WO2016166319A1 - Boramides for treating diseases - Google Patents
Boramides for treating diseases Download PDFInfo
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- WO2016166319A1 WO2016166319A1 PCT/EP2016/058396 EP2016058396W WO2016166319A1 WO 2016166319 A1 WO2016166319 A1 WO 2016166319A1 EP 2016058396 W EP2016058396 W EP 2016058396W WO 2016166319 A1 WO2016166319 A1 WO 2016166319A1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to new compounds and their use in medicine, particularly as agents able to treat and/or prevent an infection caused by a bacterium, fungi or virus and to treat and/or prevent cancer.
- cancer causes an estimated 7 million people annually which, it is estimated, will rise to 10 million in 2020.
- Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Frequently resistance is intrinsic to the cancer, but as therapy becomes more and more effective, acquired resistance has also become common.
- Boron is not a common element in pharmaceutical drugs, however it shows a unique geometry allowing the compounds the ability to interact with biological targets in a novel way. Development of these drugs in which the boron is in a plane geometry started in 2000. Some examples are the antifungal Tavaborole (AN2690) useful for topical treatment of onychomycosis (Baker, SJ, et al, Med Chem 2006, 49, 4447-50) and the antibiotic AN3365 active against Gram-negative bacteria. However AN3365 is less effective against some multidrug resistant bacteria such as A.
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl, -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C3 alkyl, excluding the compounds of formula (I) wherein Ri, R ' i, R 2 and R ' 2 are -H, wherein Ri and R ' i are -H and R 2 and R ' 2 are independently selected from -Br and -H, and wherein Ri and R ' i, are -H and R 2 and R ' 2 are independently selected from -CI and -H.
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl , -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched - Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thio-alkyl, N0 2 and NR 3 R 4 , wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C3 alkyl
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl, -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, or the pharmaceutical composition according to the invention for use in medicine.
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl , -C 6 aryl, and
- R 2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl or the pharmaceutical composition according to any of claims 14 to 18 for use in preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
- the invention relates to a compound of formula (I) or a
- Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl , -C 6 aryl, and
- R 2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C3 alkyl, excluding the compound of formula (I) wherein Ri, R ' i, R 2 and R ' 2 are -H, wherein Ri and R ' i are -H and R 2 and R ' 2 are independently selected from -Br and -H, and wherein Ri and R ' i, are -H and R 2 and R ' 2 are independently selected from -CI and -H.
- halogen or "halo" as used herein refer to an atom selected from fluorine, chlorine, bromine, iodine and astatine. In a preferred embodiment the halogen is fluorine, chlorine or bromine.
- alkyl refers to a linear or branched saturated hydrocarbon chain radical consisting of carbon and hydrogen atoms and which is attached to the rest of the molecule by a single bond.
- Ci_ 6 alkyl refers to an alkyl having between 1 and 6 carbon atoms.
- the term "Ci_6 alkyl”, as used in the present invention, is intended to include straight-chain (linear), branched and cyclic alkyl groups of from 1 to 6 carbon atoms.
- Relevant linear Ci_ 6 alkyl groups are methyl, ethyl, propyl, butyl, pentyl and hexyl.
- Ci_ 6 alkyl groups are isopropyl, sec-butyl, tert-butyl, isopentyl and isohexyl.
- cyclic groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- Ci_6 alkyl in the present context likewise includes, for example, cycloalkyl-substituted alkyl groups having from 1 to 6 carbon atoms, examples of which include groups such as (cyclopropyl)methyl, (cyclopropyl)ethyl, (cyclopropyl)propyl, (cyclobutyl)methyl, (cyclobutyl)ethyl and (cyclopentyl) methyl.
- Particularly suitable Ci_ 6 alkyl groups are often chosen among Ci_3 alkyl groups, i.e.methyl, ethyl, propyl, isopropyl and cyclopropyl.
- the Ci_ 6 alkyl is methyl.
- Substituted as used herein relates to compounds, as described herein, may be substituted with any number of substituents or functional moieties.
- substituted whether proceeded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- substituted is contemplated to include all permissible substituents of organic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
- Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
- C 6 aryl refers to a monocyclic or polycyclic aryl radical having 6 carbon atoms.
- a said optionally substituted aryl radical is typically unsubstituted or substituted with 1 , 2 or 3 substituents which may be the same or different.
- the substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups, alkoxycarbonyl groups. In an embodiment phenyl is preferred.
- Ci-6 alcoxy as used herein relates to carbon and hydrogen chain group singular bonded to oxygen from 1 to 6 carbon atoms. In a preferred embodiment, Ci- 6 alcoxy is 0-CH 3 .
- Ci_6 thioalkyl used herein refers to a substituted or unsubstituted alkyl group, as previously defined, attached to the parent molecule through a sulfur atom.
- Ri and R ' i are -H and R 2 is linear or branched -Ci_ 6 alkoxy and R ' 2 is -H. In a more preferred embodiment, wherein the linear or branched -Ci_6 alkoxy is -O-CH 3 .
- Ri and R ' i are H and R 2 and R ' 2 are independently selected from the group consisting of linear or branched -Ci_ 6 alkyl and -H. In a more preferred embodiment the linear or branched -Ci- 6 alkyl is -CH 3 .
- Ri and R ' i are H, and R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 , linear or branched -Ci_ 6 alcoxy, -N0 2 and -H, wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -3 alkyl.
- -NR 3 R 4 is -N-diethyl.
- Ri and R ' i are H and R 2 and R ' 2 are independently selected from the group consisting of -OH, linear or branched -Ci_ 6 alcoxy and -H.
- R 2 and R ' 2 are selected from the group consisting of halogen and -H and Ri and R'i are independently selected from the group consisting of linear or branched Ci- 6 alkyl and -H.
- the linear or branched Ci- 6 alkyl is -CH 3 .
- R 2 and R ' 2 are independently selected from the group consisting of -H and halogen and Ri and R'i are independently selected from the group consisting of -C 6 aryl and -H.
- C 6 aryl is -C 6 H5.
- the compound of the invention is a compound of formula (I) wherein R l s R'i, R 2 and R' 2 are as defined in the following table
- salt is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
- a counter-ion a cation or anion
- complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
- the definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts” or “pharmaceutically acceptable salts”.
- physiologically acceptable salt or “pharmaceutically acceptable salt” is understood in particular, in the context of this invention, as a salt (as defined above) formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals - or with at least one, preferably inorganic, cation which are physiologically tolerated - especially if used on humans and/or mammals.
- salts of compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
- such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stochiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.
- nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred.
- acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
- mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
- organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
- alkali addition salts examples include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, ⁇ , ⁇ -dialkylenethanolamine, triethanolamine and basic aminoacids salts. Since hydroxytyrosol has three hydroxyl groups, alkali addition salts are particularly preferred such as Na+ and NX4+ (wherein X is independently selected from H or a C1 -C4 alkyl group).
- the compounds of the invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates, alcoholates, particularly methanolates) and it is intended that both forms are within the scope of the present invention.
- Solvate may include water or non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.
- Solvates, wherein water is the solvent molecule incorporated into the crystal lattice are typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. Methods of solvation are generally known within the art.
- the compound including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
- the compounds or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs".
- polymorphs typically known as "polymorphs”.
- the disclosed compounds and solvates e.g., hydrates
- Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties.
- Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
- different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs.
- one polymorph may spontaneously convert to another polymorph under certain conditions.
- Any compound referred to herein is intended to represent such specific compound as well as certain variations or forms.
- the compounds of the present invention represented by the above described formula (I) include stereoisomers.
- stereoisomer as used herein includes any enantiomer, diastereomer or geometric isomer (E/Z) of such compound.
- compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms.
- any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof.
- stereoisomerism or geometric isomerism related to a double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same or different than the stereoisomerism of the other double bonds of the molecule. All the stereoisomers including enantiomers, diastereoisomers and geometric isomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
- any compound referred to herein may exist as tautomers.
- tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another. Common tautomeric pairs are enamine-imine, amide-imidic acid, keto-enol, lactam- lactim, etc.
- the compounds of the invention are also meant to include isotopically-labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms.
- isotopically-labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms.
- compounds having the present structures except for the replacement of at least one hydrogen atom by a deuterium or tritium, or the replacement of at least one carbon by 13 C- or 14 C-enriched carbon, or the replacement of at least one nitrogen by 15 N-enriched nitrogen are within the scope of this invention.
- the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
- pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
- Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its pharmaceutically acceptable salt, stereoisomer or solvate.
- the invention also provides "metabolites" of the compounds described in the present description.
- a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
- active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
- the term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
- cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
- the invention also provides "prodrugs" of the compounds described in the present description.
- the term "prodrug”, as used herein, is intended to represent covalently bonded carriers, which are capable of releasing the compound of formula (I) as active ingredient when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
- Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
- Prodrugs of compounds of the invention include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
- prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N- dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
- esters e.g., acetate, formate, and benzoate derivatives
- carbamates e.g., N,N- dimethylaminocarbonyl
- amides e.g., trifluoroacetylamino, acetylamino, and the like
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl, -C 6 aryl, and
- R 2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched - Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thio-alkyl, N0 2 and NR 3 R 4 , wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C3 alkyl
- “Pharmaceutical composition” as used herein, relates to compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavorable reaction as gastric disorders, dizziness and suchlike, when administered to a human or animal.
- the term “pharmaceutically acceptable” means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
- excipient refers to a vehicle, diluent or adjuvant that is administered with the active ingredient.
- Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and similars. Water or saline aqueous solutions and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as vehicles.
- Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 21 st Edition, 2005; or "Handbook of Pharmaceutical Excipients", Rowe C. R.; Paul J. S.; Marian E. Q., sixth Edition
- Ri and R ' i are H and R 2 and R ' 2 are independently selected from the group consisting of halogen and -H.
- the halogen is -Br or -CI.
- R ' i, R 2 and R ' 2 are -H
- Ri and R ' i are -H and R 2 and R ' 2 are -Br Ri and R ' i are -H
- R 2 is -Br and R ' 2 is -H
- Ri and R ' i are -H and R 2 and R ' 2 are -CI
- Ri and R ' i are -H
- R 2 is -CI and R ' 2 is -H.
- the pharmaceutical composition of the invention comprises a compound of the invention as defined above.
- a compound of formula (I) as defined above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof can be formulated with pharmaceutically acceptable excipients and/or carriers to obtain a pharmaceutical composition for use in medicine, particularly in preventing and/or treating an infection caused by a bacterium, fungi or virus or preventing and /or treating cancer.
- Suitable pharmaceutically acceptable vehicles include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, monoglycerides and diglycerides of fatty acids, fatty acid esters petroetrals, hydroxymethyl cellulose, polyvinylpyrrolidone and similars.
- compositions containing the compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof according to the invention can occur at any pharmaceutical form of administration considered appropriate for the selected administration route, for example, by systemic (e.g intravenous, subcutaneous, intramuscular injection), oral, parenteral or topical administration, for which it will include the pharmaceutically acceptable excipients necessary for formulation of the desired method of administration. Additionally, it is also possible to administer the composition comprising the compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof of the invention intranasally or sublingually which allows systemic administration by a non-aggressive mode of administration. Also, intraventricular administration may be adequate. A preferred route of delivery is intravenous.
- the compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is comprised in a composition also including a solubilizing agent and a local anesthetic to ameliorate any pain at the site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
- the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
- the composition can contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- the composition can be a liquid solution, suspension, emulsion, gel, polymer, or sustained release formulation.
- the composition can be formulated with traditional binders and carriers, as would be known in the art.
- Formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharide, cellulose, magnesium carbonate, etc., inert carriers having well established functionality in the manufacture of pharmaceuticals.
- Various delivery systems are known and can be used to administer a therapeutic of the present invention including encapsulation in liposomes, microparticles, microcapsules and the like.
- Solid dosage forms for oral administration may include conventional capsules, sustained release capsules, conventional tablets, sustained-release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, suspensions, powders, granules and gels.
- the active compounds can be mixed with at least one inert excipient such as sucrose, lactose or starch.
- Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include emulsions, solutions, suspensions, syrups and elixirs pharmaceutically acceptable containing inert diluents commonly used in the technique, such as water. Those compositions may also comprise adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening agents, flavoring and perfuming agents.
- Injectable preparations for example, aqueous or oleaginous suspensions
- sterile injectable may be formulated according with the technique known using suitable dispersing agents, wetting agents and/or suspending agents.
- suitable dispersing agents wetting agents and/or suspending agents.
- suitable vehicles and solvents water, Ringer's solution and isotonic sodium chloride solution.
- Sterile oils are also conventionally used as solvents or suspending media.
- compounds of the invention can be formulated as creams, gels, lotions, liquids, pomades, spray solutions, dispersions, solid bars, emulsions, microemulsions and similars which may be formulated according to conventional methods that use suitable excipients, such as, for example, emulsifiers, surfactants, thickening agents, coloring agents and combinations of two or more thereof.
- suitable excipients such as, for example, emulsifiers, surfactants, thickening agents, coloring agents and combinations of two or more thereof.
- the compounds of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof may be administered in the form of transdermal patches or iontophoresis devices.
- the compounds of the invention are administered as a transdermal patch, for example, in the form of sustained-release transdermal patch. Suitable transdermal patches are known in the art.
- Several drug delivery systems are known and can be used to administer the agents or compositions of the invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and similars.
- the required dosage can be administered as a single unit or in a sustained release form.
- the orally administrable form of a compound according to the invention is in a sustained release form further comprises at least one coating or matrix.
- the coating or sustained release matrix include, without limitation, natural polymers, semisynthetic or synthetic water-insoluble, modified, waxes, fats, fatty alcohols, fatty acids, natural semisynthetic or synthetic plasticizers, or a combination of two or more of the them.
- Enteric coatings may be applied using conventional processes known to experts in the art, as described in, for example, Johnson, J. L., "Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A. A. (eds), Marcel Dekker, Inc. New York, (2001), Carstensen, T., "Coating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (ed.), Marcel Dekker, Inc. New York (2001), 455- 468.
- the present invention also encompasses the combination of the compounds of formula (I) or of its pharmaceutically acceptable salt, stereoisomer or solvate with other antimicrobial drugs or cancer chemotherapeutic agents.
- a combination of at least a compound of formula (I) and at least another antimicrobial drug or cancer chemotherapeutic agents may be formulated for its simultaneous, separate or sequential administration. This has the implication that the combination of the two compounds may be administered:
- the compound of formula (I) is independently administered from the other antimicrobial drug or cancer chemotherapeutic agent (i.e in two units) but at the same time.
- the compound of formula (I) is administered first, and then the other antimicrobial drug or cancer chemotherapeutic agent is separately or sequentially administered.
- the other antimicrobial drug or cancer chemotherapeutic agent is administered first, and then the compound of formula (I) is administered, separately or sequentially, as defined.
- Antimicrobial drug relates to any drug capable of killing bacteria, viruses, fungi or parasites or inhibit their growth.
- Antimicrobial medicines can be grouped according to the microorganisms they act primarily against, antibacterial, antifungal, antiviral and antiparasitic.
- the other antimicrobial drug is an antifungal.
- cancer chemotherapeutic agent includes standard chemotherapy drugs, which generally attack any quickly dividing cell, targeted therapy agents and immunomodulatory agents.
- Illustrative non- limitative examples of cancer chemo therapeutic agents which may be in accordance to the present invention include alkylating agents, antimetabolite drugs, anthracycline antibiotics, antibodies targeted against proangiogenic factors, topoisomerase inhibitors, antimicrotubule agents ,low molecular weight tyrosine kinases inhibitors of proangiogenic growth factors and matrix metalloproteinase inhibitors.
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl, -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C3 alkyl, or the pharmaceutical composition according to the invention for use in medicine.
- the halogen is -Br or -CI.
- R ' i, R 2 and R ' 2 are -H, wherein Ri and R ' i are -H and R 2 and R ' 2 are -Br, wherein Ri and R ' i are -H, R 2 is -Br and R ' 2 is - H, wherein Ri and R ' i are -H and R 2 and R ' 2 are -CI, or wherein Ri and R ' i are -H, R 2 is -CI and R ' 2 is -H.
- the compound for use in medicine is any of the compounds previously described.
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl , -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C3 alkyl or the pharmaceutical composition according to the invention for use in preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
- the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl , -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C 3 alkyl or the pharmaceutical composition according to the invention for the preparation of a medicament for preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
- the invention relates to a method for preventing and/or treating an infection caused by a bacterium, fungi or virus or for use in preventing and/or treating cancer comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
- Ri and R ' i are independently selected from the group consisting of -H, linear or branched -Ci- 6 alkyl , -C 6 aryl, and
- R 2 and R ' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci- 6 alkyl, -OH, linear or branched -Ci_ 6 alcoxy, -SH, linear or branched -Ci_ 6 thioalkyl, N0 2 , and NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of -H and linear -C 1 -C 3 alkyl or the pharmaceutical composition according to the invention.
- the halogen is -Br or -CI.
- R ' i, R 2 and R ' 2 are -H, wherein Ri and R ' i are -H and R 2 and R ' 2 are -Br , wherein Ri and R ' i are -H, R 2 is -Br and R ' 2 is -H, wherein Ri and R ' i are -H and R 2 and R ' 2 are -CI, or wherein Ri and R ' i are -H, R 2 is -CI and R ' 2 is -H.
- the compound for use in medicine is any of the compounds previously described
- treat As used herein, the terms “treat”, “treating” and “treatment” include in general the eradication, removal, reversion, alleviation, modification, or control of the infection or cancer after its onset.
- prevention refers to the capacity of a given substance, composition or medicament to avoid, minimize or difficult the onset or development of an infection or cancer before its onset.
- infection relates to invasion by bacteria, viruses, fungi, protozoa or other microorganisms, referring to the undesired proliferation or presence of invasion of pathogenic microbes in a host organism. It includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal. Thus, a microbial infection exists when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal.
- the compound of the invention for use in preventing and/or treating an infections caused by a bacterium.
- the compound for use in preventing and/or treating an infection caused by a bacterium is a compound of formula (I) wherein R l s R ' i, R 2 and R ' 2 are as defined in the following table A or is a pharmaceutical composition comprising the same.
- bacterium refers to both gram-negative and gram-positive bacterial cells capable of infecting and causing disease in a mammalian host, as well as producing infection-related symptoms in the infected host, such as fever or other signs of inflammation, intestinal symptoms, respiratory symptoms, dehydration, and the like.
- the bacteria are gram-negative bacteria. In another embodiment the bacteria are gram-positive bacteria. In another further embodiment the bacteria are gram-positive bacteria together with gram-negative bacteria. In another embodiment there is only one bacteria specie or different bacteria species; one bacteria genus or different bacteria genus, infecting or causing disease.
- the bacteria is of a genus selected from the group consisting of Acinetobacter, Actinobacillus, Aeromonas, Aggregatibacter, Agrobacterium, Bacillus, Bordetella, Brucella, Burkholderia, Campylobacter, Chromobacterium, Cyanobacteria, Enterobacter, Erwinia, Escherichia, Franciscella, Fusobacterium, Haemophilus, Helicobacter, Hemophilus, Klebsiella, Lactobacillus, Legionella, Listeria, Micrococcus, Moraxella, Mycobacterium, Neisseria, Nitrosomas, Nocardia, Obesumbacterium, Pantoea, Pasteurella, Pediococcus, Porphyromonas, Prevotella, Proteus, Pseudomonas, Ralstonia, Rhisobium, Rhodobacter, Salmonella, Serratia, Shigella, Sta
- the bacteria is of a species selected from the group consisting of Aeromonas hydrophila, Aeromonas salmonicida, Acinetobacter baumannii, Aggregatibacter actinomycetemcomitans, Agrobacterium tumefaciens, Bacillus Cereus, Bacillus Subtilis, Burkholderia cepacia, Campylobacter jejuni, Chromobacterium violaceum, Enterobacter agglomeran, Erwinia carotovora, Erwinia chrysanthemi, Escherichia coli, Fusobacterium nucleatum, Haemophilus injluenzae, Helicobacter pylori, Lactobacillus Plantarum, Listeria Monocytogenes, Klebsiella Pneuumoniae, Micrococcus Luteus, Mycobacterium tuberculosis, Neisseria meningitidis, Neisseri
- the infection is caused by a Gram positive bacterium.
- the Gram positive bacterium is from phylum Firmicutes.
- the bacterium form phylum Firmicutes is a bacterium from genus Staphylococcus, Enterococcus, Streptococcus or Bacillus.
- the bacterium from genus Staphylococcus is Staphylococcus aureus or Staphylococcus epidermidis.
- the bacterium from genus Enterococcus is E. faecalis or E. faecium.
- the bacterium from genus Streptococcus is S. pyogenes or S. pneumoniae.
- the bacterium from genus Bacillus is B. cereus.
- the Gram positive bacterium is from phylum Actinobacteria.
- bacterium form phylum Actinobacteria are Nocardia, Corynebacterium, Mycobacterium, Streptomyces, Micromonospora, Arthobacter, Frankia, Propionibacterium, Actinomyces.
- the bacterium from phylum Actinobacteria is a bacterium from genus Mycobacterium, Nocardia, Tsukamurella or Streptomyces.
- the bacterium from the genus Mycobacterium is M. fortuitum, M. chelonae, M. abscessus
- the bacterium from genus Nocardia is Nocardia carnea or Nocardia cyriacigeorgica or the bacterium from genus Tsukamurella is Tsukamurella pulmonis.
- the Gram negative bacterium is from phylum
- “Phylum proteobacteria”, as used herein relates to a major group of gram- negative bacteria, which is defined primarily in terms of ribosomal R A sequences. They are divided into six classes Alphaproteobacteria, including the genera Brucella, Rhizobium, Agrobacterium, Caulobacter, Rickettsia, Wolbachia; Betaproteobacteria including the genera Bordetella, Ralstonia, Neisseria, Nitrosomonas; Gammaproteobacteria including the genera Acinetobacter, Escherichia, Shigella, Salmonella, Yersinia, Buchnera, Haemophilus, Vibrio, Pseudomonas; Deltaproteobacteria including the genera Desulfovibrio, Geobacter, Bdellovibrio; Epsilonproteobacteria including the genera Helicobacter, Campylobacter, Wolinella; Zetaproteobacteria including the genera Mariprofundus.
- the bacterium form phylum proteobacteria is from genus Klebsiella, Acinetobacter, Enterobacter or Escherichia.
- the Acinetobacter bacterium is Acinetobacter baumannii.
- the bacterium form genus Enterobacter is E. cloacae.
- the bacterium form genus Escherichia is E. coli.
- the compound of the invention or the pharmaceutical composition according to the invention is for use in the prevention and/or treatment an infection caused by a fungi, particularly a fungi from genus Candida, Aspergillus or Saccharomyces.
- fungi relates to an organism from kingdom Fungus, and particularly to those fungi capable of causing diseases in humans such as Aspergillus, Candida, Cryptoccocus, Histoplasma, Pneumocystis and Saccharomyces.
- the fungi from genus Candida is selected from the group consisting of Candida is C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, C. lusitaniae and C. krusei.
- the fungi from genus from genus Aspergillus is selected from the group consisting of A. niger, A.fumigatus, A. flavus and A. terreus.
- the fungi from genus Saccharomyces is S. cerevisiae.
- the compound for use in preventing and/or treating an infections caused by a fungi is a compound of formula (I) wherein R l s R ' i, R 2 and R ' 2 are as defined in the following table B or a pharmaceutical compositions comprising the same.
- the compound of the invention or the pharmaceutical composition according to the invention is for use in the prevention and/or treatment an infection caused by a virus.
- virus refers to a small infectious agent that replicates only inside the living cells of other organism.
- the virus is selected from the group consisting of adenovirus, coxsackievirus, Epstein-Bar, Hepatitis A, B or C, herpes simplex type 1, herpes simplex type 2, cytomegalovirus, herpesvirus type 8, HIV, Influenza, Measles, mumps, human papillomavirus, parainfluenza, poliovirus, rabies, respiratory syncytial, rubella, varicella-zoster.
- the virus is HIV.
- the compound for use in preventing and/or treating an infections caused by a virus is a compound of formula (I) wherein Ri , R ' i , R 2 and R ' 2 are as defined in the following table C or a pharmaceutical compositions comprising the same.
- Table C Preferred compounds for preventing and/or treating an infection caused by a virus, particularly VIH.
- the compound of the invention or the pharmaceutical composition is for use in the prevention and/or treatment of cancer.
- tumour refers to a disease characterized by uncontrolled cell division (or by an increase of survival or apoptosis resistance) and by the ability of said cells to invade other neighbouring tissues (invasion) and spread to other areas of the body where the cells are not normally located (metastasis) through the lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body.
- tumours are classified as being either benign or malignant: benign tumours are tumours that cannot spread by invasion or metastasis, i.e., they only grow locally; whereas malignant tumours are tumours that are capable of spreading by invasion and metastasis.
- cancer includes, but is not limited to, the following types of cancer: breast cancer; biliary tract cancer; bladder cancer; brain cancer including glioblastomas, in particular glioblastoma multiforme, and meduUoblastomas; cervical cancer; head and neck carcinoma; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including acute lymphocytic and myelogenous leukemia; T- cell acute lymphoblastic leukemia/lymphoma; hairy cell leukemia; chronic myelogenous leukemia, multiple myeloma; AIDS-associated leukemias and adult T-cell leukemia/lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer, hepatoma; lung cancer, pleural mesothelioma; lymphomas including Ho
- the cancer is colorectal or breast cancer.
- colonal cancer also known as “colon cancer”, “rectal cancer”, or “bowel cancer”, refers to a cancer from uncontrolled cell growth in the colon or rectum, or in the appendix.
- breast cancer relates to any malignant proliferative disorder of breast cells, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas, while those originating from lobules are known as lobular carcinomas.
- the compound for use in preventing and/or treating cancer, particularly colorectal cancer is a compound of formula (I) wherein R l s R ' i , R 2 and R' 2 are as defined in the following table D or a pharmaceutical composition comprising the same.
- the compound for use in preventing and/or treating cancer, particularly breast cancer is a compound of formula (I) wherein R l s R'i, R 2 and R' 2 are as defined in the following table E or a pharmaceutical composition comprising the same.
- the present invention covers any combination of compounds and diseases.
- the compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof or the pharmaceutical composition of the invention is present in an effective amount.
- an "effective amount or a "therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect.
- an "effective amount" of one component of the combination is the amount of that compound that is effective to provide the desired effect when used in combination with the other components of the combination.
- the dosage needed to provide an effective amount of such compound which can be adjusted by one expert in the art will vary depending on age, health, fitness, sex, diet, weight, frequency of treatment and the nature and extent of impairment or illness, medical condition of the patient, route of administration, pharmacological considerations such as activity, efficacy, pharmacokinetic and toxicology profile of the particular compound used, if using a system drug delivery, and if the compound is administered as part of a combination of drugs.
- the effective quantity of the compound of the invention can vary within a wide range and, in general, will vary depending on the particular circumstances of application, duration of the exposure and other considerations. In a particular embodiment, the dose ranges between 0.05 mg/kg and 50 mg/kg, more preferably between 1 mg/kg and 20 mg/kg.
- the effective amount is between about between about 0.005 % and about 0.04 % weight, between about 0.0075 % weight and about 0.0375 % weight, between about 0.001 % weight and about 0.035 % weight, between about 0.00125 % weight and about 0.0325 % weight, between about 0.0015 % weight and about 0.0325 % weight, between about 0.00175 % weight and about 0.03 % weight, and more preferably between about 0.0018 % weight and about 0.032 % weight.
- the effective amount is between about 0.005% and about 0.02% weight, preferably between about 0.005%> weight and about 0.015%) weight, more preferably between about 0.005%> weight and about 0.01% weight.
- the effective amount is about 0.001 % weight, about 0.002 % weight, about 0.003 % weight or about 0.004 % weight.
- the percentages (% w/w) are expressed as weight of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof by the total weight of the composition comprising the compound or by weight of the foodstuff, foodstuff package, medical device or surface.
- the effective amount is expressed in ⁇ g/mL or ⁇ g/g g of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof by mL or g of the composition comprising the compound), therefore effective amount is about 75 and about 375 ⁇ g/mL (or ⁇ ), between about 100 and about 350 ⁇ g/mL (or ⁇ ), between about 125 and about 325 ⁇ g/mL (or ⁇ ), between about 150 and about 325 ⁇ g/mL (or ⁇ ), between about 175 and about 300 ⁇ g/mL (or ⁇ ), and more preferably between about 180 and about 320 ⁇ g/mL (or ⁇ g/g).
- the effective amount is between about 50 and about 200 ⁇ g/mL (or ⁇ ), preferably between 50 and about 150 ⁇ g/mL (or ⁇ g/g), more preferably between about 50 and about 100 ⁇ g/mL (or ⁇ ). In some embodiments the effective amount is about 100 ⁇ g/mL (or ⁇ ), about 200 ⁇ g/mL (or ⁇ g/g), about 300 ⁇ g/mL (or ⁇ ) or about 400 ⁇ g/mL (or ⁇ ).
- the compound of formula (I) or a salt, solvate or isomer thereof as defined herein is present on a surface, it is preferably in an effective amount of between about 1 and about 200 ⁇ g/cm 2 , preferably between about 1 and about 100 ⁇ g/cm 2 , preferably between about 1 and about 50 ⁇ / ⁇ 2 , more preferably between about 5 and about 300
- Boramides compounds of the invention were obtained as disclosed in Tena-Perez et al., (Tetrahedron, 2014, 70: 8614-8618). Imines were prepared by treatment of a solution of the corresponding salicylaldehyde (1.00 mmol) in a 1 : 1 mixture of MeOH:THF (1.0 mL) with N3 ⁇ 4 gas during 1 min. The reaction mixture was then used for the preparation of the boramides without isolating the intermediate imines.
- IMP lmipenem
- CTX Cefotaxime
- A/C Amoxicillin/Clavulanate
- Lin Linezolid
- AMK Amikacin
- SxT Cotrimoxazole
- CIP Ciprofloxaci
- ERI Erythromycin
- GEN Gentamicin
- PEN Penicillin
- VAN Vancomycin
- RIF Rifampicin
- TET Tetracycline
- CU Clindamycin
- MER Meropenem
- CEF Ceftriazone
- LEV Levofloxacin
- TEI Teicoplanin
- CLO Chloramphenicol
- Bacterial cells suspension in sterile saline was prepared from a culture of 24-72 h, depending on bacterial species, in Mueller-Hinton Agar with 5% sheep blood. Each suspension was adjusted to a fixed size inoculum of 1-5 x 10 8 CFU/ml with a spectrophotometer (Ferraro, MJ National Committee for Clinical Laboratory Standards. 2000).
- Kirby-Bauer disk diffusion susceptibility test protocol was utilized to determine the sensitivity or resistance of pathogenic bacteria against the compounds and others antibiotics. The absence of growth around the disks is an indirect measure of the ability of this compound to inhibit an organism (Kirby, W.. et al, Antibiotics Annu. 1956- 1957:892). After 18 to 72 hours of incubation at 37°C, with or without C0 2 , under aerobic or anaerobic conditions, depending on the bacterial species, halo of growth inhibition were obtained and evaluated
- Kirby-Bauer disk diffusion susceptibility test is a common method which uses antibiotic-impregnated wafers to test whether bacteria are affected by antibiotics.
- the size of the zone of inhibition depends on how effective the antibiotic is at stopping the growth of the bacterium. A stronger antibiotic will create a larger zone, because a lower concentration of the antibiotic is enough to stop growth.
- B. cereus is bacteriostatic.
- Table V Characteristics of the fungi and yeast strains.
- Filamentous fungi and yeast cells suspensions in distilled water was prepared from a culture of 24-48 h, depending on species, in Sabouraud agar. Each suspension was adjusted to a fixed size inoculum of 1-5 x 10 8 CFU/ml with a spectrophotometer (Ferraro, MJ National Committee for Clinical Laboratory Standards. 2000).
- Antifungal susceptibility test Antifungal susceptibility tests were developed following the standardized methodology detailed in document CLSI: M44-4: Method for Antifungal Disk diffusion susceptibility testing of yeasts consisting of disk diffusion on agar Muller-Hinton (supplemented with 2 % glucose).
- Assessment of in vitro antiviral activity is usually performed to estimate parameters of antiviral potency and efficacy represented by the percentage of inhibition of HIV activity or IC50.
- the assay utilized is based on the use of recombinant viruses in which the nef gene, essential for in vitro HIV replication, has been replaced by a Renilla reporter gene so that we can quantify viral replication directly (Garcia-Peresz J et al, J Med Virol. 2007 Feb;79(2): 127-37).
- the study was development in AIDS Immunopathology Unit, Nacional Center of Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain.
- T-ll 99% 81% 0% 0% 102% 107% 41% 0%
- MTT assay For analysis of antitumoral activity of the compounds an MTT assay was performed with HT29 colorectal cancer cell line and MCF7 breast cancer cell line, both with rapid proliferation and high susceptibility to other treatments. With this assay it is known if there are metabolically active cells which indicates cell survival. After incubation with the compounds the reagent Bromide reagent 3-(4,5-dimetilthiazol-2-yl) -2,5-diphenyltetrazolium was added.
- This cell line is treated at a concentration gradient from 50nM, ⁇ , 250nm, 500nm, 750nm, 2,5 ⁇ and 5 ⁇ of each of the compounds for 24, 48 and 72 hours using as reference negative control the same line untreated, named T-0.
- the compounds T-03, T-05 y T-07 exhibit activity in HT29 colorectal tumor cell line (Table VIII).
- the compound T-03 also in MCF7 breast cancer cell line (table IX).
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Abstract
The invention relates to cyclic boramides compounds of formula (I) and their use in medicine, particularly in treating and/or preventing an infection caused by a bacterium, fungi or virus and/or in treating and/ or preventing cancer. wherein (I) Riand R'1are independently selected from the group consisting of -H, linear or branched -C1-6alkyl, -C6aryl, and R2and R'2 are independently selected from the group consisting of -H, halogen, linear or branched -C1-6salkyl, -OH, linear or branched -C1-6alcoxy, -SH, linear or branched -C1-6thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl.
Description
BORAMIDES FOR TREATING DISEASES
TECHNICAL FIELD
The present invention relates to new compounds and their use in medicine, particularly as agents able to treat and/or prevent an infection caused by a bacterium, fungi or virus and to treat and/or prevent cancer.
BACKGROUND ART
Nowadays multidrug resistance of microorganisms is considered a serious problem from the clinical and epidemiological point of view. The antibiotic resistance crisis has been attributed to the overuse and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry due to reduced economic incentives and challenging regulatory requirements.
Infections caused by these resistant microorganisms fail to respond to standard treatment, resulting in prolonged illness with increased risk of death and higher costs for society.
On the other hand, cancer causes an estimated 7 million people annually which, it is estimated, will rise to 10 million in 2020. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Frequently resistance is intrinsic to the cancer, but as therapy becomes more and more effective, acquired resistance has also become common.
Considering this situation, new chemical entities presenting novel mechanisms of action and generate more effective clinical treatments are needed.
Boron is not a common element in pharmaceutical drugs, however it shows a unique geometry allowing the compounds the ability to interact with biological targets in a novel way. Development of these drugs in which the boron is in a plane geometry started in 2000. Some examples are the antifungal Tavaborole (AN2690) useful for topical treatment of onychomycosis (Baker, SJ, et al, Med Chem 2006, 49, 4447-50) and the antibiotic AN3365 active against Gram-negative bacteria. However AN3365 is less effective against some multidrug resistant bacteria such as A. baumannii (Mendes, RE;., et al., Antimicrob Agents Chemother 2013, 57, 2849-57) and it is not effective against the yeasts Candida glabrata and Candida albicans, and it had poor activity
versus a human hepatocellular carcinoma cell line (HepG2) (Hernandez V. et al, Antimicrob Agents Chemother. 2013 Mar; 57(3): 1394-1403).
Thus, there is a need in the art for providing new compounds capable of effectively treating diseases.
BRIEF SUMMARY OF THE INVENTION
In a first aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl, -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, excluding the compounds of formula (I) wherein Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are independently selected from -Br and -H, and wherein Ri and R'i, are -H and R2 and R' 2 are independently selected from -CI and -H.
In a second aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched - Ci_6 alcoxy, -SH, linear or branched -Ci_6 thio-alkyl, N02 and NR3R4, wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl
and a pharmaceutically acceptable excipient.
In a third aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl, -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH,
linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, or the pharmaceutical composition according to the invention for use in medicine.
In a fourth aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R'2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl or the pharmaceutical composition according to any of claims 14 to 18 for use in preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Boramides activity in Acinetobacter baumannii.
Figure 2. Boramides activity in Enterobacter cloacae.
Figure 3. Boramides activity in A. fumigatus.
Figure 4. Boramides activity in C. albicans.
Figure 5. Anti-VIH activity curves of active compounds T-01 (A), T-02 (B) and (C).
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Compound of the invention
In a first aspect, the invention relates to a compound of formula (I) or a
pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R'2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, excluding the compound of formula (I) wherein Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are independently selected from -Br and -H, and wherein Ri and R'i, are -H and R2 and R' 2 are independently selected from -CI and -H.
The term "independently selected from" applied to the definition of a group of different variable groups, means that the definition of each variable of that group is independently selected from the definition of the other variable of the same group, and may have the same meaning or different meanings.
The terms "halogen" or "halo" as used herein refer to an atom selected from fluorine, chlorine, bromine, iodine and astatine. In a preferred embodiment the halogen is fluorine, chlorine or bromine.
The term "alkyl" refers to a linear or branched saturated hydrocarbon chain radical consisting of carbon and hydrogen atoms and which is attached to the rest of the
molecule by a single bond. Particularly, the term "Ci_6 alkyl" refers to an alkyl having between 1 and 6 carbon atoms. The term "Ci_6 alkyl", as used in the present invention, is intended to include straight-chain (linear), branched and cyclic alkyl groups of from 1 to 6 carbon atoms. Relevant linear Ci_6 alkyl groups are methyl, ethyl, propyl, butyl, pentyl and hexyl. Examples of branched Ci_6 alkyl groups are isopropyl, sec-butyl, tert-butyl, isopentyl and isohexyl. Examples of cyclic groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "Ci_6 alkyl" in the present context likewise includes, for example, cycloalkyl-substituted alkyl groups having from 1 to 6 carbon atoms, examples of which include groups such as (cyclopropyl)methyl, (cyclopropyl)ethyl, (cyclopropyl)propyl, (cyclobutyl)methyl, (cyclobutyl)ethyl and (cyclopentyl) methyl. Particularly suitable Ci_6 alkyl groups are often chosen among Ci_3 alkyl groups, i.e.methyl, ethyl, propyl, isopropyl and cyclopropyl. In a preferred embodiment, the Ci_6 alkyl is methyl.
"Substituted", as used herein relates to compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether proceeded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
The term "C6 aryl" refers to a monocyclic or polycyclic aryl radical having 6 carbon atoms. A said optionally substituted aryl radical is typically unsubstituted or substituted with 1 , 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups, alkoxycarbonyl groups. In an embodiment phenyl is preferred.
"Ci-6 alcoxy", as used herein relates to carbon and hydrogen chain group singular bonded to oxygen from 1 to 6 carbon atoms. In a preferred embodiment, Ci-6 alcoxy is 0-CH3.
"Ci_6 thioalkyl" used herein refers to a substituted or unsubstituted alkyl group, as previously defined, attached to the parent molecule through a sulfur atom.
In a preferred embodiment, Ri and R'i are -H and R2 is linear or branched -Ci_6 alkoxy and R' 2 is -H. In a more preferred embodiment, wherein the linear or branched -Ci_6 alkoxy is -O-CH3.
In another preferred embodiment, Ri and R'i are H and R2 and R' 2 are independently selected from the group consisting of linear or branched -Ci_6 alkyl and -H. In a more preferred embodiment the linear or branched -Ci-6 alkyl is -CH3.
In another preferred embodiment, Ri and R'i are H, and R2 and R' 2 are independently selected from the group consisting of -NR3R4, linear or branched -Ci_6 alcoxy, -N02 and -H, wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-3 alkyl. In a more preferred embodiment, -NR3R4 is -N-diethyl.
In another embodiment, Ri and R'i are H and R2 and R' 2 are independently selected from the group consisting of -OH, linear or branched -Ci_6 alcoxy and -H.
In another preferred embodiment R2 and R' 2 are selected from the group consisting of halogen and -H and Ri and R'i are independently selected from the group consisting of linear or branched Ci-6 alkyl and -H. In a more preferred embodiment, the linear or branched Ci-6 alkyl is -CH3.
In another preferred embodiment R2 and R' 2 are independently selected from the group consisting of -H and halogen and Ri and R'i are independently selected from the group consisting of -C6 aryl and -H. In a more preferred embodiment C6 aryl is -C6H5.
In a preferred embodiment, the compound of the invention is a compound of formula (I) wherein Rl s R'i, R2 and R'2 are as defined in the following table
The term "salt" is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions. The definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts".
The term "physiologically acceptable salt" or "pharmaceutically acceptable salt" is understood in particular, in the context of this invention, as a salt (as defined above) formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals - or with at least one, preferably inorganic, cation which are physiologically tolerated - especially if used on humans and/or mammals.
For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stochiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. Generally, nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of the alkali addition
salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, Ν,Ν-dialkylenethanolamine, triethanolamine and basic aminoacids salts. Since hydroxytyrosol has three hydroxyl groups, alkali addition salts are particularly preferred such as Na+ and NX4+ (wherein X is independently selected from H or a C1 -C4 alkyl group).
For those persons skilled in the art, it will be evident that the scope of the present invention also includes salts which are not pharmaceutically acceptable as possible means for obtaining pharmaceutically acceptable salts.
The compounds of the invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates, alcoholates, particularly methanolates) and it is intended that both forms are within the scope of the present invention. Solvate may include water or non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. Methods of solvation are generally known within the art.
When a disclosed compound is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compounds or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs". It is to be understood that when named or depicted by structure, the disclosed compounds and solvates (e.g., hydrates) also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
Any compound referred to herein is intended to represent such specific compound as well as certain variations or forms. The compounds of the present invention represented by the above described formula (I) include stereoisomers. The term "stereoisomer" as used herein includes any enantiomer, diastereomer or geometric isomer (E/Z) of such compound. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism related to a double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same or different than the stereoisomerism of the other double bonds of the molecule. All the stereoisomers including enantiomers, diastereoisomers and geometric isomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
Furthermore, any compound referred to herein may exist as tautomers. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another. Common tautomeric pairs are enamine-imine, amide-imidic acid, keto-enol, lactam- lactim, etc.
Unless otherwise stated, the compounds of the invention are also meant to include isotopically-labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms. For example, compounds having the present structures except for the replacement of at least one hydrogen atom by a deuterium or tritium, or the replacement of at least one carbon by 13C- or 14C-enriched carbon, or the replacement of at least one nitrogen by 15N-enriched nitrogen are within the scope of this invention.
The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a
preferred embodiment it is above 95% of the compound of formula (I), or of its pharmaceutically acceptable salt, stereoisomer or solvate.
The invention also provides "metabolites" of the compounds described in the present description. A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
The invention also provides "prodrugs" of the compounds described in the present description. The term "prodrug", as used herein, is intended to represent covalently bonded carriers, which are capable of releasing the compound of formula (I) as active ingredient when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of the invention include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N- dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
Pharmaceutical composition of the invention
In a second aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl, -C6 aryl, and
R2 and R'2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched - Ci_6 alcoxy, -SH, linear or branched -Ci_6 thio-alkyl, N02 and NR3R4, wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl
and a pharmaceutically acceptable excipient.
"Pharmaceutical composition" as used herein, relates to compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavorable reaction as gastric disorders, dizziness and suchlike, when administered to a human or animal. Preferably, the term "pharmaceutically acceptable" means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
The term "excipient" refers to a vehicle, diluent or adjuvant that is administered with the active ingredient. Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and similars. Water or saline aqueous solutions and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as vehicles. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 21st Edition,
2005; or "Handbook of Pharmaceutical Excipients", Rowe C. R.; Paul J. S.; Marian E. Q., sixth Edition
In a preferred embodiment of the pharmaceutical composition of the invention, Ri and R'i are H and R2 and R' 2 are independently selected from the group consisting of halogen and -H. In a more preferred embodiment, the halogen is -Br or -CI.
In another preferred embodiment Ri, R'i, R2 and R' 2 are -H, Ri and R'i are -H and R2 and R' 2 are -Br Ri and R'i are -H, R2 is -Br and R' 2 is -H, Ri and R'i are -H and R2 and R' 2 are -CI, or Ri and R'i are -H, R2 is -CI and R' 2 is -H.
In another preferred embodiment, the pharmaceutical composition of the invention comprises a compound of the invention as defined above.
Appropriate amounts of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof can be formulated with pharmaceutically acceptable excipients and/or carriers to obtain a pharmaceutical composition for use in medicine, particularly in preventing and/or treating an infection caused by a bacterium, fungi or virus or preventing and /or treating cancer.
Suitable pharmaceutically acceptable vehicles include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, monoglycerides and diglycerides of fatty acids, fatty acid esters petroetrals, hydroxymethyl cellulose, polyvinylpyrrolidone and similars.
The pharmaceutical compositions containing the compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof according to the invention can occur at any pharmaceutical form of administration considered appropriate for the selected administration route, for example, by systemic (e.g intravenous, subcutaneous, intramuscular injection), oral, parenteral or topical administration, for which it will include the pharmaceutically acceptable excipients necessary for formulation of the desired method of administration. Additionally, it is also possible to administer the composition comprising the compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof of the invention intranasally or sublingually which allows systemic administration by a non-aggressive mode of administration. Also, intraventricular administration may be adequate. A preferred route of delivery is intravenous.
Those skilled in the art are familiar with the principles and procedures discussed in widely known.
Where necessary, the compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is comprised in a composition also including a solubilizing agent and a local anesthetic to ameliorate any pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
In cases other than intravenous administration, the composition can contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, gel, polymer, or sustained release formulation. The composition can be formulated with traditional binders and carriers, as would be known in the art. Formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharide, cellulose, magnesium carbonate, etc., inert carriers having well established functionality in the manufacture of pharmaceuticals. Various delivery systems are known and can be used to administer a therapeutic of the present invention including encapsulation in liposomes, microparticles, microcapsules and the like.
Solid dosage forms for oral administration may include conventional capsules, sustained release capsules, conventional tablets, sustained-release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, suspensions, powders, granules and gels. At these solid dosage forms, the active compounds can be mixed with at least one inert excipient such as sucrose, lactose or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can be prepared with enteric coatings.
Liquid dosage forms for oral administration may include emulsions, solutions, suspensions, syrups and elixirs pharmaceutically acceptable containing inert diluents commonly used in the technique, such as water. Those compositions may also comprise
adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening agents, flavoring and perfuming agents.
Injectable preparations, for example, aqueous or oleaginous suspensions, sterile injectable may be formulated according with the technique known using suitable dispersing agents, wetting agents and/or suspending agents. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvents or suspending media.
For topical administration, compounds of the invention can be formulated as creams, gels, lotions, liquids, pomades, spray solutions, dispersions, solid bars, emulsions, microemulsions and similars which may be formulated according to conventional methods that use suitable excipients, such as, for example, emulsifiers, surfactants, thickening agents, coloring agents and combinations of two or more thereof.
Additionally, the compounds of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof may be administered in the form of transdermal patches or iontophoresis devices. In one embodiment, the compounds of the invention are administered as a transdermal patch, for example, in the form of sustained-release transdermal patch. Suitable transdermal patches are known in the art.
Several drug delivery systems are known and can be used to administer the agents or compositions of the invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and similars. The required dosage can be administered as a single unit or in a sustained release form.
Sustainable-release forms and appropriate materials and methods for their preparation are described in, for example, "Modified-Release Drug Delivery Technology", Rathbone, M. J. Hadgraft, J. and Roberts, M. S. (eds.), Marcel Dekker, Inc., New York (2002), "Handbook of Pharmaceutical Controlled Release Technology", Wise, D. L. (ed.), Marcel Dekker, Inc. New York, (2000). In one embodiment of the invention, the orally administrable form of a compound according to the invention is in a sustained release form further comprises at least one coating or matrix. The coating or sustained release matrix include, without limitation, natural polymers, semisynthetic or synthetic water-insoluble, modified, waxes, fats, fatty alcohols, fatty acids, natural semisynthetic or synthetic plasticizers, or a combination of two or more of the them. Enteric coatings may be applied using conventional processes known to experts in
the art, as described in, for example, Johnson, J. L., "Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A. A. (eds), Marcel Dekker, Inc. New York, (2001), Carstensen, T., "Coating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (ed.), Marcel Dekker, Inc. New York (2001), 455- 468.
The present invention also encompasses the combination of the compounds of formula (I) or of its pharmaceutically acceptable salt, stereoisomer or solvate with other antimicrobial drugs or cancer chemotherapeutic agents. A combination of at least a compound of formula (I) and at least another antimicrobial drug or cancer chemotherapeutic agents may be formulated for its simultaneous, separate or sequential administration. This has the implication that the combination of the two compounds may be administered:
-as a combination that is being part of the same medicament formulation, the two compounds being then administered always simultaneously.
-as a combination of two units, each with one of the substances giving rise to the possibility of simultaneous, sequential or separate administration. In a particular embodiment, the compound of formula (I) is independently administered from the other antimicrobial drug or cancer chemotherapeutic agent (i.e in two units) but at the same time.
In another particular embodiment, the compound of formula (I) is administered first, and then the other antimicrobial drug or cancer chemotherapeutic agent is separately or sequentially administered.
In yet another particular embodiment, the other antimicrobial drug or cancer chemotherapeutic agent is administered first, and then the compound of formula (I) is administered, separately or sequentially, as defined.
"Antimicrobial drug", as used herein, relates to any drug capable of killing bacteria, viruses, fungi or parasites or inhibit their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against, antibacterial, antifungal, antiviral and antiparasitic.
In another preferred embodiment, the other antimicrobial drug is an antifungal.
The term "cancer chemotherapeutic agent" includes standard chemotherapy drugs, which generally attack any quickly dividing cell, targeted therapy agents and immunomodulatory agents.
Illustrative non- limitative examples of cancer chemo therapeutic agents which may be in accordance to the present invention include alkylating agents, antimetabolite drugs, anthracycline antibiotics, antibodies targeted against proangiogenic factors, topoisomerase inhibitors, antimicrotubule agents ,low molecular weight tyrosine kinases inhibitors of proangiogenic growth factors and matrix metalloproteinase inhibitors.
In additional preferred embodiments, the preferences described above for the different groups and substituents in the formulae above are combined. The present invention is also directed to such combinations. Medical uses
In a third aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl, -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, or the pharmaceutical composition according to the invention for use in medicine.
In a preferred embodiment the halogen is -Br or -CI. In a more preferred embodiment of the compound for use in medicine Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are -Br, wherein Ri and R'i are -H, R2 is -Br and R' 2 is - H, wherein Ri and R'i are -H and R2 and R' 2 are -CI, or wherein Ri and R'i are -H, R2 is -CI and R' 2 is -H.
In another preferred embodiment, the compound for use in medicine is any of the compounds previously described.
In a fourth aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl or the pharmaceutical composition according to the invention for use in preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
Alternatively, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl or the pharmaceutical composition according to the invention for the preparation of a medicament for preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
Alternatively, the invention relates to a method for preventing and/or treating an infection caused by a bacterium, fungi or virus or for use in preventing and/or treating cancer comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl or the pharmaceutical composition according to the invention.
In a preferred embodiment the halogen is -Br or -CI. In a more preferred embodiment of the compound for use in medicine Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are -Br , wherein Ri and R'i are -H, R2 is -Br and R' 2 is
-H, wherein Ri and R'i are -H and R2 and R' 2 are -CI, or wherein Ri and R'i are -H, R2 is -CI and R' 2 is -H.
In another preferred embodiment, the compound for use in medicine is any of the compounds previously described
As used herein, the terms "treat", "treating" and "treatment" include in general the eradication, removal, reversion, alleviation, modification, or control of the infection or cancer after its onset.
As used herein, the terms "prevention", "preventing", "preventive", "prevent" and "prophylaxis" refer to the capacity of a given substance, composition or medicament to avoid, minimize or difficult the onset or development of an infection or cancer before its onset.
The term "infection", as used herein, relates to invasion by bacteria, viruses, fungi, protozoa or other microorganisms, referring to the undesired proliferation or presence of invasion of pathogenic microbes in a host organism. It includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal. Thus, a microbial infection exists when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal.
In another preferred embodiment, of the compound of the invention for use in preventing and/or treating an infections caused by a bacterium.
In a preferred embodiment, the compound for use in preventing and/or treating an infection caused by a bacterium is a compound of formula (I) wherein Rl s R'i, R2 and R' 2 are as defined in the following table A or is a pharmaceutical composition comprising the same.
aused a bacterium.
The term "bacterium" refer to both gram-negative and gram-positive bacterial cells capable of infecting and causing disease in a mammalian host, as well as producing infection-related symptoms in the infected host, such as fever or other signs of inflammation, intestinal symptoms, respiratory symptoms, dehydration, and the like.
In one embodiment the bacteria are gram-negative bacteria. In another embodiment the bacteria are gram-positive bacteria. In another further embodiment the bacteria are gram-positive bacteria together with gram-negative bacteria. In another embodiment there is only one bacteria specie or different bacteria species; one bacteria genus or different bacteria genus, infecting or causing disease.
In some embodiments, and without limitation, the bacteria is of a genus selected from the group consisting of Acinetobacter, Actinobacillus, Aeromonas, Aggregatibacter, Agrobacterium, Bacillus, Bordetella, Brucella, Burkholderia, Campylobacter, Chromobacterium, Cyanobacteria, Enterobacter, Erwinia, Escherichia, Franciscella, Fusobacterium, Haemophilus, Helicobacter, Hemophilus, Klebsiella, Lactobacillus, Legionella, Listeria, Micrococcus, Moraxella, Mycobacterium, Neisseria, Nitrosomas, Nocardia, Obesumbacterium, Pantoea, Pasteurella, Pediococcus, Porphyromonas, Prevotella, Proteus, Pseudomonas, Ralstonia, Rhisobium, Rhodobacter, Salmonella, Serratia, Shigella, Staphyllococcus, Streptococcus, Tannerella, Treponema, Tsukamurella, Vibrio, Xenorhabdus, Yersinia and mixtures thereof. For example, in some embodiments and without limitation, the bacteria is of a species selected from the group consisting of Aeromonas hydrophila, Aeromonas salmonicida, Acinetobacter baumannii, Aggregatibacter actinomycetemcomitans, Agrobacterium tumefaciens, Bacillus Cereus, Bacillus Subtilis, Burkholderia cepacia, Campylobacter jejuni, Chromobacterium violaceum, Enterobacter agglomeran, Erwinia carotovora, Erwinia chrysanthemi, Escherichia coli, Fusobacterium nucleatum, Haemophilus injluenzae, Helicobacter pylori, Lactobacillus Plantarum, Listeria Monocytogenes, Klebsiella Pneuumoniae, Micrococcus Luteus, Mycobacterium tuberculosis, Neisseria meningitidis, Neisseria gonorrhoeae, Nitrosomas europaea, Nocardia carnea, Obesumbacterium proteus, Pantoea stewartii, Pediococcus acidilactici, Prevotella intermedia, Porphyromonas gingivalis, Pseudomonas aureofaciens, Pseudomonas aeruginosa, Pseudomonas Phosphoreum, Pseudomonas syringae, Ralstonia solanacearum, Rhisobium etli, Rhisobium leguminosarum, Rhodobacter sphaeroides, Salmonella typhimurium, Serratia liguefaciens, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis,
Staphylococcus enteritis, Tannerella forsythensis, Treponema denticola, Tsukamurella pulmonis, Vibrio anguillarum, Vibrio fischeri, Vibrio cholerae, Vibrio harveyi, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio vulnificus, Xenorhabdus nematophilus, Yersinia enter ocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia medievalis, Yersinia ruckeri and mixtures thereof
In a preferred embodiment of the medical use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, the infection is caused by a Gram positive bacterium.
In another preferred embodiment, the Gram positive bacterium is from phylum Firmicutes.
In a preferred embodiment, the bacterium form phylum Firmicutes is a bacterium from genus Staphylococcus, Enterococcus, Streptococcus or Bacillus.
In a more preferred embodiment, the bacterium from genus Staphylococcus, is Staphylococcus aureus or Staphylococcus epidermidis. In another preferred embodiment the bacterium from genus Enterococcus is E. faecalis or E. faecium. In another preferred embodiment, the bacterium from genus Streptococcus is S. pyogenes or S. pneumoniae. In another preferred embodiment the bacterium from genus Bacillus is B. cereus.
In a more preferred embodiment, the Gram positive bacterium is from phylum Actinobacteria.
By way of illustrative non- limitative examples of bacterium form phylum Actinobacteria, are Nocardia, Corynebacterium, Mycobacterium, Streptomyces, Micromonospora, Arthobacter, Frankia, Propionibacterium, Actinomyces.
In a more preferred embodiment the bacterium from phylum Actinobacteria is a bacterium from genus Mycobacterium, Nocardia, Tsukamurella or Streptomyces.
In a more preferred embodiment, the bacterium from the genus Mycobacterium is M. fortuitum, M. chelonae, M. abscessus, the bacterium from genus Nocardia is Nocardia carnea or Nocardia cyriacigeorgica or the bacterium from genus Tsukamurella is Tsukamurella pulmonis.
In a preferred embodiment, the Gram negative bacterium is from phylum
Proteobacteria.
"Phylum proteobacteria", as used herein relates to a major group of gram- negative bacteria, which is defined primarily in terms of ribosomal R A sequences. They are divided into six classes Alphaproteobacteria, including the genera Brucella,
Rhizobium, Agrobacterium, Caulobacter, Rickettsia, Wolbachia; Betaproteobacteria including the genera Bordetella, Ralstonia, Neisseria, Nitrosomonas; Gammaproteobacteria including the genera Acinetobacter, Escherichia, Shigella, Salmonella, Yersinia, Buchnera, Haemophilus, Vibrio, Pseudomonas; Deltaproteobacteria including the genera Desulfovibrio, Geobacter, Bdellovibrio; Epsilonproteobacteria including the genera Helicobacter, Campylobacter, Wolinella; Zetaproteobacteria including the genera Mariprofundus.
In a preferred embodiment, the bacterium form phylum proteobacteria is from genus Klebsiella, Acinetobacter, Enterobacter or Escherichia.
In a particular embodiment, the Acinetobacter bacterium is Acinetobacter baumannii. In another particular embodiment, the bacterium form genus Enterobacter is E. cloacae.
In a particular embodiment, the bacterium form genus Escherichia is E. coli. In another preferred embodiment the compound of the invention or the pharmaceutical composition according to the invention is for use in the prevention and/or treatment an infection caused by a fungi, particularly a fungi from genus Candida, Aspergillus or Saccharomyces.
The term "fungi", as used herein, relates to an organism from kingdom Fungus, and particularly to those fungi capable of causing diseases in humans such as Aspergillus, Candida, Cryptoccocus, Histoplasma, Pneumocystis and Saccharomyces.
In a particular embodiment, the fungi from genus Candida is selected from the group consisting of Candida is C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, C. lusitaniae and C. krusei.
In a particular embodiment, the fungi from genus from genus Aspergillus is selected from the group consisting of A. niger, A.fumigatus, A. flavus and A. terreus.
In a preferred embodiment, the fungi from genus Saccharomyces is S. cerevisiae.
In a preferred embodiment, the compound for use in preventing and/or treating an infections caused by a fungi is a compound of formula (I) wherein Rl s R'i, R2 and R' 2 are as defined in the following table B or a pharmaceutical compositions comprising the same.
Compound Ri R'i R2 R'2
T-23 -C6H5 -C6H5 -H -H
T-25 -C6H5 -H -Br -Br
Table B. Preferred compounds for preventing and/or treating an infection caused by a fungi
In another preferred embodiment the compound of the invention or the pharmaceutical composition according to the invention is for use in the prevention and/or treatment an infection caused by a virus.
The term "virus", refers to a small infectious agent that replicates only inside the living cells of other organism.
In some embodiments, and without limitation, the virus is selected from the group consisting of adenovirus, coxsackievirus, Epstein-Bar, Hepatitis A, B or C, herpes simplex type 1, herpes simplex type 2, cytomegalovirus, herpesvirus type 8, HIV, Influenza, Measles, mumps, human papillomavirus, parainfluenza, poliovirus, rabies, respiratory syncytial, rubella, varicella-zoster. In a preferred embodiment the virus is HIV.
In a preferred embodiment the compound for use in preventing and/or treating an infections caused by a virus, preferably VIH, is a compound of formula (I) wherein Ri , R'i , R2 and R' 2 are as defined in the following table C or a pharmaceutical compositions comprising the same.
Table C. Preferred compounds for preventing and/or treating an infection caused by a virus, particularly VIH.
In another preferred embodiment, the compound of the invention or the pharmaceutical composition is for use in the prevention and/or treatment of cancer.
The term "cancer" as used herein, refers to a disease characterized by uncontrolled cell division (or by an increase of survival or apoptosis resistance) and by the ability of said cells to invade other neighbouring tissues (invasion) and spread to other areas of the body where the cells are not normally located (metastasis) through the lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body. Depending on whether or not they can spread by invasion and metastasis, tumours are classified as being either benign or malignant: benign
tumours are tumours that cannot spread by invasion or metastasis, i.e., they only grow locally; whereas malignant tumours are tumours that are capable of spreading by invasion and metastasis. As used herein, the term cancer includes, but is not limited to, the following types of cancer: breast cancer; biliary tract cancer; bladder cancer; brain cancer including glioblastomas, in particular glioblastoma multiforme, and meduUoblastomas; cervical cancer; head and neck carcinoma; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including acute lymphocytic and myelogenous leukemia; T- cell acute lymphoblastic leukemia/lymphoma; hairy cell leukemia; chronic myelogenous leukemia, multiple myeloma; AIDS-associated leukemias and adult T-cell leukemia/lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer, hepatoma; lung cancer, pleural mesothelioma; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cell carcinoma; parotid gland cancer; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; kidney cancer, suprarenal cancer; rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell cancer; cervix cancer, endometrial cancer; testicular cancer including germinal tumors such as seminoma, non-seminoma (teratomas, choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor. Other cancers will-be known to one of ordinary skill in the art.
In a preferred embodiment, the cancer is colorectal or breast cancer.
The term "colorectal cancer" also known as "colon cancer", "rectal cancer", or "bowel cancer", refers to a cancer from uncontrolled cell growth in the colon or rectum, or in the appendix.
The term "breast cancer" relates to any malignant proliferative disorder of breast cells, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas, while those originating from lobules are known as lobular carcinomas.
In a preferred embodiment, the compound for use in preventing and/or treating cancer, particularly colorectal cancer is a compound of formula (I) wherein Rl s R'i , R2
and R'2 are as defined in the following table D or a pharmaceutical composition comprising the same.
Table D. Preferred compounds for preventing and/or treating colorectal cancer
In another preferred embodiment, the compound for use in preventing and/or treating cancer, particularly breast cancer is a compound of formula (I) wherein Rl s R'i, R2 and R'2 are as defined in the following table E or a pharmaceutical composition comprising the same.
Table E. Preferred compound for preventing and/or treating breast cancer
The present invention covers any combination of compounds and diseases.
For use in the prevention and/or treatment according to the invention, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof or the pharmaceutical composition of the invention is present in an effective amount.
The term "effective" amount or a "therapeutically effective amount" of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect. In the combination therapy of the present invention, an "effective amount" of one component of the combination is the amount of that compound that is effective to provide the desired effect when used in combination with the other components of the combination.
Even though individual needs vary, determination of optimal ranges for effective amounts of the agent of the invention belongs to the common experience of those experts in the art. In general, the dosage needed to provide an effective amount of such compound, which can be adjusted by one expert in the art will vary depending on age, health, fitness, sex, diet, weight, frequency of treatment and the nature and extent of impairment or illness, medical condition of the patient, route of administration, pharmacological considerations such as activity, efficacy, pharmacokinetic and toxicology profile of the particular compound used, if using a system drug delivery, and if the compound is administered as part of a combination of drugs.
The effective quantity of the compound of the invention can vary within a wide range and, in general, will vary depending on the particular circumstances of application, duration of the exposure and other considerations. In a particular embodiment, the dose ranges between 0.05 mg/kg and 50 mg/kg, more preferably between 1 mg/kg and 20 mg/kg.
In a preferred embodiment the effective amount is between about between about 0.005 % and about 0.04 % weight, between about 0.0075 % weight and about 0.0375 % weight, between about 0.001 % weight and about 0.035 % weight, between about 0.00125 % weight and about 0.0325 % weight, between about 0.0015 % weight and about 0.0325 % weight, between about 0.00175 % weight and about 0.03 % weight, and more preferably between about 0.0018 % weight and about 0.032 % weight. In a particular embodiment, the effective amount is between about 0.005% and about 0.02% weight, preferably between about 0.005%> weight and about 0.015%) weight, more preferably between about 0.005%> weight and about 0.01% weight. In some embodiments the effective amount is about 0.001 % weight, about 0.002 % weight, about 0.003 % weight or about 0.004 % weight. The percentages (% w/w) are expressed as weight of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof by the total weight of the composition comprising the compound or by weight of the foodstuff, foodstuff package, medical device or surface.
In another embodiment the effective amount is expressed in μg/mL or μg/g g of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof by mL or g of the composition comprising the compound), therefore effective amount is about 75 and about 375 μg/mL (or μ^), between about 100 and about 350 μg/mL (or μ^), between about 125 and about 325 μg/mL (or μ^), between about 150 and about 325 μg/mL (or μ^), between about 175 and about 300 μg/mL (or μ^), and more preferably between about 180 and about 320 μg/mL (or μg/g). In a particular embodiment, the effective amount is between about 50 and about 200 μg/mL (or μ^), preferably between 50 and about 150 μg/mL (or μg/g), more preferably between about 50 and about 100 μg/mL (or μ^). In some embodiments the effective amount is about 100 μg/mL (or μ^), about 200 μg/mL (or μg/g), about 300 μg/mL (or μ^) or about 400 μg/mL (or μ^).
When the compound of formula (I) or a salt, solvate or isomer thereof as defined herein is present on a surface, it is preferably in an effective amount of between about 1 and about 200 μg/cm2, preferably between about 1 and about 100 μg/cm2, preferably
between about 1 and about 50 μ /οηι2, more preferably between about 5 and about 300
The invention will be described by way of the following examples which are to be considered as merely illustrative and not limitative of the scope of the invention.
Materials and methods
Preparation of boramide compounds
Boramides compounds of the invention were obtained as disclosed in Tena-Perez et al., (Tetrahedron, 2014, 70: 8614-8618). Imines were prepared by treatment of a solution of the corresponding salicylaldehyde (1.00 mmol) in a 1 : 1 mixture of MeOH:THF (1.0 mL) with N¾ gas during 1 min. The reaction mixture was then used for the preparation of the boramides without isolating the intermediate imines.
NaBH4 (1.15 mmol) and the corresponding salicylaldehyde (1.00 mmol) were added in small amounts to the solution of the corresponding imine (1.00 mmol) at room temperature. After 30 min under agitation, the reaction mixture was poured over iced water and the resulting crystals (colorless or light yellow) of the boramide were filtered under suction. Finally, the product may be crystalized in methanol.
The compounds are shown in Table I.
Compound Ri R'i R2 R' 2
T-01 -H -H -H -H
T-02 -H -H -Br -Br
T-03 -H -H -Br -H
T-04 -H -H -CI -CI
T-05 -H -H -CI -H
a e ompoun s o t e nventon.
Example 1-Antibiotic activity
Bacterial strains and inoculum preparation
Bacterial strains, from clinical origin, were supplied by the National Center for
Microbiology, Institute of Health Carlos III (Majadahonda, Madrid). They are detailed in Table II.
Isolation
Specie Strain year IMP CTX A/C LIN AMK SxT CIP ERI PEN VAN RIF TET CLI MER CEF TOB GEN AMP LEVO TEI CLO
N.
cyriacigeorgica 30 2005 s s R S S s R R
N.
cyriacigeorgica 199 2005 R R s R s R R
N. carnea 769 2009 S S S s S R S R
N. carnea 40 2011 R S S s R R S R
T. pulmonis 1991 2009 S S S s S S S S
T. pulmonis 40 2015 S R R R R R R R
Streptomyces spp 4 2008 S R R S S S S R
Streptomyces spp 808 2010 S S S S S R R S
M. chelonae 870 2011 R R R R R R
M. abscessus 690 2012 R S S R S R
M. fortuitum 1080 2011 R R S S R R
B. cereus 25 2014 R S S s R R
B. cereus 182 2013 R S s s S R
A. baumannii 300 2001 R R R R R S
A. baumannii 1301 2009 S S S S R s
P. aeruginosa 8 2001 S S S S R s
P. aeruginosa 14 2011 S S S R R s
S. aureus 282 2005 S R R s S R R
S. aureus 890 2010 S S R s R R R
S. epidermidis 982 2006 S R R s S R R
S. epidermidis 188 2009 S S S s S S S
K. pneumoniae 1021 2005 S S S S S S R
E. coli 1007 2010 R R S S S R
E. coli 13 2000 S S S S S R
E. cloacae 1144 2008 R R R R R R
E. cloacae 520 2000 R R S S S R
E. faecium 1418 2011 R S S R R S
E. faecium 3 2012 S 1 S R S S
E. faecalis 1110 2011 S S S R S S
E. faecalis 460 2012 S S S R R S
S. pyogenes 487 2011 R S S S R R
S. pneumoniae 900 2012 S R R S S
Table II. Characteristics of the Strains. IMP=lmipenem; CTX=Cefotaxime; A/C=Amoxicillin/Clavulanate; Lin=Linezolid; AMK=Amikacin; SxT=Cotrimoxazole; CIP=Ciprofloxaci ERI=Erythromycin; GEN=Gentamicin; PEN=Penicillin; VAN=Vancomycin; RIF=Rifampicin; TET=Tetracycline; CU=Clindamycin; MER=Meropenem; CEF=Ceftriazone; TOB=Tobramyci AMP=Ampicillin; LEV=Levofloxacin; TEI=Teicoplanin; CLO=Chloramphenicol;
Antibacterial susceptibility test
Bacterial cells suspension in sterile saline was prepared from a culture of 24-72 h, depending on bacterial species, in Mueller-Hinton Agar with 5% sheep blood. Each suspension was adjusted to a fixed size inoculum of 1-5 x 108 CFU/ml with a spectrophotometer (Ferraro, MJ National Committee for Clinical Laboratory Standards. 2000).
Kirby-Bauer disk diffusion susceptibility test protocol was utilized to determine the sensitivity or resistance of pathogenic bacteria against the compounds and others antibiotics. The absence of growth around the disks is an indirect measure of the ability of this compound to inhibit an organism (Kirby, W.. et al, Antibiotics Annu. 1956- 1957:892). After 18 to 72 hours of incubation at 37°C, with or without C02, under aerobic or anaerobic conditions, depending on the bacterial species, halo of growth inhibition were obtained and evaluated
Interpretation of susceptibility and resistance was based on the presence or absence of a zone of inhibition surrounding the disk. Kirby-Bauer disk diffusion susceptibility test is a common method which uses antibiotic-impregnated wafers to test whether bacteria are affected by antibiotics. The size of the zone of inhibition depends on how effective the antibiotic is at stopping the growth of the bacterium. A stronger antibiotic will create a larger zone, because a lower concentration of the antibiotic is enough to stop growth.
The results of antibiotic activity obtained with the Kirby-Bauer antibiotic test show the great potential of compounds, not only as molecules with specific activity against specific bacteria but also as possible structures for the development of broad spectrum antibiotics. The activity results are shown in Table III and some examples in Figures 1 and 2.
Boramides inhibition (200 μζ/άκο)
Bacterial species T01 T02 T03 T04 T05 T06 T07 T08 T09 TIO Til T12 T13 T14 T15 T16 T17 T18 T19 T20 T21 T22 T23 T24 T
S. aureus A A A
S. epidermidis A A A A A
E. faecium A A A A
Gram+ E. faecalis A A A
S. pyogenes A
S. pneumoniae A A
B. cereus A A A A A A A A A A A A
K. pneumoniae A A A A A A A A A A
Gram- A. baumannii A A A A A A A A A
E. cloacae A A A A A A A A A
E. coli A A A A A A A A A
M. fortuitum A A A
M. chelonae A A A
M. abscessus A A A
ACTINO- N.
MYCETES cyriacigeorgica A A A A A A A A A A A A A A A
N. cornea A A A A A A A A A A A A A A A A A A
T. pulmonis A A A A A A A A A A A A A A A A
Streptomyces
sp
Table III. Boramides antibiotic activity. A indicates significative activity
All compounds were tested at 200 μg/disc. The best activity was detected with cyclic boramides T-09, T-14, T-15, T-18, T-23 and T-24 which maintained activity at
Noteworthy that the activity of all boramides is bactericidal, whereas in the specie
B. cereus is bacteriostatic.
Example 2- Antifungal activity Filamentous fungi and yeasts strains and inoculum preparation:
Filamentous fungi and yeasts strains, from clinical origin, were supplied by Microbiology Service from The Princess Hospital, Madrid. They are detailed in Table IV.
Table V. Characteristics of the fungi and yeast strains.
Filamentous fungi and yeast cells suspensions in distilled water was prepared from a culture of 24-48 h, depending on species, in Sabouraud agar. Each suspension was adjusted to a fixed size inoculum of 1-5 x 108 CFU/ml with a spectrophotometer (Ferraro, MJ National Committee for Clinical Laboratory Standards. 2000).
Antifungal susceptibility test:
Antifungal susceptibility tests were developed following the standardized methodology detailed in document CLSI: M44-4: Method for Antifungal Disk diffusion susceptibility testing of yeasts consisting of disk diffusion on agar Muller-Hinton (supplemented with 2 % glucose).
Antifungal activity:
The activity results are shown in Table V. All compounds were tested at 200 μg/disc.
Table V. Antifungal activity.
The cyclic boramides T-23 and T-25 exhibited the best activity (halo of growth inhibition between 15-20 mm) (Figures 3 and 4).
Example 3-Anti-VIH activity
Antiviral susceptibility test
Assessment of in vitro antiviral activity is usually performed to estimate parameters of antiviral potency and efficacy represented by the percentage of inhibition of HIV activity or IC50. The assay utilized is based on the use of recombinant viruses in which the nef gene, essential for in vitro HIV replication, has been replaced by a Renilla reporter gene so that we can quantify viral replication directly (Garcia-Peresz J et al, J Med Virol. 2007 Feb;79(2): 127-37). The study was development in AIDS
Immunopathology Unit, Nacional Center of Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain.
Viability:
All assays for assessing anti-HIV activity were taken in parallel to determine cellular viability of the culture in the presence or absence of different concentrations of the isolated molecules. It was followed exactly the same methodology as in the anti- HIV assay except with the addition of complete DMEM medium instead of supernatant viral, in the same proportion, and the detection of the viability was performed with the viability detection kit CellTiter Glo (Promega), following manufacturer instructions. Viability is directly proportional to the luciferase activity obtained.
All data are expressed as percentage relative to a control with DMSO at the same concentration. Antiviral activity and toxicity curves were performed to the compounds at different concentrations.
A previous screening with four concentrations (1, 10, 50 y 200 μΜ) of antiviral activity was realized and further analysis of active compounds by performing antiviral activity and toxicity curves with the compounds at different concentrations.
Results:
All compounds, except T-04, exhibited toxicity at the highest concentration (200 μΜ). Only T-02 showed toxicity at 50 μΜ, whereas none was toxic at the lowest concentrations (1 and 10 μΜ). Most compounds were active in the initial screening at 50 μΜ. However, the activity at 10 μΜ was only demonstrated for some compounds and was very slight (T-02 under 50%). All results are shown in Table VI.
HIV (NL4.3-Ren) Viability
1 μΜ 10 μΜ 50 μΜ 200 1 μΜ 10 μΜ 50 μΜ 200 μΜ μΜ
T-01 55% 63% 18% 0% 121% 128% 143% 16%
T-02 65% 40% 0% 0% 101% 112% 5% 2%
T-03 85% 71% 10% 0% 96% 105% 121% 40%
T-04 84% 69% 26% 6% 102% 101% 141% 85%
T-05 94% 80% 4% 0% 94% 98% 112% 22%
T-08 93% 80% 10% 0% 89% 78% 91% 0%
T-09 94% 86% 1% 0% 88% 94% 71% 1%
T-10 86% 61% 0% 0% 90% 95% 23% 3%
T-ll 99% 81% 0% 0% 102% 107% 41% 0%
T-12 110% 86% 37% 26% 99% 100% 138% 117%
T-13 125% 100% 4% 0% 132% 120% 165% 110%
T-14 124% 67% 0% 0% 113% 111% 0% 0%
T-15 134% 99% 0% 0% 77% 80% 12% 0%
T-17 134% 53% 0% 0% 94% 95% 0% 0%
T-18 123% 85% 0% 0% 79% 91% 2% 0%
T-21 112% 97% 8% 0% 102% 112% 118% 0%
T-23 107% 76% 4% 0% 115% 118% 125% 0%
T-24 131% 110% 13% 0% 118% 124% 133% 2%
Table VI. Anti-VIH and viability assays.
Three active compounds with low toxicity were selected for calculating its IC50 (T-01 , T-02, T-04) and the results are shown in Table VII and Figure 5.
Table VII. Anti-VIH and viability assays
Activity tests were carried out on the virus entry with T-01 , T-02, T-04 and T-13 compounds. In this assay the infection was made, in parallel, with HIV virus (NL4.3- Ren) and HIV virus pseudotyped with the envelope of VSV (NL4.3-VSV-Luc). The
compounds inhibited both viruses with the same potency, suggesting its activity is not dependent on virus entry.
Example 4-Antitumoral activity
Matherial and methods:
For analysis of antitumoral activity of the compounds an MTT assay was performed with HT29 colorectal cancer cell line and MCF7 breast cancer cell line, both with rapid proliferation and high susceptibility to other treatments. With this assay it is known if there are metabolically active cells which indicates cell survival. After incubation with the compounds the reagent Bromide reagent 3-(4,5-dimetilthiazol-2-yl) -2,5-diphenyltetrazolium was added.
Those cells that remain active convert this reagent, through SDH (succinate dehydrogenase) enzyme, to formazan. This compound has a purple hue. The more active cells are in the medium the more formazan appears and obtain more color. With subsequent absorbance reading we are able to compare cultures in different times by simple statistical analysis.
Starting from an amount of 10,000 cells per well is left about 24 hours to adhere to the plate before treatment. All tests are always in triplicate. This cell line is treated at a concentration gradient from 50nM, ΙΟΟηΜ, 250nm, 500nm, 750nm, 2,5μΜ and 5 μΜ of each of the compounds for 24, 48 and 72 hours using as reference negative control the same line untreated, named T-0.
Results:
The compounds T-03, T-05 y T-07 exhibit activity in HT29 colorectal tumor cell line (Table VIII). The compound T-03 also in MCF7 breast cancer cell line (table IX).
Table VIII Antitumoral activity in the HT29 cell line (A indicates activity)
750nM ΙμΜ 2,5μΜ
T-03 A A A
Tabla IX. Antitumoral activity in MCF7cell line.
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, excluding the compounds of formula (I) wherein Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are independently selected from -Br and -H, and wherein Ri and R'i, are -H and R2 and R' 2 are independently selected from -CI and -H.
2. The compound according to claim 1 wherein Ri and R'i are -H and R2 is linear or branched -Ci_6 alkoxy and R' 2 is -H.
3. The compound according to claim 2, wherein the linear or branched -Ci_6 alkoxy is -O-CH3.
4. The compound according to claim 1 wherein Ri and R'i are H and R2 and R' 2 are independently selected from the group consisting of linear or branched -Ci_6 alkyl and -H.
5. The compound according to claim 4 wherein the linear or branched -Ci-6 alkyl is -CH3.
6. The compound according to claim 1 wherein Ri and R'i are H, and R2 and R' 2 are independently selected from the group consisting of -NR3R4, linear or branched -Ci_6 alcoxy, -N02 and -H, wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-3 alkyl.
7. The compound according to claim 6 wherein the -NR3R4 is -N-diethyl.
8. The compound according to claim 1 wherein Ri and R'i are H and R2 and R' 2 are independently selected from the group consisting of -OH, linear or branched -Ci_6 alcoxy and -H.
9. The compound according to claim 1 wherein R2 and R' 2 are selected from the group consisting of halogen and -H and Ri and R'i are independently selected from the group consisting of linear or branched Ci-6 alkyl and -H.
10. The compound according to claim 9 wherein the linear or branched Ci-6 alkyl is -CH3.
11. The compound according to claim 1 wherein R2 and R' 2 are independently selected from the group consisting of -H and halogen and Ri and R'i are independently selected from the group consisting of -C6 aryl and -H.
12. The compound according to claim 11 wherein -C6 aryl is -C6¾.
13. The compound according to claim 1 wherein Rl s R'i, R2 and R' 2 are as defined in the following table
14. Pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thio-alkyl, N02 and NR3R4, wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl
and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition according to claim 14 wherein Ri and R'i are H and R2 and R' 2 are independently selected from the group consisting of halogen and -H.
16. The pharmaceutical composition according to claim 15, wherein the halogen is -Br or -CI.
17. The pharmaceutical composition according to claim 16 wherein Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are -Br , wherein Ri and R'i are -H, R2 is -Br and R' 2 is -H, wherein Ri and R'i are -H and R2 and R' 2 are -CI, or wherein Ri and R'i are -H, R2 is -CI and R' 2 is -H.
18. The pharmaceutical composition according to claim 14 wherein the compound is as defined in any of claims 2 to 13.
19. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl, -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl, or the pharmaceutical composition according to any of claims 14 to 18 for use in medicine.
20. The compound for use according to claim 19, wherein the halogen is -Br or -CI.
21. The compound for use according to claim 20 wherein Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are -Br , wherein Ri and R'i are -H, R2 is -Br and R' 2 is -H, wherein Ri and R'i are -H and R2 and R' 2 are -CI, or wherein Ri and R'i are -H, R2 is -CI and R' 2 is -H.
22. The compound for use according to claim 18 wherein the compound is as defined in any of claims 2 to 13.
23. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof
(I)
wherein
Ri and R'i are independently selected from the group consisting of -H, linear or branched -Ci-6 alkyl , -C6 aryl, and
R2 and R' 2 are independently selected from the group consisting of -H, halogen, linear or branched -Ci-6 alkyl, -OH, linear or branched -Ci_6 alcoxy, -SH, linear or branched -Ci_6 thioalkyl, N02, and NR3R4 wherein R3 and R4 are independently selected from the group consisting of -H and linear -C1-C3 alkyl or the pharmaceutical composition according to any of claims 14 to 18 for use in preventing and/or treating an infection caused by a bacterium, fungi or virus and/or for use in preventing and/or treating cancer.
24. The compound for use according to claim 23, wherein the halogen is -Br or -CI.
25. The compound for use according to claim 24 wherein Ri, R'i, R2 and R' 2 are -H, wherein Ri and R'i are -H and R2 and R' 2 are -Br , wherein Ri and R'i are -H, R2 is -Br and R' 2 is -H, wherein Ri and R'i are -H and R2 and R' 2 are -CI, or wherein Ri and R'i are -H, R2 is -CI and R' 2 is -H.
26. The compound for use according to claim 23, wherein the compound is as defined in any of claims 2 to 13.
27. The compound or the pharmaceutical composition for use according to any of claims 23 to 26, wherein the bacterium is a Gram positive bacterium.
28. The compound or the pharmaceutical composition for use according to claim 27, wherein the Gram positive bacterium is from phylum Firmicutes.
29. The compound or the pharmaceutical composition for use according to claim 28, wherein the bacterium from phylum Firmicutes is a bacterium from genus Staphylococcus, Enter ococcus, Streptococcus or Bacillus.
30. The compound or the pharmaceutical composition for use according to claim 29, wherein the bacterium from genus Staphylococcus is Staphylococcus aureus or Staphylococcus epidermidis, the bacterium from genus Enterococcus is E.faecalis or E.faecium, the bacterium from genus Streptococcus is S. pyogenes or S. pneumoniae or the bacterium from genus Bacillus is B. cereus.
31. The compound or the pharmaceutical composition for use according to claim 27, wherein the Gram positive bacterium is from phylum Actinobacteria.
32. The compound or the pharmaceutical composition for use according to claim 31 wherein the bacterium from phylum Actinobacteria is a bacterium from genus Mycobacterium, Nocardia, Tsukamurella or Streptomyces.
33. The compound or the pharmaceutical composition for use according to claim 32, wherein the bacterium from the genus Mycobacterium is M. fortuitum, M. chelonae, M. abscessus, the bacterium from genus Nocardia is Nocardia carnea or Nocardia cyriacigeorgica or the bacterium from genus Tsukamurella is Tsukamurella pulmonis.
34. The compound or the pharmaceutical composition for use according to any of claims 23 to 26, wherein the bacterium is a Gram negative bacterium.
35. The compound or the pharmaceutical composition for use according to claim 34, wherein the Gram negative bacterium is from phylum proteobacteria.
36. The compound or the pharmaceutical composition for use according to claim 35 wherein the bacterium from phylum proteobacteria is from genus Klebsiella, Acinetobacter, Enterobacter or Escherichia.
37. The compound or the pharmaceutical composition for use according to claim 36, wherein the bacterium from genus Klebsiella is K. pneumoniae, the bacterium from genus Acinetobacter is Acinetobacter baumanii, the bacterium form genus Enterobacter is E. cloacae or the bacterium from genus Escherichia is E. coli.
38. The compound or the pharmaceutical composition for use according to any of claims 23 to 26 wherein the virus is VIH.
39. The compound or the pharmaceutical composition for use according to any of claims 23 to 26 wherein the infectious is caused by fungi.
40. The compound or the pharmaceutical composition for use according to claim 39 wherein the fungi is selected from genus Candida, Aspergillus or Saccharomyces.
41. The compound or the pharmaceutical composition for use according to claim 40 wherein the fungi from genus Candida is C. albicans, C. parapsilosis, C glabrata, C tropicalis, C lusitaniae or C. krusei, the fungi from genus Aspergillus is A. niger, A. fumigatus, A. flavus or A. terreus or the fungi from genus Saccharomyces is S. cerevisiae.
42. The compound or the pharmaceutical composition for use according to any of claims 23 to 26, wherein the cancer is colorectal or breast cancer.
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