Composition of dispersions for biomedical applications, process for their preparation and use thereof - Patents.com

Abstract

The present invention relates to the use of oligo(ethylene oxide) dendritic molecules to stabilize fluorocarbon-based nanoemulsions, to fluorocarbon-based nanoemulsions comprising such dendritic molecules and their use in biomedical applications, in particular as imaging agents, drug carriers or oxygenating agents.

Description

[Technical field]

[0001] The present invention is in the field of dispersion systems for biomedical applications.

[0002] More particularly, the present invention relates to the use of certain dendritic molecules (dendrons) to stabilize fluorocarbon-based nanoemulsions, fluorocarbon-based nanoemulsions comprising such dendritic molecules and their use in biomedical applications, in particular as imaging agents. [Background technology]

[0003] Gaseous microbubbles are currently the subject of intense research in the field of medical diagnostics and therapy. In combination with various ultrasound techniques, microbubbles are used clinically for cardiovascular imaging and early detection of cancer. In this context, the potential of microbubbles for ultrasound diagnosis, therapy (delivery of therapeutic agents under focused ultrasound), therapeutic energy delivery (tissue disruption, embolotherapy, sonothrombolysis and tissue ablation), as well as for enhancing oxygen-dependent cancer therapy (radiotherapy and chemotherapy, dynamic photo(sono)therapy) are being intensively studied. Other potential applications include cell therapy and the treatment of neurodegenerative diseases (Alzheimer's, Parkinson's) by crossing the blood-brain barrier.

[0004] The versatility of functionalizing the surface of microbubbles allows to graft and / or incorporate therapeutic agents, biomarkers, various nanoparticles that are functional in themselves, photo(sono)sensitizers adding other diagnostic (e.g., fluorescent and photoacoustic) as well as therapeutic (e.g., photothermal) modalities, leading to the evaluation of several theranostic platforms that significantly increase the field of application, ensure better diagnosis / guidance and thus improve therapy.

[0005] In many of these applications, the micrometer size of the microbubbles, which trap them in the vasculature, and their short lifetime in the circulation are important limitations. In particular, microbubbles are unable to penetrate tumor tissue. To overcome these problems, one approach consists in injecting nanometer droplets of liquid fluorocarbons (nanoemulsions) and then vaporizing them with ultrasound pulses after they have reached their target. This approach is particularly promising in the treatment of cancer. It has been shown that nanodroplets tend to accumulate in tumor tissue; the application of ultrasound can then vaporize the liquid fluorocarbons. Thus, the nanoemulsion droplets are transformed into microbubbles that can be used as contrast agents when subjected to low acoustic power ultrasound. The generated microbubbles can also be destroyed by cavitation to deliver incorporated therapeutic components.

[0006] Fluorocarbon-based nanoemulsions usually comprise an aqueous continuous phase in which nanodroplets of a liquid fluorocarbon are dispersed, said nanodroplets being stabilized by an interfacial film of at least one surfactant. Commonly used surfactants are selected from among long-chain fluoroalkylated surfactants or phospholipids.

[0007] However, the use of long-chain fluoroalkylated surfactants (C≧7) is highly questionable, since perfluoroalkyl substances (PFAS) tend to diffuse, bioaccumulate and persist in the environment, and some of these compounds are toxic (Marie Pierre Krafft and Jean G. Riess, "Per- and polyfluorinated substances (PFASs): Environmental challenges", Elsevier-Current Opinion in Colloid & Interface Science, 20 (2015) 192-212. Their production and use are currently strictly regulated in Western countries and Japan. In addition, the use of phospholipid surfactants, optionally mixed with other surfactants such as, for example, sodium dodecyl sulfate (SDS), to stabilize fluorocarbon-based emulsions is not entirely satisfactory, since it leads to emulsions whose average size of the dispersed droplets is on the micrometer scale or emulsions that do not generate stable gaseous microbubbles after ultrasonic activation.

[0008] Thus, the main limitation to the development of activatable microbubbles is the lack of surfactants specifically designed to 1) effectively stabilize fluorocarbon nanodroplets in fluorocarbon-based emulsions, 2) provide control of droplet activation into microbubbles, and 3) stabilize the microbubbles to avoid side effects such as pulmonary embolism, increase their intravascular persistence, and facilitate diagnosis.

[0009] The inventors set themselves the goal of developing a solution to overcome these drawbacks, in particular to obtain stable fluorocarbon-based nanoemulsions that can be easily activated into stable microbubbles with an average diameter not exceeding 2-3 μm.

[0010] The first objective of the present invention is to provide a class of dendritic molecules that can be used in fluorocarbon-based nanoemulsions or phase change emulsions (PCEs) that can be activated by various stimuli, including ultrasound or temperature, to generate stable microbubbles. These dendritic molecules are able to (i) control the size and stabilize fluorocarbon nanodroplets, (ii) precisely control the phase change phenomenon, (iii) obtain microbubbles with a defined size and size distribution, and (iv) stabilize these microbubbles. Depending on the nature of their substituents, some of these dendritic molecules can also be grafted onto metal oxide nanoparticles, which are particularly useful as medical imaging tools, in particular optical imaging tools or magnetic resonance imaging (MRI) tools, more specifically as MRI contrast agents, or as hyperthermia and / or radiosensitizers for treating tumors or other pathological tissues.

[0011] A second object of the present invention is also to provide a class of dendritic molecules that are effective and useful for controlling the properties of nanoemulsions and microbubbles independent of the phase change process.

[0012] These objectives are achieved by virtue of the use of specifically designed dendritic molecules of formula (I), as will be described in detail hereinafter. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Marie Pierre Krafft and Jean G. Riess, "Per-and polyfluorinated substances (PFASs): Environmental challenges", Elsevier-Current Opinion in Colloid & Interface Science, 20 (2015) 192-212 Summary of the Invention

[0014] A first object of the present invention is to provide a compound of formula (I): JPEG2025511985000001.jpg33128 (in the formula: -R 1 teeth, * an alkyl radical having at least 2 carbon atoms or an alkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group; *Group-OR 4 or -COOR 4 (In the formula, R 4 represents a straight chain alkyl radical having at least 4 carbon atoms or an alkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group, and *A phosphonate group of the formula (PG): JPEG2025511985000002.jpg5161 (in the formula, R 5 each represents a hydrogen atom or a straight chain alkyl radical having at least one carbon atom, and the asterisk represents the point of attachment of the group of formula (PG) to the phenyl ring; -R 2 each represents a straight chain alkyloxy radical having 1 to 20 carbon atoms; -R 3 represents a linear alkyloxy radical having 1 to 20 carbon atoms, a carboxyl group or the group -COOtBu (where tBu means tert-butyl); - n is an integer ranging from 1 to 16; -p is an integer ranging from 1 to 16; -m is an integer ranging from 1 to 4, preferably m=1 or 2, more preferably m=2; -q is an integer ranging from 1 to 3, except that R 1 represents a phosphonate group PG, then q=2. Use of an oligo(ethylene oxide) dendritic molecule of the formula The use of a fluorocarbon-based nanoemulsion consisting of a dispersion of nanodroplets of a liquid fluorocarbon stabilized in a continuous aqueous phase, stabilized by a thin lipid film present at the interface between said aqueous phase and said liquid fluorocarbon, said lipid film comprising phospholipid(s) and at least one oligo(ethylene oxide) dendron of formula (I).

[0015] Thanks to these specially designed dendritic molecules, it is now possible to follow fluorocarbon-based nanoemulsions that have improved stability, are easy to prepare, do not involve the use of long-chain fluoroalkylated surfactants, and can be easily activated into stable gaseous microbubbles not exceeding 2-3 μm in diameter, making them particularly useful in different biomedical applications.

[0016] More specifically, the oligo(ethylene oxide) dendritic molecules of formula (I) exhibit (1) very good miscibility with phospholipid monolayers (widely used in the formulation of medical microbubbles) and (2) good affinity with fluorocarbons encapsulated by the lipid film, especially if the dendritic molecules are fluorinated, allowing, after controlled activation of the nanoemulsion by ultrasound or temperature, (3) redistillation of the interfacial film at the surface of the microbubbles by controlling the lateral interactions within the lipid monolayer, and finally, 4) sufficient anchoring at the gas / water interface to ensure the stability of the microbubbles.

[0017] The innovation therefore consists in obtaining microbubbles by controlled activation of stable fluorocarbon-based nanoemulsions with much longer intravascular persistence than micron-sized microbubbles that allow accumulation in tumors. Oligo(ethylene) dendritic compounds represent a versatile platform onto which ligands can be grafted for targeted delivery as required.

[0018] In addition, q=2 and R 1Oligo(ethylene oxide) dendritic molecules of formula (I), in which represents a phosphonate group of formula PG, can be grafted to magnetic nanoparticles, which combine the advantages of magnetic nanoparticles, allowing for example guidance (monitoring) during magnetic resonance imaging.

[0019] In this specification, the terms "oligo(ethylene glycol) dendritic molecule of formula (I)" and "dendron of formula (I)" are synonymous.

[0020] R 1 With respect to "linear alkyl radical having at least 2 carbon atoms" means a hydrocarbon group having a linear chain of at least 2 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms. Examples of said groups are methyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups.

[0021] R 1 and R 4 With respect to "an alkyl radical having at least two carbon atoms and containing a terminal fluorinated group" means a hydrocarbon group having a straight or branched chain of at least two carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and having at least one fluorinated group at the end of said chain. Non-limiting examples of fluorinated groups are -CF2-CF3 and -CF(-CF3)2.

[0022] R 4 In the context of "linear alkyl radical having at least 4 carbon atoms" means a hydrocarbon group having a linear chain of at least 4 carbon atoms, preferably 4 to 12 carbon atoms, more preferably 4 to 8 carbon atoms. Examples of said groups are butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups.

[0023] R 5With respect to "linear alkyl radical having at least one carbon atom" means a hydrocarbon group having a linear chain of at least one carbon atom, preferably from 2 to 12 carbon atoms, more preferably from 2 to 8 carbon atoms. Examples of said groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups.

[0024] R 2 and R 3 With respect to "linear alkyloxy radical having 1 to 20 carbon atoms" means a hydrocarbon group having a linear chain having 1 to 20 carbon atoms, preferably 1 to 4 carbon atoms, more preferably only 1 carbon atom, said linear chain of carbon atoms being bonded to an oxygen atom. Examples of such groups are methyloxy, ethyloxy, propyloxy and butyloxy groups.

[0025] According to a preferred embodiment of the present invention, n is an integer ranging from 4 to 6, inclusive, and even more preferably n=4.

[0026] According to another preferred embodiment of the present invention, p is an integer ranging from 4 to 10, inclusive, even more preferably p=4 or p=9.

[0027] According to certain preferred embodiments of the present invention, the oligo(ethylene oxide) dendritic molecule of formula (I) has q=2 and R 1 Formula (PG) (wherein R 5 Each of R represents a hydrogen atom or an alkyl group having 4 to 12 carbon atoms, more preferably R 5 is an alkyl group selected from among octyl, decanyl, and dodecanyl.

[0028] According to this particular embodiment, R 5When R is a hydrogen atom, said oligo(ethylene oxide) dendritic molecules of formula (I) can be grafted to magnetic nanoparticles, preferably metal oxide nanoparticles, and even more particularly iron oxide nanoparticles. Always according to this particular embodiment, said nanoparticles are grafted thanks to phosphonate groups (PG) which can adsorb or react with hydroxyl groups present on the surface of said nanoparticles to form covalent bonds. According to this embodiment, the metal oxide nanoparticles obtained have q=2 and R 1 Formula (PG) (wherein R 5 each of which represents a hydrogen atom) and is used according to the first object of the present invention, namely to stabilize a fluorocarbon-based nanoemulsion consisting of a dispersion of nanodroplets of a liquid fluorocarbon stabilized in a continuous aqueous phase by means of a thin lipid film present at the interface between said aqueous phase and said liquid fluorocarbon, said lipid film comprising phospholipid(s) and said functionalized metal oxide nanoparticles.

[0029] According to this embodiment, the term "reaction" comprises the adsorption of said dendritic molecule on the surface of said nanoparticles via an ionic or covalent bond between at least one OH radical of a PG group and at least one OH radical of a metal oxide nanoparticle.

[0030] Examples of metal oxide nanoparticles can include those used and disclosed in International Application Publication WO2005 / 150502.

[0031] According to another particular embodiment of the invention, the oligo(ethylene oxide) dendritic molecule of formula (I) has q=2 and R 1 represents an alkyl group selected from among octyl, decanyl and dodecanyl, or a fluorinated group selected from among -(CH2)6-CF2CF3 and -(CH2)2-CF(CF3)2.

[0032] According to another particular embodiment of the invention, the oligo(ethylene oxide) dendritic molecule of formula (I) has q=2 and R 1 But the group -OR 4 or -COOR 4 (In the formula, R 4 represents an alkyl group selected from among octyl, decanyl, and dodecanyl, or a fluorinated group selected from among -(CH2)6-CF2CF3 and -(CH2)2-CF(CF3)2).

[0033] According to certain preferred embodiments of the present invention, the oligo(ethylene oxide) dendritic molecule of formula (I) is 2 are compounds in which each represents a methyloxy group.

[0034] According to another particularly preferred embodiment of the present invention, the oligo(ethylene oxide) dendritic molecule of formula (I) is 3 represents a methyloxy group, a carboxyl group or the group -COOtBu (tBu stands for tert-butyl).

[0035] According to the most preferred embodiment of the present invention, the oligo(ethylene oxide) dendritic molecule of formula (I) is 1 ~R 5 The meanings of m, n, p and q are as follows: The compound is selected from the compounds of formulae (IA) to (IT) shown in JPEG2025511985000003.jpg134170.

[0036] Of the compounds specifically listed in Table 1 above, the compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), (IP), (IQ), (IR), (IS) and (IT) are most preferred.

[0037] R 1 Formula (PG) (wherein R 5 has the same meaning as in formula (I) above, except for hydrogen atoms, q=2, n=p, R 2 and R 3are identical and represent an alkyloxy group as defined above in formula (I), the dendritic molecule of formula (I) being represented by the following formula (II): JPEG2025511985000004.jpg99113 (in the formula, R 5 has the same meaning as in formula (I) above, except for a hydrogen atom, and m has the same meaning as in formula (I) above), and a compound of formula (III): JPEG2025511985000005.jpg45118, where n=p and has the same definition as in formula (I) above, and R 2 and R 3 are identical and represent an alkyloxy group as defined in formula (I)) to obtain the corresponding compound of formula (I).

[0038] The reaction of the compounds of formula (II) and (III) can be carried out by mixing a solution of the compound of formula (II) in a suitable solvent, such as, for example, ethyl acetate, in the presence of a catalyst, such as palladium / C, at room temperature, i.e., at a temperature in the range of 18-25° C., with a solution of the compound of formula (III) in a suitable 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 practices known to those skilled in the art.

[0039] The compound of formula (III) can be prepared by at least the following steps: -Formula R 6 -(OCH2CH2) n OH(IV) (wherein, R 6 represents a linear alkyloxy radical having 1 to 20 carbon atoms) with tosyl chloride to obtain a compound represented by the following formula (VI): JPEG2025511985000006.jpg45115 (in the formula, R 6 and n has the same meaning as in formula (III); - reacting the compound of formula (VI) with methyl gallate to obtain a compound of formula (VIII): JPEG2025511985000007.jpg49115 (where n, p, R 2 and R 3 has the same meaning as in formula (III); - deprotection of the carboxyl function of the compound of formula (VIII) thus obtained to obtain the corresponding compound of formula (III), It can be prepared according to a process comprising:

[0040] The process for the preparation of compounds of formula (III) can be represented by the following Scheme 1: JPEG2025511985000008.jpg92152

[0041] According to the process depicted in Scheme 1, in the presence of an amine, such as triethylamine, R 6 is R in the compound of formula (III) above 2 and R 3 (R 2 and R 3 is the same) in a suitable solvent, such as dichloromethane, 6 has the same meaning as in formula (IV) above (R 2 and R 3 are identical) with a compound of formula (V) at room temperature under mixing until a compound of formula (VI) is obtained. The compound of formula (VI) is then reacted with a solution of a compound of formula (VII) (methyl gallate) in a suitable solvent, 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 R 2 R 3and the alkyl group is as defined above in formula (I) to obtain a compound of formula (VIII). The carboxyl group of compound of formula (VIII) is then deprotected by reacting said compound of formula (VIII) dissolved in a suitable solvent, such as a lower alcohol, i.e. methanol or a mixture of lower alcohols, particularly a mixture of methanol and water, with water, particularly a mixture of methanol and water, in the presence of an alkalizing agent, such as sodium hydroxide, at room temperature to obtain the corresponding compound of formula (III).

[0042] The compound of formula (II) can be prepared by at least the following steps: -Formula R 5 -OH(IX) (where R 5 has the same meaning as in the above formula (I) except for a hydrogen atom) with trimethyl phosphite (a compound of formula (X)) to obtain a compound of the following formula (XI): JPEG2025511985000009.jpg5393 (in the formula, R 5 has the same meaning as in formula (I) above, except for the hydrogen atom; The compound of formula XI thus obtained is reacted with 3,5-bis(bromomethyl)phenol (a compound of formula (XII)) to obtain a compound of formula (XIII): JPEG2025511985000010.jpg78136 (in the formula, R 5 has the same meaning as in formula (I) above, except for the hydrogen atom; and - reacting the compound of formula (XIII) thus obtained with the compound of formula (XIV): JPEG2025511985000011.jpg91101 (wherein m has the same meaning as in formula (I)) to obtain the corresponding compound of formula (II). It can be prepared according to a process comprising:

[0043] The process for the preparation of compounds of formula (II) can be represented by the following Scheme 2: JPEG2025511985000012.jpg124151

[0044] According to the process depicted in Scheme 2, a compound of formula (X) (trimethylphosphite) can be prepared by reacting R 5 is added to an alcohol of formula (IX) having the same meaning as in formula (I) above, the alcohol of formula (IX) being preheated at a temperature of 30 to 75° C. The resulting mixture is then heated to a temperature of 130 to 230° C. for 5 to 16 hours under an argon atmosphere to obtain R 5 has the same meaning as in formula (I) above. Compound (XI) can be separated from the remaining alcohol of formula (IX) by, for example, distillation. Compound (XI) is then contacted with compound of formula (XII) under stirring at a temperature of about 110-150° C. for a period ranging from 8 to 16 hours to obtain compound (XI) of formula (XI). 5 A compound of formula (XIII) is obtained in which m has the same meaning as in formula (I) above, except for a hydrogen atom. A compound of formula (XIV) in which m has the same meaning as in formula (I) is added to a solution of a compound of formula (XIII) in a suitable solvent, for example toluene, which contains an alkalizing agent, for example potassium hydroxide and potassium iodide, and is heated in advance at a temperature of 60-90° C. The resulting mixture is maintained at a temperature of 60-90° C. and stirred for 8-16 hours to obtain a compound of formula (II), which can be recovered and purified by conventional techniques well known to those skilled in the art.

[0045] The compound of formula (XIV) can be prepared in advance according to the process depicted in Scheme 3 below: JPEG2025511985000013.jpg80157

[0046] According to the process depicted in Scheme 3, a solution of a 2-azidoalkanol, where m has the same meaning as in formula (I), in a suitable solvent, for example dichloromethane, is reacted with tosyl chloride in the presence of trimethylamine at room temperature for 8-16 hours to give a compound of formula (XIV), where m has the same meaning as in formula (I).

[0047] R 1 is a phosphonate group (PG) (wherein R 5has the same meaning as in formula (I) above, except for hydrogen atoms, q=2, n and p are the same or different, R 2 is an alkyloxy group as defined above in formula (I), R 3 The dendritic molecule of formula (I) in which is a carboxyl group or a group -COOtBu can be prepared by at least the following steps: - reacting methyl gallate (a compound of formula (VII) as defined above) with benzyl bromide to obtain a compound of formula (XV) JPEG2025511985000014.jpg119121-Formula R 2 -(CH2CH2) n OH(IV') (wherein, R 2 and n has the same meaning as in formula (I) above) with tosyl chloride (a compound of formula (V) as defined above) to produce a compound of formula (VI'): JPEG2025511985000015.jpg82118 (in the formula, R 2 and n has the same meaning as in formula (I) above; - reacting the compound of formula (XV) with the compound of formula (VI') thus obtained to obtain a compound of formula (XVI): JPEG2025511985000016.jpg118170 (in the formula, R 2 and n has the same meaning as in formula (I) above; - by deprotecting the carboxylic acid function of the compound of formula (XVI) thus obtained, to give a compound of formula (XVII) JPEG2025511985000017.jpg118170 (in the formula, R 2 and n has the same meaning as in formula (I) as defined above; - reacting the compound of formula (XVII) thus obtained with a compound of formula (II) as defined above to give a compound of formula (XVIII) JPEG2025511985000018.jpg59142 (in the formula, R 5 has the same meaning as in formula (I) above, except for hydrogen atoms, and R 2, m and n have the same meanings as in formula (I) above; - the benzyl group of the compound of formula (XVIII) thus obtained is hydrolyzed to obtain a compound of formula (XIX): JPEG2025511985000019.jpg78167 (in the formula, R 5 has the same meaning as in formula (I) above, except for hydrogen atoms, and R 2 , m and n have the same meanings as in formula (I) above; - reacting the compound of formula (XIX) thus obtained with the compound of formula (XX): JPEG2025511985000020.jpg24146, in which p has the same meaning as in formula (I) and has a value identical or different to the value of n in the compound in formula (XIX) defined above, to obtain a compound of formula (XXI): JPEG2025511985000021.jpg57147 (in the formula, R 5 has the same meaning as in formula (I) above, except for hydrogen atoms, and R 2 m, n and p have the same meaning as in formula (I) above, p has the same meaning as in formula (I) and is the same or different from the value of n in the compound of formula (XIX) defined above, R 3 has a value corresponding to the particular compound of formula (I) in which is the group -COOtBu; and optionally; - deprotecting the carboxylic acid function of the compound of formula (XXI) thus obtained to give R 3 obtaining the corresponding dendritic molecule of formula (I) in which is the group -COOH The composition can be prepared according to a process comprising:

[0048] n and p are the same or different, and R 2 is an alkyloxy group as defined above in formula (I), R 3 A process for the preparation of dendritic molecules of formula (I) in which is a carboxyl group can be represented by the following Scheme 4: JPEG2025511985000022.jpg183166

[0049] According to the process depicted in Scheme 4, a compound of formula (VII) as defined above in Scheme 1 in a suitable solution, such as, for example, dimethylformamide, is reacted with benzyl bromide in the presence of potassium bicarbonate and potassium iodide at room temperature for 8-24 hours to give a compound of formula (XV). 2 is as defined above in formula (I), in a suitable solvent, such as dichloromethane, 2 is contacted with a compound of formula (V) at room temperature under mixing until a compound of formula (VI') is obtained, where R is the same as in formula (I) above. A solution of a compound of formula (XV) in a suitable solvent, for example acetone, is then reacted with the compound of formula (VI') thus obtained in the presence of an alkalizing agent, for example potassium carbonate and potassium iodide. The mixture obtained is then heated to reflux for 8 to 24 hours to obtain R 2 and n has the same meaning as in the compound of formula (VI'), the carboxyl group of the compound of formula (XVI) thus obtained is then deprotected by reacting said compound of formula (XVI) dissolved in a suitable solvent, such as a lower alcohol, i.e. methanol or a mixture of lower alcohols, with water, in particular a mixture of methanol and water, in the presence of an alkalizing agent, such as sodium hydroxide, at room temperature, to give the corresponding compound of formula (XVI), R 2 and obtaining the corresponding compound of formula (XVII), in which n has the same meaning as in the compound of formula (XVI). 5 The reaction of the compound of formula (II), in which, except for a hydrogen atom, has the same meaning as in formula (I) above and m has the same meaning as in formula (I), with the compound of formula (XVII) thus obtained is carried out by mixing a solution of the compound of formula (II) in a suitable solvent, such as, for example, ethyl acetate, in the presence of a catalyst, such as palladium / C, at room temperature, with a solution of the compound of formula (XVII) in a suitable solvent, such as, for example, dichloromethane, in the presence of oxalyl chloride, dimethylformamide and then N,N-diisopropylethylamine, R 5has the same meaning as in formula (I) above, except for hydrogen atoms, and R 2 The corresponding compound of formula (XVIII), wherein m and n have the same meaning as in formula (I), can then be obtained. A solution of the resulting compound of formula (XVIII) in a suitable solvent, e.g., ethyl acetate, containing a catalyst, e.g., palladium / C, can then be purged with hydrogen atmosphere for 5-24 hours at room temperature with stirring to give R 5 has the same meaning as in formula (I) above, except for hydrogen atoms, and R 2 The corresponding compound of formula (XIX), in which m and n have the same meanings as in formula (I), is obtained. A solution of the compound of formula (XIX) thus obtained in a suitable solvent, for example acetone, is then contacted with a compound of formula (XX), in which p has the same meaning as in formula (I) above and the value of p is equal to or different from the value of n in the compound of formula (XIX), in the presence of potassium carbonate and potassium iodide. The mixture obtained is then heated under reflux for 8 to 24 hours to obtain R 5 has the same meaning as in formula (I) above, except for hydrogen atoms, and R 2 , m, n and p are as previously defined. The compound of formula (XXI) is obtained by reacting R 3 corresponds to the compound of formula (I) where is the group -COOtBu. The compound of formula (XXI) obtained can then be deprotected by adding a strong acid, for example trifluoroacetic acid, to a solution of said compound of formula (XXI) in a suitable solvent, for example dichloromethane, and stirring at room temperature for 1-2 hours to obtain the corresponding compound of the expected formula (I). Compounds of formula (XXI) and formula (I) can be recovered and purified according to the usual practices known to those skilled in the art.

[0050] The compound of formula (XX) can be prepared by reacting tosyl chloride with a compound of formula (XXII): OHCH2CH2-(OCH2CH2) p-1 -C(O)Ot-butyl, where p has the same meaning as in formula (I) above. This process can be represented by Scheme 5 below: JPEG2025511985000023.jpg60158

[0051] According to the process represented by Scheme 5, tosyl chloride is reacted with a solution of a compound of formula (XXII), in which p has the same meaning as in the compound of formula (I) and p can have the same value as n or a value different from n, in a suitable solvent, such as, for example, dichloromethane, in the presence of an amine, such as, for example, trimethylamine, at room temperature for 8 to 24 hours. The compound of formula (XXII) thus obtained can then be recovered and purified by techniques well known to those skilled in the art.

[0052] q=2, and R 1 The grafting of metal oxide nanoparticles onto compounds of formula (I), in which represents a phosphonate group (PG), can be carried out according to the process described in published international application WO2015 / 150502.

[0053] R 1 but, * an alkyl radical having at least 2 carbon atoms or an alkylalkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group; or *Group-OR 4 Or -COOR 4 (In the formula, R 4 represents a straight chain alkyl radical having at least 4 carbon atoms or an alkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group; The compound of formula (I) may be represented by formula (II'): JPEG2025511985000024.jpg9184, where m is as defined in formula (I) and R 1 is an alkyl radical having at least two carbon atoms or an alkyl radical having at least two carbon atoms and containing a terminal fluorinated group, or a group -OR 4 Or -COOR 4 (In the formula, R 4represents a linear alkyl radical having at least 4 carbon atoms or an alkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group, and q is an integer ranging from 1 to 3, and a compound of formula (I) in which n and p are the same or different and R 2 R 3 and the compound of formula (III) above, or in the desired compound of formula (I), n and p are the same or different, and R 2 is an alkyloxy group as defined above in formula (I), R 3 When is a carboxyl group, it can be prepared according to a process comprising the step of reacting with a compound of formula (XVII) above.

[0054] The above mentioned conditions for reacting a compound of formula (II) with a compound of formula (III) or with a compound of formula (XVII) also apply to the reaction of a compound of formula (II') with a compound of formula (III) or with a compound of formula (XVII), respectively.

[0055] Compounds of formula (II') that may not be commercially available are well known to those skilled in the art and can be similarly prepared, for example, according to the method described in "Spacing-dependent dipolar interactions in dendronized magnetic iron oxide nanoparticle 2D arrays and powders." Solenne Fleutot, et al., Nanoscale, 2013, 5, 1507.

[0056] R 1 -COOR 4 (R 4 represents a linear alkyl radical having at least 4 carbon atoms), and q is an integer ranging from 1 to 3, the compound of formula (II') (the compound of formula (II'a)) is -5-hydroxyisophthalic acid and a compound of formula R 4 -OH(in the formula, R 4is a linear alkyl radical having at least 4 carbon atoms) to produce an alcohol of formula (XXIII): JPEG2025511985000025.jpg77124 (in the formula, R 4 has the same meaning as for the compound of formula (II'a), a compound of formula (XXIII) and the following formula (XXIV): JPEG2025511985000026.jpg70108, where m is as defined in formula (I), to give the corresponding compound of formula (II'a).

[0057] 5-hydroxybenzene-1,3-dicarboxylic acid and the compound of formula R 4 The reaction of -OH with an alcohol can be carried out in the presence of benzenesulfonic acid in a suitable solvent such as, for example, toluene and heated at reflux for 2-4 days.

[0058] The reaction of the compound of formula (XXIII) thus obtained with the compound of formula (XXIV) can be carried out in a suitable solvent, such as, for example, dry acetone, at a temperature of about 80° C. for about 10 to 12 hours in the presence of potassium carbonate and potassium iodide.

[0059] R 1 -COOR 4 (R 4 represents an alkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group) and q is an integer ranging from 1 to 3, the compound of formula (II') (compound of formula (II'b)) can be prepared by the following process: i) reacting 5-(benzyloxy)benzene-1,3-dicarboxylic acid (CAS No. 114274-39-4) with oxalyl chloride to obtain a compound of formula (XXV): JPEG2025511985000027.jpg115129ii) The compound of formula (XXV) thus obtained and the compound of formula R 4 -OH(in the formula, R 4is an alkyl radical having at least two carbon atoms and containing a terminal fluorinated group) to produce an alcohol of the following formula (XXVI): JPEG2025511985000028.jpg114138 (in the formula, R 4 is an alkyl radical having at least two carbon atoms and containing a terminal fluorinated group, iii) The compound of formula (XXVI) thus obtained is deprotected to give a compound of formula (XXVII): JPEG2025511985000029.jpg66139 (in the formula, R 4 has the same meaning as for the compound of formula (XXVI), and iv) Reacting the compound of formula (XXVII) thus obtained with the compound of formula (XXIV): JPEG2025511985000030.jpg71108, wherein m is as defined in formula (I), to obtain the corresponding compound of formula (II'b). It can be prepared by a process comprising:

[0060] According to this process: step i) can be carried out in solution in a suitable solvent, such as, for example, toluene, dimethylformamide and mixtures thereof, step ii) can be carried out in the presence of N,N-diethylamine in a suitable solvent such as, for example, dichloromethane, - step iii) is preferably a hydrogenation reaction carried out in the presence of H2 and a hydrogenation catalyst, such as, for example, palladium on carbon (Pd / C), in a suitable solvent, such as, for example, ethyl acetate, at room temperature (about 20-25°C). - Step iv) can be carried out in a suitable 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 to 12 hours.

[0061] R 1 is a PG group (wherein R 5Compounds of formula (I), wherein R represents a hydrogen atom, can be prepared as described in International Application Publication WO2015150502.

[0062] A second object of the present invention is a fluorocarbon-based nanoemulsion comprising an aqueous continuous phase and a dispersion of nanodroplets consisting of a membrane of a lipid phase encapsulating at least one liquid fluorocarbon, the lipid phase comprising at least one phospholipid and at least one oligo(ethylene oxide) dendritic molecule of formula (I) as defined above according to the first object of the present invention.

[0063] As used herein, the term "nanoemulsion" refers to an emulsion of nanodroplets in an aqueous medium. The term "nanodroplets" refers to submicron droplets comprising a liquid fluorocarbon.

[0064] As used herein, the term "fluorocarbon" (FC) refers to a substance in which most or all of the carbon-hydrogen bonds are replaced by carbon-fluorine bonds.

[0065] FC may be substituted with a halogen atom, such as, for example, bromine.

[0066] The FC may comprise linear or branched fluorocarbon chains ranging in carbon length from 4 to about 10 carbon atoms.

[0067] Useful FCs include perfluorobutane, perfluoropentane, 2H,3H-perfluoropentane, perfluorohexane, perfluoroheptane, perfluorooctane, perfluorononane, perfluorodecalin, perfluorooctyl bromide, and perfluorotripropylamine. Preferred PFCs include perfluoropentane, 2H,3H-perfluoropentane, perfluorohexane, and perfluorooctyl bromide. Perfluorohexane is most preferred.

[0068] The concentration of FC in the nanoemulsion according to the invention may vary from about 1 to 30% w / w, preferably from about 2.5 to 20% w / w, even more preferably from about 5 to 10% w / w.

[0069] As used herein, "phospholipid" refers to a class of lipids whose molecules have a hydrophilic head containing a phosphate group and two hydrophobic chains derived from fatty acids linked by an alcohol residue (usually a glycerol molecule).

[0070] Phospholipids useful according to the invention can have any suitable carbon chain length, ranging from about 12 carbon atoms to about 18 carbon atoms (e.g., 12, 13, 14, 15, 16, 17, 18) in length. Phospholipid molecules can also contain unsaturation. Examples of phospholipids useful according to the invention include phosphatidylcholine derivatives, such as, for example, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine.

[0071] The concentration of phospholipids in the nanoemulsion according to the invention may vary from about 0.25 to 10% w / w, preferably from about 0.4 to 5% w / w, even more preferably from about 0.6 to 2.5% w / w.

[0072] The concentration of the oligo(ethylene oxide) dendritic molecules of formula (I) in the final nanoemulsion according to the invention may vary from about 0.07% to 0.7% w / w, preferably from about 0.11% to 0.50% w / w, and even more preferably from about 0.13% to 0.38% w / w.

[0073] Among the oligo(ethylene oxide) dendritic molecules of formula (I), nanoemulsions in which the lipid phase comprises dendrons of formula (IP), (IQ), (ID), (IE), (IA), (IB) or (IC) are particularly preferred.

[0074] According to certain preferred embodiments of the present invention, the molar ratio of phospholipids of formula (I) to oligo(ethylene oxide) dendritic molecules varies from about 5:1 to 50:1, more preferably from about 7:1 to 30:1, and even more preferably from about 9:1 to 25:1.

[0075] The average mean diameter of the nanodroplets may vary from about 50 to 900 nm, preferably from about 150 to 600 nm, and even more preferably from about 200 to 400 nm.

[0076] This average mean diameter can be adjusted by varying the phospholipid / dendritic molecule ratio, and it can also be adjusted by varying the preparation parameters, such as the homogenization pressure or the number of cycles of the nanoemulsion through a high-pressure homogenizer.

[0077] The aqueous phase of the nanoemulsion can comprise water, e.g., water for injection (WFI), saline, or a buffer solution such as phosphate buffered saline (PBS) or HEPES buffer solution.

[0078] The fluorocarbon-based nanoemulsions defined according to the second object of the present invention can be prepared by any method known to the person skilled in the art, in particular by a process comprising: (i) dispersing phospholipids and oligo(ethylene oxide) dendritic molecules of formula (I) in an aqueous phase at an appropriate temperature to obtain a dispersion; (ii) adding a liquid fluorocarbon to the dispersion obtained in (i); and (iii) homogenizing the mixture obtained to obtain a dispersion of nanodroplets consisting of a membrane of a lipid phase encapsulating at least one liquid fluorocarbon or perfluorocarbon, the lipid phase comprising at least one phospholipid and at least one oligo(ethylene oxide) dendritic molecule of formula (I).

[0079] As used herein, "suitable temperature" refers to a temperature higher than the phospholipid transition temperature. Depending on the nature of the phospholipids present in the nanoemulsion, the suitable temperature may vary from about 25°C to 80°C, preferably from about 25°C to 50°C.

[0080] Homogenization may be performed using any suitable device, such as advanced sonication, low energy devices and / or high pressure homogenization devices.

[0081] After step (iii), the resulting nanoemulsion can be centrifuged, filtered, or subjected to any other desired procedures before characterization and use.

[0082] The nanoemulsions defined according to the second object of the invention can be used in different biomedical applications, in particular as imaging agents.

[0083] The fluorocarbon-based nanoemulsions defined according to the second object of the present invention may find different biomedical applications, in particular as imaging agents.

[0084] Therefore, a third object of the present invention is the use of a fluorocarbon-based nanoemulsion as defined according to the second object of the present invention as a contrast agent, for example in bimodal diagnostic methods.

[0085] According to a particular embodiment, said bimodal diagnostic method is echosonography or magnetic resonance imaging (MRI) in the case of nanoemulsions comprising metal oxide nanoparticles, in particular iron oxide nanoparticles.

[0086] The fluorocarbon-based nanoemulsions defined according to the second object of the present invention may also be used in different therapeutic treatment methods, such as drug carriers or oxygenators.

[0087] Thus, a fourth object of the invention is a fluorocarbon-based nanoemulsion as defined according to the second object of the invention, for use as a drug carrier or oxygenator in a therapeutic treatment method.

[0088] According to this embodiment, the use comprises: -ultrasound-guided and spatially confined delivery of therapeutic agents, such as drugs or genetic materials, to targeted areas; - treatment of hypoxia (useful in oncology) This property is based on the fact that fluorocarbons are known to be good solvents for gases, especially respiratory gases such as oxygen and carbon dioxide. [Brief description of the drawings]

[0089] Further advantages and embodiments of the present invention are given by the following accompanying examples and figures: [Figure 1] 1A and 1B are graphs representing the droplet size distribution in a reference nanoemulsion stabilized only by dipalmitoylphosphatidylcholine (FIG. 1a) and in a nanoemulsion according to the invention, namely stabilized by dipalmitoylphosphatidylcholine and a dendron of formula (IP) (FIG. 1b). In FIGS. 1a and 1b, the intensity (%) is expressed as a function of the diameter at t=0, i.e. immediately after the preparation of the nanoemulsion (dotted curve) and after storage for 2 months at a temperature of 25° C. (solid curve). [Diagram 2] FIG. 1 is a graph representing the evolution of the average mean diameter (nm) of the droplets as a function of time (days) for a reference nanoemulsion stabilized only by dipalmitoylphosphatidylcholine (curve with black squares) and for a nanoemulsion according to the invention, namely a nanoemulsion stabilized by dipalmitoylphosphatidylcholine and a dendron of formula (IP) (curve with black disks). [Diagram 3] 1 is a graph representing the average diameter (nm) of the nanodroplets as a function of time (days) for a nanoemulsion according to the invention, i.e. a nanoemulsion containing DMPC and a dendron of formula (IP) (curve with filled circles), compared to a reference nanoemulsion not forming part of the invention, i.e. containing only dimyristoylphosphatidylcholine (DMPC) (curve with filled squares). [Figure 4]1 is a graph representing the average diameter (nm) of the nanodroplets as a function of time (days) for a reference nanoemulsion not forming part of the invention, i.e. containing DMPC only (square symbols), compared to a nanoemulsion according to the invention, i.e. containing DMPC and a dendron of formula (IE) (circles) or a nanoemulsion according to the invention, i.e. containing DMPC and a dendron of formula (ID) (asterisks). [Diagram 5] 1 is a graph showing the frequency (%) as a function of microbubble diameter (μm) of a microbubble dispersion obtained by activating a nanoemulsion stabilized with a dendritic compound of formula (IP) immediately after its preparation. [Figure 6] FIG. 2 is a graph representing the frequency (%) as a function of microbubble diameter (μm) of a microbubble dispersion obtained by activating a nanoemulsion stabilized with a dendritic compound of formula (IP) after 7 hours at room temperature. [Figure 7] FIG. 7 is an optical photograph of the microbubble dispersion of FIG. [Figure 8] 8A-8B are optical photographs of the phase shift of nanoemulsion droplets of the nanoemulsion of Example 14 prepared using dendrons of formula (IF) into microbubbles observed at 37° C. using cryogenic transmission electron microscopy at the beginning of the evaporation process (FIG. 8a) and after 15 minutes at 37° C. (FIG. 8b). [Figure 9] FIG. 2 is a graph representing the compression isotherms (surface pressure π (mN m-1) expressed as a function of molecular area A (Å2)) of Langmuir monolayers formed by dendritic compounds of formula (IA) (solid curve), dendritic compounds of formula (IB) (dashed curve), dendritic compounds of formula (IC) (dotted curve) or comparative dendritic compounds of formula (DM) not forming part of the present invention (alternating dashed and dotted curves). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0090] Example 1: Synthesis of dendritic molecules of formula (IA) according to the invention In this example, a dendritic molecule of formula (IA) was prepared: JPEG2025511985000031.jpg69169

[0091] 1.1 Step 1 - Preparation of 2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate (compound 1) JPEG2025511985000032.jpg4712930.1 mmol (1 eq.) of tetraethylene glycol monomethyl ether was dissolved in 170.0 mL of dichloromethane at room temperature, then 5 mL of triethylamine (Et3N) (36.2 mmol, 1.2 eq.) was added and the reaction was stirred for 10 minutes. 22.3 g (36.2 mmol, 1.2 eq.) of tosyl chloride (solid) was added slowly. The resulting mixture was stirred at room temperature overnight.

[0092] Thin layer chromatography (TLC) analysis (stained phosphomolybdic acid (PMA) solution) showed complete consumption of PEG-OMe. The mixture was filtered through Celite to remove salts. The solvent was then evaporated under reduced pressure.

[0093] Purification by flash chromatography (100% dichloromethane (DCM) then 100% ethyl acetate (AcOEt)) gave a clear liquid (10.1 g, 93%).

[0094] analysis: 1 H NMR(400MHz,MeOD)δ 7.85(d,J=8.4Hz,2H),7.50(dd,J=8.6,0.8Hz,2H),4.23-4.14(m,3H),3.74- 3.68(m,3H),3.68-3.64(m,7H),3.62-3.55(m,7H),3.40(s,3H),2.51(s,3H).

[0095] 1.2 Step 2 - Preparation of Compound (2) JPEG2025511985000033.jpg34153 To a solution of 8.8 mmol (1.0 equiv.) of methyl gallate in acetone (60 mL) was added 18.1 mmol (3.2 equiv.) of potassium carbonate (K2CO3), 0.6 mmol (0.1 equiv.) of potassium iodide (KI) and 18.9 mmol (3.3 equiv.) of compound (1) as prepared in step 1 above. The resulting solution was heated to reflux for 42 h.

[0096] The reaction mixture was cooled to room temperature, the solvent was removed, and the solid was suspended in dichloromethane (CH2Cl2), filtered through Celite, washed with aqueous sodium thiosulfate (Na2S2O3) 2N and brine, dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (CH2Cl2 / MeOH 98 / 2 to 96 / 4 to 9 / 1) gave 3.9 g (89%) of a yellowish oil.

[0097] analysis: 1 H NMR(400MHz,chloroform-d)δ 7.46(d,2H:Ar-H),4.15(dd,J=5.6,4.2Hz,6H:-O-CH2-R),3.86(s,3H:CH3-OC=OR),3.85-3.81(m,6H:-O-CH2-CH2- R),3.70-3.66(m,6H:-O-CH2-R),3.63-3.56(m,24H:-O-CH2-R),3.51-3.47(m,6H:-O-CH2-R),3.33(s,9H:CH3-O-).

[0098] 1.3 Step 3 - Preparation of compound (3) To a solution of 6.0 g (6.9 mmol - 1.0 equiv.) of compound (2) in methanol (MeOH) was added 1.1 g (34.5 mmol - 5.0 equiv.) of sodium hydroxide (NaOH) and 15.0 mL of distilled water successively. The yellow solution was stirred at room temperature (RT) overnight.

[0099] TLC analysis showed consumption of compound (2). The solvent was removed by rotary evaporation, and then the crude product was dissolved in CH2Cl2. HCl 2N (20.0 mL) was added and stirring was continued for 15 min. The organic product was collected with CH2Cl2, the aqueous layer was washed with CH2Cl2 (5 times), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound (3) (5.1 g, 6.8 mmol, 99%) as a yellow oil.

[0100] analysis: 1 H NMR(400MHz,chloroform-d)δ 7.46(d,2H:Ar-H),4.15(dd,J=5.6,4.2Hz,6H:-O-CH2-R),3.85-3.81(m,6H:-O-CH2-CH2-R),3.70-3.6 6(m,6H:-O-CH2-R),3.63-3.56(m,24H:-O-CH2-R),3.51-3.47(m,6H:-O-CH2-R),3.33(s,9H:CH3-O-).

[0101] Step 1.4 Preparation of 3,5-bis(bromomethyl)phenol (compound (4)) JPEG2025511985000035.jpg689172 mL of lithium aluminum hydride 1M (LiAlH4) (72 mmol-1.8 equiv.) was dissolved in 150 mL of tetrahydrofuran (THF) at 0° C. Then 8.40 g (40 mmol-1 equiv.) of dimethyl 5-hydroxyisophthalate was carefully added. The resulting solution was stirred at RT for 5 h, then EtOAc (30.0 mL) and a 10% aqueous solution of H2SO4 (60.0 mL) were carefully added at 0° C. Stirring was continued overnight. Additional 10% aqueous solution of H2SO4 (60.0 mL) was added. Stirring was continued at RT for another 24 h.

[0102] Once the aluminum salts were completely dissolved, the aqueous layer was washed with EtOAc (at least 5 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 8.3831 g of an orange oil. The crude benzyl alcohol was then dissolved in 100 mL of acetic acid (AcOH), followed by careful addition of 36 mL of hydrobromic acid (HBr 33% w / w in AcOH) (200 mmol-5.0 equiv.) at 0°C. The resulting mixture was stirred at RT for 2 days.

[0103] TLC analysis showed complete consumption of bisbenzyl alcohol, an intermediate formed but not isolated after reduction of dimethyl 5-hydroxyisophthalate with LiAlH4. The organic product was washed with brine (1x), the aqueous layer with EtOAc (at least 5x), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (CH2Cl2 / EtOAc 1 / 0 - 96 / 4 - 9 / 1) gave a yellowish solid. Recrystallization with a mixture of petroleum ether / diethyl oxide (EtP / Et2O) gave compound (4) (10.40 g, 37.4 mmol, 93.6%) as a white solid.

[0104] analysis: 1 H NMR (400MHz, chloroform-d) δ 6.99(s,1H:Ar-H),6.81(d,J=1.43Hz,2H:Ar-H),4.41(s,4H:-CH2-Ar).

[0105] 1.5. Step 5 - Preparation of Compound (5) JPEG2025511985000036.jpg77108 In a 100 mL two-neck flask connected to a Dean-Stark, 33.9 mL of octanol (107.25 mmol-6 equiv.) was added and the reaction setup was then stirred and passed under a stream of argon for 10 min.

[0106] The liquid was then heated to 75° C. and the flow was replaced by two balloons of argon. 4.23 mL of trimethylphosphite (35.8 mmol-1 equiv.) was added slowly via syringe and the setup was then heated at 220° C. for 6 h.

[0107] The setup was then cooled to ambient temperature and the Dean Stark containing the methanol formed during the reaction was removed. An orange oil was obtained.

[0108] Vacuum distillation was used to separate the remaining octanol from the compound (5) formed at 160°C.

[0109] 9.205 g of orange oil was recovered (yield=61%)

[0110] analysis: 1 H-NMR (400 MHz, chloroform-d): δ 3.77 (q, J = 6.9 Hz, 6H, O-CH2-R), 1.61-1.57 (m, 6H, O-CH2-CH2-R), 1.28-1.25 (m, 30H, CH2), 0.86 (t, J = 6.7 Hz, 9H, CH3-R). 31P-NMR (400MHz, CDCl3):δ 139.15

[0111] 1.6. Step 6 - Preparation of Compound (6) JPEG2025511985000037.jpg73163152 mg (0.543 mmol-1 eq.) of compound (4) and 916 mg (2.188 mmol-4.0 eq.) of compound (5) were added to a 50 mL flask. The reaction was stirred and heated to 140° C. overnight. A yellow-orange oil was obtained and TLC was performed (petroleum ether / EtOAc 1 / 1):

[0112] The next day, the solution was cooled and then a petroleum ether / EtOAc chromatography column was prepared (1 / 1-2 / 3).

[0113] 248 mg of compound (6) was recovered (yield=64%).

[0114] analysis: 1 H NMR(400MHz,CDCl3)δ 6.81(s,2H,Ar-H),6.64(s,1H,Ar-H),4.02-3.77(m,8H,P-CH2),3.28-2.81(m,4H,Ar-CH2-P ),1.58(m,8H,P-CH2-CH2),1.42-1.14(m,44H,C-CH2),0.95-0.77(t,J=7.1Hz,12H,C-CH3). 31 P NMR (162 MHz, CDCl3) δ 26.51.

[0115] 1.7. Step 7 - Preparation of Linker 2 (L2) JPEG2025511985000038.jpg941211.7.1. Step 7.1 - Preparation of Linker 1 (L1) JPEG2025511985000039.jpg377010.0 g (77.6 mmol-1 equiv.) of 2-bromoethanol (97%) was dissolved in 12 mL of water, then 6.12 g (93.2 mmol-1.2 equiv.) of sodium azide (NaN3) was added at RT. The mixture was heated at 80° C. overnight. Monitoring was performed by TLC (DCM / MeOH, 95:5, SM Rf=0, EP Rf=0, 5).

[0116] After overnight TLC showed only traces of starting material, the mixing was stopped and then 10 mL of DCM was added. The phases were separated. The water was extracted with 20 mL of DCM and solid NaCl was added with each extraction. The organic phase was directly involved in the next step without evaporation or further purification.

[0117] 1.7.2. Step 7.- Preparation of Linker 2 (L2) To 6.76 g (77.6 mmol-1 equiv.) of Linker 1 in DCM, 16.4 mL (116.0 mmol-1.5 equiv.) of Et3N was slowly added, the mixture was stirred for 10 min, and then 17.9 g (93.2 mmol-1.2 equiv.) of tosyl chloride (TsCl) was slowly added.

[0118] After overnight, TLC (petroleum ether, AcOEt 7:3, KMnO4) showed traces of starting material. The mixture was concentrated and the TsCl salt was precipitated in AcOEt, filtered through a Celite pad, and washed three times with AcOEt to give the desired linker 2 (22 g, brown oil).

[0119] It was then purified by flash chromatography, Interchim-220g-30, liquid deposition in EtP / AcOEt (9:1), eluents: 15 min EtP / AcOEt (9:1), isocratic 10 min EtP / AcOEt (8:2) and 10 min EtP / AcOEt (7:3).

[0120] 12.13 g of Linker 2 was recovered as a colorless oil.

[0121] 1 H NMR(400MHz,MeOD)δ 7.84(d,J=8.4Hz,2H),7.49(d,J=7.8Hz,2H),4.25-4.12(m,2H),3.54-3.40(m,3H),2.49(s,3H).

[0122] 1.8. Step 8 - Preparation of compound (7) JPEG2025511985000040.jpg1121652In a 5 mL flask, 297.0 mg (1.23 mmol-1.8 equiv.) of compound (6) was added in 15 mL of toluene with 57.2 mg (1.02 mmol-1.5 equiv.) of potassium hydroxide (KOH) and 11.3 mg (0.068 mmol-0.1 equiv.) of KI. The solution was stirred for 20 min and heated to 60° C. to dissolve the reagents. 500.0 mg (0.684 mmol-1.0 equiv.) of linker 2 (as prepared above in step 1.7 of Example 1) was added and the reaction was left stirring overnight.

[0123] The flask was cooled to RT and then the toluene was evaporated off under reduced pressure. The crude product, dissolved in DCM, was then filtered through Celite. The chromatography column was run with DCM / MeOH (1 / 0 to 98 / 2 to 96 / 4). In this way, 530 mg of compound (7) (97%) was recovered.

[0124] analysis: 1 H NMR(400MHz,MeOD)δ 6.90-6.82(m,3H,Ar-H),4.17(t,J=4.9Hz,2H,O-CH2-CH2-N3),3.98(m,8H,PO-CH2),3.59(t,J=4.8Hz,2H,O-CH2-CH2-N3),3.27-3 .16(BX,J=21.9Hz,4H,Ar-CH2-P),1.67-1.55(m,8H,PO-CH2-CH2),1.41-1.26(m,40H,C-CH2),0.95-0.85(t,J=6.5Hz,12H,C-CH3). 13 C NMR(101MHz,MeOD)δ 160.00,134.57,134.51,134.45,125.49,115.95(C-Ar),68.46,67.76,67.73,67.69,51. 32,34.29,33.01,32.92,31.67,31.64,31.61,30.41,30.29,26.70,23.75,14.47(C-CH3). 31 P NMR (162MHz, MeOD) δ 27.11.

[0125] 1.9. Step 9 - Preparation of dendritic molecules of formula (IA) To a solution of 350.0 mg (0.434 mmol-1.1 equiv.) of compound (7) in 15 mL of EtOAc, 120 mg (0.1 equiv.) of Pd / C 10% was added as a catalyst. The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h. In a separate flask, 300 mg (0.398 mmol-1 equiv.) of compound (3) was dissolved in 10.0 mL of CHCl, followed by the addition of 0.22 mL (1.2 mmol-3.0 equiv.) of oxalyl chloride (COCl) and 4 drops of dimethylformamide (DMF). The orange solution was stirred at RT for 5 h. Upon complete consumption of compound (7) by TLC, the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chlorides were simultaneously concentrated under reduced pressure and dissolved in 10 mL of CH2Cl2, then the crude primary amine (the intermediate product formed but not purified) and 0.16 mL (0.916 mmol-2.3 equiv.) of N,N-diisopropylethylamine (DIPEA) were added successively at 0° C. The resulting solution was stirred at RT overnight.

[0126] The reaction mixture was diluted with brine. The aqueous layer was extracted with CH2Cl2 (5 times) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 7.17 g of an orange oil. Purification by flash chromatography (100% EtOAc, then CH2Cl2 / EtOAc / MeOH 80 / 12 / 8 to 6 / 0 / 4) was performed to separate pure and impure fractions to give the dendritic molecule of formula (IA) (487.2 mg, 81%) as a colorless oil.

[0127] analysis: 1 H NMR(400MHz,MeOD)δ 7.23(s,2H),6.85(m Hz,3H),4.22(m,4H),4.17(t,J=5.7Hz,2H),3.97(m,8H),3.91-3.84(t,J=4.6Hz,2H),3.83-3.7 6(m,2H),3.78-3.68(m,6H),3.69-3.57(m,20H),3.56-3.48(m,6H),3.33(m,9H),3.24-3.14(AB X,J=22Hz,4H),1.60(m,8H),1.29(m,38H),0.90(t,J=6.8Hz,12H). 31 P NMR (162 MHz, CDCl3) δ 25.88.

[0128] Example 2: Synthesis of dendritic molecules of formula (IB) according to the invention In this example, a dendritic molecule of formula (IB) was prepared: JPEG2025511985000041.jpg58140

[0129] 2.1. Step 1 - Preparation of Compound (8) JPEG2025511985000042.jpg73100 In a 100 mL two-neck flask connected to a Dean-Stark, 91.4 mL (469.0 mmol-6.0 equiv.) of decanol was added and the reaction setup was then stirred and passed under a stream of argon for 10 min.

[0130] The liquid was then heated to 75° C. and the flow was replaced by two balloons of argon. 9.51 mL (78.2 mmol-1.0 equiv.) of trimethylphosphite was added slowly via syringe and the setup was then heated at 220° C. for 6 h.

[0131] The setup was then cooled to ambient temperature and the Dean Stark containing the methanol formed during the reaction was removed. An orange oil was obtained.

[0132] The remaining decanol was separated from the compound (8) thus formed using vacuum distillation at 160°C.

[0133] 36.2 g of compound (8) was recovered as a colorless oil (yield=92%).

[0134] analysis: 1H NMR(400MHz,CDCl3)δ 3.77(m,6H),1.64-1.55(m,6H),1.41-1.18(m,44H),0.87(t,J=6.8Hz,9H). 13 C NMR(101MHz,CDCl3)δ 62.48,62.37,32.04,32.02,31.33,31.28,29.76,29.75,29.71,29.67,29.64,29.47,29.43,26.00,22.82,14.23. 31P-NMR (400MHz, CDCl3):δ 139.19.

[0135] 2.2. Step 2 - Preparation of Compound (9) JPEG2025511985000043.jpg69142 2.0 g (7.14 mmol-1.0 eq) of compound (4) prepared in step 1.4 of Example 1 above and 14.4 g (28.6 mmol-4.0 eq) of compound (8) were added to a 100 mL flask. The reaction was stirred and heated to 140° C. overnight. A yellow-orange oil was obtained and TLC was performed (petroleum ether / EtOAc 1 / 1).

[0136] The next day, the solution was cooled and then a petroleum ether / EtOAc chromatography column was prepared (1 / 1-2 / 3).

[0137] 4.9 g of compound (9) was recovered (yield=81%).

[0138] analysis: 1 H NMR(400MHz,CDCl3)δ 6.81-6.77(m,2H),6.67(s,1H),3.92(m,8H),3.11-3.01(m,4H),1.67-1.51(m,8H),1.26(m,56H),0.94-0.82(t,J=6.9Hz,12H). 31 P NMR(162MHz,CDCl3) δ 26.40 HRMS:m / z theo:C 48 H 92 O7P284 2.63 g.mol -1,Measurement:C 48 H 92 O7P2Na: 866.235 g.mol -1

[0139] 2.3. Step 3 - Preparation of Compound (10) JPEG2025511985000044.jpg103152In a 100 mL flask, 2.45 g (2.91 mmol-1.0 equiv.) of compound (9) was added, 0.25 g (4.36 mmol-1.5 equiv.) of KOH and 49 g (0.3 mmol-0.1 equiv.) of KI in 50 mL of toluene. The solution was stirred for 20 min and heated to 60° C. to dissolve the reagents. 1.05 g (4.36 mmol-1.5 equiv.) of linker 2 (as prepared above in step 1.7 of Example 1) was added and the reaction was left stirring overnight.

[0140] The flask was cooled to room temperature, and then the toluene was evaporated off under reduced pressure. The crude product was then dissolved in DCM and filtered through Celite. The chromatography column was run with DCM / MeOH (1 / 0 to 98 / 2 to 96 / 4). In this way, 2.1 g of compound (10) (79%) was recovered.

[0141] analysis: 1 H NMR(400MHz,MeOD)δ 6.90-6.82(m,3H),4.17(t,J=4.8Hz,2H),3.98(m,8H),3.63-3.56(t,J=4.9Hz,2H),3.25 -3.13(d,J=22Hz,4H),1.62(p,J=6.6Hz,8H),1.32(m,54H),0.96-0.85(t,J=6.5Hz,12H). 13 C NMR(101MHz,MeOD)δ 160.00,134.57,134.45,125.47,115.96,68.46,67.77,67.73,67.70,51.32,34.31, 33.12,32.94,31.67,31.64,31.61,30.75,30.74,30.51,30.33,26.71,23.78,14.48. 31P NMR (162MHz, MeOD) δ 31.03.

[0142] 2.4. Step 4 - Preparation of dendritic molecules of formula (IB) To a solution of 237 mg (0.259 mmol-1.1 equiv.) of compound (10) in 15 mL of EtOAc and 251 mg (0.1 equiv.) of Pd / C 10% as catalyst. The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h. In a separate flask, 175 mg (0.236 mmol-1.0 equiv.) of compound (3) prepared above in step 1.3 of Example 1 was dissolved in 15 mL of CHCl, followed by the addition of 0.13 mL (0.71 mmol-3.0 equiv.) of (COCl) and 4 drops of DMF. The orange solution was stirred at RT for 5 h. Once TLC confirmed the complete consumption of compound (3), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chlorides were simultaneously concentrated under reduced pressure and dissolved in CH2Cl2, then the crude primary amine and 0.11 mL (0.916 mmol-2.3 equiv) of DIPEA were added successively at 0° C. The resulting solution was stirred at RT overnight.

[0143] The reaction mixture was diluted with brine. The aqueous layer was extracted with CH2Cl2 (5 times) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange oil. Purification by flash chromatography (100% EtOAc, then CH2Cl2 / EtOAc / MeOH 80 / 12 / 8 to 6 / 0 / 4) was performed to separate pure and impure fractions to give the dendritic molecule of formula (IB) (293 mg, 67%) as a colorless oil.

[0144] analysis: 1H NMR(400MHz,MeOD)δ 7.23(s,2H),6.85(m,2H),4.26-4.13(m,6H),4.08-3.90(m,8H),3.88-3.85(t,J=4.2Hz,2H),3.81-3.78(m,1H) ,3.76(t,J=5.7Hz,1H),3.71(m,4H),3.67-3.57(m,19H),3.55-3.49(m,4H),3.37-3.31(bs,9H),3.24-3.14(AB x ,J=21.9Hz,4H),1.67-1.55(m,8H),1.29(m,55H),0.90(t,J=6.9Hz,12H). 31 P NMR (162MHz, MeOD) δ 27.14.

[0145] Example 3: Synthesis of dendritic molecules of formula (IC) according to the invention In this example, a dendritic molecule of formula (IC) was prepared: JPEG2025511985000045.jpg64153

[0146] 3.1. Step 1 - Preparation of Compound (11) JPEG2025511985000046.jpg66110 In a 250 mL two-neck flask connected to a Dean-Stark, 107.0 mL (469.0 mmol-6.0 equiv.) of dodecanol was added, and the reaction setup was then stirred and passed under a stream of argon for 10 min.

[0147] The liquid was then heated to 75° C. and the flow was replaced by two balloons of argon. 9.51 mL (78.2 mmol-1.0 equiv.) of trimethylphosphite was added slowly via syringe and the setup was then heated at 220° C. for 6 h.

[0148] The setup was then cooled to ambient temperature and the Dean Stark containing the methanol formed during the reaction was removed. An orange oil was obtained.

[0149] Residual dodecanol was separated from the compound (11) thus formed using vacuum distillation at 160°C.

[0150] 43.0 g of compound (11) was recovered as a colorless oil (yield=94%).

[0151] analysis: 1 H NMR(400MHz, CDCl3)δ 3.78(m,6H),1.64-1.51(m,6H),1.26(m,65H),0.91-0.83(t,J=6.5Hz,9H). 13 C NMR(101MHz,CDCl3)δ 62.97,62.94,62.44,62.33,32.88,32.03,31.29,31.24,29.79,29.76,29.73,29.72,29.58,29.47,29.44,25.96,25.89,22.79,14.17. 31 P NMR (162 MHz, CDCl3) δ 139.19.

[0152] 3.2. Step 2 - Preparation of Compound (12) JPEG2025511985000047.jpg93153 1.0 g (3.57 mmol-1.0 eq) of compound (4) prepared in step 1.4 of Example 1 above and 8.39 g (14.3 mmol-4.0 eq) of compound (11) were added to a 100 mL flask. The reaction was stirred and heated to 140° C. overnight. A yellow-orange oil was obtained and TLC was performed (petroleum ether / EtOAc 1 / 1).

[0153] The next day, the solution was cooled and then a petroleum ether / EtOAc chromatography column was prepared (1 / 1-2 / 3).

[0154] 2.28 g of compound (12) was recovered (yield=67%).

[0155] analysis: 1H NMR(400MHz,CDCl3)δ 6.80(s,2H),6.66(s,1H),3.92(dq,J=13.0,8.0Hz,8H),3.11-3.01(m,4H),1.58(t,J=6.6Hz,8H),1.25(s,75H),0.88(t,J=6.9Hz,12H). 13 C NMR(101MHz,CDCl3)δ 157.61,132.68,122.76,115.79(C,Ar),66.45(CH2-OR),31.94,30.61,29.70 ,29.68,29.64,29.59,29.38,29.25,25.53,23.84,22.70(CH2),14.12(CH3). 31 P NMR (162 MHz, CDCl3) δ 26.40. C 48 H 92 NaO7P2 m / z calculated: 978,3898, m / z observed: 978,3990.

[0156] 3.3. Step 3 - Preparation of Compound (13) JPEG2025511985000048.jpg107159In a 100 mL flask, 500 mg (0.523 mmol-1.0 equiv.) of compound (12) in 25 mL of toluene was added with 44.0 mg (0.785 mmol-1.5 equiv.) of KOH and 26 mg (0.157 mmol-0.1 equiv.) of KI. The solution was stirred for 20 min and heated to 60° C. to dissolve the reagents. 252.4 mg (0.785 mmol-1.5 equiv.) of linker 2 (as prepared above in step 1.7 of Example 1) was added and the reaction was left stirring overnight.

[0157] The flask was cooled to room temperature, and then the toluene was evaporated off under reduced pressure. The crude product was then dissolved in DCM and filtered through Celite. The chromatography column was run with DCM / MeOH (1 / 0 to 98 / 2 to 96 / 4). In this way, 500 mg of compound (13) (93%) was recovered.

[0158] analysis: 1H NMR(400MHz,CDCl3)δ 6.87-6.68(m,3H),4.13(t,J=5.0Hz,2H),4.01-3.85(m,8H),3.56(d,J=5.1Hz,2H),3.08(AB X ,J=21.9Hz,4H),1.64-1.52(m,8H),1.32-1.20(m,72H),0.88(t,J=6.6Hz,12H). 31 P NMR (162 MHz, CDCl3) δ 25.94.

[0159] 3.4. Step 4 - Preparation of dendritic molecules of formula (IC) To a solution of 305 mg (0.297 mmol-1.1 equiv.) of compound (13) in 15 mL of EtOAc, 320 mg (0.1 equiv.) of Pd / C 10% was added as a catalyst. The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h. In a separate flask, 200 mg (0.270 mmol-1.0 equiv.) of compound (3) prepared above in step 1.3 of Example 1 was dissolved in 15 mL of CHCl, followed by the addition of 0.15 mL (0.81 mmol-3.0 equiv.) of (COCl) and 4 drops of DMF. The orange solution was stirred at RT for 5 h. Upon complete consumption of compound (3) by TLC, the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chlorides were simultaneously concentrated under reduced pressure and dissolved in CH2Cl2, then the crude primary amine and 0.11 mL (0.916 mmol-2.3 equiv) of DIPEA were added successively at 0° C. The resulting solution was stirred at RT overnight.

[0160] The reaction mixture was diluted with brine. The aqueous layer was extracted with CH2Cl2 (5 times) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (100% EtOAc, then CH2Cl2 / EtOAc / MeOH 80 / 12 / 8 to 6 / 0 / 4) was performed to separate pure and impure fractions to give the dendritic molecule of formula (IC) (265 mg, 58%) as a colorless oil.

[0161] analysis: 1 H NMR(400MHz,CDCl3)δ 7.12(s,2H),6.74(m,3H),4.19(m,4H),4.09(t,J=5.8Hz,2H),3.90(m,8H),3.82(t,J=4.8Hz ,2H),3.78-3.71(m,4H),3.61(m,19H),3.51-3.48(m,4H),3.35-3.27(m,9H),3.10-2.97(AB X ,J=21.8Hz,4H),1.55(h,J=6.2Hz,8H),1.22(m,76H),0.84(t,J=6.4Hz,12H). 31 P NMR (162 MHz, CDCl3) δ 25.88.

[0162] Example 4: Synthesis of dendritic molecules of formula (ID) according to the invention In this example, a dendritic molecule of formula (ID) was prepared: JPEG2025511985000049.jpg61133

[0163] 4.1. Step 1 - Preparation of Compound (14) JPEG2025511985000050.jpg101101To a solution of 30 g (163 mmol-1 equiv.) of methyl gallate in 150 mL of DMF, 49.1 g (489 mmol-4.5 equiv.) of KHCO3, 0.136 g (0.82 mmol-0.006 equiv.) of KI and 21.3 mL (163 mmol-1.0 equiv.) of benzyl bromide (BnBr) were added successively. The resulting mixture was stirred at RT for 36 h.

[0164] The solid was filtered through Celite and the filtrate was acidified with an aqueous solution of HCl 2N (50.0 mL). The aqueous mixture was extracted with EtOAc (3 times) and the combined organic layers were washed with a saturated aqueous solution of NaHCO3 (2 times), brine (3 times), dried over Na2SO4, filtered, concentrated under reduced pressure and dried under vacuum overnight. Purification by chromatography column (DCM / MeOH, 100:0 to 98:2 to 96:4 to 90:10) gave a translucent oil. The mixture was then dissolved in a small amount of AcOEt and slowly poured with petroleum ether until precipitation occurred. Compound (14) was obtained as a white solid (16.5 g, 38%).

[0165] analysis: 1 H NMR(400MHz,MeOD)δ 7.53-7.44(m,2H,Ar-H),7.30(qd,J=6.9,3.7Hz,3H,Ar-H),7.01(d,J=1.3Hz,2H,Ar-H),5.14(s,2H,Ar-CH2),3.82(d,J=1.5Hz,3H,O-CH3). 13 C NMR(101MHz,MeOD)δ 168.49,151.90,139.62,138.80,129.87,129.19,129.16,129.11,126.44 (12C,C-Ar),110.07(1C,C-COOR),75.12(1C,Ar-CH2),52.46(1C,O-CH3).

[0166] 4.2. Step 2 - Preparation of Compound (15) JPEG2025511985000051.jpg129132To a solution of 5.81 g (16.1 mmol-2.2 equiv.) of compound (14) in 150.0 mL of acetone, 3.22 g (23.4 mmol-3.2 equiv.) of K2CO3, 0.12 g (0.73 mmol-0.4 equiv.) of KI, and 2.0 g (7.3 mmol-1.0 equiv.) of compound (1) prepared in step 1.1 of Example 1 was added. The resulting solution was heated to reflux overnight.

[0167] The reaction mixture was cooled to RT, the solvent was removed, the solid was suspended in CH2Cl2, filtered through Celite, washed with an aqueous solution of Na2S2O32N and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (CH2Cl2 / MeOH 98 / 2 to 96 / 4 to 9 / 1) gave 3.3 g (71%) of compound (15) in the form of a yellowish oil.

[0168] analysis: 1 H NMR(400MHz,chloroform-d)δ 7.46(d,2H:Ar-H),7.35-7.20(m,5H:Ar-H),5.09(s,2H:-CH2-OAr),4.15(dd,J=5.6,4.2Hz,4H:-O-CH2-R),3.86(s,3H:CH3-OC=OR),3.85-3 .81(m,4H:-O-CH2-CH2-R),3.70-3.66(m,4H:-O-CH2-R),3.63-3.56(m,16H:-O-CH2-R),3.51-3.47(m,4H:-O-CH2-R),3.33(s,6H:CH3-O-). 13 C NMR(101MHz,CDCl3)δ 169.26,153.95,142.97,139.17,129.74,129.22,129.01,127.17,109.6 7,75.95,72.93,71.83,71.65,71.57,71.50,71.32,70.81,69.98,59.06.

[0169] 4.3. Step 3 - Preparation of Compound (16) JPEG2025511985000052.jpg1291321.01 g (25.22 mmol-5.0 equiv.) of NaOH was added to a solution of 3.3 g (5.04 mmol-1.0 equiv.) of compound (15) in 27 mL of MeOH and 3 mL of distilled water. The orange solution was stirred at RT overnight.

[0170] The solvent was removed, the crude product was suspended in CH2Cl2, quenched with an aqueous solution of HCl 2N, the aqueous layer was extracted with CH2Cl2 (5 times), and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound (16) (3.05 g, 95%) as a pale yellow oil.

[0171] analysis: 1 H NMR(400MHz,chloroform-d)δ 7.46(d,2H:Ar-H),7.35-7.20(m,5H:Ar-H),5.09(s,2H:-CH2-OAr),4.15(dd,J=5.6,4.2Hz,4H:-O-CH2-R),3.85-3.81(m,4H:- O-CH2-CH2-R),3.70-3.66(m,4H:-O-CH2-R),3.63-3.56(m,16H:-O-CH2-R),3.51-3.47(m,4H:-O-CH2-R),3.33(s,6H:CH3-O-).

[0172] 4.4. Step 4 - Preparation of Compound (17) JPEG2025511985000053.jpg60130 To a solution of 1.67 g (2.09 mmol-1.0 eq) of compound (7) prepared in step 1.8 of Example 1 in 40 mL of EtOAc, 1.1 g (0.1 eq) of Pd / C 10% was added as a catalyst. The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h. When TLC confirmed complete consumption of compound (7), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. In parallel, compound (16) (1.00 equiv., 2.09 mmol, 1.34 g) was dissolved in DCM (67.0 mL), then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.50 equiv., 3.13 mmol, 612 mg) and DMAP (0.10 equiv., 0.21 mmol, 26 mg) were added, and the reaction was stirred for 10 min before the addition of the crude primary amine. The resulting mixture was stirred overnight at RT. Monitored by TLC DCM / MeOH, 6:4, KMnO4. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2 40.0 g, solid deposit in DCM, eluent: DCM / MeOH 100 / 0 to 90 / 10) to give the expected product (17) (2.55 g, 89% yield) as a colorless oil.

[0173] analysis: 1H NMR(400 MHz, MeOD): δ 7.54 - 7.52 (m, 2H, Ar - H), 7.36 - 7.28 (m, 3H, Ar - H), 7.21 (s, 2H, Ar - H), 6.86 - 6.85 (m, 3H, Ar - H), 5.49 (s, 3H,?), 5.10 (s, 2H, O - CH2 - Ar), 4.19 (t, 4H, Ar - O - CH2 - CH2 - O, J), 4.18 (t, 2H, O - CH2 - CH2 - N, J), 3.99 - 3.94 (m, 9H, P - O - CH2 - CH2), 3.88 - 3.86 (m, 4H, Ar - O - CH2 - CH2 - O), 3.77 - 3.74 (t, 2H, O - CH2 - CH2 - N, J), 3.72 - 3.69 (m, 4H, O - CH2 - CH2 - O), 3.63 - 3.54 (m, 17H, O - CH2 - CH2 - O), 3.49 - 3.47 (m, 4H, …), 3.31 (s, 6H, O - CH3), 3.19 (d, 4H, P - CH2, J), 1.62 - 1.58 (m, 9H, P - O - CH2 - CH2 -), 1.33 - 1.28 (m, 44H), 0.89 (t, 12H, CH2 - CH3, J). 13 13C NMR(101 MHz, MeOD) δ 169.56, 160.38, 154.04, 141.70, 139.20, 130.67, 129.73, 129.22, 129.00, 115.98, 107.49, 75.94, 72.93, 71.83, 71.64, 71.56, 71.51, 71.32, 70.82, 69.99, 67.74, 67.71, 67.67, 67.54, 59.09, 54.80, 34.29, 32.98, 31.65, 31.62, 31.59, 30.69, 30.38, 30.26, 26.68, 23.73, 14.49. 31 31P NMR(400 MHz, Methano - d4): δ 27.16

[0174] 4.5. Preparation of Engineering 5 - Compound (18) To a solution of 2.55 g (1.83 mmol-1.0 equiv.) of compound (17) in 40.0 mL of EtOAc was added 355.0 mg of Pd / C 10% as a catalyst. The heterogeneous solution was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT overnight, the catalyst was filtered off through Celite, and the crude product was concentrated under reduced pressure to give 2.32 compound (18) as a colorless oil (97%).

[0175] analysis: 1 H NMR(400MHz,MeOD)δ 7.24(s,2H),6.85(m,3H),4.25-4.18(m,4H),4.16(t,J=5.7Hz,2H),4.13-4.05(m,1H),4.06-3.90(m,8H) ,3.91-3.84(m,4H),3.78-3.69(m,6H),3.68-3.58(m,19H),3.55-3.47(m,4H),3.33(s,6H),3.24-3.13(AB X ,J=21.9Hz,4H),1.59(m,8H),1.37-1.20(m,44H),0.90(t,J=6.85Hz,12H). 13 C NMR(101MHz,MeOD)δ 169.79,148.23,141.70,125.33,115.98,108.36,72.96,71.66,71.58,71.53,71.36,70.77,70.03,67.74,67.67,61. 53,59.09,58.32,40.71,34.28,33.00,31.66,31.60,30.67,30.40,30.27,26.69,23.74,20.86,18.37,14.49,14.46. 31 P NMR (162MHz, MeOD) δ 27.17.

[0176] 4.6. Step 6 - Preparation of Linker 3 (L3) To 3.00 g (6.02 mmol-1 equiv.) of t-butyl 1-hydroxy-3,6,9,12,15,18,21,24 octaoxaheptacosane-27-oate in 50 mL of DCM was slowly added 1.69 mL (12.04 mmol-2 equiv.) of Et3N, the mixture was stirred for 10 min, and then 2.32 g (12.04 mmol-2 equiv.) of tosyl chloride was slowly added.

[0177] After overnight, TLC (EtP, AcOEt 7:3, KMnO4) showed no trace of starting material. The mixture was concentrated and the tosyl chloride salt was precipitated in AcOEt, filtered through a celite pad and washed three times with AcOEt to give the crude product (orange oil). This was then purified by flash chromatography, Interchim-80g-50, liquid sediment in EtP / AcOEt (9:1), eluent: 15 min EtP / AcOEt (9:1), isocratic 10 min EtP / AcOEt (8:2) and 10 min EtP / AcOEt (7:3).

[0178] 3.52 g of linker 3 was recovered as a colorless oil (90%).

[0179] analysis: 1 H NMR(400MHz,MeOD)δ 7.80(d,J=8.3Hz,2H),7.45(d,J=8.2Hz,2H),4.14(t,J=4.5Hz,2H),3.77-3.50(m,32H),2.51-2.43(m,5H),1.45(s,9H).

[0180] 4.7. Step 7 - Preparation of Compound (19) To a solution of 11.0 g (0.76 mmol-1.0 equiv.) of compound (18) in 25 mL of acetone, 0.48 g (0.84 mmol-1.1 equiv.) of linker 3, 51.3 mg (0.30 mmol-0.4 equiv.) of KI, and 340 mg (2.45 mmol-3.2 equiv.) of K2CO3 were added successively. The resulting reaction mixture was heated to reflux overnight.

[0181] The reaction mixture was cooled to RT, the solvent was removed, the crude product was suspended in CH2Cl2, the solid was filtered off; the crude product was concentrated under reduced pressure. Purification by flash chromatography (CH2Cl2 / MeOH 95 / 5-8 / 2-6 / 4) afforded 827 mg of pure compound (19) as a yellowish oil (65% yield).

[0182] analysis: 1 H NMR(400MHz,MeOD)δ 7.26(s,2H),6.86(m,3H),4.29-4.22(m,6H),4.18(t,J=5.6Hz,2H),3.97(m,8H) ,3.91-3.86(m,4H),3.78(m,3H),3.73-3.50(m,48H),3.34(s,6H),3.25-3.11(AB X ,J=21.9Hz,4H),2.48(t,J=6.2Hz,2H),1.67-1.55(m,8H),1.41-1.23(m,44H),0.94-0.86(t,J=6.7Hz 12H). 13 C NMR(101MHz,MeOD)δ 172.76,169.27,153.62,140.98,134.50,131.15,116.01,107.25,81.74,7 3.60,72.94,71.51,71.44,71.29,71.25,71.23,71.15,71.10,71.05,70.99 ,70.51,69.57,67.85,67.75,67.68,67.51,59.16,58.32,40.80,37.18,34.27,32.99,31.67,31.61,30.40,30.27,28.41,26.69,23.74,18.37,14.49. 31 P NMR (162MHz, MeOD) δ 27.17.

[0183] 4.8. Step 8 - Preparation of dendritic molecules of formula (ID) In a flask containing 826 mg (0.48 mmol-1.0 equiv.) dissolved in 8 mL of DCM, 1.23 mL (15.9 mmol, 33 equiv.) of trifluoroacetic acid (TFA) was added dropwise. The mixture was stirred for 2 h and then evaporated under reduced pressure to give the dendritic molecule of formula (ID) as a colorless oil (91%).

[0184] analysis: 1 H NMR(400MHz,MeOD)δ 7.25(s,2H),6.86(m,3H),4.28-4.20(m,6H),4.17(t,J=5.6Hz,2H),3.97(m,8H),3.92-3. 85(m,4H),3.82-3.73(m,4H),3.76-3.53(m,45H),3.55-3.48(m,4H),3.33(s,6H),3.20(AB X ,J=21.9Hz,4H),2.54(t,J=6.2Hz,2H),1.67-1.53(m,8H),1.31(m,44H),0.90(t,J=7.0Hz,11H). 13 C NMR(101MHz,MeOD)δ 167.99,152.31,129.42,114.57,106.20,72.22,71.56,70.20,70.10,70.00,69.92,69.88,69.85,69.26,68.43, 66.38,66.35,66.28,66.13,57.73,39.41,34.37,32.87,31.59,30.26,30.20,28.99,28.87,25.29,22.33,13.08. 31 P NMR (162MHz, MeOD) δ 27.17.

[0185] Example 5: Synthesis of dendritic molecules of formula (IE) according to the invention JPEG2025511985000057.jpg601345.1. Step 1 - Preparation of compound (20) JPEG2025511985000058.jpg60133 To a solution of 1.64 g (1.80 mmol-1.0 eq.) of compound (10) prepared in step 3 of Example 4 in 40 mL of EtOAc was added 960 mg (0.1 eq.) of Pd / C 10% as a catalyst. The resulting mixture was purged with a hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h.

[0186] Once TLC confirmed complete consumption of compound (10), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. In parallel, compound (16) (1.1 equiv., 1.98 mmol, 1.27 g) was dissolved in DCM (60.0 mL), then EDC (1.50 equiv., 2.7 mmol, 529 mg) and DMAP (0.10 equiv., 0.18 mmol, 22 mg) were added and the reaction was stirred for 10 min before the addition of the crude primary amine. The resulting mixture was stirred overnight at RT. TLC monitoring: DCM / MeOH, 6:4, KMnO4. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography.

[0187] (SiO2 40.0 g, solid deposit in DCM, eluent: DCM / MeOH 100 / 0 to 90 / 10) to give the expected product (20) (2.41 g, 88% yield) as a colorless oil.

[0188] analysis: 1 H NMR(400MHz,MeOD)δ 7.46-7.39(s,2H),7.28-7.14(m,3H),7.11(s,2H),6.79-6.72(m,3H),5.00(s,2H),4.13-4.03(m,6H),3.91-3.81(m,8H), 3.79-3.75(m,4H),3.65(t,J=5.6Hz,2H),3.62-3.59(m,4H),3.55-3.42(m,17H),3.40-3.36(m,4H),3.21(s,6H),3.09(AB X ,J=21.4Hz,4H),1.56-1.44(m,8H),1.31-1.11(m,56H),0.79(t,J=6.7Hz,12H). 13C NMR (101MHz, MeOD) δ 169.55,160.40,154.06,141.75,139.23,130.67,129.73,129.22,128.99,116.01,107.50,75.94,72.95,71.85,71.67,71.58,71.53,71.35,70.84,70.00,67.75,67.68,67.55,59.09,54.80,40.78,34.31,33.11,32.94,31.67,31.61,30.75,30.73,30.67,30.52,30.32,26.70,23.78,14.50. 31 P NMR (162MHz, MeOD) δ 27.15.

[0189] 5.2. Step 2 - Preparation of Compound (21) To a solution of 2.41 g (1.6 mmol-1.0 equiv.) of compound (20) in 40 mL of EtOAc was added 340.0 mg of Pd / C 10% as a catalyst. The heterogeneous solution was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h, the catalyst was filtered off through Celite, and the crude product was concentrated under reduced pressure to give 2.25 g of compound (21) as a colorless oil (99%).

[0190] analysis: 1 H NMR(400MHz,MeOD)δ 7.24(s,2H),6.85(m,3H),4.22-4.20(m,4H),4.16(t,J=5.7Hz,2H),4.13-4.07(m,2H),4.01-3.92(m,8 H),3.89-3.85(m,3H),3.77-3.71(m,6H),3.69-3.57(m,26H),3.54-3.47(m,4H),3.33(s,6H),3.19(AB X ,J=22.0Hz,4H),1.66-1.55(m,8H),1.29(m,56H),0.90(d,J=7.3Hz,12H). 13C NMR(101MHz,MeOD):δ 172.97,169.77,148.23,141.71,125.32,115.99,108.37,72.97,71.67,71.58,71.54,71.36,70.77,70.03,67.75,67.67,61.53,59.10 ,58.32,40.71,34.30,33.12,32.94,31.67,31.64,31.61,30.75,30.73,30.67,30.52,30.32,26.70,23.78,20.86,18.37,14.50,14.47. 31 P NMR (162MHz, MeOD) δ 27.16.

[0191] 5.3. Step 3 - Preparation of Compound (22) To a solution of 1.01 g (0.705 mmol-1.0 equiv.) of compound (21) in 25 mL of acetone, 0.440 g (0.775 mmol-1.1 equiv.) of linker 3 prepared in step 6 of Example, 48 mg (0.282 mmol-0.4 equiv.) of KI and 313 mg (2.26 mmol-3.2 equiv.) of K2CO3 were added successively. The resulting reaction mixture was heated to reflux overnight.

[0192] The reaction mixture was cooled to RT, the solvent was removed, the crude product was suspended in CH2Cl2, the solid was filtered off; the crude product was concentrated under reduced pressure. Purification by flash chromatography (CH2Cl2 / MeOH 95 / 5-8 / 2-6 / 4) afforded 736 mg of compound (22) as a yellowish oil (yield 59%).

[0193] analysis: 1 H NMR(400MHz,MeOD)δ 7.27(s,2H),6.86(m,3H),4.30-4.22(m,6H),4.18(t,J=5.6Hz,2H),4.03-3.91(m,8 H),3.93-3.86(m,4H),3.81-3.75(m,3H),3.76-3.46(m,48H),3.34(s,6H),3.20(AB X,J=21.9Hz,4H),2.48(t,J=6.2Hz,2H),1.60(m,8H),1.45(s,9H),1.29(s,56H),0.90(t,J=6.7Hz,12H). 13 C NMR(101MHz,MeOD)δ 153.63,116.02,107.32,81.74,72.95,71.52,71.46,71.30,70.53,69.60,67.86,67.75,59.1 5,58.32,37.19,33.11,31.67,31.61,30.75,30.73,30.51,30.32,28.40,26.70,23.77,14.49. 31 P NMR (162MHz, MeOD) δ 27.16.

[0194] 5.4. Step 4 - Preparation of dendritic molecules of formula (IE) 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. The mixture was stirred for 2 h and then evaporated under reduced pressure to give 645 mg of the dendritic molecule of formula (IE) as a colorless oil (93%).

[0195] analysis: 1 H NMR(400MHz,MeOD)δ 7.15(s,2H),6.76(m,3H),4.18-4.11(m,6H),4.07(t,J=5.6Hz,2H),3.94-3.82(m,8 H),3.81-3.77(m,4H),3.71-3.45(m,48H),3.44-3.40(m,4H),3.23(s,6H),3.10(AB X ,J=21.8Hz,4H),2.48(t,J=6.2Hz,2H),1.50(q,J=6.7Hz,8H),1.30-1.14(m,56H),0.84-0.73(m,12H).

[0196] Example 6: Synthesis of dendritic molecules of formula (IF) according to the invention JPEG2025511985000061.jpg621396.1. Step 1 - Preparation of compound (23) JPEG2025511985000062.jpg61133To a solution of 300 mg (0.312 mmol-1.1 equiv.) of compound (13) prepared in step 3 of Example 3 in 15 mL of EtOAc, 120 mg (0.1 equiv.) of Pd / C 10% was added as a catalyst. The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h. In a separate flask, 200 mg (0.260 mmol-1.0 equiv.) of compound (16) prepared in step 3 of Example 4 was dissolved in 10 mL of CHCl, followed by the addition of 0.1 mL (1.3 mmol-3.0 equiv.) of (COCl) and 4 drops of DMF. The orange solution was stirred at RT for 5 h. Upon complete consumption of compound (13) by TLC, the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chlorides were simultaneously concentrated under reduced pressure and dissolved in CH2Cl2, then the crude primary amine and 0.16 mL (0.916 mmol-2.3 equiv) of DIPEA were added successively at 0° C. The resulting solution was stirred at RT overnight.

[0197] The reaction mixture was diluted with brine. The aqueous layer was extracted with CH2Cl2 (5 times) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (100% EtOAc, then CH2Cl2 / EtOAc / MeOH 80 / 12 / 8 to 6 / 0 / 4) was performed to separate pure and impure fractions to give compound (23) (487.2 mg, 81%) as a colorless oil.

[0198] analysis: 1 H NMR(400MHz,MeOD)δ 7.24(s,2H),6.85(m,3H),4.22-4.20(m,4H),4.16(t,J=5.7Hz,2H),4.13-4.07(m,2H),4.01-3.92(m,8 H),3.89-3.85(m,3H),3.77-3.71(m,6H),3.69-3.57(m,26H),3.54-3.47(m,4H),3.33(s,6H),3.19(AB X,J=22.0Hz,4H),1.66-1.55(m,8H),1.29(m,78H),0.90(d,J=7.3Hz,12H). 13 C NMR(101MHz,MeOD)δ 173.10,169.67,148.33,141.71,125.32,116.02,108.47,72.97,71.67,71.58,71.54,71.36,70.83,70.03,67.75,67.67,61.53,59.10 ,58.32,40.71,34.30,33.12,32.94,31.67,31.64,31.61,30.75,30.73,30.67,30.52,30.32,26.70,23.78,20.86,18.37,14.50,14.47. 31 P NMR (162MHz, MeOD) δ 27.16.

[0199] 6.2. Step 2 - Preparation of Compound (24) To a solution of 382 mg (0.236 mmol-1.0 equiv.) of compound (23) in 40 mL of EtOAc was added 150.0 mg of Pd / C 10% as a catalyst. The heterogeneous solution was purged with hydrogen atmosphere (5 times) and then vigorously stirred at RT for 5 h, the catalyst was filtered off through Celite, and the crude product was concentrated under reduced pressure to give 320 mg of compound (24) as a colorless oil (89%).

[0200] analysis: 1 H NMR(400MHz,MeOD)δ 7.24(s,2H),6.85(m,3H),4.25-4.18(m,4H),4.16(t,J=5.7Hz,2H),4.13-4.05(m,1H),4.06-3.90(m,8H) ,3.91-3.84(m,4H),3.78-3.69(m,6H),3.68-3.58(m,19H),3.55-3.47(m,4H),3.33(s,6H),3.24-3.13(AB X ,J=21.9Hz,4H),1.59(m,8H),1.37-1.20(m,78H),0.90(t,J=6.85Hz,12H). 13 C NMR(101MHz,MeOD)δ 169.82,148.27,141.74,125.30,116.0,108.40,72.93,71.71,71.60,71.53,71.33,70.77,70.03,67.74,67.67,61. 53,59.09,58.35,40.73,34.27,33.02,31.66,31.60,30.67,30.40,30.27,26.69,23.74,20.86,18.39,14.51,14.46. 31 P NMR (162MHz, MeOD) δ 27.17.

[0201] 6.3. Step 3 - Preparation of Compound (25) To a solution of 20 mg (0.209 mmol-1.0 equiv.) of compound (24) in 40 mL of acetone, 0.145 g (0.219 mmol-1.05 equiv.) of linker 3 prepared in step 6 of Example 4, 33 mg (0.02 mmol-0.1 equiv.) of KI and 45 mg (0.315 mmol-1.5 equiv.) of K2CO3 were added successively. The resulting reaction mixture was heated to reflux overnight.

[0202] The reaction mixture was cooled to RT, the solvent was removed, the crude product was suspended in CH2Cl2, the solid was filtered off; the crude product was concentrated under reduced pressure to give an orange oil. Purification by flash chromatography (CH2Cl2 / MeOH 95 / 5-8 / 2-6 / 4) gave 321 mg of compound (25) as a yellowish oil (76% yield).

[0203] analysis: 1 H NMR(400MHz,MeOD)δ 7.27(s,2H),6.86(m,3H),4.30-4.22(m,6H),4.18(t,J=5.6Hz,2H),4.03-3.91(m,8 H),3.93-3.86(m,4H),3.81-3.75(m,3H),3.76-3.46(m,48H),3.34(s,6H),3.20(AB X,J=21.9Hz,4H),2.48(t,J=6.2Hz,2H),1.60(m,8H),1.45(s,8H),1.29(s,78H),0.90(t,J=6.7Hz,12H). 13 C NMR(101MHz,MeOD)δ 153.63,116.02,107.32,81.74,72.95,71.52,71.46,71.30,70.53,69.60,67.86,67.75,59.1 5,58.32,37.19,33.11,31.67,31.61,30.75,30.73,30.51,30.32,28.40,26.70,23.77,14.49. 31 P NMR (162MHz, MeOD) δ 27.16.

[0204] 6.4. Step 4 - Preparation of dendritic molecules of formula (IF) In a flask containing 321 mg (0.159 mmol-1.0 equiv.) of compound (25) dissolved in DCM, 30 equiv. of TFA was added dropwise. The mixture was stirred for 2 h and then evaporated under reduced pressure to give 271 mg of the dendritic molecule of formula (IF) as a colorless oil (87%).

[0205] analysis: 1 H NMR(400MHz,MeOD)δ 7.25(s,2H),6.86(m,3H),4.28-4.20(m,6H),4.17(t,J=5.6Hz,2H),3.97(m,8H),3.92-3. 85(m,4H),3.82-3.73(m,4H),3.76-3.53(m,45H),3.55-3.48(m,4H),3.33(s,6H),3.20(AB X ,J=21.9Hz,4H),2.54(t,J=6.2Hz,2H),1.67-1.53(m,8H),1.31(m,78H),0.90(t,J=7.0Hz,12H). 13C NMR(101MHz,MeOD)δ 168.00,152.33,129.45,114.59,106.23,72.25,71.58,70.22,70.15,70.02,69.94,69.86,69.87,69.23,68.44, 66.39,66.37,66.25,66.14,57.69,39.41,34.37,32.87,31.59,30.24,30.21,28.99,28.85,25.29,22.33,13.08. 31 P NMR (162MHz, MeOD) δ 27.16.

[0206] Example 7: Synthesis of dendritic molecules of formula (IR) according to the invention JPEG2025511985000065.jpg601467.1. Step 1 - Preparation of compound (26) A solution of 5-hydroxyisophthalic acid (1.00 equiv, 27.45 mmol, 5.00 g), octan-1-ol (3.60 equiv, 38.92 mmol, 5.43 mL) and p-toluenesulfonic acid monohydrate (3.6 equiv, 190.22 mmol, 7.42 g) in toluene (50.00 mL) was refluxed under Dean-Stark for 3 days. After removal of the solvent in vacuum, the residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give compound (26) (6.51 g, 16.01 mmol, 58%) as an off-white solid.

[0207] 1 H NMR(400MHz,CDCl3):δ 7.99(s,1H),7.52(df,2H),4.22(t,J=4.0Hz,4H),1.72-1.65(m,4H),1.41-1.18(m,20H),0.82-0.78(m,6H)ppm 13 C NMR (400MHz, CDCl3): δ 165.78,157.87,131.95,120.84,65.11,31.57,28.96,28.36,25.78,22.30,13.02.

[0208] 7.2. Step 2 - Preparation of Compound (27) JPEG2025511985000067.jpg119140To 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) prepared according to step 1.7 of Example 1 was added. The reaction mixture was heated at 80° C. overnight. The mixture was filtered through a pad of Celite, washed with dichloromethane, and concentrated. The crude product was purified by flash chromatography (SiO2, EtP / EtOAc, 100:0 to 9:1) and the pure fractions were purified to give 123.7 mg (53% yield) of compound (27) in the form of a colorless oil.

[0209] 1 H NMR(400MHz,chloroform-d)δ 8.30(t,J=1.4Hz,1H),7.76(d,J=1.5Hz,2H),4.33(t,J=6.7Hz,4H),4.28-4.19(m, 2H),3.70-3.59(m,2H),1.88-1.68(m,5H),1.50-1.15(m,21H),0.97-0.76(m,7H).

[0210] 7.3. Step 3 - Preparation of Compound (28) JPEG2025511985000068.jpg64134 A catalytic amount of Pd / C 10% (0.5 equiv., 0.13 mmol, 13.8 mg) was added to a solution of compound (27) (1.10 equiv., 0.26 mmol, 123.7 mg) obtained above in step 7.2 in ethyl acetate (5 mL). The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred overnight at room temperature. 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 a coupling reaction with compound (16) prepared according to step 4.3 of example 4.

[0211] In parallel, EDC (1.2 equiv., 0.28 mmol, 54 mg) and DMAP (0.1 equiv., 0.024 mmol, 3 mg) were successively added to a solution of compound (16) (1.00 equiv., 0.24 mmol, 152 mg) in DCM (5 mL). The yellow solution thus obtained was stirred at RT for 15 min, after which a solution of the crude product in DCM (1 mL, 0.26 mmol / mL) was added. The yellow solution thus obtained was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, DCM / MeOH, 100:0 to 9:1) to give 131.4 mg (51% yield) of compound (28) in the form of a colorless oil.

[0212] 1 H NMR(400MHz, methanol-d4)δ 8.19(t,J=1.4Hz,1H),7.79(d,J=1.5Hz,2H),7.56-7.51(m,2H),7.40-7.26(m,3 H),7.17(s,2H),5.09(s,2H),4.40-4.27(m,7H),4.22-4.13(m,4H),3.90-3.84(m ,4H),3.81(t,J=5.4Hz,2H),3.75-3.67(m,4H),3.66-3.52(m,15H),3.52-3.42(m ,3H),3.31(s,7H),1.91-1.73(m,4H),1.61-1.17(m,13H),0.89(d,J=7.0Hz,3H). 13 C NMR(101MHz,MeOD)δ 14.47,23.73,27.18,29.74,30.38,32.99,40.81,59.08,66.70,68.14,69.94,70.83,71.32,71.50,71.55,71.65,71.81,72.9 3,75.93,107.45,120.74,123.64,129.01,129.22,129.77,130.69,133.51,139.20,141.66,154.04,160.58,166.83,169.84.

[0213] 7.4. Step 4 - Preparation of Linker 3' (L3') JPEG2025511985000069.jpg34120KI (2.00 equiv, 1.90 mmol, 315.32 mg) was added to a solution of linker 3 (1.00 equiv, 0.95 mmol, 620.00 mg) prepared according to step 4.6 of Example 4 in acetone (14.00 mL) at RT. The resulting solution was heated to reflux overnight. The reaction mixture was filtered through Celite and the solvent was evaporated. The crude product was dissolved in ethyl acetate, washed with an aqueous solution of Na2S2O3 2M, dried over Na2SO4, filtered and concentrated under reduced pressure to give compound (L3') (749.1 mg, 1.23 mmol, 82%) as a yellow liquid.

[0214] 1H NMR (400MHz, MeOD): 3.76-3.59 (m, 34H), 2.49 (t, J=6.0Hz, 2H), 1.46 (s, 9H).

[0215] 7.5. Step 5 - Preparation of Compound (IR) To a solution of compound (28) (1.00 equiv., 0.12 mmol, 131.4 mg) obtained above in step 7.3 in ethyl acetate (5 mL) was added Pd / C 10% (0.1 equiv., 0.012 mmol, 11.7 mg). The heterogeneous mixture was charged with hydrogen (balloon) five times and then stirred vigorously at RT overnight. The catalyst was then filtered through Celite and 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 equiv., 0.18 mmol, 25 mg), KI (0.10 equiv., 0.012 mmol, 2 mg) and compound (L3') (1.05 equiv., 0.13 mmol, 82 mg) prepared above in step 7.4 were added. The resulting suspension was heated to reflux for 16 h and cooled to RT. The solvent was removed and the crude product was suspended in CH2Cl2, filtered through Celite, concentrated under reduced pressure and then purified by flash chromatography (SiO2, DCM / MeOH, 100:0 to 9:1) to give 120 mg of compound (IR) (68% yield) in the form of a light brown oil.

[0216] 1H NMR(400MHz, methanol-d4)δ 8.09(t,J=1.4Hz,1H),7.68(d,J=1.5Hz,2H),7.11(s,2H),4.25-4.18(m,6H),4.14-4.11(m,6H),3.80-3.75(m,4H),3.73-3.68(m,4H) ,3.66-3.44(m,51H),3.45-3.38(m,4H),3.23(s,6H),2.36(t,J=6.3Hz,2H),1.72-1.64(m,4H),1.43-1.14(m,27H),0.87-0.74(m,6H). 13 C NMR(101MHz,MeOD)δ 172.75,169.63,166.82,160.57,153.73,141.97,133.54,130.66,123.65,12 0.72,107.78,81.71,73.60,72.95,71.66,71.62,71.60,71.53,71.51,71.48, 71.44, 71.40, 71.38, 71.35, 71.33, 71.30, 70.73, 69.94, 68.18, 67.88, 66.70, 59.12, 40.79, 37.22, 32.98, 30.78, 30.36, 29.74, 28.39, 27.17, 23.71, 14.46.

[0217] Example 8: Synthesis of dendritic molecules of formula (IJ) according to the invention Trifluoroacetic acid (TFA) (1.00 equiv.) was added to a solution of compound (IR) (1.00 equiv.) obtained above in step 7.5 of Example 7 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 C 18 , H2O / acetonitrile + 0.1% TFA) to give the final compound (IG).

[0218] Example 9: Synthesis of dendritic molecules of formula (IS) according to the invention JPEG2025511985000071.jpg721659.1. Step 1 - Preparation of compound (29) JPEG2025511985000072.jpg112124 Dimethylformamide (100.00 μL) and oxalyl chloride (6.00 equiv, 33.10 mmol, 2.85 mL) were added to a solution of 5-(benzyloxy)benzene-1,3-dicarboxylic acid (1.00 equiv, 5.51 mmol, 1.50 g). The solution was heated to reflux for 3 h. The volatiles were then pumped off and the product was isolated as a yellowish solid. The raw compound (29) was then used in the next step.

[0219] 9.2. Step 2 - Preparation of Compound (30) JPEG2025511985000073.jpg158126 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 h. Water was added and a separate oil was extracted with DCM. The organic layer was washed with dilute HCl solution and dried over MgSO4. The organic solvent was evaporated to give an orange oil. The crude product was purified as a solid by column chromatography (silica gel, DCM / hexane 2:1). 1.30 g of compound (30) was thus obtained in the form of a white solid (yield 36%).

[0220] 1 H NMR (500 MHz, chloroform-d) δ 8.29 (t, J = 1.5 Hz, 1H), 7.84 (d, J = 1.4 Hz, 2H), 7.60-7.30 (m, 5H), 5.15 (s, 2H), 4.40 (q, J = 7.1 Hz, 5H), 1.41 (t, J = 7.1 Hz, 7H). 19 F NMR(471MHz,CDCl3)δ-83.16,-53.20,-53.19,-53.17,-53.16,-53.08.

[0221] 9.3.- Preparation of compound (31) JPEG2025511985000074.jpg108124A catalytic amount of Pd / C 10% (0.5 eq., 0.98 mmol, 104.11 mg) was added to a solution of compound (30) (1 eq., 1.96 mmol, 1.30 g) obtained above in step 8.2. The heterogeneous phase was purged with hydrogen atmosphere (5 times) and then stirred vigorously at RT for 5 h. The catalyst was filtered off through Celite and the crude product was concentrated under reduced pressure to give 799.20 mg (72% yield) of compound (31) as a white solid.

[0222] 1 H NMR (400 MHz, chloroform-d) δ 8.25 (t, J = 1.5 Hz, 1H), 7.77 (d, J = 1.5 Hz, 2H), 4.40 (q, J = 7.1 Hz, 4H), 1.41 (t, J = 7.1 Hz, 6H). 13 C NMR(126MHz,CDCl3)δ 165.74,155.83,132.49,123.23,120.74,61.63,14.44. 19 F NMR(376MHz,MeOD)δ-53.18,-83.16.

[0223] 9.4.- Preparation of compound (32) JPEG2025511985000075.jpg138124To a solution of compound (31) (1 eq., 1.39 mmol, 799 mg) in 21 mL of dry acetonitrile kept under argon, K2CO3 (3 eq., 4.17 mmol, 576.84 mg) and KI (0.6 eq., 0.83 mmol, 138.58 mg) were added and the reaction mixture was stirred at RT for 15 min. Then, the linker L2 (1.5 eq., 2.09 mmol, 503.53 mg) obtained according to step 1.7 of Example 1 was added. The reaction mixture was heated at 80° C. overnight. The mixture was filtered through a pad of Celite, washed with DCM and concentrated. The crude product was purified by flash chromatography (SiO2, EtP / EtOAc, 100:0 to 9:1) and the pure fractions afforded 335.3 mg (37% yield) of compound (32) as a white solid.

[0224] 1 H NMR (500 MHz, chloroform-d) δ 8.32 (t, J = 1.4 Hz, 1H), 7.77 (d, J = 1.4 Hz, 2H), 4.41 (q, J = 7.1 Hz, 5H), 4.24 (t, J = 5.0 Hz, 2H), 3.65 (t, J = 4.9 Hz, 3H), 1.41 (t, J = 7.1 Hz, 7H). 13 C NMR(126MHz,CDCl3)δ 14.46,18.59,50.22,61.65,67.58,119.83,123.69,132.41,158.38,165.72. 19 F NMR(471MHz,CDCl3)δ-83.16,-72.91,-53.16.

[0225] 9.5.- Preparation of compound (33) JPEG2025511985000076.jpg61151 A catalytic amount of Pd / C 10% (0.5 equiv., 0.10 mmol, 10.75 mg) was added to a solution of compound (32) (1.10 equiv., 0.20 mmol, 130 mg) obtained above in step 8.4 in ethyl acetate (5 mL). The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred overnight at room temperature. 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 a coupling reaction with compound (16) prepared according to step 4.3 of example 4.

[0226] In parallel, EDC (1.2 equiv., 0.22 mmol, 42.26 mg) and DMAP (0.1 equiv., 0.018 mmol, 2.24 mg) were successively added to a solution of compound (16) (1.00 equiv., 0.18 mmol, 117.70 mg) in DCM (5 mL). The yellow solution thus obtained was stirred at RT for 15 min, after which a solution of the crude product in DCM (1 mL, 0.20 mmol / mL) was added. The yellow solution thus obtained was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, DCM / MeOH, 100:0 to 9:1) to give 107.2 mg (48% yield) of compound (33) in the form of a colorless oil.

[0227] 1 H NMR(400MHz,メタノール-d4)δ 8.19(dt,J=3.7,1.4Hz,1H),7.78(dt,J=3.7,1.3Hz,2H),7.56-7.47(m,2H),7.40-7.2 4(m,3H),7.17(s,2H),5.09(s,2H),4.38(qd,J=7.1,0.9Hz,5H),4.31-4.26(m,2H),4. 18(td,J=4.0,3.4,1.7Hz,4H),3.92-3.83(m,4H),3.80(t,J=5.4Hz,2H),3.75-3.67(m ,4H),3.66-3.50(m,16H),3.51-3.43(m,4H),3.30(s,7H),1.39(td,J=7.2,0.6Hz,5H). 13 C NMR(101MHz,メタノール-d4)δ 169.85,166.83,160.54,154.04,141.69,139.20,133.51,130.71,129.76,129.22,129.00,123.67,120.74, 107.48,75.94,72.92,71.81,71.64,71.55,71.50,71.32,70.83,69.96,68.15,62.63,59.07,40.80,14.58. 19 F NMR(471MHz,メタノール-d4)δ-54.55,-84.67,-86.99,-119.41.

[0228] 9.6.-Preparation of compound (IS) To a solution of compound (33) (1.00 equiv., 0.086 mmol, 107.2 mg) obtained above in step 8.5 in ethyl acetate (5 mL) was added Pd / C 10% (0.1 equiv., 0.0086 mmol, 8.19 mg). The heterogeneous mixture was charged with hydrogen (balloon) five times and then stirred vigorously at RT overnight. The catalyst was then filtered through Celite and 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 added K2CO3 (1.50 equiv., 0.12 mmol, 16 mg), KI (0.10 equiv., 0.0077 mmol, 1.27 mg) and compound (L3') prepared above in step 7.4 of Example 7 (1.05 equiv., 0.081 mmol, 53 mg). The resulting suspension was heated to reflux for 16 h and cooled to RT. The solvent was removed and the crude product was suspended in CHCl, filtered through Celite, concentrated under reduced pressure and then purified by flash chromatography (SiO, DCM / MeOH, 100:0 to 9:1) to give 50 mg of compound (IS) (43% yield) in the form of a light brown oil.

[0229] Example 10: Synthesis of dendritic molecules of formula (IL) according to the invention JPEG2025511985000077.jpg58153 Trifluoroacetic acid (TFA) (1.00 equiv., 0.031 mmol, 2.37 μL) was added to a solution of compound (IS) (1.00 equiv., 0.031 mmol, 50 mg) obtained above in step 9.6 of Example 9 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 C 18 , H2O / acetonitrile + 0.1% TFA) to give the final compound (IL).

[0230] Example 11: Synthesis of dendritic molecules of formula (IT) according to the invention JPEG2025511985000078.jpg7116911.1. Step 1 - Preparation of compound (35) JPEG2025511985000079.jpg142126A solution of compound (29) (1 eq., 3.59 mmol, 1.11 g) as obtained above in step 9.1 of Example 9, 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 h. Water was added and a separate oil was extracted with DCM. The organic layer was washed with dilute HCl solution and dried over MgSO4. The organic solvent was evaporated to give an orange oil. The crude product was purified as a solid by column chromatography (silica gel, DCM / hexane 2:1).

[0231] In this way, 980.1 mg of compound (35) was obtained in the form of a colourless oil (yield 40%).

[0232] 1 H NMR(400MHz, methanol-d4)δ 8.15(d,J=2.3Hz,1H),7.79-7.68(m,2H),7.48-7.28(m,5H),5.14(d,J=5.1Hz,2H),4 .31(t,J=6.6Hz,4H),2.08(m,4H),1.87-1.69(m,5H),1.69-1.54(m,5H),1.47(m,8H). 13 C NMR(101MHz,MeOD)δ 21.34,21.37,21.41,26.52,26.80,29.12,29.50,29.58,29.75,31.15,31.37,31.58,6 6.45,71.45,120.98,123.64,128.64,129.15,129.63,133.33,137.84,160.28,166.77. 19 F NMR(376MHz,MeOD)δ-119.40,-86.98,-86.98,-86.97.

[0233] 11.2.- Preparation of compound (36) JPEG2025511985000080.jpg95124A catalytic amount of Pd / C 10% (0.5 eq., 0, 72 mmol, 77 mg) was added to a solution of compound (35) (1 eq., 1.45 mmol, 980 mg) obtained above in step 9.1 in 12 mL of ethyl acetate. The heterogeneous phase was purged with hydrogen atmosphere (5 times) and then stirred vigorously at RT for 5 h. The catalyst was filtered off through Celite and the crude product was concentrated under reduced pressure to give 789.90 mg (94% yield) of compound (36) as a white solid.

[0234] 1 H NMR (400 MHz, chloroform-d) δ 8.24 (t, J = 1.4 Hz, 1H), 7.73 (d, J = 1.4 Hz, 2H), 4.34 (t, J = 6.6 Hz, 4H), 2.12-1.96 (m, 4H), 1.84-1.76 (m, 5H), 1.66-1.58 (m, 7H), 1.52-1.42 (m, 9H). 13 C NMR(126MHz,CDCl3)δ 166.13,165.82,158.47,156.47,132.29,132.20,123.67,122.86,121.06,120.77,120.4 8,120.19,119.93,118.50,118.21,118.05,117.92,117.75,116.35,116.05,115.75,115 .46, 114.05, 113.75, 77.41, 77.36, 77.16, 76.91, 67.62, 65.59, 65.55, 65.39, 53.56, 50.18, 30.87, 30.69, 30.52, 28.87, 28.57, 28.54, 25.83, 23.42, 20.38, 20.35, 20.35, 20.32. 19 F NMR(376MHz,MeOD)δ-118.25,-85.48

[0235] 11.3.- Preparation of compound (37) JPEG2025511985000081.jpg124124To a solution of compound (36) (1 eq, 1.35 mmol, 789.9 mg) in 16 mL of dry acetonitrile kept under argon, K2CO3 (3 eq, 4.04 mmol, 558.41 mg) and KI (0.6 eq, 0.81 mmol, 134.15 mg) were added and the reaction mixture was stirred at RT for 15 min. Then, the linker L2 (1.5 eq, 2.02 mmol, 487.44 mg) obtained according to step 1.7 of Example 1 was added. The reaction mixture was heated at 80 ° C overnight. The mixture was filtered through a celite pad, washed with DCM and concentrated. The crude product was purified by flash chromatography (SiO2, EtP / EtOAc, 100:0 to 9:1) and the pure fractions afforded 449.4 mg (51% yield) of compound (37) as a colorless oil.

[0236] 1 H NMR(500MHz,chloroform-d)δ 8.30(d,J=1.6Hz,1H),7.76(d,J=1.5Hz,2H),4.35(t,J=6.6Hz,4H),4.24(t,J=4.9Hz,2H),3.65(t,J=4.9Hz,2 H),2.02(dt,J=26.8,9.2Hz,4H),1.80(p,J=6.8Hz,4H),1.71-1.60(m,4H),1.48(tq,J=10.8,5.8,4.5Hz,8H). 13 C NMR(126MHz,CDCl3)δ 20.33,20.35,20.36,20.39,25.83,28.58,28.88,30.53,30.70,30.88 ,31.08,50.19,65.46,67.62,119.88,123.66,132.33,158.44,165.69. 19 F NMR(471MHz,CDCl3)δ-118.26,-118.22,-118.18,-85.44.

[0237] 11.4.- Preparation of compound (38) JPEG2025511985000082.jpg64161 A catalytic amount of Pd / C 10% (0.5 equiv., 0.11 mmol, 12 mg) was added to a solution of compound (37) (1.10 equiv., 0.23 mmol, 150 mg) obtained above in step 9.3 in ethyl acetate (5 mL). The resulting mixture was purged with hydrogen atmosphere (5 times) and then vigorously stirred overnight at room temperature. 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 a coupling reaction with compound (16) prepared according to step 4.3 of example 4.

[0238] In parallel, EDC (1.2 equiv., 0.25 mmol, 48 mg) and DMAP (0.1 equiv., 0.021 mmol, 2.54 mg) were successively added to a solution of compound (16) (1.00 equiv., 0.21 mmol, 133.3 mg) in DCM (5 mL). The yellow solution thus obtained was stirred at RT for 15 min, after which a solution of the crude product in DCM (1 mL, 0.23 mmol / mL) was added. The yellow solution thus obtained was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, DCM / MeOH, 100:0 to 9:1) to give 142.4 mg (54% yield) of compound (38) in the form of a colorless oil.

[0239] 1H NMR(500MHz,メタノール-d4)δ 8.18(q,J=1.5Hz,1H),7.78(t,J=1.7Hz,2H),7.52(d,J=7.4Hz,2H),7.39-7.24(m,3H),7.16(s,2H),5. 08(s,2H),4.34(t,J=6.5Hz,4H),4.29(t,J=5.4Hz,2H),4.17(t,J=4.6Hz,4H),3.85(t,J=4.5Hz,4H),3 .80(t,J=5.4Hz,2H),3.69(dd,J=5.7,3.7Hz,4H),3.63-3.59(m,4H),3.59-3.52(m,12H),3.49-3.44(m ,4H),3.30(s,9H),2.18-2.05(m,5H),1.80(t,J=6.8Hz,5H),1.62(p,J=6.8Hz,5H),1.52-1.46(m,10H). 13 C NMR(126MHz,MeOD)δ 169.82,166.81,160.60,154.04,141.68,139.21,133.46,130.69,129.76,129. 22,129.00,123.64,121.85,120.78,119.59,117.63,117.33,107.46,75.93,72. 92,71.81,71.64,71.55,71.50,71.32,70.83,69.95,68.15,66.50,59.07,40.81,31.54,31.36,31.19,30.67,29.75,29.52,26.83,26.80,21.42,21.39,21.36. 19 F NMR(471MHz,MeOD)δ-119.38,-86.98.

[0240] 11.5.-Preparation of compound (IT) To a solution of compound (38) (1.00 equiv., 0.11 mmol, 142.4 mg) obtained above in step 11.4 in ethyl acetate (5 mL) was added Pd / C 10% (0.1 equiv., 0.011 mmol, 11 mg). The heterogeneous mixture was charged with hydrogen (balloon) five times and then stirred vigorously at RT overnight. The catalyst was then filtered through Celite and 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 (3 mL) and K2CO3 (1.50 equiv., 0.16 mmol, 23 mg), KI (0.10 equiv., 0.011 mmol) and compound (L3') prepared above in step 7.4 of Example 7 (1.05 equiv., 0.12 mmol, 75 mg) were added. The resulting suspension was heated to reflux for 16 h and cooled to RT. The solvent was removed and the crude product was suspended in CH2Cl2, filtered through Celite, concentrated under reduced pressure and then purified by flash chromatography (SiO2, DCM / MeOH, 100:0 to 9:1) to give 105.9 mg of compound (IT) (yield 59%) in the form of a brown oil.

[0241] 1 H NMR(500MHz, methanol-d4)δ 8.20(d,J=1.6Hz,1H),7.79(d,J=1.5Hz,2H),7.20(s,2H),4.35(t,J=6.6Hz,4H),4. 30(t,J=5.4Hz,2H),4.26-4.17(m,6H),3.88-3.86(m,4H),3.80(q,J=5.4,4.9Hz,4H ),3.75-3.54(m,56H),3.51-3.49(m,4H),3.32(s,4H),2.46(t,J=6.2Hz,2H),2.22- 2.02(m,5H),1.85-1.78(m,5H),1.67-1.57(m,5H),1.52-1.49(m,9H),1.45(s,10H). 13C NMR(126MHz,MeOD)δ 172.76,169.71,166.80,160.60,153.78,142.31,133.49,130.46,129.79,126.96,12 3.64,120.75,107.89,81.70,73.59,72.96,71.74,71.66,71.62,71.56,71.54,71.54 ,71.53,71.52,71.51,71.50,71.48,71.39,71.35,71.31,70.81,70.05,67.89,66.51,59.10,49.85,37.21,31.53,31.35,31.18,29.75,29.53,28.37,28.36,26.81,21.39. 19 F NMR(471MHz,MeOD)δ-86.97,-119.36,-119.40,-119.44.

[0242] Example 12: Synthesis of dendritic molecules of formula (IK) according to the invention Trifluoroacetic acid (TFA) (1.00 equiv., 0.064 mmol, 5 μL) was added to a solution of compound (IT) (1.00 equiv., 0.064 mmol, 105.9 mg) obtained above in step 11.5 of Example 11 in DCM (1.5 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 C 18 , H2O / acetonitrile + 0.1% TFA) to give the final compound (IK).

[0243] Example 13: Preparation of a nanoemulsion according to the invention material and method Nanoemulsions containing perfluorocarbons, phospholipids and oligo(ethylene glycol) (OEG) dendritic molecules of formula (I) according to the present invention were prepared according to the following general procedure: Phospholipids and dendrons of formula (I) were dispersed by magnetic stirring in a buffer solution at a temperature higher than the phospholipid transition temperature. Perfluorocarbons were added dropwise to the dispersion and the mixture was prehomogenized with a low-energy device. The resulting dispersion was then subjected to sonication or high-pressure homogenization. After cooling to room temperature, the dispersion was centrifuged and the clear phase was filtered through a 0.44 μm membrane. A 1.5 mL aliquot was taken and diluted with buffer for size analysis by photosedimentation (e.g., Horiba-Capa 700) or dynamic light scattering (e.g., DLS, Malvern Zeta Sizer Nano ZS). - Perfluorohexane (PFH, Fluorochem, Hadfield, UK), - perfluoropentane (PFP, Fluorochem, Hadfield, UK), -perfluorooctyl bromide (Alliance Pharmaceutical, San Diego, CA, USA), -Dipalmitoylphosphatidylcholine (DPPC): Avanti Polar Lipids, -Dimyristoylphosphatidylcholine (DMPC): Avanti Polar Lipids, -HEPES buffer (Sigma-Aldrich).

[0244] Example 13.1: Preparation of a nanoemulsion containing perfluorohexane (PFH), dipalmitoylphosphatidylcholine (DPPC) and a dendron of formula (IP) The dendron of formula (IP) can be represented as follows: JPEG2025511985000084.jpg65150

[0245] DPPC(9×10 -3 molL -1 , 6.60gL -1 ) and dendrons of formula (IP) (0.5 × 10-3 molL -1 , 0.64gL -1 ) was dispersed in 4 mL of HEPES buffer at 50 °C by magnetic stirring for 2 h. PFH (400 μL) was added dropwise to the dispersion, and the mixture was homogenized on a vortex mixer for 2 min. The resulting dispersion was subjected to tip sonication (Vibracell Sonicator, Bioblock Scientific, Illkirch) for 5 min at 25 °C. After cooling to room temperature, the dispersion was centrifuged at 3000 rpm for 3 min and filtered through a 0.44 μm membrane. The average diameter of the perfluorocarbon droplets in the resulting nanoemulsion was 170 ± 10 nm after preparation, as measured by DLS.

[0246] As a comparative example that does not form part of the present invention, a reference nanoemulsion prepared in exactly the same conditions, but containing only DPPC and PFH rather than the dendron of formula (IP), resulted in a coarser nanoemulsion (230 nm after preparation).

[0247] The average diameter of the perfluorocarbon droplets for each of these two prepared nanoemulsions was measured again by DLS at different times during a 2-month storage period at 25° C. (t=3 days, 10 days, 15 days, 30 days, 40 days, and 60 days).

[0248] The results are reported in the attached figures 1 and 2. Figure 1a corresponds to the droplet size distribution in a reference nanoemulsion stabilized by DPPC only, and figure 1b corresponds to the droplet size distribution in a nanoemulsion according to the invention, namely stabilized by DPPC and dendrons of formula (IP). In figures 1a and 1b, the intensity (%) is expressed as a function of the diameter at t=0, i.e. immediately after the preparation of the nanoemulsion (dotted curve) and after 2 months of storage at a temperature of 25°C (solid curve). Figure 2 shows the evolution of the average mean diameter (nm) of the droplets as a function of time (days) for each nanoemulsion. In figure 2, the curve with black squares corresponds to the reference nanoemulsion stabilized by DPPC, and the curve with black disks corresponds to the nanoemulsion according to the invention, namely stabilized by DPPC and dendrons of formula (IP).

[0249] As can be seen from these figures, the stability of nanoemulsions containing PFH droplets is significantly improved when said nanoemulsions are stabilized with both DPPC and the dendron of formula (IP) compared to a reference nanoemulsion in which the PFH droplets are stabilized only with DPPC. Indeed, the average diameter of the PFH droplets in the nanoemulsions according to the invention did not change significantly after 2 months at 25° C. (average 190±10 nm, FIG. 1b and FIG. 2), whereas it did change significantly in the reference nanoemulsions with droplet sizes larger than 600 nm after 2 months at 25° C. (FIG. 1a and FIG. 2).

[0250] Example 13.2: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IP) The protocol of Example 13.1 above was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendrons of formula (IP) (1 × 10 -3 molL -1 , 1.28gL -1After addition of PFH (400 μL), homogenization by vortex mixer and tip sonication followed by membrane filtration, a stable PFH nanoemulsion was obtained with a mean droplet diameter of 130 ± 10 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0251] Example 13.3: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IP) The protocol of Example 13.1 above was repeated with DPPC (4.5 × 10 -3 molL -1 , 3.30gL -1 ) and dendrons of formula (IP) (0.5 × 10 -3 molL -1 , 0.64gL -1 After addition of PFH (200 μL), homogenization by vortex mixer and tip sonication followed by membrane filtration, a stable PFH nanoemulsion was obtained with a mean droplet diameter of 130 ± 8 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0252] Example 13.4: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IQ) The dendron of formula (IQ) can be represented as follows: JPEG2025511985000085.jpg65152

[0253] The protocol of Example 13.1 above was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendron of formula (IQ) (1×10 -3 molL -1 , 1.45gL -1 After addition of PFH (400 μL), homogenization by vortex mixer and tip sonication followed by membrane filtration, a stable PFH nanoemulsion was obtained with a mean droplet diameter of 145 ± 10 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0254] Example 13.5: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IQ) The protocol described above in Example 13.1 was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendron of formula (IQ) (0.5 × 10 -3 molL -1 , 0.72gL -1 After addition of PFH (400 μL), homogenization by vortex mixer and tip sonication followed by membrane filtration, a stable PFH nanoemulsion was obtained with a mean droplet diameter of 185 ± 15 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0255] Example 13.6: Preparation of a nanoemulsion containing perfluoropentane (PFP), DPPC and a dendron of formula (IP) The protocol in Example 7.1 above was repeated with DPPC (9 x 10 -3 molL -1 , 6.60gL -1 ) and dendrons of formula (IP) (1 × 10 -3 molL -1 , 1.28gL -1 ). After addition of PFP (400 μL), homogenization with a vortex mixer and tip sonication followed by membrane filtration, a stable PFP nanoemulsion was obtained with a mean droplet diameter of 250 ± 21 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0256] Example 13.7: Preparation of a nanoemulsion containing PFP, DPPC and a dendron of formula (IP) The protocol of Example 13.1 above was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendrons of formula (IP) (0.5 × 10 -3 molL -1 , 0.64gL-1 ). After addition of PFP (400 μL), homogenization with a vortex mixer and tip sonication followed by membrane filtration, a stable PFP nanoemulsion was obtained with a mean droplet diameter of 202 ± 12 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0257] Example 13.8: Preparation of a nanoemulsion containing PFP, DPPC and a dendron of formula (IQ) The protocol of Example 13.1 above was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendron of formula (IQ) (0.5 × 10 -3 molL -1 , 0.72gL -1 ). After addition of PFP (400 μL), homogenization with a vortex mixer and tip sonication followed by membrane filtration, a stable PFP nanoemulsion was obtained with a mean droplet diameter of 202 ± 12 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0258] Example 13.9: Preparation of a nanoemulsion containing perfluorooctyl bromide (PFOB), DPPC and a dendron of formula (IP) The protocol of Example 13.1 above was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendrons of formula (IP) (1 × 10 -3 molL -1 , 1.28gL -1 After addition of PFOB (400 μL), homogenization with a vortex mixer and tip sonication followed by membrane filtration, a stable PFOB nanoemulsion was obtained with a mean droplet diameter of 90 ± 8 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0259] Example 13.10: Preparation of a nanoemulsion containing PFOB, DPPC and a dendron of formula (IQ) The protocol of Example 13.1 above was repeated with DPPC (9 × 10 -3 molL -1 , 6.60gL -1 ) and dendron of formula (IQ) (1×10 -3 molL -1 , 1.45gL -1 After addition of PFOB (400 μL), homogenization with a vortex mixer and tip sonication followed by membrane filtration, a stable PFOB nanoemulsion was obtained with a mean droplet diameter of 105 ± 10 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0260] Example 13.11: Preparation of a nanoemulsion containing PFP, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (IP) The protocol of Example 10.1 above was repeated for DMPC (9 × 10 -3 molL -1 , 6.10gL -1 ) and dendrons of formula (IP) (0.5 × 10 -3 molL -1 , 0.64gL -1 ). After addition of PFP (400 μL), homogenization with a vortex mixer and tip sonication followed by membrane filtration, a stable PFP nanoemulsion was obtained with a mean droplet diameter of 154 ± 8 nm (DLS). The mean droplet diameter did not change significantly after 2 months at 25 °C.

[0261] Example 13.12: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (IP) The protocol of Example 13.1 above was repeated for DMPC (3 × 10 -2 molL -1 , 20.0gL -1 ) and dendrons of formula (IP) (1.2 × 10 -3 molL -1 , 1.5gL -1After addition of PFH (400 μL), homogenization by vortex mixer and tip sonication followed by membrane filtration, a stable PFH nanoemulsion was obtained with a mean droplet diameter of 257 ± 10 nm (DLS).

[0262] Example 13.13: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (IP) DMPC(3×10 -2 molL -1 , 20.0gL -1 ) and dendrons of formula (IP) (1.2 × 10 -3 molL -1 , 1.5gL -1 ) was dispersed by magnetic stirring in 4 mL of HEPES buffer at room temperature for 2 h. PFH (400 μL) was added dropwise to the dispersion at room temperature and the mixture was homogenized for 2 min with an IKA T10 Basic Ultra-Turrax mixer. The resulting dispersion was then subjected to high-pressure homogenization (B15, Avestin, Canada) at 4 bar (6 cycles). The average diameter of the perfluorocarbon droplets measured by DLS was 221 ± 10 nm.

[0263] As a comparative example that does not form part of the present invention, a reference nanoemulsion prepared in exactly the same conditions, but containing only DMPC and PFH, and not the dendron of formula (IP), resulted in a coarser nanoemulsion (270 nm after preparation).

[0264] The average diameter of the perfluorocarbon droplets for each of these two prepared nanoemulsions was measured again by DLS at different times during a one-month storage period at 25°C.

[0265] The results are reported in attached FIG.

[0266] In this figure, the average diameter of the droplets (nm) is represented as a function of time (days) for each nanoemulsion: the curve with filled squares corresponds to the reference nanoemulsion stabilized by DMPC and the curve with filled circles corresponds to the nanoemulsion according to the invention, i.e. the nanoemulsion stabilized by DMPC and dendrons of formula (IP).

[0267] As can be seen in figure 3, the stability of nanoemulsions containing PFH droplets is significantly improved when said nanoemulsions are stabilized with both DMPC and with the dendron of formula (IP) compared to a reference nanoemulsion not forming part of the invention in which the PFH droplets are stabilized only with DMPC. Indeed, the average diameter of the PFH droplets in a nanoemulsion according to the invention is less than 400 nm after 2 months at 25°C, but more than 550 nm after the same period.

[0268] Example 13.14: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (ID) The protocol described in Example 13.13 was repeated with DMPC (3 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (ID) (1.2×10 -3 molL -1 , 1.93gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 4 bar, 6 cycles), the average droplet diameter was 144±10 nm and the zeta potential was −30 mV. It is noteworthy that the zeta potential of the reference nanoemulsion, which does not form part of the present invention since it contains only DMPC, was −6 mV.

[0269] These results demonstrate that the stability of the nanoemulsion according to the invention is much better than that of the reference nanoemulsion, since it is well known that in a dispersed system, the higher the zeta potential, the more the droplets tend to repel each other, which is favorable for the stabilization of nanoemulsions. In particular, as is generally accepted and reported in the literature, a colloidal dispersion is considered "stable" if its zeta potential is at least 30 mV (absolute value).

[0270] Example 13.15: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (ID) The protocol described in Example 13.13 was repeated with DMPC (3 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (ID) (1.2×10 -3 molL -1 , 1.87gL -1 ). After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 6 passes), the average droplet diameter was 231±10 nm and the zeta potential was −46.1 mV. The zeta potential of a reference nanoemulsion, which was formulated with DMPC only and therefore does not form part of the present invention, was −3.5 mV.

[0271] Example 13.16: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (ID) The protocol described in Example 13.12 was repeated with DMPC (3 × 10 -2 molL -1 , 20gL -1 ) and dendron of formula (ID) (1.9 × 10 -3 molL -1 , 3.2gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 6 cycles), the average droplet diameter was 227±10 nm and the zeta potential was −16 mV.

[0272] Example 13.17: Preparation of nanoemulsions containing PFH, dimyristoylphosphatidylcholine (DMPC) and dendrons of formulas (IE) The protocol described in Example 13.12 was repeated with DMPC (3 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IE) (1.2×10 -3 molL -1 , 2.1gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 6 cycles), the average droplet diameter was 216±10 nm and the zeta potential was −25 mV.

[0273] As a comparative example that does not form part of the present invention, a reference nanoemulsion prepared in exactly the same conditions, but containing only DMPC and PFH, and not the dendron of formula (IE), resulted in a coarser nanoemulsion (260 nm after preparation).

[0274] The average diameter of the perfluorocarbon droplets for each of these two prepared nanoemulsions and the nanoemulsion prepared here according to Example 13.15 was measured again by DLS at different times during the 20 day storage period at 25°C.

[0275] The results are reported in attached FIG.

[0276] In this figure, the average diameter of the droplets (nm) is represented as a function of time (days) for each nanoemulsion: the curve with black squares corresponds to the reference nanoemulsion stabilized by DMPC, the curve with black circles corresponds to the nanoemulsion of Example 13.15 according to the invention stabilized by DMPC and the dendron of formula (ID) and the curve with black stars corresponds to the nanoemulsion according to this Example 13.16, i.e. a nanoemulsion stabilized by DMPC and the dendron of formula (IE).

[0277] As can be seen in figure 4, the stability of nanoemulsions containing PFH droplets is significantly improved when said nanoemulsions are stabilized with both DMPC and dendrons of formula (ID) or (IE) compared to a reference nanoemulsion not forming part of the invention in which the PFH droplets are stabilized only with DMPC. Indeed, the average diameter of the PFH droplets in the nanoemulsions according to the invention did not change significantly after 10 days at 25°C, whereas it did in the reference nanoemulsion, with a droplet size reaching 400 nm after 20 days at 25°C.

[0278] Example 13.18: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (IA) DMPC(3×10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IA) (1.2×molL -1 , 1.75gL -1 ) was dispersed in 4 mL of HEPES buffer by magnetic stirring for 2 h at 25 °C. PFH (400 μL) was added dropwise to this dispersion at 25 °C and subjected to ultrasonic treatment. The average diameter of the perfluorocarbon droplets measured by DLS was 550 ± 20 nm. The zeta potential was -2.1 mV.

[0279] Example 13.19: Preparation of a nanoemulsion containing PFH, dimyristoylphosphatidylcholine (DMPC) and a dendron of formula (IB) DMPC(3×10 -2 molL -1 , 20.0gL -1 ) and the dendron of formula (IB) (1.5×molL -1 , 1.75gL -1) was dispersed in 4 mL of HEPES buffer by magnetic stirring for 2 h at 25 °C. PFH (400 μL) was added dropwise to this dispersion at 25 °C and subjected to ultrasonic treatment. The average diameter of the perfluorocarbon droplets measured by DLS was 515 ± 8 nm. The zeta potential was -4.0 mV.

[0280] Example 13.20: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IS) DPPC (1.36 × 10 -2 molL -1 , 10.0gL -1 ) and the dendron of formula (IS) (5.4×10 -4 molL -1 , 0.8gL -1 ) was dispersed in 3 mL of HEPES buffer by magnetic stirring at 50 °C for 2 h. PFH (300 μL) was added dropwise to the dispersion and the mixture was homogenized with an IKA T10 Basic Ultra-Turrax mixer for 2 min. The resulting dispersion was then subjected to high-pressure homogenization (B15, Avestin Canada) at 6 bar (4 cycles). The average diameter of the perfluorocarbon droplets measured by DLS was 212 ± 10 nm. The zeta potential was -2.7 mV. There is no significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion during a storage period of 1 month at 4 °C.

[0281] Example 13.21: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IS) The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IS) (1.36×10 -3 molL -1 , 2.2gL -1After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 140±10 nm and the zeta potential was −2.4 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4° C.

[0282] Example 13.22: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IT) The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IT) (5.4×10 -4 molL -1 , 0.9gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 165±10 nm and the zeta potential was −7.8 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4° C.

[0283] Example 13.23: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IT) The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IT) (1.36×10 -3 molL -1 , 2.2gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 226 ± 10 nm and the zeta potential was -12.4 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4 °C.

[0284] Example 13.24: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IR) The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IR) (5.4×10 -4 molL -1 , 0.8gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 162±10 nm and the zeta potential was −4.3 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4° C.

[0285] Example 13.25: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IR) The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IR) (1.36×10 -3 molL -1 , 1.9gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 277±10 nm and the zeta potential was −6.2 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4°C. Example 13.26: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IF)

[0286] The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IF) (5.4×10-4 molL -1 , 1.0gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 171 ± 10 nm and the zeta potential was -38.0 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4 °C.

[0287] Example 13.27: Preparation of a nanoemulsion containing PFH, DPPC and a dendron of formula (IF) The protocol described in Example 13.20 was repeated with DPPC (1.36 × 10 -2 molL -1 , 20gL -1 ) and the dendron of formula (IF) (1.36×10 -3 molL -1 , 2.6gL -1 After being subjected to high pressure homogenization (B15, Avestin Canada, 6 bar, 4 cycles), the average droplet diameter was 188±10 nm and the zeta potential was −56.0 mV. No significant change in the average diameter of the perfluorocarbon droplets of this nanoemulsion was observed during a storage period of 1 month at 4° C.

[0288] Example 14: Control of Microbubble Size after Vaporization and Activation of Perfluorocarbon Nanoemulsions A general method for phase-shifting the following perfluorocarbon nanoemulsions into stable microbubbles is described below: Dendron-based perfluorocarbon nanoemulsions were activated into microbubbles by ultrasound or light irradiation. The microbubble mean diameter was determined immediately after preparation and monitored over time by optical microscopy and acoustic attenuation determination.

[0289] Example 14.1: Phase shift of 10% v / v concentrated PFH nanoemulsion. The above protocol was applied to a nanoemulsion prepared according to Example 13.1 above, a 10% v / v concentrated PFH nanoemulsion (mean diameter: 202±12 nm), using two successive ultrasonic pulses of 2.2 MHz and 1.1 MPa at 37° C.

[0290] The accompanying Figures 5 and 6 show the average diameter (frequency (%) as a function of microbubble diameter (μm)) of the microbubble dispersions obtained immediately after preparation (Figure 5) and after 7 hours at room temperature (Figure 6).

[0291] FIG. 7 is an optical microscope photograph of the microbubble dispersion obtained after 7 hours at room temperature.

[0292] The results shown in these figures show that the mean diameter of the resulting microbubble dispersion was 2.5 ± 0.7 μm after preparation, as assessed by optical microscopy and determination of the acoustic attenuation coefficient (Figure 5). The microbubble mean diameter did not change significantly after 7 hours at room temperature (Figures 6 and 7), demonstrating the excellent stability of the microbubble dispersion.

[0293] Example 14.2: Phase shift of 5% v / v concentrated PFH nanoemulsion. The above protocol was applied to a nanoemulsion prepared according to Example 13.3 above, a 5% v / v concentrated PFH5 nanoemulsion (mean diameter: 130±8 nm), using two successive ultrasound pulses at 2.2 MHz and 1.1 MPa at 37° C. The microbubble mean diameter after preparation was 1.8±0.6 μm, as assessed by optical microscopy and determination of the acoustic attenuation coefficient. The microbubble mean diameter did not change significantly after 7 hours at room temperature.

[0294] Example 14.3: Phase shift of 5% v / v concentrated PFH nanoemulsion. The above protocol was applied to the nanoemulsion prepared according to Example 13.26 above, a 5% v / v concentrated PFP nanoemulsion (mean diameter: 171 ± 10 nm), using two successive ultrasonic pulses at 2.2 MHz and 1.1 MPa at 37 °C. The shift of the nanoemulsion droplets into microbubbles observed at 37 °C was evaluated by cryogenic transmission electron microscopy. The results are reported in the attached Figure 8. Figure 8a shows the start of the vaporization process (white areas) occurring for each perfluorohexane liquid nanodroplet. Figure 8b shows that after 15 minutes at 37 °C, most of the nanoemulsion droplets were transformed into micron-sized gaseous microbubbles.

[0295] Example 15: Evaluation of dendron immobilization at the air / water interface The assessment of the anchoring ability of the dendrons in the interfacial film of microbubbles was evaluated by investigating the isothermal compression of the Langmuir monolayer formed by these molecules at the air / water interface. The Langmuir monolayer constitutes a two-dimensional experimental model of the interfacial film of nanoemulsions. In the above experiment, two mobile barriers (initial area: 365 × 75 mm) were 2 , Compression speed: 10cm 2 minutes -1 , which is about 3.6% -1 Surface pressure (π) versus molecular area (A) isotherms were recorded using a Langmuir mini-trough (KSV NIMA, Finland) equipped with a 1000-μm sieve (which corresponded to the reduction in the total area of ​​the solution). π was measured using the Wilhelmy plate (paper) method. The trough was maintained at 25 ± 0.5 °C. Oligo(ethylene oxide) dendrons (1 mmol L -1 A solution of 1000g of 1,2-dichloroethane (1,2-dichloroethane) in chloroform was spread on the surface of water (320 mL). The chloroform was then allowed to evaporate for 15 min and the film was allowed to equilibrate before compression was initiated. All experiments were performed at least three times. Since our Langmuir trough only allowed for a surface area compression of about 10, isotherms were recorded in three separate experiments.

[0296] These experiments were carried out using dendritic compounds of formulae (IA), (IB) and (IC) according to the invention as well as comparative dendritic molecules not forming part of the invention having the following formula DM: JPEG2025511985000086.jpg190125

[0297] The results are shown in Figure 8. Surface pressure π (mN m -1 ) to the molecular area A (Å 2 ) in which the solid curves correspond to experiments carried out using dendritic compounds of formula (IA), the dashed curves correspond to experiments carried out using dendritic compounds of formula (IB), the dotted curves correspond to experiments carried out using dendritic compounds of formula (IC) and the alternating dashed and dotted curves correspond to experiments carried out using dendritic compounds of formula (DM), which do not form part of the present invention since the alkyl chains present on the phosphonate groups have only two carbon atoms and do not contain terminal fluorinated groups.

[0298] These results indicate that grafted alkyl chains having at least four carbon atoms on the bisphosphonate group of the dendron (dendrons of formula IA, dendrons of formula IB and dendrons of formula IC) have a much higher collapse pressure, e.g., about 45 mN m -1 (Figure 8). For example, the structurally related comparative dendron DM, which contains an alkyl chain with only two carbon atoms and no terminal fluorinated group, has a lower stability at the air / water interface, about 10 mN m -1 exhibited a much lower surface pressure, which revealed weaker anchoring at the interface.

Claims

1. The following equation (I): (In the formula: -R １ teeth, * Alkyl radicals having at least two carbon atoms or alkyl radicals having at least two carbon atoms and containing a terminal fluorinating group, *Base-OR ４ or -COOR ４ (In the formula, R ４ (This represents a linear alkyl radical having at least four carbon atoms or an alkyl radical having at least two carbon atoms and containing a terminal fluorinated group), and *The phosphonate group in the following formula (PG): (In the formula, R ５ Each of these represents a linear alkyl radical having a hydrogen atom or at least one carbon atom, and the asterisk represents the bonding point of the group of formula (PG) to a phenyl ring. The group is selected from these; -R ２ Each of these represents a linear alkyloxy radical having 1 to 20 carbon atoms; -R ３ represents a linear alkyloxy radical having 1 to 20 carbon atoms, a carboxyl group, or a group -COOtBu (where tBu means ter-butyl); -n is an integer in the range of 1 to 16; -p is an integer in the range of 1 to 16; -m is an integer in the range of 1 to 4, preferably m = 1 or 2, more preferably m = 2; -q is an integer in the range of 1 to 3, however R １ (If q represents the phosphonate group PG, then q = 2.) The use of oligo(ethylene oxide) dendritic molecules, The present invention relates to stabilizing a fluorocarbon-based nanoemulsion, which consists of a dispersion of nanodroplets of liquid fluorocarbon stabilized in a continuous aqueous phase, by a thin lipid film present at the interface between the aqueous phase and the liquid fluorocarbon, wherein the lipid film contains phospholipids (or more) and at least one oligo(ethylene oxide)dendron of formula (I).

2. The oligo(ethylene oxide) dendrimer of the formula (I) has q = 2, and R １ is a compound represented by the formula (PG) (where each of R ５ represents a hydrogen atom or an alkyl group having 4 to 12 carbon atoms) and represents a phosphonate group, the use according to claim 1.

3. The use according to claim 2, wherein the oligo(ethylene oxide) dendritic molecule of formula (I) is grafted onto magnetic nanoparticles.

4. The oligo(ethylene oxide) dendritic molecule in formula (I) above has q = 2, and R １ is an alkyl group selected from octyl, decanyl, and dodecanyl, or -(CH ２ ) ６ -CF ２ CF ３ and - (CH ２ ) ２ -CF (CF ３ ) ２ The use according to claim 1, wherein the compound represents a fluorinating group selected from among them.

5. The oligo(ethylene oxide) dendritic molecule in formula (I) above has q = 2, and R １ However, base-OR ４ or -COOR ４ (In the formula, R ４ The alkyl group is selected from octyl, decanyl, and dodecanyl or -(CH ２ ) ６ -CF ２ CF ３ and - (CH ２ ) ２ -CF (CF ３ ) ２ The use according to claim 1, which is a compound representing a fluorinated group selected from among the following.

6. The oligo(ethylene oxide) dendritic molecule of formula (I) above, ２ The use according to any one of claims 1 to 5, wherein each of the compounds represents a methyloxy group.

7. The oligo(ethylene oxide) dendritic molecule of formula (I) above, ３ The use according to any one of claims 1 to 5, wherein is a compound representing a methyloxy group, a carboxyl group, or the group -COOtBu (where tBu means ter-butyl).

8. The oligo(ethylene oxide) dendritic molecule of formula (I) above, １ ~R ５ The meanings of m, n, p, and q are shown in Table 1 below: The use according to any one of claims 1 to 5, wherein the compound is selected from the compounds of formulas (I-A) to (I-T) shown.

9. A fluorocarbon-based nanoemulsion comprising an aqueous continuous phase and a dispersion of nanodroplets comprising a lipid phase membrane encapsulating at least one liquid fluorocarbon, wherein the lipid phase comprises at least one phospholipid and at least one oligo(ethylene oxide) dendritic molecule of formula (I) as described in any one of claims 1 to 5.

10. The fluorocarbon-based nanoemulsion according to claim 9, wherein the at least one fluorocarbon is selected from perfluorobutane, perfluoropentane, 2H,3H-perfluoropentane, perfluorohexane, perfluoroheptane, perfluorooctane, perfluorononane, perfluorodecalin, perfluorooctyl bromide, and perfluorotripropylamine.

11. The fluorocarbon-based nanoemulsion according to claim 9, wherein the concentration of fluorocarbons varies from 1 to 30% w / w.

12. The fluorocarbon-based nanoemulsion according to claim 9, wherein at least one phospholipid is selected from dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine.

13. The fluorocarbon-based nanoemulsion according to claim 9, wherein the concentration of at least one phospholipid varies from 0.25 to 10% w / w.

14. The fluorocarbon-based nanoemulsion according to claim 9, wherein the concentration of the oligo(ethylene oxide) dendritic molecule of formula (I) varies from 0.07% to 0.7% w / w.

15. The fluorocarbon-based nanoemulsion according to claim 9, wherein the molar ratio of phospholipid / oligo(ethylene oxide) dendritic molecule in formula (I) varies from about 5:1 to 50:

1.

16. Use of the fluorocarbon-based nanoemulsion described in claim 9 as a contrast agent.

17. A fluorocarbon-based nanoemulsion according to claim 9 for use as a drug carrier or oxygenating agent in therapeutic treatment methods.

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