteroatoms such as O, N, or S. Heterocyclyl groups include heteroaryl groups or hétérocycîoalkyîe.

Groups "heteroaryl" refers to mono or bicyclic aromatic ring systems, and having from 5 to 7 members (ring atoms), including 5 to 6 members, including one or more heteroatoms selected from 3 nitrogen, oxygen or sulfur ,. Among the heteroaryl radicals include imidazolyl, pyrazinyl, ihiényle, oxazolyl, furazanyl the yrrolyîe.

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

The term "pharmaceutically acceptable salts" refers to the addition salts of inorganic and organic acids, pharmaceutically acceptable, and the addition salts of pharmaceutically acceptable bases of compounds of the present invention. These salts include acid addition salts, that is to say, organic acid salts or mineral of a compound having a basic function such as an amine, or basic addition salts is -to say, alkali or organic salts of a compound having an acidic function such as a carboxylic acid. These salts can be prepared in situ during the final isolation and / or purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound with an organic or inorganic acid and isolating the salt thus formed. Examples of acid addition salts there are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate , maleate, furnarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphthoates, genti.sique acid, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinateslaurylsuîfonate, and the like. (See for example SM Berge et al, "Pharmaceutical Salts," J. Pharm Sci., 66:. P.1-19 (1977)).

Basic addition salts may also be prepared by separately reacting the purified compound in its acid form with an organic or inorganic base and isolating the salt thus formed. Examples of base addition salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum.

Sodium and potassium salts are preferred. Basic addition salts can in particular be prepared from hydrides or alkali metal hydroxides or alkaline earth metal which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, hydroxide lithium, magnesium hydroxide, zinc hydroxide.

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

As used herein, the term "stereoisomer" refers to optical isomers related to the two asymmetric carbon atoms located in positions 3 and position 7 of the formula (I), and includes enantiomers and diastereomers thereof.

Other features of the invention appear in the following examples. These examples are given to illustrate the invention and are not intended to be limiting thereof.

Examples

I. Synthesis of compounds of formula (I)

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

The synthesized chemical structures were all verified by proton NMR analysis ( ? H) and / or carbon ( I3 C) in deuterated chloroform CDCl 3 or CD 3 OD deuterated methanol on a Bruker AC-type apparatus 300. Chemical shifts δ are expressed in ppm. Records frequencies of nuclei and references used are as follows:

RMN du 1H: 300 MHz, Si (CH 3 ) 4

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

The abbreviations used for writing the 1H spectrum are the following:

- s = singulet

- d = doublet

- 1 = triplet

- q = quadruplet

- m = mass

Mass spectra were conducted Spectropôle Aix-Marseille III. They are performed on the dry product and using a triple quadrupole spectrometer Sciex API III Plus. The sample is dissolved in 500 L of CH2Cl2 and then diluted 1:10 4 in a MeOH solution containing 3 mM ammonium acetate. The extract solution is introduced into the ionization source infusion (pump syringe pump Harvard Apparatus) at a rate of 5

The compounds of formula (I) were prepared according to the reaction scheme below:

Synthesis of 7-kétocholcst-5-ene-3-ol 1

In a reactor equipped with a mechanical stirrer, 50 g of cholesterol were placed (0.129 mol), 22 g of hydroxyphtalamide (0.135 mol) and 1.5 L of a mixture of ethyl acetate / acetone (1 / 1). Was heated to 50 ° C. Is added 200 mg of benzoyl peroxide and air is made builer during 72h by adjusting the solvent level and following manipulation by chromatography plate. After 72 hours, evaporate the solvent in vacuo. The residue is dissolved in petroleum ether and washed with sodium carbonate until the orange color disappears. The organic phases are washed with a NaCl saturated solution and dried over MgS0 4 . The solvent was removed in vacuo and the sterol is dissolved in pyridine (200 mL). Cooled to 0 ° C and adding 1 g of CuCl 2 . The solution was stirred 24h (return from 0 ° C to room temperature). The obtained solution is thrown on a water / ice mixture. Acetate extracted with ethyl and washed with a solution of CuS0 4 saturated. After phase separation, the organic phase is washed with a HC1 solution at 0, lN, and dried over MgS0 4 . After evaporating the solvent, the residue is chromatographed on silica gel (Petroleum ether / Ethyl acetate 1/1). The expected ketone is obtained as a white solid with a yield of 70%.

RMN Ή : δ = 5.45-5.75 (m, 1H), 3.475-3.75 (m, 1H), 2.125-2.75 (m, 4H), 1.75-2.075 (m, 6H), 0.8-1.7 (m, 37H), 0.45-0.75 (m, 4H) ; i3C : 6 = 202.81, 165.59, 126.49, 70.89, 55.17, 50.34, 45.80, 43.49, 39.87, 38.67, 36.57, 36.1 1, 28.40, 26.72, 24.22, 23.22, 22.96, 21.61, 19.26, 17.71 , 12.37.

Synthesis of 7-kétocholest-5-ene-3-acetate 2

In a two-necked flask equipped with a condenser was dissolved 3 mmol 7-kétocholest-5-ene-3pol 1 in pyridine (25 mL) and is added 9 mmol of acetic anhydride. Magnetic stirring is continued for 24 hours in an ice bath. Evaporated under vacuum pyridine, then the solid obtained was resuspended in CH 2 Cl 2 (15 mL). Extraction of copper sulphate is then carried out, and the organic phase is dried over MgS0 4 , filtered and then dried under high vacuum. By chromatography the product is purified on silica gel (eluent: petroleum ether / ethyl acetate 9/1) (Yield 94%).

RMN ιΉ. : δ = 5.65-5.7 (d, 1H), 4.6-4.75 (m,lH), 0.6-2.6 (m, 44H); 13C : δ = 201.90, 170.24, 163.81 , 126.68, 72.19, 54.75, 49.93, 49.78, 45.38, 43.08, 39.44, 38.64, 38.28, 37.72, 36.15, 35.98, 35.69, 31.90, 28.50, 27.96, 27.32, 26.28, 23.80, 22.77, 22.52, 21.24, 21.14, 18.84, 17.22, 1 1.93.

Synthesis of 7-kétocholestan 3P-acetate 3

In a steel reactor was charged 3.04 g (6.87 mmol) of 7-kétocholestane 3-ol 2 and 1.1 g (about 15 mol%) of Pd / C (10%) in 50 ml of CH 2 C1 2 . The reactor is placed under 50 bar of hydrogen with vigorous stirring for 12 h. After filtration on celite and evaporation under vacuum the solvent product is obtained pure and almost quantitative yield. It will be used as such in the next step.

RMN Ή : 6 = 4.62-4.70 (m,lH), 0.64-2.39 (m, 47H); 13C : δ = 211.44, 170.38, 72.71 , 54.95, 49.90, 48.82, 46.43, 45.34, 42.45, 39.42, 38.65, 36.09, 35.89, 35.60, 33.79, 28.35, 27.93, 26.34, 24.93, 23.72, 22.74, 22.51, 22.15, 21.27, 18.73, 12.01, 1 1.65.

Synthesis of mixture of 7p-hydroxycholestane-3p-ol 4a and 7a-hydroxycholestane-3p-ol 4b

In a flask necked flask were placed 530 mg of lithium aluminum hydride (13.8 mmol) in 100 mL of anhydrous THF. is added slowly at 0 ° C a solution of 7-kétocholestane 3-3 -acetate (1.5g, 3.3 mmol) dissolved in 15 mL of THF. After 12 h stirring at room temperature, hydrolyzed with a solution of KOH (30%) (1.2 mL). lh stirring was continued and then filtered through Celite, rinsed with MeOH and the solvents evaporated in vacuo. Is purified by chromatography the product as a mixture of isomers (α / β 50:50) on silica gel (eluent: petroleum ether / ethyl acetate 8/2) (Yield 95%).

RMN lH : δ = 0.6-3.82 (m, 48H); 13C : δ = 75.11 , 71.08, 70.99, 67.96, 62.57, 56.45, 56.08, 55.68, 55.19, 51.85, 50.51, 45.83, 43.95, 43.35, 42.60, 42.00, 39.46, 37.62, 37.1 1 , 36.54, 36.24, 35.73, 35.51 , 34.88, 31.30, 29.82, 28.05, 27.95, 26.86, 23.79, 23.71, 22.76, 22.51, 21.56, 20.96, 18.60, 12.40, 12.1 1 , 1 1.79, 1 1.20.

Synthèse du 3-keto-7 -hydroxycholestane 5a et 3-keto-7a-hydroxychoIestane 5b

A single-necked flask fitted with a Dean-Stark trap was placed 1.28 g of mixture 7P-hydroxycholestane-3p-ol 4a and 7a-hydroxycholestane-3p-ol 4b in 150 mL of toluene and 3.6 g of silver carbonate on Celite . Toluene is refluxed for 24 hours. After cooling the mélangest Filte Celite. Is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate 7/3) and thereby obtaining two pure isomers 5b (fraction I) and 5a (fraction 2) with non-optimized yields of 31 and 25% respectively.

5a RMN Ή ; δ = 3.05-3.55 (m, 1H), 2.2-2.6 (m, 3H), 0.4-1.92 (m, 42H) ; i3C : δ = 211.55, 74.66, 55.61 , 55.24, 51.83, 44.18, 43.94, 43.66, 39.90, 39.54, 38.12, 35.72, 35.16, 28.75, 28.06, 23.89, 22.87, 22.62, 21.80, 18.84, 12.22, 1 1.63.

5b RMN 1H : δ = 3.3-3.85 (m, 1Η), 0.60-2.65 (m, 45H) ; 13C: δ = 211.36, 71.08, 57.18, 56.53, 54.33, 47.13, 39.86, 38.32, 37.07, 36.49, 36.08, 31.10, 30.44, 28.43, 28.39, 24.38, 24.20, 23.20, 22.93, 21.92, 19.03, 13.53, 12.40.

derived from synthesis Minos téroïdiens SA1-SA12

The aminostéroïdiens derivatives were all produced according to the same procedure. Consider the example of the SA-1 molecule.

In a two-necked flask placed under argon, 3.3 equivalents of spermine (171 mg, 0.82 mmol) were dissolved in 5 mL of MeOH, then added 300 of Ti (0 / ' -Pr) 4 (1 mmol). After 5 minutes of stirring, the mixture was added 102 mg of 3-keto-7o hydroxycholestane 5b (0.25 mmol). After 24 hours under stirring, the flask was placed at - 78 ° C, then 40 mg of NaBH 4 (1 mmol) are added under stirring. After 2 hours and returning to room temperature, 1 mL of water was added to terminate the reaction. After additional lh of stirring, the mixture was filtered through Celite. The filtrate was evaporated in vacuo the product was purified by chromatography on silica gel (eluent: CH 2 Cl 2 MeOH / NH 4 OH 7/3/1)).

Rdt: 54%. RMN Ή : δ = 3.16 (m, 1H), 2.44-2.65 (m,13H), 1.96 (m, 5H), 0.89-1.64 (m, 57H); 13C : 5 - 71.65, 57.46, 56.03, 51.04, 47.98, 47.64, 46.61, 45.34, 42.76, 40.80, 40.60, 40.02, 39.82, 39.74, 38.62, 37.16, 34.58, 33.12, 29.45, 28.30, 28.12, 25.1 1 , 24.30, 24.28, 22.68, 20.91, 18.73, 13.56, 11.92.

3p-spermino-7 -hydroxy-5a-cholestane SA-2

Rdt: 49%. RMN Ή : δ = 3.05 (m, 1H), 2.44-2.65 (m,13H), 1.95 (m, 5H), 0.89-1.63 (m, 57H); ! C : δ = 73.95, 57.46, 56.03, 51.04, 47.98, 47.64, 46.84, 45.84, 42.66, 41.80, 40.75, 40.39, 39.82, 39.65, 37.45, 37.26, 36.28, 26.26, 34.58, 33.97, 29.45, 28.30, 28.08, 25.35, 25.12, , 24.30, 24.28, 21.98, 20.90, 18.73, 13.54, 1 1.89.

3P-Norspermidino-7 -hydroxy-5a-choleslanc SA-3

Rdt: 46%. RMN ]H : δ = 3.14 (m, 1H), 2.55-2.65 (m,8H), 2.01 (m, 4H), 1.01-1.83 (m, 50H); 13C : δ = 73.46, 57.64, 56.03, 52.39, 47.47, 46.54, 45.98, 42.79, 41.20, 40.78, 40.54, 40.22, 40.10, 37.12, 37.02, 36.28, 36.26, 34.58, 33.91 , 29.41, 29.12, 28.23, 25.62, 23.41 , 23.12, 22.68, 20.84, 18.74, 13.68, 11.97.

3 - (l, 3-diamino-Oil -7β h y dro-5α-cholestane-4 SA

Rdt: 54%. RMN Ή : δ - 3.21 (m, 1H), 2.53-2.60 (m, 4H), 0.89- 1.81 (m, 51H); 13C : δ = 71.22, 57.33, 55.89, 52.02, 46.01 , 41.78, 40.96, 40.35, 39.92, 39.25, 39.02, 37.98, 37.1 1, 36.58, 36.45, 34.75, 34.25, 29.68, 28.64, 28.02, 23.56, 23.12, 22.68, 20.87, 18.98, 14.02,1 1.92.

3p-(l,4~diaminobutane)-7p-hydroxy~5a-cholestane SA-5

Rdt: 48%. RMN Ή : 8 = 3.17 (m, 1H), 2.55-2.63 (m,4H), 0.99-1.83 (m, 53H); 13C : δ - 71.23, 56.03, 55.66, 51.02, 48.29, 42.78, 41.19, 40.98, 40.02, 39.74, 39.65, 38.54, 37.14, 36.54, 36.45, 35.02, 34.89, 29.54, 29.45, 28.30, 28.08, 25.33, 24.85, 24.12, 22.67, 20.91, 18.76, 13.56, 11.90.

3 β- (T ris (2 aminocth l)amine)-7p-hydroxy-5tt-cholestane SA-6

Rdt: 29%. RMN Ή : δ = 3.12 (m, ÎH), 2.42-2.75 (m,10H), 1.89 (m, 6H), 1.01-1.87 (m, 47H); 13C : δ = 71.35, 57.70, 56.32, 55.24, 54.44, 51.04, 43.59, 42.98, 40.80, 40.12, 40.02, 40.00,

38.88, 38.32, 36.27, 35.97, 35.85, 35.02, 34.87, 29.18, 28.30, 28.08, 24.22, 23.85, 22.67,

20.89, 18.79, 13.54, 1 1.94.

3p-(l,5-diaminopentane)-7 -hydroxy-5a-cholestane SA-7

Rdt; 32%. RMN 1H : Ô = 3.14 (m, 1H), 2.54-2.60 (m,5H), 0.95-1.89 (m, 54H); 13C : δ = 71.90, 56.87, 52.43, 51.92, 48.71 , 47.38, 43.37, 42.57, 41.02, 40.51 , 39.71, 36.81, 36.51, 36.46, 36.38, 34.38, 34.12, 32.10, 29.84, 29.34, 28.68, 24.89, 22.44, 18.56, 12.34.

3p-(l,4-bis (3-aminopropyl)piperazïne)-7p-hydroxy-5«-choIestane SA-8

SA-8

Rdt: 48%. RMN Ή : δ = 3.21 (m, 1H), 2.52-2.66 (m,6H), 0.97-1.95 (m, 63H); Î3C : δ = 73.12, 56.42, 52.4, 51.91, 48.70, 47.32, 43.35, 42.55, 41.0, 40.57, 39.77, 36.89, 36.59, 36.40, 36.34, 34.38, 34.14, 32.12, 29.85, 29.37, 28.62, 24.88, 22.41, 22.41, 18.13 , 12.33.

3p-(l,4-bis-(3-aminopropoxy)butane)-7p-hydroxy-5tt-cholestane SA-9

claims

1. A compound of formula (I):

in which :

Ri is selected from H, S0 3 H, alkyl Ci-Cg, an aryl group of C 6 -C 10 , C (= 0) R 3 ,

R2 est -(CR3R4)m-(X)P-(CR5R6)n-[(Y) -(CR7Rs)o]q-NR9R10,

R 3 , R 4, R 5 , R &, R7, Rs are, at each occurrence, identical or different, each independently selected from H, alkyl Ci-Cg, C 6 -C 0 aryl and
;

R9, Rio, same or different are each independently selected from H, C | -C 8 alkyl, - (CH 2) r -NH 2 , or together form a heterocyclyl group having 5 to 7 ring members optionally substituted by one to three groups R M ;

X, Y, are the same or different at each occurrence, each independently selected from NR ! 3 , O, or heterocyclyl nitrogen-containing 5 to 6 members,

Rn, R12 are each independently selected from alkyl, Ci-Cs, an aryl group of C 6 -Cio,

R 13 is H, Ci-C 6 alkyl, or a group - (CH 2 ) S -NH 2;

Ri4 is = 0, = S;

m is an integer between 1 and 5;

n is an integer between 1 and 5,

o is an integer between 1 and 5,

p is 0 or 1,

q is 0, 1, 2, or 3,

r is an integer between 1 and 4,

s is an integer between 1 and 5,

and stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof, for use in treating bacterial, fungal, viral, parasitic or in the treatment of cancer in humans or animals.

2. A compound of formula (I) for use according to claim 1, wherein the compound 3 - (norspermine) -7a-hydroxy-5a-cholestane and the following compounds of formula are excluded:

SA-Z

3. A compound of formula (I) for use according to claim 1, wherein the compounds for which p ~ i, q = 0, m = 3, n = 3 or 4, and X = NH are excluded.

4. A compound of formula (I) for use according to Claim 1, -in which it is understood that:

when p = l and q = 0, then n + ≠ 6 and 7,

when p = 0 and q = l, then m + n + o ≠ 6 and 7.

5. A compound of formula (I) for use according to any preceding claim, wherein Ri is H.

6. A compound of formula (I) for use according to any one of the preceding claims, wherein X is NR13, preferably NH.

7. A compound of formula (I) for use according to any preceding claim, wherein R9 and / or R are H.

8. A compound of formula (I) for use according to any one of the preceding claims, wherein m is 2, 3, 4, or 5, preferably 3.

9. A compound of formula (I) for use according to any one of the preceding claims, wherein the group -NHR 2 is selected from:

NH,

Compound of formula (I) for use according to claim 1 selected from

3 p-spermino-7a-hydroxy-5a-cholestane (S A- 1 )

3p-spermino-7p-hydroxy-5a-cholestane (SA- 2)

3 p -Norsp errnidino-7 p -hydroxy- 5 α-cho lestane (SA- 3 )

3β-(1 ,3-diaminopropane)-7p~hydroxy-5a-cholestane (SA-4)

3β-( ,4-diaminobutane)-7β-hydΓoxy-5α-cl olestane (SA-5)

3 β -(Tris(2aminoethyl)amine)- 7 β -hydroxy- 5 α-chol estane (S A-6)

3β-(l,5-diaminopentane)-7α-hydroxy-5α-choIestane (SA-7)

3p-(l,4-bis (3-aminopropyI)piperazine)-7p~hydroxy-5a-cholestane (SA- 8)

3β-(l,4-bis-(3-aInino ropoxy) utane)-7β~hydroxy-5 -cholesίane (SA- 9)

3 -(l-(3-aminopropyl)inaidazole)-7a-hydroxy-5a-cholestane (SA-11) - 3 -(l-(3-amino ropyl)morpholine)- α-hydΓo y-5 -cholestane (SA-12)

1 1. A compound of formula (I) for use according to any one of the preceding claims, wherein the infection is a bacterial infection, including gram + or gram -.

12. A compound of formula (I) for use according to any one of the preceding claims, in animai, particularly in dogs, cats, or ruminants.

13. A compound of formula (I) for use according to any one of the preceding claims, for the treatment of mastitis, metritis, dental infections, or otitis pyoderma in animals.

14. A compound of formula (I) for use according to any one of the preceding claims, wherein the compound of formula (I) is administered in combination with another antibiotic compound.

15. A pharmaceutical or veterinary composition comprising a compound of formula (I) or a stereoisomer, mixture of stereoisomers and / or a pharmaceutically acceptable salt of a compound of formula (I) according to claim 1 and a pharmaceutically acceptable excipient.

16. Pharmaceutical or veterinary composition according to claim 15, wherein the compound 3 - (norspermine) -7a-hydroxy-5a-cholestane and the following compounds of formula are excluded:

SA-Z

17. Pharmaceutical or veterinary composition according to claim 15 or 16, further comprising a second antibiotic compound.

18. A compound of formula (I) as defined in claim 1.

19. A process for preparing a compound of formula (I) according to claim I comprising a reductive amination step with a compound of formula (II) in the presence of an amine NH R ui ar this is taken into the o ed

Ri, R 2 being as defined in claim 1.