Dendritic molecules, processes for their preparation and uses thereof - Patents.com

Abstract

The present invention relates to polyfunctional organic dendritic molecules derived from alkylphosphonates or esters, processes for their preparation and their use, especially as drug carriers or imaging agents.

Description

[Technical field]

[0001] The present invention is in the field of dendritic molecules.

[0002] More particularly, the present invention relates to polyfunctional organic dendritic molecules, processes for their preparation and their use, especially as drug carriers or imaging agents. [Background technology]

[0003] Dendrimers and their basic units, called "dendrons", are synthetically produced as monodisperse polymeric nanostructures with tree-like, highly branched architectures. They are routinely synthesized as tunable "nanostructures" that can be designed and regulated as a function of their size, shape, surface chemistry and internal void space. They are typically 2-20 nm in diameter. A variety of structures are available, each with properties such as multivalency, self-assembly, electrostatic interactions, chemical stability, low cytotoxicity and solubility.

[0004] Dendrimers and dendrons offer a multitude of applications deriving not only from the inherent properties of the polymers, but also in particular from their features: easily accessible functions on the surface, porosity, flexibility of the internal branching, the presence of functionalized cavities, accessibility to the core, and of course multivalency and cooperativity. They are highly adaptable materials in terms of their structure, flexibility, porosity or morphology, all of which can be adjusted at will. Their applications depend on chemistry (synthesis, analysis, catalysis...), materials science (films, layers and hybrids), pharmacology (drugs, pharmaceuticals), nanoscience (nanoparticles), biology and medicine (immunology). Dendrimers and dendrons have been widely explored and exploited in biomedical applications, since they have multiple surface functional groups that can be used to target or label for imaging and drug delivery applications.

[0005] Dendrimers and dendrons have found applications in transdermal drug delivery systems and show potential in gene delivery and for improving the oral bioavailability of problematic drugs. The presence of a large number of surface groups makes dendrimers suitable carriers for delivering high drug payloads. The interior space of the branched structures can be used to conjugate or encapsulate drugs. They are utilized as delivery vehicles for nonsteroidal anti-inflammatory drugs (NSAIDs), anticancer drugs, and other drugs such as simvastatin, famotidine or quinolones. Drug-dendrimer conjugates show high solubility, reduced systemic toxicity and selective accumulation in solid tumors.

[0006] The multivalent nature of dendrimers and dendrons has also placed these well-defined hyperconnected macromolecules in the foreground in the development of new contrast agents for medical imaging or diagnostic platforms with retention times and biodistribution properties tunable according to their generation / size, their flexibility and / or their hydrophilicity. In addition to the chemical properties, the characterization of these structures and their physicochemical properties were studied in detail.

[0007] Dendritic approaches as coating strategies for the design of functional nanoobjects are of particular interest in the field of cancer diagnostics. The appeal of such strategies stems from the intrinsic properties of dendritic structures that can be chemically tuned to reach ideal biodistribution or highly and efficient targeting effects. To improve tumor targeting efficacy and obtain better in vivo imaging properties, several studies have investigated the multivalent effect of dendrimers or of dendritic surface functionalization of nanomaterials. Due to their cone-like structure and focal points, dendritic structures are of particular interest as coatings for ultrasmall nanoparticles (NPs) with very high surface curvatures. Indeed, such conical shapes are predicted to improve steric resistance towards macromolecules such as proteins while better preventing particle aggregation compared to their linear counterparts.

[0008] A first object of the present invention is to provide a new class of dendritic molecules that allow the delivery and targeting of many diagnostic and / or therapeutic agents.

[0009] A second object of the present invention is to provide a new class of dendritic molecules that can be used in phase change emulsions (PCEs) to (i) control the size and stabilize nanodroplets, (ii) precisely control the phase change phenomenon, (iii) obtain predetermined microbubble sizes and size distributions, and (iv) stabilize these microbubbles.

[0010] A third object of the present invention is also to provide a new class of dendritic molecules that are effective and useful for controlling the properties of nanoemulsions and microbubbles, independent of PCE.

[0011] Finally, a fourth object of the present invention is to provide a preparative process that allows the synthesis of this new class of dendritic molecules.

[0012] These objectives are achieved by the dendritic molecules of formula (I) and the process for their preparation which are described in detail hereinafter. Summary of the Invention

[0013] A first object of the present invention is to provide a compound of formula (I): JPEG2025512340000001.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): JPEG2025512340000002.jpg5161 (in the formula, R 5 each represents a straight chain alkyl radical having at least 4 carbon atoms, 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 where q=2, and q=2 represents a phosphonate group PG.

[0014] 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.

[0015] R 1 and R 4 With respect to "an alkyl radical having at least 2 carbon atoms and containing a terminal fluorinated group" means a hydrocarbon group having a straight or branched chain of at least 2 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. An example of a fluorinated group is -CF 2 -CF 3 and -CF(-CF 3 ) 2 It is.

[0016] R 4 and R 5 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] According to a particular preferred embodiment of the invention, q=2 and R 1 Formula (PG) (wherein R 5 Each of R represents an alkyl group having 4 to 12 carbon atoms, more preferably R 5 represents a phosphonate group of the formula:

[0021] According to another particular embodiment of the invention, q=2 and R 1 is an alkyl group selected from among octyl, decanyl and dodecanyl, or -(CH 2 ) 6 -CF 2CF 3 and -(CH 2 ) 2 -CF(CF 3 ) 2 represents a fluorinated group selected from among

[0022] According to another particular embodiment of the invention, q=2 and R is a group -OR 4 or -COOR 4 (In the formula, R 4 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 represents a fluorinated group selected from among

[0023] According to a particular preferred embodiment of the present invention, R 2 Each of represents a methyloxy group.

[0024] According to another particularly preferred embodiment of the present invention, R 3 represents a methyloxy group, a carboxyl group or a group -COOtBu (tBu means tert-butyl).

[0025] According to the most preferred embodiment of the present invention, the compounds of formula (I) according to the present invention are 1 ~R 5 The meanings of m, n, p and q are shown in Table 1 below. The compound is selected from the compounds of formulas (IA) to (IR) shown in JPEG2025512340000003.jpg119166.

[0026] The second object of the present invention is to 1 is a phosphonate group of formula (PG), q=2, n=p, and R 2 and R 3are identical and represent an alkyloxy group as defined above in formula (I), said process comprising the steps of: JPEG2025512340000004.jpg99113 (in the formula, R 5 and m has the same meaning as in formula (I) above) with a compound of formula (III): JPEG2025512340000005.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).

[0027] 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.

[0028] The compound of formula (III) can be prepared by at least the following steps: -Formula R 6 -(OCH 2 CH 2 ) 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): JPEG2025512340000006.jpg45115 (in the formula, R 6 has the same meaning as in formula (IV); - reacting the compound of formula (VI) with methyl gallate to obtain a compound of formula (VIII): JPEG2025512340000007.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:

[0029] The process for the preparation of compounds of formula (III) can be represented by the following Scheme 1: JPEG2025512340000008.jpg92152

[0030] 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).

[0031] 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 formula (I)) with trimethyl phosphite (a compound of formula (X)) to obtain a compound of formula (XI): JPEG2025512340000009.jpg5393 (in the formula, R 5 has the same meaning as in formula (I); 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): JPEG2025512340000010.jpg88117 (in the formula, R 5 has the same meaning as in formula (I); and - reacting the compound of formula (XIII) thus obtained with the compound of formula (XIV) below: JPEG2025512340000011.jpg10382 (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:

[0032] The process for the preparation of compounds of formula (II) can be represented by the following Scheme 2: JPEG2025512340000012.jpg124151

[0033] 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 The compound of formula (XIII) is obtained, where m has the same meaning as in formula (I) above. The compound of formula (XIV) where m has the same meaning as in formula (I) is added to a solution of the 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 the compound of formula (II), which can be recovered and purified by conventional techniques well known to those skilled in the art.

[0034] The compound of formula (XIV) can be prepared in advance according to the process depicted in Scheme 3 below: JPEG2025512340000013.jpg80157

[0035] 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).

[0036] The third object of the present invention is to 1 is a phosphonate group (PG), q=2, n and p are the same or different, and R 2is an alkyloxy group as defined above in formula (I), R 3 is a carboxyl group or a group -COOtBu, said process comprising 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) JPEG2025512340000014.jpg119121-Formula R 2 -(CH 2 CH 2 ) 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'): JPEG2025512340000015.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): JPEG2025512340000016.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) JPEG2025512340000017.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) JPEG2025512340000018.jpg59142 (in the formula, R 5 , R 2 wherein 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 the following formula (XIX): JPEG2025512340000019.jpg78167 (in the formula, R 5 , R 2 wherein 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): JPEG2025512340000020.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): JPEG2025512340000021.jpg57147 (in the formula, R 5 , 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 Includes.

[0037] 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: JPEG2025512340000022.jpg183166

[0038] 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 and m have the same meaning as in formula (I), with the compound of formula (XVII) thus obtained is carried out by mixing a solution of said 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 a 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 5 , R 2The 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 at room temperature for 5-24 hours with stirring to obtain R 5 , R 2 , to obtain the corresponding compound of formula (XIX), in which m and n have the same meanings as in formula (I). 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 , 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.

[0039] The compound of formula (XX) can be prepared by reacting tosyl chloride with a compound of formula (XXII): OHCH 2 CH 2 -(OCH 2 CH 2 ) p-1 -C(O)Ot-butyl, where p has the same meaning as in formula (I) above.

[0040] This process can be represented by Scheme 5 below: JPEG2025512340000023.jpg49158

[0041] 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.

[0042] R 1 but, * 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; 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'): JPEG2025512340000024.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 4 represents 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), R3 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.

[0043] 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.

[0044] Compounds of formula (II') that may not be commercially available are well known to those skilled in the art and can be similarly prepared according to the methods described, for example, in https: / / pubs.rsc.org / en / Content / ArticleLanding / 2013 / NR / C2NR32117C, Solenne Fleutot, et al., Nanoscale, 2013, 5, 1507.

[0045] 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 4 is a linear alkyl radical having at least 4 carbon atoms) to produce an alcohol of formula (XXIII): JPEG2025512340000025.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): JPEG2025512340000026.jpg70108, where m is as defined in formula (I), to give the corresponding compound of formula (II'a).

[0046] 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.

[0047] 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.

[0048] 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): JPEG2025512340000027.jpg115129ii) The compound of formula (XXV) thus obtained and the compound of formula R 4 -OH(in the formula, R 4 is an alkyl radical having at least two carbon atoms and containing a terminal fluorinated group) to produce an alcohol of the following formula (XXVI): JPEG2025512340000028.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): JPEG2025512340000029.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): JPEG2025512340000030.jpg71108, where m is as defined in formula (I), to obtain the corresponding compound of formula (II'b). It can be prepared by a process comprising:

[0049] 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) preferably comprises the steps of: 2 and a hydrogenation reaction carried out in the presence of a hydrogenation catalyst, such as palladium on carbon (Pd / C), in a suitable solvent, such as 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.

[0050] The dendritic molecules of formula (I) according to the present invention are useful as drug carriers, in particular as delivery vehicles for drugs, in particular non-steroidal anti-inflammatory drugs (NSAIDs), anti-cancer drugs, fragment antibodies, nanobodies and other drugs such as simvastatin, famotidine or quinolones.

[0051] Therefore, another object of the present invention is the use of a dendritic molecule of formula (I) defined according to the first object of the present invention as a drug carrier.

[0052] In particular, R 3 Dendritic molecules of formula (I) in which is a carboxyl group are particularly preferred for use as drug carriers since they can be easily functionalized with ligands or active ingredients.

[0053] The dendritic molecules of formula (I) according to the present invention are useful, for example, as imaging agents, such as biocompatible fluorescent dyes, conventional small molecule contrast agents or metal ion / chelator complexes, or as contrast agents for medical imaging or diagnostic platforms after functionalization with at least one metal or metal oxide nanoparticle. In particular, the dendritic molecules of formula (I) are grafted to metal oxide nanoparticles and can be used as medical imaging tools, in particular optical or magnetic imaging tools, more particularly magnetic resonance imaging contrast agents or magnetic particle imaging tracers, or as hyperthermia and / or radiosensitizers for treating tumors or other pathological tissues.

[0054] Therefore, another object of the present invention is a dendritic molecule of formula (I) as defined according to the first object of the present invention, in combination with at least one imaging agent, for use as a contrast agent for medical imaging or diagnostic platforms.

[0055] The dendritic molecules of formula (I) according to the present invention are also particularly useful in phase change emulsions (PCEs) to (i) control the size and stabilize nanodroplets, (ii) precisely control the phase change phenomenon, (iii) obtain predetermined microbubble sizes and size distributions, and (iv) stabilize these microbubbles.

[0056] The dendritic molecules of formula (I) according to the invention are also ultimately useful for controlling the properties of nanoemulsions and microbubbles, independent of the PCE.

[0057] Further advantages and embodiments of the present invention are given by the following examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0058] Example 1: Synthesis of dendritic molecules of formula (IA) according to the invention In this example, a dendritic molecule of formula (IA) was prepared: JPEG2025512340000031.jpg69169

[0059] 1.1 Step 1 - Preparation of 2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate (compound 1) JPEG2025512340000032.jpg4712930.1 mmol (1 equivalent) of tetraethylene glycol monomethyl ether was dissolved in 170.0 mL of dichloromethane at room temperature, and then 5 mL of triethylamine (Et 3 N) (36.2 mmol, 1.2 equiv.) was added and the reaction was stirred for 10 min. 22.3 g (36.2 mmol, 1.2 equiv.) of tosyl chloride (solid) was added slowly. The resulting mixture was stirred at room temperature overnight.

[0060] 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.

[0061] Purification by flash chromatography (100% dichloromethane (DCM) then 100% ethyl acetate (AcOEt)) gave a clear liquid (10.1 g, 93%).

[0062] 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).

[0063] 1.2 Step 2 - Preparation of Compound (2) JPEG2025512340000033.jpg341538.8 mmol (1.0 equiv.) of methyl gallate in acetone (60 mL) was dissolved in 18.1 mmol (3.2 equiv.) of potassium carbonate (K2 CO 3 ), 0.6 mmol (0.1 eq.) of potassium iodide (KI) and 18.9 mmol (3.3 eq.) of compound (1) as prepared in step 1 above were added. The resulting solution was heated to reflux for 42 h.

[0064] The reaction mixture was cooled to room temperature, the solvent was removed, and the solid was dissolved in dichloromethane (CH 2 Cl 2 ), filtered through Celite, and sodium thiosulfate (Na 2 S 2 O 3 ) 2N and brine, and then washed with sodium sulfate (Na 2 SO 4 ), filtered and concentrated under reduced pressure. 2 Cl 2 Purification with 100% methanol / MeOH 98 / 2 to 96 / 4 to 9 / 1) gave 3.9 g (89%) of a yellowish oil.

[0065] analysis: 1 H NMR(400MHz,chloroform-d)δ 7.46(d,2H:Ar-H),4.15(dd,J=5.6,4.2Hz,6H:-O-CH 2 -R), 3.86(s, 3H:CH 3 -OC=OR), 3.85-3.81(m, 6H: -O-CH 2 -CH 2 -R), 3.70-3.66(m, 6H: -O-CH 2 -R), 3.63-3.56(m,24H:-O-CH 2 -R), 3.51-3.47(m, 6H: -O-CH 2 -R), 3.33(s, 9H:CH 3 -O-).

[0066] 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.

[0067] TLC analysis showed the consumption of compound (2). The solvent was removed by rotary evaporation, and the crude product was then purified by CH 2 Cl 2 HCl 2N (20.0 mL) was added and stirring was continued for 15 min. The organic product was dissolved in CH 2 Cl 2 The aqueous layer was collected in CH 2 Cl 2 (5 times), and the combined organic layers were washed with brine and Na 2 SO 4 The mixture was evaporated in vacuo, dried at 40° C., filtered and concentrated under reduced pressure to give compound (3) (5.1 g, 6.8 mmol, 99%) as a yellow oil.

[0068] analysis: 1 H NMR(400MHz,chloroform-d)δ 7.46(d,2H:Ar-H),4.15(dd,J=5.6,4.2Hz,6H:-O-CH 2 -R), 3.85-3.81(m, 6H: -O-CH 2 -CH 2 -R), 3.70-3.66(m, 6H: -O-CH 2 -R), 3.63-3.56(m,24H:-O-CH 2 -R), 3.51-3.47(m, 6H: -O-CH 2 -R), 3.33(s, 9H:CH 3 -O-).

[0069] Step 1.4 Preparation of 3,5-bis(bromomethyl)phenol (compound (4)) JPEG2025512340000035.jpg689172 mL of 1M lithium aluminum hydride (LiAlH 4) (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 and then diluted with EtOAc (30.0 mL) and H 2 SO 4 A 10% aqueous solution (60.0 mL) was carefully added at 0° C. Stirring was continued overnight. Additional H 2 SO 4 A 10% aqueous solution (60.0 mL) was added. Stirring was continued at RT for another 24 h.

[0070] Once the aluminum salts were completely dissolved, the aqueous layer was washed with EtOAc (at least 5 times). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., 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.

[0071] TLC analysis showed that LiAlH 4 The results showed complete consumption of bisbenzyl alcohol, an intermediate formed but not isolated following reduction of dimethyl 5-hydroxyisophthalate with 1,2-dichlorophenyl ether. The organic product was washed with brine (1×), the aqueous layer was washed with EtOAc (at least 5×), and the combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. 2 Cl 2 Purification with petroleum ether / diethyl oxide (EtP / Et 2 Recrystallization from a mixture of 1H, 2H, and 3H afforded compound (4) (10.40 g, 37.4 mmol, 93.6%) as a white solid.

[0072] analysis: 1H NMR(400MHz,chloroform-d)δ 6.99(s,1H:Ar-H),6.81(d,J=1.43Hz,2H:Ar-H),4.41(s,4H:-CH 2 -Ar).

[0073] 1.5. Step 5 - Preparation of Compound (5) JPEG2025512340000036.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.

[0074] 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.

[0075] 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.

[0076] Vacuum distillation was used to separate the remaining octanol from the formed compound (5) at 160°C.

[0077] 9.205 g of orange oil was recovered (yield=61%)

[0078] analysis: 1 H-NMR (400MHz, chloroform-d): δ 3.77 (q, J = 6.9Hz, 6H, O-CH 2 -R), 1.61-1.57(m,6H,O-CH 2 -CH 2 -R), 1.28-1.25(m, 30H, CH 2 ), 0.86(t,J=6.7Hz,9H,CH 3 -R). 31P-NMR (400MHz, CDCl 3 ): δ 139.15

[0079] 1.6. Step 6 - Preparation of Compound (6) JPEG2025512340000037.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):

[0080] The next day, the solution was cooled and then a petroleum ether / EtOAc chromatography column was prepared (1 / 1-2 / 3).

[0081] 248 mg of compound (6) was recovered (yield=64%).

[0082] analysis: 1 H NMR (400 MHz, CDCl 3 )δ 6.81(s,2H,Ar-H),6.64(s,1H,Ar-H),4.02-3.77(m,8H,P-CH 2 ), 3.28-2.81(m,4H,Ar-CH 2 -P), 1.58(m,8H,P-CH 2 -CH 2 ), 1.42-1.14(m,44H,C-CH 2 ),0.95-0.77(t,J=7.1Hz,12H,C-CH 3 ). 31 P NMR (162MHz, CDCl 3 )δ 26.51.

[0083] 1.7. Step 7 - Preparation of Linker 2 (L2) JPEG2025512340000038.jpg941211.7.1. Step 7.1 - Preparation of Linker 1 (L1) JPEG2025512340000039.jpg377010.0 g (77.6 mmol-1 equiv.) of 2-bromoethanol (97%) was dissolved in 12 mL of water and then cooled to RT with 6.12 g (93.2 mmol-1.2 equiv.) of sodium azide (NaN 3 ) was added. The mixture was heated at 80° C. overnight. It was monitored by TLC (DCM / MeOH, 95:5, SM Rf=0, EP Rf=0, 5).

[0084] 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.

[0085] 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 Et 3 N was added slowly and the mixture was stirred for 10 min, then 17.9 g (93.2 mmol-1.2 equiv.) of tosyl chloride (TsCl) was added slowly.

[0086] After overnight, TLC (petroleum ether, AcOEt 7:3, KMnO 4 ) 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).

[0087] 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).

[0088] 12.13 g of Linker 2 was recovered as a colorless oil.

[0089] 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).

[0090] 1.8. Step 8 - Preparation of compound (7) JPEG2025512340000040.jpg1121652In a 5 mL flask, 297.0 mg (1.23 mmol-1.8 equiv.) of compound (6) was added in 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 in 15 mL of toluene. 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.

[0091] 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.

[0092] analysis: 1 H NMR(400MHz,MeOD)δ 6.90-6.82(m,3H,Ar-H),4.17(t,J=4.9Hz,2H,O-CH 2 -CH 2 -N 3 ), 3.98(m,8H,PO-CH 2 ), 3.59(t, J=4.8Hz, 2H, O-CH 2 -CH 2 -N 3 ),3.27-3.16(BX,J=21.9Hz,4H,Ar-CH 2 -P), 1.67-1.55(m,8H,PO-CH 2 -CH2 ), 1.41-1.26(m,40H,C-CH 2 ),0.95-0.85(t,J=6.5Hz,12H,C-CH 3 ). 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-CH 3 ). 31 P NMR (162MHz, MeOD) δ 27.11.

[0093] 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 CH 2 Cl 2 After dissolving in 0.22 mL (1.2 mmol-3.0 equiv.) of oxalyl chloride (COCl) 2 and 4 drops of dimethylformamide (DMF) were added. The orange solution was stirred at RT for 5 h. Once TLC showed complete consumption of compound (7), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chloride was simultaneously concentrated under reduced pressure and washed with 10 mL of CH 2 Cl 2 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.

[0094] The reaction mixture was diluted with brine. The aqueous layer was 2 Cl 2 (5 times), and the combined organic layer was washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 7.17 g of an orange oil. Flash chromatography (100% EtOAc, then CH 2 Cl 2 Purification with hexane / 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.

[0095] 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 (162MHz, CDCl 3 )δ 25.88.

[0096] Example 2: Synthesis of dendritic molecules of formula (IB) according to the invention In this example, a dendritic molecule of formula (IB) was prepared: JPEG2025512340000041.jpg58140

[0097] 2.1. Step 1 - Preparation of Compound (8) JPEG2025512340000042.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.

[0098] 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.

[0099] 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.

[0100] The remaining decanol was separated from the compound (8) thus formed using vacuum distillation at 160°C.

[0101] 36.2 g of compound (8) was recovered as a colorless oil (yield=92%).

[0102] analysis: 1 H NMR (400 MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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, CDCl 3 ):δ 139.19.

[0103] 2.2. Step 2 - Preparation of Compound (9) JPEG2025512340000043.jpg691422.0 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).

[0104] The next day, the solution was cooled and then a petroleum ether / EtOAc chromatography column was prepared (1 / 1-2 / 3).

[0105] 4.9 g of compound (9) was recovered (yield=81%).

[0106] analysis: 1 H NMR (400 MHz, CDCl 3 )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, CDCl 3 ) δ 26.40 HRMS:m / z theo:C 48 H 92 O 7 P 2 842.63 g.mol -1 ,Measurement:C 48 H 92 O 7 P 2 Na: 866.235 g.mol -1

[0107] 2.3. Step 3 - Preparation of Compound (10) JPEG2025512340000044.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.

[0108] 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.

[0109] 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. 31 P NMR (162MHz, MeOD) δ 31.03.

[0110] 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 CH 2 Cl 2 After dissolving in 0.13 mL (0.71 mmol - 3.0 equiv.) of (COCl) 2 and 4 drops of DMF were added. The orange solution was stirred at RT for 5 h. Once TLC showed complete consumption of compound (3), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chloride was simultaneously concentrated under reduced pressure to give CH 2 Cl 2 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.

[0111] The reaction mixture was diluted with brine. The aqueous layer was 2 Cl 2 (5 times), and the combined organic layer was washed with Na 2 SO 4 The mixture was dried over 500 ml of ethyl acetate, filtered and concentrated under reduced pressure to give an orange oil. Flash chromatography (100% EtOAc, then CH 2 Cl 2 Purification with hexane / 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.

[0112] 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.

[0113] Example 3: Synthesis of dendritic molecules of formula (IC) according to the invention In this example, a dendritic molecule of formula (IC) was prepared: JPEG2025512340000045.jpg64153

[0114] 3.1. Step 1 - Preparation of Compound (11) JPEG2025512340000046.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.

[0115] 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.

[0116] 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.

[0117] Residual dodecanol was separated from the compound (11) thus formed using vacuum distillation at 160°C.

[0118] 43.0 g of compound (11) was recovered as a colorless oil (yield=94%).

[0119] analysis: 1 H NMR (400 MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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 (162MHz, CDCl 3 )δ 139.19.

[0120] 3.2. Step 2 - Preparation of Compound (12) JPEG2025512340000047.jpg70162 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).

[0121] The next day, the solution was cooled and then a petroleum ether / EtOAc chromatography column was prepared (1 / 1-2 / 3).

[0122] 2.28 g of compound (12) was recovered (yield=67%).

[0123] analysis: 1H NMR (400 MHz, CDCl 3 )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(CH 2 -OR),31.94,30.61,29.70,29.68,29.64,29.59,29.38,29.25,25.53,23.84,22.70(CH 2 ), 14.12(CH 3 ). 31 P NMR (162MHz, CDCl 3 )δ 26.40. C 48 H 92 NaO 7 P 2 Calculated m / z: 978,3898, Measured m / Z: 978,3990.

[0124] 3.3. Step 3 - Preparation of Compound (13) JPEG2025512340000048.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.

[0125] 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.

[0126] analysis: 1 H NMR (400 MHz, CDCl 3 )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 (162MHz, CDCl 3 )δ 25.94.

[0127] 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 added to 15 mL of CH 2 Cl 2 After dissolving in 0.15 mL (0.81 mmol - 3.0 equiv.) of (COCl) 2 and 4 drops of DMF were added. The orange solution was stirred at RT for 5 h. Once TLC showed complete consumption of compound (3), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chloride was simultaneously concentrated under reduced pressure to give CH 2 Cl 2Then 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.

[0128] The reaction mixture was diluted with brine. The aqueous layer was 2 Cl 2 (5 times), and the combined organic layer was washed with Na 2 SO 4 Drying at 40° C., filtration, and concentration under reduced pressure were performed using flash chromatography (100% EtOAc, then CH 2 Cl 2 Purification by elution with hexane / 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.

[0129] analysis: 1 H NMR (400 MHz, CDCl 3 )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 (162MHz, CDCl 3 )δ 25.88.

[0130] Example 4: Synthesis of dendritic molecules of formula (ID) according to the invention In this example, a dendritic molecule of formula (ID) was prepared: JPEG2025512340000049.jpg61133

[0131] 4.1. Step 1 - Preparation of Compound (14) JPEG2025512340000050.jpg10110130 g (163 mmol-1 equiv.) of methyl gallate in 150 mL of DMF was dissolved in 49.1 g (489 mmol-4.5 equiv.) of KHCO 3 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.

[0132] The solids were 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 NaHCO 3 (twice), brine (three times), and Na 2 SO 4 The mixture was dried at 4° C., 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%).

[0133] 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-CH 2 ), 3.82(d, J=1.5Hz, 3H, O-CH 3 ). 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-CH 2 ), 52.46(1C,O-CH 3 ).

[0134] 4.2. Step 2 - Preparation of Compound (15) JPEG2025512340000051.jpg1291325.81 g (16.1 mmol - 2.2 equivalents) of compound (14) in 150.0 mL of acetone was dissolved in 3.22 g (23.4 mmol - 3.2 equivalents) of K 2 CO 3 To the mixture was added 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. The resulting solution was heated to reflux overnight.

[0135] The reaction mixture was cooled to RT, the solvent was removed, and the solid was separated by CH 2 Cl 2 The mixture was suspended in 100 ml of ethyl acetate and filtered through Celite. 2 S 2 O 3 Wash with 2N and brine solutions of Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. 2 Cl 2 / MeOH 98 / 2 - 96 / 4 - 9 / 1) gave 3.3 g (71%) of compound (15) in the form of a yellowish oil.

[0136] 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:-CH 2 -OAr),4.15(dd,J=5.6,4.2Hz,4H:-O-CH 2 -R), 3.86(s, 3H:CH 3 -OC=OR), 3.85-3.81(m, 4H: -O-CH 2 -CH 2 -R), 3.70-3.66(m, 4H: -O-CH 2 -R), 3.63-3.56(m, 16H: -O-CH 2 -R), 3.51-3.47(m, 4H: -O-CH 2-R), 3.33(s, 6H:CH 3 -O-). 13 C NMR (101 MHz, CDCl 3 )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.

[0137] 4.3. Step 3 - Preparation of Compound (16) JPEG2025512340000052.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.

[0138] The solvent was removed and the crude product was 2 Cl 2 The mixture was quenched with an aqueous solution of 2N HCl and the aqueous layer was 2 Cl 2 (5 times), and the combined organic layer was washed with Na 2 SO 4 The mixture was evaporated in water, dried at 40° C., filtered and concentrated under reduced pressure to give compound (16) (3.05 g, 95%) as a pale yellow oil.

[0139] 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:-CH 2 -OAr),4.15(dd,J=5.6,4.2Hz,4H:-O-CH 2 -R), 3.85-3.81(m, 4H: -O-CH 2 -CH 2 -R), 3.70-3.66(m, 4H: -O-CH 2 -R), 3.63-3.56(m, 16H: -O-CH 2-R), 3.51-3.47(m, 4H: -O-CH 2 -R), 3.33(s, 6H:CH 3 -O-).

[0140] 4.4. Step 4 - Preparation of Compound (17) JPEG2025512340000053.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) and 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. TLC monitoring by DCM / MeOH, 6:4, KMnO4. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO 2 Purification by elution with 40.0 g, solid precipitated in DCM, eluent: DCM / MeOH 100 / 0 to 90 / 10) gave the expected product (17) (2.55 g, 89% yield) as a colorless oil.

[0141] analysis: 1H NMR(400MHz,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-CH 2 -Ar), 4.19(t,4H,Ar-O-CH 2 -CH 2 -O,J),4.18(t,2H,O-CH 2 -CH2 -N,J),3.99-3.94(m,9H,PO-CH 2 -CH 2 ),3.88-3.86(m,4H,Ar-O-CH 2 -CH 2 -O),3.77-3.74(t,2H,O-CH 2 -CH 2 -N,J),3.72-3.69(m,4H,O-CH 2 -CH 2 -O),3.63-3.54(m,17H,O-CH 2 -CH 2 -O),3.49-3.47(m,4H,…),3.31(s,6H,O-CH 3 ),3.19(d,4H,P-CH 2 ,J),1.62-1.58(m,9H,PO-CH 2 -CH 2 -),1.33-1.28(m,44H),0.89(t,12H,CH 2 -CH 3 ,J). 13 C NMR(101MHz,MeOD)δ 169.56,160.38,154.04,141.70,139.20,130.67,129.73,129.22,12 9.00,115.98,107.49,75.94,72.93,71.83,71.64,71.56,71.51,71. 32,70.82,69.99,67.74,67.71,67.67,67.54,59.09,54.80,34.29.3 2.98,31.65,31.62,31.59,30.69,30.38,30.26,26.68,23.73,14.49. 31 P NMR(400MHz,Methano-d4):δ 27.16

[0142] 4.5.5-5-inch (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%).

[0143] 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.

[0144] 4.6. Step 6 - Preparation of Linker 3 (L3) JPEG2025512340000055.jpg731483.00 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 mixed with 1.69 mL (12.04 mmol-2 equiv.) of Et 3 N was added slowly and the mixture was stirred for 10 min, then 2.32 g (12.04 mmol-2 equiv.) of tosyl chloride was added slowly.

[0145] After overnight, TLC (EtP, AcOEt 7:3, KMnO 4 ) showed no traces 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), eluents: 15 min EtP / AcOEt (9:1), isocratic 10 min EtP / AcOEt (8:2) and 10 min EtP / AcOEt (7:3).

[0146] 3.52 g of linker 3 was recovered as a colorless oil (90%).

[0147] 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).

[0148] 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 K were added.2 CO 3 was added continuously. The resulting reaction mixture was heated to reflux overnight.

[0149] The reaction mixture was cooled to RT, the solvent was removed and the crude product was purified by CH 2 Cl 2 The solid was filtered off; the crude product was concentrated under reduced pressure. 2 Cl 2 Purification with 1,2-dichloromethane / MeOH 95 / 5-8 / 2-6 / 4) afforded 827 mg of pure compound (19) as a yellowish oil (65% yield).

[0150] 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.

[0151] 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%).

[0152] 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.

[0153] Example 5: Synthesis of dendritic molecules of formula (IE) according to the invention JPEG2025512340000057.jpg601345.1. Step 1 - Preparation of compound (20) JPEG2025512340000058.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.

[0154] 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.

[0155] (SiO 2 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

[0156] 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). 13 C 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.

[0157] 5.2. Step 2 - Preparation of Compound (21) JPEG2025512340000059.jpg651432.41 g (1.6 mmol-1.0 equiv.) of compound (20) in 40 mL of EtOAc was added with 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%).

[0158] 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.

[0159] 5.3. Step 3 - Preparation of Compound (22) JPEG2025512340000060.jpg621371.01 g (0.705 mmol-1.0 equivalent) of compound (21) in 25 mL of acetone was added to a solution of 0.440 g (0.775 mmol-1.1 equivalent) of linker 3 prepared in step 6 of Example 6, 48 mg (0.282 mmol-0.4 equivalent) of KI, and 313 mg (2.26 mmol-3.2 equivalent) of K. 2 CO 3 was added continuously. The resulting reaction mixture was heated to reflux overnight.

[0160] The reaction mixture was cooled to RT, the solvent was removed and the crude product was purified by CH 2 Cl 2 The solid was filtered off; the crude product was concentrated under reduced pressure. 2 Cl 2 / MeOH 95 / 5-8 / 2-6 / 4) gave 736 mg of compound (22) as a yellowish oil (59% yield).

[0161] analysis: 1H 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.

[0162] 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%).

[0163] 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).

[0164] Example 6: Synthesis of dendritic molecules of formula (IF) according to the invention JPEG2025512340000061.jpg621396.1. Step 1 - Preparation of compound (23) JPEG2025512340000062.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 a 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 CH 2 Cl 2 After dissolving in 0.1 mL (1.3 mmol-3.0 equiv.) of (COCl) 2 and 4 drops of DMF were added. The orange solution was stirred at RT for 5 h. After TLC showed complete consumption of compound (13), the catalyst was filtered through Celite and the crude product was concentrated under reduced pressure at RT. The acyl chloride was simultaneously concentrated under reduced pressure to give CH 2 Cl 2 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.

[0165] The reaction mixture was diluted with brine. The aqueous layer was 2 Cl 2 (5 times), and the combined organic layer was washed with Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated under reduced pressure. Flash chromatography (100% EtOAc, then CH 2 Cl 2Purification with 1,2-dichloromethane / 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.

[0166] 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.

[0167] 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%).

[0168] 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.

[0169] 6.3. Step 3 - Preparation of Compound (25) To a solution of 20 mg (0.209 mmol-1.0 equivalent) of compound (24) in 40 mL of acetone, 0.145 g (0.219 mmol-1.05 equivalent) of linker 3 prepared in step 6 of Example 4, 33 mg (0.02 mmol-0.1 equivalent) of KI and 45 mg (0.315 mmol-1.5 equivalent) of K were added. 2 CO 3 was added continuously. The resulting reaction mixture was heated to reflux overnight.

[0170] The reaction mixture was cooled to RT, the solvent was removed and the crude product was purified by CH 2 Cl 2 The crude product was concentrated under reduced pressure to give an orange oil. 2 Cl 2 Purification with 100% methanol / MeOH 95 / 5-8 / 2-6 / 4) afforded 321 mg of compound (25) as a yellowish oil (76% yield).

[0171] 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.

[0172] 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%).

[0173] 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). 13 C 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.

[0174] Example 7: Synthesis of dendritic molecules of formula (IP) according to the invention JPEG2025512340000065.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.

[0175] 1 H NMR (400 MHz, CDCl 3 ):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 (400 MHz, CDCl 3 ):δ 165.78,157.87,131.95,120.84,65.11,31.57,28.96,28.36,25.78,22.30,13.02.

[0176] 7.2. Step 2 - Preparation of Compound (27) To a solution of compound (26) (1 equiv., 0.49 mmol, 200 mg) in dry acetonitrile (ACN) (10 mL) kept under argon was added K 2 CO 3 (1.5 equiv, 0.74 mmol, 102 mg) and KI (0.5 equiv, 0.25 mmol, 41 mg) were added and the reaction mixture was stirred at room temperature for 15 min. Linker 2 (1.8 equiv, 0.88 mmol, 213.6 mg), prepared according to step 1.7 of Example 1, was then 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.

[0177] 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).

[0178] 7.3. Step 3 - Preparation of Compound (28) JPEG2025512340000068.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.

[0179] In parallel, EDC (1.2 equiv., 0.28 mmol, 54 mg) and DMAP (0.1 equiv., 0.024 mmol, 3 mg) were added successively 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 (SiO 2 , DCM / MeOH, 100:0 to 9:1) to give 131.4 mg (51% yield) of compound (28) in the form of a colorless oil.

[0180] 1 H NMR (400MHz, methanol-d 4 )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.

[0181] 7.4. Step 4 - Preparation of Linker 3' (L3') JPEG2025512340000069.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 and Na 2 S 2 O 3 Wash with 2M aqueous solution of Na 2 SO 4 The mixture was evaporated in vacuo, dried at 40° C., filtered and concentrated under reduced pressure to give compound (L3') (749.1 mg, 1.23 mmol, 82%) as a yellow liquid.

[0182] 1H NMR (400MHz, MeOD): 3.76-3.59 (m, 34H), 2.49 (t, J=6.0Hz, 2H), 1.46 (s, 9H).

[0183] 7.5. Step 5 - Preparation of Compound (IP) 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 K 2 CO 3 (1.50 equiv., 0.18 mmol, 25 mg), KI (0.10 equiv., 0.012 mmol, 2 mg) and the compound (L3') prepared above in step 7.4 (1.05 equiv., 0.13 mmol, 82 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 purified by HCl. 2 Cl 2 The mixture was suspended in 100 ml of ethyl acetate, filtered through Celite, concentrated under reduced pressure, and then purified by flash chromatography (SiO 2 , DCM / MeOH, 100:0 to 9:1) to give 120 mg of compound (IP) (68% yield) in the form of a light brown oil.

[0184] 1 H NMR (400MHz, methanol-d 4 )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.

[0185] 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 (IP) (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 , H 2 Purification by elution with 0 / acetonitrile + 0.1% TFA) afforded the final compound (IJ).

[0186] Example 9: Synthesis of dendritic molecules of formula (IQ) according to the invention JPEG2025512340000071.jpg721689.1. Step 1 - Preparation of compound (29) JPEG2025512340000072.jpg113122 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.

[0187] 9.2. Step 2 - Preparation of Compound (30) JPEG2025512340000073.jpg158126 Compound (29) (1 equiv., 5.5 mmol, 1.7 g), triethylamine (2.5 equiv., 13.75 mmol, 1.91 mL) and CH 2 OH-CH 2 -CF(CF 3 ) 2 A solution of (Sigma Aldrich, 2.5 equiv., 13.75 mmol, 2.01 mL) in DCM (50 mL) was stirred at RT for 12 h. Water was added and the separate oil was extracted with DCM. The organic layer was washed with dilute HCl solution and MgSO 4 The mixture was dried at rt. 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%).

[0188] 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.

[0189] 9.3.- Preparation of compound (31) JPEG2025512340000074.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.

[0190] 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 (126 MHz, CDCl 3 )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. 9.4.- Preparation of compound (32) JPEG2025512340000075.jpg138124

[0191] A solution of compound (31) (1 equiv., 1.39 mmol, 799 mg) in 21 mL of dry acetonitrile kept under argon was diluted with K 2 CO 3 (3 equiv., 4.17 mmol, 576.84 mg) and KI (0.6 equiv., 0.83 mmol, 138.58 mg) were added and the reaction mixture was stirred at RT for 15 min. Then, linker L2 (1.5 equiv., 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 (SiO 2 , EtP / EtOAc, 100:0 to 9:1) and the pure fractions were purified to give 335.3 mg (37% yield) of compound (32) as a white solid.

[0192] 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). 13C NMR (126 MHz, CDCl 3 )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, CDCl 3 )δ-83.16,-72.91,-53.16.

[0193] 9.5.- Preparation of compound (33) JPEG2025512340000076.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.

[0194] In parallel, EDC (1.2 equiv., 0.22 mmol, 42.26 mg) and DMAP (0.1 equiv., 0.018 mmol, 2.24 mg) were added successively 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 (SiO 2 , DCM / MeOH, 100:0 to 9:1) to give 107.2 mg (48% yield) of compound (33) in the form of a colorless oil.

[0195] 1 H NMR (400MHz, methanol-d 4)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, methanol-d 4 )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, methanol-d 4 )δ-54.55,-84.67,-86.99,-119.41.

[0196] 9.6. Preparation of Compound (IQ) 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 K 2 CO 3(1.50 equiv., 0.12 mmol, 16 mg), KI (0.10 equiv., 0.0077 mmol, 1.27 mg) and the compound (L3') prepared above in step 7.4 of Example 7 (1.05 equiv., 0.081 mmol, 53 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 purified by HCl. 2 Cl 2 The mixture was suspended in 100 ml of ethyl acetate, filtered through Celite, concentrated under reduced pressure, and then purified by flash chromatography (SiO 2 , DCM / MeOH, 100:0 to 9:1) to give 50 mg of compound (IQ) (43% yield) in the form of a light brown oil.

[0197] Example 10: Synthesis of dendritic molecules of formula (IL) according to the invention Trifluoroacetic acid (TFA) (1.00 equiv., 0.031 mmol, 2.37 μL) was added to a solution of compound (IQ) (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 , H 2 Purification by elution with 0 / acetonitrile + 0.1% TFA) gave the final compound (IL).

[0198] Example 11: Synthesis of dendritic molecules of formula (IR) according to the invention JPEG2025512340000078.jpg7216911.1. Step 1 - Preparation of compound (35) JPEG2025512340000079.jpg142126 Compound (29) as obtained above in step 9.1 of Example 9 (1 eq., 3.59 mmol, 1.11 g), triethylamine (2.5 eq., 8.98 mmol, 1.26 mL) and CH 2 OH-(CH 2 ) 5 -CF 2 CF 3A solution of (Sigma Aldrich, 2.5 equiv., 8.98 mmol, 1.24 mL) in DCM (33 mL) was stirred at RT for 12 h. Water was added and the separate oil was extracted with DCM. The organic layer was washed with dilute HCl solution and MgSO 4 The mixture was dried at rt. 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).

[0199] In this way, 980.1 mg of compound (35) was obtained in the form of a colourless oil (yield 40%).

[0200] 1 H NMR (400MHz, methanol-d 4 )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.

[0201] 11.2.- Preparation of compound (36) JPEG2025512340000080.jpg95124A catalytic amount of Pd / C 10% (0.5 eq., 0.72 mmol, 77 mg) was added to a solution of compound (35) obtained above in step 9.1 (1 eq., 1.45 mmol, 980 mg) 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.

[0202] 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 (126 MHz, CDCl 3 )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.

[0203] 19 F NMR(376MHz,MeOD)δ-118.25,-85.48

[0204] 11.3.- Preparation of compound (37) To a solution of compound (36) (1 equiv, 1.35 mmol, 789.9 mg) in 16 mL of dry acetonitrile kept under argon was added K 2 CO 3 (3 equiv., 4.04 mmol, 558.41 mg) and KI (0.6 equiv., 0.81 mmol, 134.15 mg) were added and the reaction mixture was stirred at RT for 15 min. Then, linker L2 (1.5 equiv., 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 pad of Celite, washed with DCM and concentrated. The crude product was purified by flash chromatography (SiO 2 , EtP / EtOAc, 100:0 to 9:1) and the pure fractions were purified to give 449.4 mg (51% yield) of compound (37) as a colorless oil.

[0205] 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 (126 MHz, CDCl 3 )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, CDCl 3 )δ-118.26,-118.22,-118.18,-85.44.

[0206] 11.4.- Preparation of compound (38) JPEG2025512340000082.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.

[0207] In parallel, EDC (1.2 equiv., 0.25 mmol, 48 mg) and DMAP (0.1 equiv., 0.021 mmol, 2.54 mg) were added successively 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 at RT overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO 2 , DCM / MeOH, 100:0 to 9:1) to give 142.4 mg (54% yield) of compound (38) in the form of a colorless oil.

[0208] 1 H NMR (500MHz, methanol-d 4)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.

[0209] 11.5. Modulation of compounds (IR) 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 K 2 CO 3 (1.50 equiv., 0.16 mmol, 23 mg), KI (0.10 equiv., 0.011 mmol) and the 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 purified by HCl. 2 Cl 2 The mixture was suspended in 100 ml of ethyl acetate, filtered through Celite, concentrated under reduced pressure, and then purified by flash chromatography (SiO 2 , DCM / MeOH, 100:0 to 9:1) to give 105.9 mg of compound (IR) (59% yield) in the form of a brown oil.

[0210] 1 H NMR (500MHz, methanol-d 4 )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.

[0211] 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 (IR) (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 , H 2 Purification by elution with 0 / acetonitrile + 0.1% TFA) afforded the final compound (IK).

Claims

1. The following equation (I): (In the formula: -R １ teeth, * An alkyl radical having at least two carbon atoms, or an alkyl radical 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 at least four carbon atoms, and the asterisk represents a bond 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 A dendritic molecule (where q = 2, if represents a phosphonate group PG).

2. q = 2, and R １ represents a phosphonate group of formula (PG) (each of R ５ represents an alkyl group having 4 to 12 carbon atoms), the dendrimer according to claim 1.

3. R ５ The dendritic molecule according to claim 2, wherein each of represents an alkyl group selected from octyl, decanyl, and dodecanyl.

4. A dendritic molecule according to any one of claims 1 to 3, wherein n is an integer in the range of 4 to 6.

5. A dendritic molecule according to any one of claims 1 to 3, wherein p is an integer in the range of 4 to 10.

6. R ２ A dendritic molecule according to any one of claims 1 to 3, wherein each of the members represents a methyloxy group.

7. R ３ The dendritic molecule according to any one of claims 1 to 3, wherein the group represents a methyloxy group, a carboxyl group, or the group -COOtBu (where tBu means ter-butyl).

8. The aforementioned dendritic molecule, R １ ~R ５ The meanings of m, n, p, and q are shown in Table 1 below: A dendritic molecule according to any one of claims 1 to 3, selected from the compounds of formulas (I-A) to (I-R) shown.

9. R １ is the phosphonate group of formula (PG), where q=2, n=p, and R ２ and R ３ A process for preparing a dendritic molecule of formula (I) according to claim 1, wherein the following formula (II): (In the formula, R ５ And a compound of formula (I) and the following formula (III): (In the formula, n = p, and has the same definition as formula (I), and further R ２ and R ３ A process comprising at least one step of reacting a compound of the same type (which represents an alkyloxy group as defined by formula (I)) with a compound of the same type (which represents an alkyloxy group as defined by formula (I)) to obtain the corresponding compound of formula (I).

10. The compound of formula (III) is produced by at least the following steps: -Formula R ６ - (OCH ２ CH ２ ) ｎ OH(IV) (wherein R ６ The following formula (VI) is obtained by reacting an alcohol of a linear alkyloxy radical having 1 to 20 carbon atoms with tosyl chloride: (In the formula, R ６ The process of obtaining a compound of formula (IV), which has the same meaning as formula (IV); - The compound of formula (VI) above is reacted with methyl gallate to obtain the following compound (VIII): (In the formula, n, p, R ２ and R ３ The process of obtaining a compound of formula (III), where (III) has the same meaning as formula (III); - A step of deprotecting the carboxyl functional group of the compound of formula (VIII) obtained in this manner to obtain the corresponding compound of formula (III). The process according to claim 9, which is prepared according to a process including a process.

11. The compound of formula (II) is produced by at least the following steps: -Formula R ５ -OH(IX) (wherein R ５ The alcohol (which has the same meaning as formula (I)) is reacted with trimethyl phosphite to produce the following formula (XI): (In the formula, R ５ The process of obtaining a compound of formula (I) (where (I) has the same meaning); -The compound of formula XI obtained in this manner is reacted with 3,5-bis(bromomethyl)phenol to obtain the following compound (XIII): (In the formula, R ５ The process of obtaining a compound of formula (I) (where (I) has the same meaning); - The compound of formula (XIII) obtained in this manner, and the compound of formula (XIV) below: A step of reacting a compound of formula (I) with a compound of formula (II) to obtain the corresponding compound of formula (II). The process according to claim 9, which is prepared according to a process including a process.

12. As described in claim 1, R １ is a phosphonate group (PG), q=2, n and p are the same or different, R ２ is an alkyloxy group defined by formula (I), and R ３ A process for preparing a dendritic molecule of formula (I) in which is a carboxyl group or the group -COOtBu, comprising at least the following steps: - The step of reacting methyl gallate with benzyl bromide to obtain a compound of the following formula (XV): -Formula R ２ - (CH ２ CH ２ ) ｎ OH(IV') (wherein R ２ The alcohol and n (where n has the same meaning as formula (I) described in claim 1) and tosyl chloride are reacted independently to obtain the following formula (VI'): (In the formula, R ２ A step of obtaining a compound of formula (I) as described in claim 1; - The compound of formula (XV) is reacted with the compound of formula (VI') obtained in this manner to produce the following formula (XVI): (In the formula, R ２ A step of obtaining a compound of formula (I) as described in claim 1; - By deprotecting the carboxylic acid functional group of the compound of formula (XVI) obtained in this manner, the following formula (XVII) is obtained: (In the formula, R ２ A step of obtaining a compound of formula (I) as described in claim 1; - The compound of formula (XVII) obtained in this manner is reacted with the compound of formula (II) described in claim 10 to obtain the following compound (XVIII): (In the formula, R ５ , R ２ A step of obtaining a compound of formula (I) described in claim 1, where m and n have the same meanings as those described in claim 1; - The benzyl group of the compound of formula (XVIII) obtained in this manner is hydrolyzed to obtain the following formula (XIX): (In the formula, R ５ , R ２ A step of obtaining a compound of formula (I) described in claim 1, where m and n have the same meanings as those described in claim 1; - The compound of formula (XIX) obtained in this manner, and the following formula (XX): By reacting with a compound of the following formula (XXI): (wherein p has the same meaning as formula (I) described in claim 1, and has the same or different value as the value of n in the compound of formula (XIX) defined above) the following formula (XXI): (In the formula, R ５ , 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 as or different from the value of n in the compound of formula (XIX) defined above, R ３ A step of obtaining a compound having a value corresponding to a specific compound of formula (I) in which the group is -COOtBu; and optionally; - The carboxylic acid functional group of the compound of formula (XXI) obtained in this manner is deprotected, R ３ A step to obtain the corresponding dendritic molecule of formula (I) in which the group is -COOH. A process that includes this.

13. The compound of formula (XX) is tosyl chloride and formula (XXII): OHCH ２ HH ２ -(OCH ２ HH ２ ) ｐ－１ -C(O)O-t-ブテル(XXXII) The process according to claim 12, which is prepared by a process comprising the step of reacting with a compound of formula (I) (wherein p has the same meaning as formula (I) described in claim 1).

14. Use of a dendritic molecule of formula (I) as described in any one of claims 1 to 3 as a drug carrier.

15. A dendritic molecule of formula (I) according to any one of claims 1 to 3, in combination with at least one imaging agent, for use as a contrast agent for a medical imaging or diagnostic platform.

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