Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
  • C08G83/002—Dendritic macromolecules
  • C08G83/003—Dendrimers
• • 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
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4056—Esters of arylalkanephosphonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
  • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • 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
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4025—Esters of poly(thio)phosphonic acids

Definitions

• the invention belongs to the field of dendritic molecules. More particularly, the invention relates to polyfunctional organic dendritic molecules, to a process for preparing the same and to the use thereof, in particular as drug carriers or contrast agents.
• BACKGROUND Dendrimers and their elementary unit called “dendron”, are synthetically produced as monodisperse polymeric nanostructures with a tree-like, highly branched architecture. They are routinely synthesized as tunable “nanostructures” that may be designed and regulated as a function of their size, shape, surface chemistry and interior void space. They are typically 2 to 20 nm in diameter.
• Dendrimers and dendrons offer a plethora of applications deriving from the intrinsic properties of polymers but also and especially from their characteristics: on-surface easily accessible functions, porosity, flexibility of the internal branches, presence of functionalized cavities, accessibility to the core, and of course multivalency and cooperativity. They are extremely adaptable materials, with respect to their structure, flexibility, porosity or morphology, which can all be tuned at will.
• Dendrimers and dendrons are widely investigated and utilized in biomedical applications, as they have multiple surface functional groups that can be used to target or label for imaging and drug delivery applications. Dendrimers and dendrons have found application in transdermal drug delivery systems and show potential in gene delivery and for enhancing the oral bioavailability of problematic drugs. The presence of numerous surface groups makes dendrimers suitable carriers for delivering high drug payloads.
• the interior space of the branched structures can be used to conjugate or encapsulate drugs.
• NSAIDs nonsteroidal anti- inflammatory drugs
• anticancer drugs and other drugs such as simvastatin, famotidine, or quinolones.
• Drug–dendrimer conjugates show high solubility, reduced systemic toxicity, and selective accumulation in solid tumors.
• the multivalent character of dendrimers and dendrons also positioned these well-defined and hyper connected macromolecules to the foreground in the development of new contrast agents for medical imaging or diagnosis platforms with adjustable retention times and bio distribution properties according to their generation/size, to their flexibility and/or their hydrophilicity.
• the characterization and the physicochemical properties of these structures were studied in detail.
• a dendritic approach as a coating strategy for the design of functional nano-objects is particularly interesting in the field of cancer diagnostics.
• the appeal of such strategy is due to the unique properties of the dendritic structures which can be chemically tuned to reach ideal biodistribution or highly and efficient targeting efficacies.
• To improve tumor targeting efficacy and to obtain better in vivo imaging properties several studies explored the multivalency effect of dendrimers or of a dendritic surface functionalization of nanomaterials. Due to their conical-like architecture and focal points, dendritic structures are of particular interest as coatings of ultrasmall nanoparticles (NPs) with very high surface curvature.
• NPs ultrasmall nanoparticles
• a first objective of the present invention is to provide a new class of dendritic molecules that makes possible the delivery and targeting of many diagnostic and/or therapeutic agents.
• a second objective of the present invention is to provide a new class of dendritic molecules that can be used in phase change emulsions (PCEs) and able to (i) control the size and stabilize nanodroplets, (ii) precisely control the phase change phenomenon, (iii) obtain predetermined microbubbles sizes and size distributions, and (iv) stabilize these microbubbles.
• PCEs phase change emulsions
• a third objective of the present invention is also to provide a new class of dendritic molecules effective and useful in controlling the properties of nanoemulsions and microbubbles, independently of the PCE.
• a fourth objective of the present invention is to provide a preparation process allowing the synthesis of this new class of dendritic molecules.
• a first object of the present invention is a dendritic molecule of formula (I) below: (I) wherein : - R 1 is a group selected among: * an alkyl radical having at least 2 carbon atoms or an alkyl radical having at least 2 carbon atoms and comprising a terminal fluorinated group, * a group –OR 4 or –COOR 4 in which R 4 represents a linear alkyl radical having at least 4 carbon atoms or an alkyl radical having at least 2 carbon atoms and comprising a terminal fluorinated group, and * a phosphonate group of the following formula (PG): in which each of R 5 represents a linear alkyl radical having at least 4 carbon atoms and the star represents the attachment point of said group of formula (PG) to the phenyl cycle; - each of R 2 represents a linear alkyloxy radical having from 1 to 20 carbon atoms; - R 3 represents a linear alkyloxy radical having from 1 to 20 carbon atoms,
• linear alkyl radical having at least 2 carbon atoms means a hydrocarbon group with a linear chain of at least 2 carbon atoms, preferably from 2 to 12 carbon atoms and more preferably from 2 to 8 carbon atoms.
• Examples of said groups are methyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups.
• alkyl radical having at least 2 carbon atoms and comprising a terminal fluorinated group means a hydrocarbon group with a linear or branched chain of at least 2 carbon atoms, preferably from 2 to 12 carbon atoms, and more preferably from 2 to 8 carbon atoms, and bearing at the end of said chain, at least one fluorinated group.
• fluorinated groups are –CF2-CF3 and –CF(-CF3)2.
• linear alkyl radical having at least 4 carbon atoms means a hydrocarbon group with a linear chain of at least 4 carbon atoms, preferably from 4 to 12 carbon atoms and more preferably from 4 to 8 carbon atoms. Examples of said groups are butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups.
• linear alkyloxy radical having from 1 to 20 carbon atoms means a hydrocarbon group with a linear chain of 1 to 20 carbon atoms, preferably from 1 to 4 carbon atoms, and more preferably having only one carbon atom, said linear chain of carbon atoms being linked to an oxygen atom.
• Examples of said group are methyloxy, ethyloxy, propyloxy and butyloxy groups.
• R represents a group –OR 4 or –COOR 4 in which R 4 represents an alkyl group selected among octyl, decanyl, and dodecanyl or a fluorinated group selected among -(CH2)6-CF2CF3 and -(CH2)2-CF(CF3)2.
• each of R 2 represents a methyloxy group.
• R 3 represents a methyloxy group, a carboxyl group or a group –COOtBu in which tBu means ter-butyl.
• compounds of formula (I) according to the present invention are selected among compounds of formulae (I-A) to (I-R) whose significations of R 1 to R 5 , m, n, p, and q are given in the following Table 1: TABLE 1 q 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
• the reaction of compounds of formulae (II) and (III) can be carried out at room temperature, i.e. at a temperature ranging from 18 to 25°C, by mixing a solution of a compound of formula (II) in an appropriate solvent such as for example ethyl acetate, in the presence of a catalyst such as palladium/C, with a solution of a compound of formula (III) in an appropriate solvent such as for example dichloromethane in the presence of oxalyl chloride, dimethylformamide and N,N-diisopropylethylamine.
• the resulting compound of formula (I) can then be recovered and purified according to the usual practice known from one skilled in the art.
• Compounds of formula (III) may be prepared according to a process comprising at least the following steps: - reacting an alcohol of formula R 6 -(OCH2CH2)nOH (IV) in which R 6 represents a linear alkyloxy radical having from 1 to 20 carbon atoms with tosyl chloride to obtain a compound of formula (VI) below: wherein R 6 has the same meaning as in formula (IV); - reacting said compound of formula (VI) with methyl gallate to obtain a compound of formula (VIII) below: wherein n, p, R 2 and R 3 have the same meaning as in formula (III); and - unprotecting the carboxyl function of compound of formula (VIII) thus obtained to lead to the corresponding compound of formula (III).
• the process for the preparation of compounds of formula (III) can be represented by the following Scheme 1:
• the compound of formula (VI) is then reacted with a solution of compound of formula (VII) (methylgallate) in an appropriate solvent such as for example acetone, in the presence of potassium carbonate and potassium iodide and heated to reflux under mixing for about 8 to 16 hours to obtain a compound of formula (VIII) in which R 2 is identical to R 3 and is an alkyl group as defined above in formula (I).
• the carboxyl group of compound of formula (VIII) is then unprotected by reacting said compound of formula (VIII) dissolved in an appropriate solvent such a lower alcohol, i.e.
• Compounds of formula (II) may be prepared according to a process comprising at least the following steps: - reacting an alcohol of formula R 5 -OH (IX) wherein R 5 has the same meaning as in formula (I) with trimethylphosphite (compound of formula (X)) to obtain a compound of formula (XI) below: (XI) wherein R 5 has the same meaning as in formula (I); - reacting the compound of formula XI thus obtained with 3,5- bis(bromomethyl)phenol (compound of formula (XII)) to obtain a compound of formula (XIII) below: 5 5 wherein R 5 has the same meaning as in formula (I); and - reacting the compound of formula (XIII) thus obtained with a compound of formula (XIV)
• Compound of formula (XI) is then contacted with a compound of formula (XII) under stirring at a temperature of about 110 to 150°C for a period of time ranging from 8 to 16 hours to lead to compound of formula (XIII) in which R 5 has the same meaning as in formula (I) above.
• a compound of formula (XIV) in which m has the same meaning as in formula (I) is added to a solution of the compound of formula (XIII) in an appropriate solvent such as for example toluene, said solution comprising an alkalinizing agent such as for example potassium hydroxide and potassium iodide and being previously heated at a temperature of 60 to 90°C.
• Butyl SCHEME 4 According to the process represented on Scheme 4, a compound of formula (VII) as defined above in Scheme 1 in solution in an appropriate solvent such as for example dimethylformamide is reacted with benzyl bromide in the presence of potassium hydrogen carbonate and potassium iodide at room temperature for 8 to 24 hours to lead to compound of formula (XV).
• a solution of the compound of formula (XIX) thus obtained in an appropriate solvent such as for example acetone is then contacted with a compound of formula (XX) in which p has the same meaning as in formula (I) above, the value of p being equal of different to the value of n in the compound of formula (XIX), in the presence of potassium carbonate and potassium iodide.
• the resulting mixture is then heated at reflux for 8 to 24 hours to lead to the corresponding compound of formula (XXI) in which R 5 , R 2 , m, n and p are as defined previously.
• Compounds of formula (XXI) correspond to compounds of formula (I) in which R 3 is a group –COOtBu.
• the resulting compound of formula (XXI) can then be unprotected by addition of a strong acid, such as for example trifluoroacetic acid, into a solution of said compound of formula (XXI) in an appropriate solvent such as for example dichloromethane, and stirring at room temperature for 1 to 2 hours to lead to the expected corresponding compound of formula (I).
• a strong acid such as for example trifluoroacetic acid
• an appropriate solvent such as for example dichloromethane
• Compounds of formula (XX) can be prepared according to a process comprising the step of reacting tosyl chloride with a compound of formula (XXII): OHCH2CH2-(OCH2CH2)p-1-C(O)O-t-Butyl wherein p has the same meaning as in formula (I) above.
• reaction of 5-hydroxybenzene-1,3-dicarboxylic acid with said alcohol of formula R 4 -OH to obtain compound of formula (XXIII) can be carried out in an appropriate solvent such as for example toluene, in the presence of benzenesulfonic acid and heated to reflux for 2 to 4 days.
• the reaction of compound of formula (XXIII) such obtained with compound of formula (XXIV) can be carried out in an appropriate solvent such as for example dry acetone, at a temperature of about 80°C for about 10-12 hours in the presence of potassium carbonate and potassium iodide.
• - step i) can be carried out in solution in an appropriate solvent such as for example toluene, dimethylformamide and mixtures thereof
• - step ii) can be carried out in the presence of N,N-diethylamine, in solution in an appropriate solvent such as for example dichloromethane
• - step iii) is a hydrogenation reaction preferably carried out in the presence of H2 and an hydrogenation catalyst such as for example palladium on carbon (Pd/C) in an appropriate solvent such as ethyl acetate, at room temperature (about 20 to 25°C)
• step iv) can be carried out in an appropriate solvent such as for example acetone, in the presence of potassium carbonate and potassium iodide, preferably at a temperature of about 80°C for about 10-12 hours.
• the dendritic molecules of formula (I) according to the present invention are useful as drug carriers, in particular as delivery vehicles of drugs, in particular of nonsteroidal anti-inflammatory drugs (NSAIDs), anticancer drugs, fragment antibodies, nanobodies, and other drugs such as simvastatin, famotidine, or quinolones. Therefore, another object of the present invention is the use of a dendritic molecule of formula (I) as defined according to the first object of the present invention, as a drug carrier.
• the dendritic molecule of formula (I) in which R 3 is a carboxyl group are particularly preferred for a use as a drug carrier, since they can be easily functionalized with a ligand or an active principle.
• dendritic molecules of formula (I) are useful as contrast agents for medical imaging or diagnosis platforms after functionalization with at least one imaging agent such as for example biocompatible fluorescent dyes, traditional small molecular contrast agents, or metal ion/chelator complexes or with at least one metallic or metallic oxide nanoparticle.
• at least one imaging agent such as for example biocompatible fluorescent dyes, traditional small molecular contrast agents, or metal ion/chelator complexes or with at least one metallic or metallic oxide nanoparticle.
• dendritic molecules of formula (I) can be grafted to metallic oxide nanoparticles and used as medical imaging tool, in particular optical imaging tool or magnetic imaging tool, more particularly magnetic resonance imaging contrast agent, or magnetic particle imaging tracer, or as a hyperthermia and/or radiosensitizing agent for the treatment of tumors or other pathological tissues.
• another object of the present invention is a dendritic molecule of formula (I) as defined according to the first object of the present invention in combination with at least one imaging agent, for its use as contrast agent for medical imaging or diagnosis platforms.
• the dendritic molecules of formula (I) according to the invention are also particularly useful in phase change emulsions (PCEs) to (i) control the size and stabilize nanodroplets, (ii) precisely control the phase change phenomenon, (iii) obtain predetermined microbubbles sizes and size distributions, and (iv) stabilize these microbubbles.
• PCEs phase change emulsions
• the dendritic molecules of formula (I) according to the invention are also finally useful in controlling the properties of nanoemulsions and microbubbles, independently of the PCE.
• EXAMPLE 1 Synthesis of a dendritic molecule of formula (I-A) according to the invention
• a dendritic molecule of the following formula (I-A) was prepared: 1.1 Step 1 - Preparation of 2,5,8,11-tetraoxatridecan-13-yl 4- methylbenzenesulfonate (compound 1) (1) 30.1 mmol (1 Eq.) of tetraethyleneglycol monomethyl ether were dissolved in 170.0 mL of dichloromethane at room temperature, then 5 mL of triethylamine (Et3N) (36.2 mmol, 1.2 Eq.) were added and the reaction stirred for 10 min.
• Et3N triethylamine
• Step 7 Preparation of linker 2 (L2) To 6.76 g (77.6 mmol – 1 Eq.) of Linker 1 in DCM, were added 16.4 mL (116.0 mmol – 1.5 Eq.) of Et3N slowly, the mixture was stirred 10 min, then 17.9 g (93.2 mmol – 1.2 Eq.) of tosyl chloride (TsCl) were added slowly. After the night TLC (petroleum ether, AcOEt 7:3, KMnO4) showed traces of the starting material.
• Step 9 Preparation of a dendritic molecule of formula (I-A) To a solution of 350.0 mg (0.434 mmol – 1.1 Eq.) of compound (7) in 15 mL of EtOAc were added 120 mg (0.1 Eq.) of Pd/C 10% as catalyst. The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at RT for 5h.
• the acyl chloride was simultaneously concentrated under reduced pressure, dissolved in 10 mL of CH2Cl2 then the crude primary amine (intermediate product formed but not purified) and 0.16 mL (0.916 mmol – 2.3 Eq.) of N,N-Diisopropylethylamine (DIPEA) were successively added at 0°C. The resulting solution was stirred at RT overnight. The reaction mixture was diluted with brine. The aqueous layer was extracted with CH2Cl2 (five times), the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 7.17 g orange oil.
• DIPEA N,N-Diisopropylethylamine
• Step 3 Preparation of compound (10) (10)
• 10 10
• the solution was stirred for 20 min and heated to 60°C. to dissolve the reagents.
• 1.05 g (4.36 mmol – 1.5 Eq.) of Linker 2 (as prepared above in step 1.7. of example 1) were added and the reaction was left to stir overnight.
• Step 4 Preparation of a dendritic molecule of formula (I-B) To a solution of 237 mg (0.259 mmol – 1.1 Eq.) of compound (10) in 15 mL of EtOAc and 251 mg (0.1 Eq.) of Pd/C 10% as catalyst. The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at RT for 5h. In a separate flask, 175 mg (0.236 mmol – 1.0 Eq.) of compound (3) as prepared above at step 1.3.
• 500 mg (0.523 mmol – 1.0 Eq.) of compound (12) 44.0 mg (0.785 mmol – 1.5 Eq.) of KOH and 26 mg (0.157 mmol – 0.1 Eq.) of KI in 25 mL of toluene.
• the solution was stirred for 20 min and heated to 60°C. to dissolve the reagents.
• 252.4 mg (0.785 mmol – 1.5 Eq.) of Linker 2 (as prepared above in step 1.7. of example 1) were added and the reaction was left to stir overnight.
• the flask was cooled to room temperature, then the toluene was evaporated off under reduced pressure.
• Step 4 Preparation of a dendritic molecule of formula (I-C) To a solution of 305 mg (0.297 mmol – 1.1 Eq.) of compound (13) in 15 mL of EtOAc were added 320 mg (0.1 Eq.) of Pd/C 10% as catalyst. The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at RT for 5h. In a separate flask, 200 mg (0.270 mmol – 1.0 Eq.) of compound (3) as prepared above at step 1.3.
• Step 1 – Preparation of compound (14) (14) To a solution of 30 g (163 mmol – 1 Eq.) of methyl gallate in 150 mL of DMF were successively added 49.1 g (489 mmol – 4.5 Eq.) of KHCO3, 0.136 g (0.82 mmol – 0.006 Eq.) of KI and 21.3 mL (163 mmol – 1.0 Eq.) of benzyl bromide (BnBr). The resulting mixture was stirred at RT for 36h. The solids were filtered over Celite, the filtrate was acidified with an aqueous solution of HCl 2N (50.0 mL).
• Step 2 Preparation of compound (15) ( 15 ) To a solution of 5.81 g (16.1 mmol – 2.2 Eq.) of compound (14) in 150.0 mL of acetone were added 3.22 g (23.4 mmol – 3.2 Eq.) of K2CO3,0.12 g (0.73 mmol – 0.4 Eq.) of KI and 2.0 g (7.3 mmol – 1.0 Eq.) of compound (1) as prepared in step 1.1 of example 1. The resulting solution was heated to reflux overnight.
• Step 4 Preparation of To a solution of 1.67 g (2.09 mmol – 1.0 Eq.) of compound (7) as prepared at step 1.8 of example 1 in 40 mL of EtOAc were added 1.1 g (0.1 Eq.) of Pd/C 10% as catalyst. The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at RT for 5h. When TLC confirmed the full consumption of compound (7), the catalyst was filtered over Celite and the crude product was concentrated under reduced pressure at RT.
• Step 7 – Preparation of compound (19) To a solution of 1.0 g (0.76 mmol – 1.0 Eq) of compound (18) in 25 mL of acetone, 0.48 g (0.84 mmol – 1.1 Eq.) of Linker 3, 51.3 mg (0.30 mmol – 0.4 Eq.) of KI and 340 mg (2.45 mmol – 3.2 Eq.) of K2CO3 were successively added. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT, the solvent was removed, the crude product was suspended in CH2Cl2, the solids were filtered off; the crude product was concentrated under reduced pressure.
• EXAMPLE 5 Synthesis of a dendritic molecule of formula (I-E) according to the invention 5.1.
• Step 1 – Preparation of To a solution of 1.64 g (1.80 mmol – 1.0 Eq.) of compound (10) as prepared at step 3 of example 4 in 40 mL of EtOAc were added 960 mg (0.1 Eq.) of Pd/C 10% as catalyst. The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at RT for 5 h. When TLC confirmed the full consumption of compound (10), the catalyst was filtered over Celite and the crude product was concentrated under reduced pressure at RT.
• Step 3 Preparation of To a solution of 1.01 g (0.705 mmol – 1.0 Eq.) of compound (21) in 25 mL of acetone, 0.440 g (0.775 mmol – 1.1 Eq.) of Linker 3 as prepared at step 6 of example 48 mg (0.282 mmol – 0.4 Eq.) of KI and 313 mg (2.26 mmol – 3.2 Eq.) of K2CO3 were successively added. The resulting reaction mixture was heated to reflux overnight.
• Step 4 Preparation of a dendritic molecule of formula (I-E) In a flask containing 736 mg (0.406 mmol – 1.0 Eq.) of compound (22) dissolved in DCM, 30 Eq. of TFA was added dropwise.
• EXAMPLE 6 Synthesis of a dendritic molecule of formula (I-F) 6.1. Step 1 – Preparation of compound (23) To a solution of 300 mg (0.312 mmol – 1.1 Eq.) of compound (13), as prepared at step 3 of example 3, in 15 mL of EtOAc were added 120 mg (0.1 Eq.) of Pd/C 10% as catalyst. The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at RT for 5h.
• Step 3 – Preparation of compound (25)
• compound (24) To a solution of 320 mg (0.209 mmol – 1.0 Eq.) of compound (24) in 40 mL of acetone, 0.145 g (0.219 mmol – 1.05 Eq.) of Linker 3 as prepared at step 6 of example 4, 33 mg (0.02 mmol – 0.1 Eq.) of KI and 45 mg (0.315 mmol – 1.5 Eq.) of K2CO3 were successively added.
• the resulting reaction mixture was heated to reflux overnight.
• the reaction mixture was cooled to RT, the solvent was removed, the crude product was suspended in CH2Cl2, the solids were filtered off; the crude product was concentrated under reduced pressure to yield an orange oil.
• Step 4 Preparation of a dendritic molecule of formula (I-F)
• compound (25) dissolved in DCM
• 30 Eq. of TFA was added dropwise. The mixture was stirred for 2h, then evaporated under reduced pressure, affording 271mg of the dendritic molecule of formula (I-F) as a colorless oil (87%).
• EXAMPLE 7 Synthesis of a dendritic molecule of formula (I-P) according to the invention 7.1.
• Step 1 – Preparation of compound (26) A solution of 5-hydroxyisophthalic acid (1.00 eq., 27.45 mmol, 5.00g), octan-1-ol (3.60 eq., 38.92 mmol, 5.43 mL), and p-toluenesulfonic acid monohydrate (3.6 eq., 190.22 mmol, 7.42 g) in toluene (50.00 mL) was refluxed under Dean-Stark for 3 days.
• Step 2 Preparation of ) To a solution of compound (26) (1 eq., 0.49 mmol, 200 mg) in dry acetonitrile (ACN) (10 mL) kept under argon, K2CO3 (1.5 eq, 0.74 mmol, 102 mg) and KI (0.5 eq, 0.25 mmol, 41 mg) were added and the reaction mixture was stirred at room temperature for 15 min. Then Linker 2 (1.8 eq, 0.88 mmol, 213.6 mg) as prepared according to example 1, step 1.7 was added. Reaction mixture was heated at 80°C overnight. The mixture was filtered over a celite pad, washed with dichloromethane, and concentrated.
• ACN dry acetonitrile
• Step 3 – Preparation of compound (28) A catalytic amount of Pd/C 10% (0.5 eq, 0.13 mmol, 13.8 mg) was added to a solution of compound (27) obtained above at step 7.2 (1.10 eq, 0,26 mmol, 123.7 mg) in ethyl acetate (5 mL). The resulting mixture was purged with an atmosphere of hydrogen (five times), then vigorously stirred at room temperature for overnight. The catalyst was filtered off and the crude product was concentrated under reduced pressure at room temperature. The crude product thus obtained was further used in the coupling reaction with compound (16) as prepared according to example 4, step 4.3.
• Step 5 Preparation of compound (I-P) To a solution of compound (28) as obtained above in step 7.3 (1.00 eq, 0.12 mmol, 131.4 mg) in ethyl acetate (5 mL) was added Pd/C 10% (0.1 eq, 0.012 mmol, 11.7 mg). The heterogeneous mixture was backfilled with hydrogen (balloon) five times, then vigorously stirred at RT overnight.
• the catalyst was next filtered over Celite, the crude product was concentrated under reduced pressure and used in the following Williamson reaction without further purification.
• the crude product was dissolved in DMF (1.5 mL) and K2CO3 (1.50 eq, 0.18 mmol, 25 mg), KI (0.10 eq, 0.012 mmol, 2 mg) and compound (L3’) as prepared above in step 7.4 (1.05 eq, 0.13 mmol, 82 mg) were added.
• the resulting suspension was heated to reflux for 16 h, cooled to RT.
• EXAMPLE 8 Synthesis of a dendritic molecule of formula (I-J) according to the invention Trifluoroacetic acid (TFA) (1.00 eq, ) was added to a solution of compound (I-P) obtained above in example 7, step 7.5 (1.00 eq) in DCM kept at 0°C. The solution was stirred at 0°C. The mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (reverse phase silica gel C18, H2O/acetonitrile + 0.1% of TFA), to give the final compound (I-J).
• EXAMPLE 9 Synthesis of a dendritic molecule of formula (I-Q) according to the invention Q) 9.1.
• Step 1 Preparation of Dimethylformamide (100.00 ⁇ L) and oxalyl chloride (6.00 eq, 33.10 mmol, 2.85 mL) were added to a solution of 5-(benzyloxy)benzene-1,3- dicarboxylic acid (1.00 eq, 5.51 mmol, 1.50 g). The solution was heated at reflux for 3h. Then volatiles were pumped off and the product was isolated as a yellowish solid. The raw compound (29) was then used in the next step.
• Step 2 Preparation of A solution of compound (29) (1 Eq, 5.5 mmol, 1.7 g), triethylamine (2.5 Eq., 13.75 mmol, 1.91 mL) and CH2OH-CH2-CF(CF3)2 (Sigma Aldrich, 2.5 Eq., 13.75 mmol, 2.01 mL ) in DCM (50 mL) was stirred at RT for 12 hours. Water was added and the separate oil was extracted with DCM. The organic layer was washed with diluted HCl solution, and dried over MgSO4. The organic solvent was evaporated to yield an orange oil. The crude product was purified by column chromatography (silica gel, DCM/hexane 2:1) as a solid.
• EXAMPLE 10 Synthesis of a dendritic molecule of formula (I-L) according to the invention Trifluoroacetic acid (TFA) (1.00 eq, 0.031 mmol, 2.37 ⁇ L) was added to a solution of compound (I-Q) obtained above in example 9, step 9.6 (1.00 eq, 0.031 mmol, 50 mg) in DCM (1 mL) kept at 0°C. The solution was stirred at 0°C. The mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (reverse phase silica gel C18, H2O/acetonitrile + 0.1% of TFA), to give the final compound (I-L).
• TFA Trifluoroacetic acid
• EXAMPLE 11 Synthesis of a dendritic molecule of formula (I-R) according to the invention R) 11.1.
• Step 1 – Preparation of compound (35) A solution of compound (29) such as obtained above in example 9, step 9.1 (1 Eq., 3.59 mmol, 1.11 g), triethylamine (2.5 Eq., 8.98 mmol, 1.26 mL) and CH2OH-(CH2)5-CF2CF3 (Sigma Aldrich, 2.5 Eq., 8.98 mmol, 1.24 mL) in DCM (33 mL) was stirred at RT for 12 hours. Water was added and the separate oil was extracted with DCM. The organic layer was washed with diluted HCl solution, and dried over MgSO4.

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