CONJUGATES AND PRODRUGS FOR USE IN THE TREATMENT OF CANCER AND INFLAMMATORY DISEASES

Abstract

The present invention relates to the field of cancer and inflammatory diseases. More particularly, it aims to provide for these purposes new conjugated forms of active ingredients belonging to the dolastatin family and of the following formula: It also aims to provide prodrug forms of these conjugates.

Description

FIELD OF INVENTION

[0001] The present invention relates to the field of cancer and inflammatory diseases. More particularly, the present invention aims to provide new conjugated forms of active ingredients belonging to the dolastatin family. TECHNOLOGICAL BACKGROUND

[0002] Cancer and inflammatory diseases are among the most common pathologies today. In particular, cancer is now one of the leading causes of death in France and most industrialized countries. Among the various treatment options, chemotherapy is the only one effective against circulating tumors, such as lymphomas and leukemias, and metastases.

[0003] Among the potential agents for chemotherapy are certain natural peptide compounds, such as dolastatin 10, a linear natural compound derived from marine sources, composed of four amino acids, three of which are specific to it. Synthetic derivatives of dolastatin 10 are also available and preferred today. These include, in particular, auristatin PE, auristatin E, and monomethyl auristatin E (MMAE). Dolastatin, auristatin E, and their derivatives have the property of inhibiting tubulin polymerization and thus preventing cell division (antimitotic).

[0004] However, these dolastatin-based drugs, like other clinically used anticancer agents, unfortunately lack satisfactory selectivity for tumor cells. In fact, they also target healthy tissues. This non-selective destruction leads to severe side effects and, in most cases, results in premature discontinuation of treatment.

[0005] The development of new anticancer agents capable of selectively destroying tumors without affecting healthy organs is therefore of major interest in the fight against cancer.

[0006] One approach to overcome this lack of selectivity relies on the development of conjugates of these active ingredients. These conjugates, also called prodrugs, are most often obtained by grafting the active ingredient with an entity whose functions are to inactivate it in its prodrug form, to transport it to the target tissues or cells, to promote its release there, and thus restore its curative biological activity. This approach is based more specifically on the observation of characteristics unique to tumor tissues. For example, it is known that the tumor microenvironment differs from healthy tissues by a more acidic pH, a higher reducing potential, increased permeability to macromolecules, and the presence of a relatively high concentration of certain enzymes, such as β-glucuronidase.Similarly, it has been shown that diseased tissues are distinguished from healthy tissues by the fact that malignant cells overexpress on their surface membrane receptors or antigens that differentiate them from healthy cells, such as folic acid receptors or the CD33 antigen.

[0007] Consequently, derivatives of conventional assets have already been developed to take advantage of these differences in order to increase, in particular, their selectivity for tumor cells.

[0008] Thus, monomethyl auristatin E (MMAE) was conjugated to an anti-CD30 antibody via a cleavable arm (US 7,829,531). However, such a conjugate exhibits excessive specificity for its target and proves to be ineffective, if at all, against non-CD30-dependent cancers and / or inflammatory diseases.

[0009] Teming et al. (2006, Bioconjugate Chem) conjugated a molecule of monomethyl auristatin E (MMAE) to an albumin motif, via a cleavable linker, in order to target tumor tissues.

[0010] More recently, Legigan et al. (2013, Eur. J. Med. Chem.) and Tranoy-Opalinski et al. (2014, Eur. J. Med. Chem.) conjugated a molecule of monomethyl auristatin E (MMAE) to a glucuronyl motif via a self-reactive arm. This conjugated form of MMAE, also known as the prodrug, is inactive, and only cleavage within the tumor by β-glucuronidases, primarily extracellular, allows MMAE to exert its antimitotic biological activity. However, rapid elimination of this prodrug by the kidneys is observed. Since the half-life of this prodrug is significantly reduced, it is necessary to increase the dosage, which is associated with deleterious side effects.

[0011] Legigan et al. (2012, Angew. Chem. Int. Ed.) also proposed a monomethyl auristatin E (MMAE) bi-functionalized with a galactoside group and a folic acid receptor-binding group, both groups being carried by a self-reactive arm. However, this prodrug requires a cellular internalization step before being cleaved by an intracellular β-galactosidase and releasing monomethyl auristatin E (MMAE).

[0012] Consequently, although these pro-drug forms of monomethyl auristatin E are specifically delivered to the tumor site, their cytotoxic efficacy remains relative, and does not allow for the consideration of an effective clinical treatment of a tumor.

[0013] Therefore, there remains a need for pro-drugs from the dolastatin family, capable of delivering this type of active ingredient with very high specificity and, in inactive form, to diseased tissues or cells.

[0014] There is also a need for pro-drugs from the dolastatin family whose cytotoxicity is effectively expressed in a specific manner at the level of the tumor microenvironment.

[0015] There is still a need for pro-drugs of the dolastatin family whose tumor efficacy does not require excessive amounts of active ingredient, in order to prevent the occurrence of deleterious side effects, particularly on healthy cells, tissues or organs. SUMMARY OF THE INVENTION

[0016] The present invention is specifically designed to satisfy these needs.

[0017] According to a first aspect, the present invention relates to a conjugate of general formula (I): in which: A represents a radical from the dolastatin family or one of its derivatives, L represents a radical capable of reacting with an amino, hydroxy or thiol function, and preferably a thiol function, G comprises and preferably represents a glucuronyl radical or one of its derivatives, Y represents H, or an electron-withdrawing radical, in particular chosen from NO2, CF3 and a halogen, R1< and R2< represent, independently of each other, H or an alkyl radical in C1 to C10, linear or branched, saturated or unsaturated, Z represents a hydrocarbon spacer radical comprising at each of its ends covalent bonding functions, X represents -O- or -NR3<COO-, with R3< being able to represent a hydrogen atom or an alkyl radical in C1 to C10, linear or branched, saturated or unsaturated, the bond with the radical G being ensured by the oxygen atom (-O), one of its isomers and / or one of its pharmaceutically acceptable salts.

[0018] Unexpectedly, the inventors observed that a conjugate of general formula (I) and derived from monomethyl auristatin E possesses therapeutic efficacy in vivo significantly improved compared to non-functionalized monomethyl auristotin E.

[0019] Consequently, a conjugate according to the invention proves to be particularly interesting for the clinical treatment of cancers, with regard to its selectivity and therapeutic dosage.

[0020] According to a second aspect, the present invention relates to a pro-drug comprising at least one molecule of a conjugate of general formula (I) according to the invention, said molecule of said conjugate being linked by a covalent bond to a molecule of albumin, in particular endogenous, or one of its derivatives.

[0021] As detailed below, the chemical structure of a conjugate according to the invention is particularly conducive to its interaction with an albumin molecule, especially an endogenous one, and more particularly a serum albumin molecule. More specifically, this interaction is notably established in vivo This is achieved by favoring a radical L type with an affinity for the sulfur atom of cysteine ​​at position 34 of endogenous albumin. This interaction with the sulfur atom of cysteine ​​can notably occur through a Michael reaction. Establishing a covalent bond between a conjugate molecule and an albumin molecule via a Michael reaction thus makes it possible to exploit the phenomenon of albumin accumulation in the tumor microenvironment and to achieve improved targeting of a conjugate according to the invention.

[0022] According to another aspect, the present invention also relates to a pharmaceutical composition comprising at least an effective amount of at least one conjugate of general formula (I) according to the invention, or a coupled form of said conjugate with at least one molecule of albumin and preferably a prodrug of general formula (VI), as defined according to the invention.

[0023] According to another aspect, the present invention relates to a conjugate of general formula (I), according to the invention, for its use in the prevention and / or treatment of cancer and / or inflammatory disease.

[0024] According to another aspect, the present invention relates to a coupled form of said conjugate with at least one molecule of albumin, and in particular a pro-drug of general formula (VI) according to the invention, for its use in the prevention and / or treatment of cancer and / or inflammatory disease.

[0025] According to another aspect, the present invention relates to a composition, according to the invention, for its use in the prevention and / or treatment of cancer and / or inflammatory disease.

[0026] According to another aspect, the invention relates to a method of treating cancer and / or an inflammatory disease comprising the administration of a conjugate of general formula (I) according to the present invention.

[0027] According to another aspect, the present invention also relates to a method of treating cancer and / or inflammatory disease comprising administering a coupled form of said conjugate with at least one molecule of albumin and in particular a pro-drug of general formula (VI) according to the present invention.

[0028] Finally, according to a last aspect, the present invention also relates to a method of treating cancer and / or inflammatory disease comprising the administration of a pharmaceutical composition according to the present invention. FIGURE CAPTIONS

[0029] There Figure 1 illustrates a reaction scheme for the synthesis of a conjugate of formula (III). Figure 2 This illustrates the volume evolution of a Mia Paca-type human pancreatic tumor grafted orthotopically into mice. Two injections of non-functionalized MMAE (0.3 mg / kg) or a formula (III) conjugate, i.e., bifunctionalized MMAE (2 or 4 mg / kg), are administered on days 7 and 14 post-graft. Tumor volume is assessed by ultrasound for 70 days post-graft. An inset represents this evolution on a 30-day post-graft timescale. Figure 3illustrates the evolution of the volume of a MIA-PaCa type pancreatic tumor grafted orthotopically and monitored by ultrasound (5 animals per group). The formula conjugate (III), at a dose of 4 mg / kg, ( A ) and the excipient ( B ) were administered intravenously once a week for 9 weeks. The Figure 4 illustrates the evolution of the volume of a human MDA-MB-231 breast tumor grafted orthotopically and monitored by ultrasound (6 animals per group). Animals treated with MMAE ( B ) received a dose of 0.5 mg / kg (intravenous) once a week for 5 weeks. Animals treated with the bifunctionalized MMAE conjugate (formula (III) conjugate ( C )) received a dose of 4 mg / kg (intravenous) once a week for 5 weeks. Control animals were treated with the excipient (vehicle ( A )). DETAILED DESCRIPTION OF THE INVENTION • Conjugated

[0030] As stated above, a conjugate according to the invention corresponds to the general formula (I): in which: A represents a radical from the dolastatin family or one of its derivatives, L represents a radical capable of reacting with an amino, hydroxy or thiol function, and preferably a thiol function, G comprises and preferably represents a glucuronyl radical or one of its derivatives, Y represents H, or an electron-withdrawing radical, in particular chosen from NO2, CF3 and a halogen, R1< and R2< represent, independently of each other, H or an alkyl radical in C1 to C10, linear or branched, saturated or unsaturated, Z represents a hydrocarbon spacer radical comprising at each of its ends covalent bonding functions, X represents -O- or -NR3<COO-, with R3< being able to represent a hydrogen atom or an alkyl radical in C1 to C10, linear or branched, saturated or unsaturated, the bond with the radical G being ensured by the oxygen atom (-O), one of its isomers and / or one of its pharmaceutically acceptable salts.

[0031] Within the framework of the present invention, a " derivative "of the dolastatin family, refers to a structurally very similar compound with equivalent biological properties, notably the ability to inhibit tubulin polymerization, in order to inhibit, In short, Cellular mitosis. This can include substitution or deletion derivatives.

[0032] Within the framework of the present invention, a " radical capable of reacting with an amino, hydroxy or thiol function"Refers to a radical, generally hydrocarbon, possessing a chemical function, or motif, capable of interacting with a free amino, hydroxy, or thiol group and thus establishing a covalent bond between a conjugate molecule and a distinct chemical entity bearing this compatible function. In the context of the present invention, this distinct chemical entity is more particularly a macromolecule naturally present in a living organism and advantageously an endogenous albumin molecule, such as human serum albumin."

[0033] Within the framework of the present invention, a " radical electroattractor " refers to the property of an atom or group of atoms to attract electrons.

[0034] Within the framework of the present invention, a " isomer" refers to a molecule in which the position of at least two chemical groups on an asymmetric carbon is reversed compared to the reference molecule. In particular, a radical in the dolastatin family has many asymmetric carbons. Furthermore, the term " isomer » refers exclusively to a molecule capable of performing one or more biological activity(ies) identical or similar to that of the reference molecule.

[0035] It is understood that the invention extends to both isolated enantiomers and the corresponding racemic mixture.

[0036] Within the scope of the present invention, a "pharmaceutically acceptable salt" "may be a salt of a conjugate, or of a prodrug according to the invention, and of an alkali metal, of an alkaline earth metal, or of ammonium, including salts obtained with organic ammonium bases, or salts of a conjugate, or of a prodrug according to the invention, and of organic or inorganic acid.

[0037] Salts more particularly suitable for the invention may be sodium, potassium, calcium, magnesium salts, quaternary ammonium salts such as tetramethylammonium or tetraethylammonium, and addition salts with ammonia and pharmaceutically acceptable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris-(2-hydroxyethyl)-amine.

[0038] Salts of a conjugate, or of a prodrug according to the invention, and of an inorganic acid suitable for the invention can be obtained with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid.

[0039] Salts of a conjugate, or of a prodrug according to the invention, and of an organic acid suitable for the invention can be obtained with carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. • Radical of the dolastatin family and their derivatives (radical A)

[0040] The dolastatin family represents a class of compounds with a structure of at least 4 amino acids, of which at least 3 are specific to it, that is to say, different from the 20 most commonly found amino acids in nature.

[0041] Reference may be made in particular to document WO 2004 / 010957, the contents of which are incorporated by reference, which describes compounds conforming to those suitable for the present invention.

[0042] In a particularly preferred embodiment of the invention, A represents a radical derived from dolastatin 10, auristatin PE, auristatin E, monomethyl auristatin E and their derivatives, preferably a radical derived from monomethyl auristatin E or one of its derivatives.

[0043] The structural difference between dolastatin 10 and synthetic compounds of the auristatin subfamily lies in the substitution of the amino thiazolephenethyl group in the C-terminal position of dolastatin 10, by a norephedrine unit in the case of auristatin PE, auristatin E or monomethyl auristatin.

[0044] In the context of the present invention, and in a particularly preferred embodiment, the radical from the dolastatin family is advantageously chosen from monomethyl auristatin E (MMAE) and one of its derivatives.

[0045] According to the invention, a derivative of dolastatin 10, auristatin PE, auristatin E or monomethyl auristatin E has a chemical structure very similar to at least one of its active ingredients and possesses antimitotic properties attributed to compounds of the dolastatin family.

[0046] Its structural difference(s) may include, for example, a substitution on at least one side chain of at least one of the four amino acids that compose it. This substitution may be made in such a way as to contain or represent an alkyl group, linear, cyclic and / or branched, an aryl group, a heterocycle, or a carbocycle.

[0047] This structural difference may also consist of a modification of a molecule of dolostatin 10, auristatin PE or auristatin E, for example at the level of its tertiary amine in the N-terminal position, to make this function compatible with the establishment of a covalent bond with the binding arm in question.

[0048] It is within the general knowledge of a person skilled in the art to select the most suitable modifications for these purposes. • Radical L

[0049] As can be seen from the above, the conjugates according to the invention have the originality of being doubly functionalized and in particular of being functionalized by a radical capable of giving them an ability to interact with a macromolecule, particularly an endogenous macromolecule, and more particularly, a serum albumin molecule.

[0050] Insofar as biological macromolecules, and in particular endogenous albumin, are now known to accumulate through the " EPR » ( Enhanced Permeability and Retention "") in the microenvironment of solid tumors, the coupling in situ of a conjugate according to the invention with an endogenous albumin molecule makes it possible to target the coupled entity thus formed, also called the prodrug, in the tumor microenvironment and thus overcome the lack of selectivity of the free forms of dolastatin derivatives. It should be noted that such an effect " EPR " applies to the microenvironment of inflamed tissues.

[0051] It is also worth noting that this principle of targeting diseased tissues and / or cells via a macromolecule has already been proposed for doxorubicin (Legigan et al. 2012, J. Med. Chem). However, while this prodrug has an improved half-life compared to a prodrug functionalized with a single glucuronyl group, it does not offer any gain in efficacy compared to non-functionalized doxorubicin, which has the disadvantage of being very ineffective and therefore requiring high doses, which are not easily tolerated by patients.

[0052] As will be detailed below (example 2 and Figure 2 ), a conjugate according to the invention and administered parenterally, is shown to have significantly improved efficacy compared to that of a compound from the dolastatin family taken in an isolated state, i.e. non-functionalized.

[0053] In the case where the intended prodrug is intended to be generated in vivo , that is to say by establishing a covalent bond between a conjugate of general formula (I) and a macromolecule such as albumin, it is particularly advantageous to favour, at the level of the conjugate, a radical L comprising a motif capable of interacting with a free thiol function, in order to favour the affinity of the conjugate for serum albumin.

[0054] Such a pattern allows us to establish in vivo a covalent bond with a free thiol (-SH) function of serum albumin, notably by interaction with the free thiol (-SH) function of cysteine ​​at position 34. This covalent bond, i.e. a thioether bond, is advantageously made by a Michael reaction.

[0055] Thus, in a particularly preferred embodiment, the invention relates to a conjugate, in which L represents a maleimidocaproyl type motif.

[0056] However, if the prodrug is to be synthesized prior to administration, the conjugate of formula (I) may contain a radical L comprising a motif capable of reacting with an amino (-NH2), hydroxyl (-OH), or thiol (-SH) group. These reactive groups allow for covalent bonding between, on the one hand, the conjugate of formula (I), via the radical L, and, on the other hand, a macromolecule or a fragment of a macromolecule.

[0057] The choice of the motif carried by the radical L and capable of reacting with an amino (-NH2), hydroxy (-OH) or thiol (-SH) function is made with regard to the nature of the function present on the macromolecule to be coupled and clearly falls within the competence of the person skilled in the art. • Glucuronyl radical and its derivatives (G radical)

[0058] In the context of the present invention, the glucuronyl radical (radical G) is intended to be eliminated enzymatically, thereby ensuring an intramolecular rearrangement of the binding arm associating it with the molecule of the dolastatin family and consequently leading to a release of this active molecule (radical A).

[0059] Furthermore, a glucuronyl radical according to the invention, which is enzymatically hydrolyzable, can confer tissue and / or cell specificity to the conjugates and pro-drugs according to the present invention.

[0060] It is known that β-glucuronidase is an enzyme naturally present in high concentrations in the vicinity of many tumors. The conjugates and prodrugs of the invention comprising a glucuronyl group can therefore be advantageously activated at the extracellular level during prodrug monotherapy (PMT). Within the scope of the invention, by " activation"Reference is made to the release at the tumor site, for example, of the radical of the dolastatin family, which are thus able to exert their antimitotic biological activity.

[0061] Furthermore, β-glucuronidase is a lysosomal enzyme present in most malignant cells. Therefore, the activation of a glucuronidated prodrug by β-glucuronidase can potentially occur within the intracellular environment after internalization by endocytosis.

[0062] According to one embodiment, an enzymatically hydrolyzable glucuronyl radical suitable for the invention may in particular be a polysaccharide comprising 2 to 20, in particular 3 to 10, and more particularly 4 to 6 glucuronyl units or its derivatives.

[0063] Within the framework of the present invention, a " derivativeThe term "glucuronyl radical" refers to a structurally very similar compound with equivalent biological properties, notably the ability to serve as the enzymatic substrate for a β-glucuronidase. These may include derivatives resulting from the substitution or deletion of one or more hydroxyl (-OH) or carboxyl (-COOH) groups.

[0064] This glucuronyl radical can advantageously interact with the bonding arm considered according to the invention via one of its hydroxyl functions and the covalent bond represented by X is then an oxygen atom.

[0065] As mentioned previously, -XG can also be represented by a carbamoyl-glucuronide derivative. • Bonding arm between radicals A, L and G

[0066] As stated previously, the conjugates according to the invention have a dedicated linking arm, on the one hand, to bring together, in the form of a single molecule, the different functionalities represented by the radicals A, L and G, and on the other hand, to allow the release of the active molecule (radical A) in response to the enzymatic hydrolysis of the glucuronyl (radical G).

[0067] Moreover, this connecting arm is such that it: does not alter the anti-cancer and / or anti-inflammatory properties carried by the dolastatin family compound (radical A), does not compromise the labile properties of the glucuronyl radical (radical G), intended to be cleaved by a β-glucuronidase in the microenvironment of the tissue to be treated, thereby allowing the rearrangement of the conjugated molecule and the release of the radical A carrying the active principle, allows the interactions between a molecule of a conjugate of general formula (I) and a macromolecule, in other words, maintains the accessibility of the function capable of reacting with the amino, hydroxy or thiol function of endogenous albumin, and does not affect the half-life of the conjugate in the organism in which it is likely to be administered.

[0068] A connecting arm particularly suited to the implementation of the present invention is described in particular in document WO 2011 / 145068, which is also incorporated by reference.

[0069] This connecting arm conforms in particular to the following formula (II):

[0070] The groups R1<, R2< and Y are as defined above.

[0071] Z 1< represents an L-click link function, as detailed below and part of the spacer radical Z of the conjugate of formula (I).

[0072] In a particularly preferred embodiment of the invention, Y represents NO 2 in ortho position to X, and R 1< and R 2< represent H. • Radical spacer Z

[0073] As stated above, the connecting arm is linked via the function Z 1< to the rest of the radical Z of the conjugate of formula (I) described in the present invention.

[0074] Thus, Z is represented by the sequence -Z 1< -Z 2< -(Z 3< ) m -, for which: m represents 0 or 1, Z1< represents an L-click bonding function between the carbon bearing the R1< and R2< functions, and the Z2< function, Z2< represents a linear or branched, saturated or unsaturated, C1-C10 alkylene group, optionally interrupted by one or more heteroatoms chosen from O or N, a glycosyl radical, an O-(CHR4<-CHR5<-O-)p or N-(CHR4<-CHR5<-O-)p radical in which p is a natural number ranging from 1 to 20, and R4< and R5< represent, independently of each other, H or CH3, provided that R4< and R5< do not simultaneously represent CH3, a group from an amino acid or peptide, or a combination of these groups, one end of Z2< forming a covalent bond with L, i.e. directly via an ether function, or indirectly via a Z 3< function, Z 3< , if present, represents an ester, amide, ether, carbamate or carbonate type function between Z 2< and the L radical.

[0075] Within the framework of the invention, a " L-click binding function " refers to the product of the reaction of two functional groups adapted to click chemistry. Click chemistry encompasses a set of reaction processes well known to those skilled in the art and allows for the simple and rapid formation of covalent bonds between two reactive or functionalized groups. In this regard, reference can be made in particular to the review by Kolb et al. (2004, Angew. Chem. Int. Ed.)."

[0076] It is within the competence of a person skilled in the art to choose a Z 1< function suitable for establishing a covalent bond with the reactive function activable by click chemistry.

[0077] According to a preferred embodiment, Z 1< can be the result of the reaction of 2 chemistry-activatable reactive functions chosen from -C≡CR 6< , -N 3 , -SH, -C=CH2, cyclooctynes, maleimide, -SO 2 N 3 , or -COSR 6< , with R 6< representing H or an alkyl radical, linear or branched, saturated or unsaturated, in C 1 to C 10 .

[0078] According to another preferred embodiment, Z 1< can be the result of the reaction of 2 chemistry-activatable reactive functions chosen from -C≡CH, -N 3 , -SH, -C=CH 2 , cyclooctynes, maleimide, -SO 2 N 3 , or -COSR 6< , with R 6< as described above.

[0079] According to a more particularly preferred embodiment, Z 1< can be the result of the reaction between a reactive function -C≡CH and a reactive function -N 3 .

[0080] In a particularly preferred embodiment of the invention, Z 2< represents a radical O-(CHR 4< -CHR 5< -O-) p , in which p represents a natural number ranging from 1 to 20, and R 4< and R 5< represent, independently of each other, H or CH3, provided that R 4< and R 5< do not simultaneously represent CH3, a group from an amino acid or a peptide, or a combination of these groups.

[0081] In another preferred embodiment of the invention, Z 2< represents a radical O-(CH 2 -CH 2 -O-) p , in which p is a natural number ranging from 1 to 20.

[0082] In another particularly preferred embodiment of the invention, Z 2< represents a radical O-(CH 2 -CH 2 -O-) 10 .

[0083] Thus, in a particular embodiment, the present invention relates to a conjugate of the following formula (III): one of its isomers and / or one of its pharmaceutically acceptable salts. • Synthesis of conjugates conforming to the present invention

[0084] A conjugate of general formula (I), according to the present invention, can be synthesized from a precursor molecule of the linker arm of formula (II), as represented by the following general formula (IV): in which: X' can represent -OH or -NR 3< COOH, with R 3< being able to represent a hydrogen atom or an alkyl radical in C 1 to C 10, linear or branched, saturated or unsaturated, Y can represent H, or an electron-withdrawing group, in particular chosen from NO 2 , CF3 and a halogen, R 1< and R 2< can represent, independently of each other, H or an alkyl radical in C 1 to C 10, linear or branched, saturated or unsaturated, F represents a reactive function activable by click chemistry.

[0085] This type of compound is described in particular in publication WO 2011 / 145068, which is also incorporated by reference.

[0086] The integration of the different groups or radicals present falls within the general skills of a person skilled in the art.

[0087] In a particularly preferred embodiment, this compound is the compound with the following formula (V):

[0088] It is understood that a person skilled in the art, by virtue of this general knowledge, can determine the order of reactions to be implemented in order to form, from such a compound, a conjugate of general formula (I).

[0089] The reactions that successively establish a covalent bond between a compound of formula (IV) or (V) and i) a glucuronyl radical (radical G), ii) a radical from the dolastatin family (radical A), iii) a hydrocarbon spacer radical (Z) are well known to those skilled in the art and do not present any particular difficulties in execution. Moreover, such reactions are described, for example, in the documents Legigan et al. (2013, Eur. J. Med. Chem.) and Legigan et al. (2012, J. Med. Chem.). If necessary, protective reactions with respect to alcohol (-OH), amine (-NH2), or other functional groups may be considered prior to the coupling reactions.

[0090] The reaction enabling the establishment of a covalent bond between a hydrocarbon spacer radical (Z radical) and a radical capable of reacting with a thiol function (L radical) is notably described in the document Legigan et al. (2012, J. Med. Chem).

[0091] The conditions suitable for carrying out these reactions, the methods of purification, the methods of evaluating the purity of the synthesized compounds are part of the general knowledge of a person skilled in the art. • Pro-drugs

[0092] According to another aspect, the invention relates to a pro-drug comprising at least one molecule of conjugate according to the invention, linked by a covalent bond to at least one molecule of albumin or one of its derivatives.

[0093] In the sense of the invention, " pro-drug » refers to a molecule capable of transporting a compound from the dolastatin family in an inactivated form within an organism, and releasing it into a specifically targeted organ, tissue or cells, under the action of a β-glucuronidase.

[0094] More specifically, such a prodrug advantageously meets the following general formula (VI): for which the radicals A, G, X, Y, Z, R 1< and R 2< are such as defined above.

[0095] The motif L', for its part, derives from the reaction between on the one hand a radical L comprising a motif capable of reacting with a free amino, hydroxy or thiol function and in particular with a free thiol function carried by a macromolecule, advantageously an albumin molecule, even more advantageously serum albumin.

[0096] Within the framework of the present invention, the prodrug can be formed in vivo Or in vitro with a macromolecule, preferably with an albumin molecule.

[0097] Thus, an endogenous or exogenous albumin can be considered, and in particular a human serum albumin, a recombinant albumin or even a fragment of an albumin.

[0098] In a first preferred embodiment of the invention, the covalent bond between a molecule of the conjugate, as described by the present invention, and an endogenous albumin molecule, in particular a human serum albumin molecule, or one of its derivatives, is achieved in vivo.

[0099] In a more particularly preferred embodiment, a pro-drug according to the invention comprises at least one molecule of conjugate according to the invention linked by a thioether bond with the sulfur of cysteine ​​at position 34 of an endogenous albumin molecule.

[0100] It has been shown, in fact, that a covalent bond forms spontaneously. in vivo , for example, between on the one hand a compound bearing a radical capable of reacting with a thiol function and the thiol function of cysteine ​​at position 34 of human serum albumin (Kratz et al. 2002, J. Med. Chem.).

[0101] According to a particularly preferred embodiment, the invention also relates to a prodrug, which has the following formula (VII): one of its isomers and / or one of its pharmaceutically acceptable salts.

[0102] According to a second particular embodiment, a prodrug according to the invention can also be formed in vitro by at least one molecule of the conjugate linked by a covalent bond to an albumin molecule, a recombinant albumin molecule or a fragment of an albumin molecule or one of its derivatives.

[0103] In the context of the invention, it is important that the " fragment of an albumin molecule " refers to a fragment of an albumin molecule of sufficient size to ensure satisfactory bioavailability, permeability to tumor tissues and impermeability to the endothelial barrier of healthy tissues, of the pro-drug thus generated.

[0104] In this particular embodiment, the coupling in vitro between a conjugate of general formula (I), by its radical L, and an albumin molecule, a recombinant albumin molecule or a fragment of an albumin molecule can be made with a free and complementary reactive function present at the level of the albumin molecule, the recombinant albumin molecule or the fragment of an albumin molecule.

[0105] In a particular embodiment, the fragment of an albumin molecule may include the cysteine ​​corresponding to the cysteine ​​at position 34 of the endogenous albumin sequence.

[0106] Contrary to expectations, the coupling of a conjugate of general formula (I) and an albumin molecule does not affect the ability of the prodrug thus formed to: to be transported and targeted specifically in the microenvironment of the tissue to be treated, to be cleaved in the microenvironment of the tissue to be treated by a β-glucuronidase, and to undergo, after cleavage of the glucuronyl radical, a rearrangement of the binding arm so as to release the radical representing a compound of the dolastatin family.

[0107] Furthermore, the coupling between a conjugate of general formula (I), by its radical L, and the amino, hydroxy or thiol function of an albumin molecule, in particular endogenous, does not in any way affect the ability of the compound of the dolastatin family thus released, to exert its biological activity, that is to say its antimitotic activity.

[0108] Finally, the coupling between a conjugate of general formula (I), via its L radical, and the amino, hydroxy, or thiol function of an albumin molecule, particularly endogenous albumin, limits the elimination of the prodrug by the kidneys. The blood half-life of a prodrug according to the invention is thus increased compared to that of a prodrug represented by a dolastatin family compound functionalized with a glucuronyl radical.

[0109] In another embodiment of the invention, the albumin molecule, or albumin fragment, of the pro-drug may be further modified, in particular by glycosylation or by pegylation. • Compositions, uses and processing methods according to the invention

[0110] According to another aspect, the present invention relates to a pharmaceutical composition comprising at least an effective amount of at least one conjugate or prodrug, as defined above.

[0111] These pharmaceutical compositions may be in a solid or liquid state and may be presented in all pharmaceutical forms commonly used in human and / or veterinary medicine, such as plain or coated tablets, pills, tablets, capsules, drops, granules, injectable preparations, ointments, creams or gels.

[0112] These pharmaceutical compositions can be prepared according to the usual methods. The active ingredient can be incorporated into excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, paraffinic derivatives, glycols, various wetting, dispersing or emulsifying agents, and preservatives.

[0113] The invention also relates to a conjugate of general formula (I), a prodrug of general formula (VI) or a pharmaceutical composition, as defined in the present invention, for its use in the prevention and / or treatment of cancer and / or inflammatory disease.

[0114] The invention also relates to a method of treating cancer and / or inflammatory disease comprising administering a conjugate of general formula (I), a prodrug of general formula (VI) or a pharmaceutical composition, according to the present invention.

[0115] The invention also relates to a method of treating cancer and / or inflammatory disease comprising administering a conjugate of formula (I), a prodrug of general formula (VI) or a pharmaceutical composition according to the invention, in association with another treatment selected from a group including chemotherapy, radiotherapy, treatment with at least one anti-inflammatory agent and their combination. • Cancer

[0116] A conjugate of general formula (I), a prodrug of general formula (VI), or a pharmaceutical composition according to the present invention can be implemented for use in the prevention and / or treatment of a solid cancer, preferably selected from a group comprising neuroblastoma, glioblastoma, osteosarcoma, retinoblastoma, soft tissue sarcoma, central nervous system cancer, nephroblastoma, lung cancer, breast cancer, prostate cancer, colorectal cancer, thyroid cancer, cervical cancer, endometrial cancer, ovarian cancer, kidney cancer, liver cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, skin cancer, small bowel cancer, stomach cancer, pleural cancer, esophageal cancer, laryngeal cancer, and cancer of the bladder.

[0117] In one particular embodiment, the solid cancer is chosen from a group comprising pancreatic cancer, lung cancer, and breast cancer.

[0118] In a particular embodiment, a conjugate of general formula (I), a prodrug of general formula (VI) or a pharmaceutical composition according to the present invention can be implemented, for its use in the prevention and / or treatment of metastases. • Inflammatory diseases

[0119] As for inflammatory diseases, these include chronic bowel diseases, or rheumatoid diseases. • Methods of administration

[0120] A conjugate of general formula (I), a prodrug of general formula (VI) or a pharmaceutical composition, as described in the present invention, may be administered orally, parenterally (subcutaneously, intravenously or intramuscularly) or locally by topical application to the skin and mucous membranes.

[0121] The present invention also relates to the use of conjugates, pro-drugs or pharmaceutical compositions, as defined above, for the preparation of drugs.

[0122] Such medications can be used alone or in combination.

[0123] Conjugates, prodrugs or pharmaceutical compositions according to the present invention may in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination, for example with other therapeutic agents, in particular anti-cancer agents, antimitotic agents but also in combination with anti-inflammatory agents.

[0124] A dosage suitable for the invention can be determined using a routine approach commonly employed in the art. Its adjustment clearly falls within the general skills of a person skilled in the art.

[0125] It is indeed dependent, in particular, on the weight, age, sex of the individual to be treated, and the stage of the disease to be treated. EXAMPLES Example 1 Synthesis of a conjugate of formula (III) (see Figure 1) 1) Synthesis of compound 1

[0126]

[0127] 17.9 g (48 mmol; 1 eq.) of peracetylated glucuronide are suspended in 36 mL of 33% HBr in acetic acid. After 4 h of stirring, the starting compound is completely consumed. The reaction mixture is then poured into an ice-water mixture, and the resulting aqueous phase is extracted three times with dichloromethane. The organic phase is then neutralized with a saturated NaHCO3 solution, dried over MgSO4, and evaporated. 3 mL of absolute ethanol are added to the crude product, and the mixture is stored overnight in a refrigerator. The precipitate formed is collected by filtration and then washed with petroleum ether. After vacuum drying, 17.4 g (43.8 mmol; Yield = 91%) of the compound 1 are isolated in the form of a beige solid. 2) Synthesis of compound 2

[0128]

[0129] In a 250 mL three-necked flask equipped with a condenser and an addition funnel, 648 mg (24 mmol; 6.25 eq.) of aluminum and a catalytic amount of HgCl₂ are covered with 10 mL of anhydrous THF. 2 mL (24 mmol; 6.25 eq.) of an 80% propargyl bromide solution in toluene are added dropwise. The reaction starts when heat release and the solution darkens. When the addition is complete, the mixture is heated under reflux for 6 hours. The solution is cooled to 0°C, and a solution of 650 mg (3.84 mmol; 1 eq.) of 4-hydroxy-3-nitrobenzaldehyde in 5 mL of anhydrous THF is added dropwise. After 30 minutes of stirring, the aldehyde has completely disappeared and the reaction is hydrolyzed with 10 mL of a 1N HCl solution and then extracted three times with ethyl acetate.The organic phase is dried over MgSO4 and then evaporated to yield a brown oil which is purified by flash chromatography (Eluent: EP / AcOEt 70 / 30). The compound... 2 The product is then obtained as a yellow oil contaminated with traces of products from the Wurtz reaction. A basic extraction removes these impurities. For this purpose, the oil is dissolved in 30 mL of dichloromethane. The organic phase is extracted three times with a 1N NaOH solution. The resulting aqueous phase is acidified with a concentrated HCl solution and then extracted three times with chloroform to yield, after evaporation, the compound 2 (754 mg; 3.6 mmol) in the form of a brown oil, with a yield of 94%. 3) Synthesis of compound 3

[0130]

[0131] 33.7 g (122.25 mmol; 3.7 eq.) of Ag₂CO₃ are suspended in 33 mL of acetonitrile, and 6.3 mL (23.12 mmol; 0.7 eq.) of HMTTA are added. The mixture is stirred and protected from light for 2 h. 4.56 g (22.03 mmol; 1 eq.) of compound 2 and 13.10 g (33.04 mmol; 1.5 eq.) of compound 1 are added in solution to 20 mL of acetonitrile. The mixture is stirred for 4 hours, then water is added. This aqueous phase is extracted three times with ethyl acetate. The organic phase is washed three times with 1 M HCl solution, dried over MgSO4, and evaporated. Purification by flash chromatography of the crude reaction mixture (EP / AcOEt eluent 60 / 40; 50 / 50; 40 / 60) yields 7.62 g (14.56 mmol; Yield = 66%) of the compound 3 in the form of a white solid (2 diastereomers). 4) Synthesis of compound 4

[0132]

[0133] 180 mg (0.34 mmol; 1 eq.) of benzyl alcohol and 140 mg (0.68 mmol; 2 eq.) of paranitrophenol chloroformate were dissolved in 3.5 mL of anhydrous dichloromethane. 70 µL of pyridine (0.87 mmol; 2.5 eq.) were added dropwise at 0°C. After 1 h of stirring at room temperature, the starting material was completely consumed. The reaction was hydrolyzed with a saturated NaHCO3 solution. The organic phase was extracted with dichloromethane. The resulting organic phases were dried and evaporated to dryness. Flash chromatography (60 / 40 EP / AcOEt) isolated 235 mg (0.343 mmol) of the compound. 4 in the form of a white solid with a quantitative yield. 5) Synthesis of compound 5

[0134]

[0135] The compound 4 (57.5 mg; 0.0835 mmol) and MMAE (60 mg; 1 eq.) are dissolved in 2 mL of a DMF / pyridine (8 / 2) mixture. 11.3 mg of HOBt (0.0835 mmol; 1 eq.) and 17 µL of DIPEA (0.1 mmol; 1.2 eq.) are added. Stirring is maintained for 36 h at room temperature. The solvent is removed under vacuum and the residue is purified by flash chromatography (Eluent: DCM / MeOH 3%–5%). 70 mg of the compound 5 are obtained (0.055 mmol; 66%) in the form of a white solid. 6) Synthesis of compound 6

[0136]

[0137] The compound 5 (70 mg; 0.055 mmol) is dissolved in anhydrous DCM (2.8 mL) in the presence of azide of the formula NH₂-(CH₂)₂-(O-CH₂-CH₂)₁₀-N₃ (37.8 mg; 0.0717 mmol; 1.3 eq). 30 mg (0.08 mmol; 1.5 eq) of Cu(MeCN)₄PF₆ is added, and the mixture is stirred for 20 h at room temperature under a nitrogen atmosphere. A solution of disodium EDTA (350 mg in 5.2 mL of 0.2 M phosphate buffer) is added, and stirring is maintained for 5 h. The mixture is extracted three times with dichloromethane. The organic phases are dried over MgSO₄, filtered, and evaporated under vacuum. The crude product obtained is purified on preparation plates (DCM / MeOH eluent, 2-5%). The compound 6 corresponding (53 mg; 0.029 mmol) is isolated with a yield of 53.5%. 7) Synthesis of the compound with formula (III)

[0138]

[0139] The compound 6 (53 mg; 0.029 mmol) is dissolved in MeOH (2.2 mL) at 0°C. A solution of LiOH·H₂O (10.6 mg; 0.259 mmol) in 2.2 mL of H₂O, previously cooled to 0°C, is added dropwise. The reaction mixture is kept under stirring at this temperature. TLC monitoring indicates the disappearance of the starting material after 15 minutes. The mixture is then neutralized by adding IRC-50 resin. After 30 minutes, the resin is filtered and the reaction mixture is evaporated under vacuum. The crude product is immediately reconstituted in DMSO (0.7 mL) in the presence of the compound. 7 (1.2 eq.; 11 mg). Stirring is maintained for 12 h at room temperature. After evaporation of the solvent under vacuum, the crude reaction mixture is purified by semi-preparative HPLC. 18 mg of formula (III) conjugate are thus isolated (0.0097 mmol) with a purity greater than 95% and an overall yield of 33% (calculated over 3 steps: click-deprotection-semi-preparative HPLC purification). SMHR (ESI) : C 88 H 41 N 11 O 31 [M+2H]2+ : theoretical: 923.9638 ; found: 923.9892 8) HPLC Monitoring

[0140] Reaction monitoring and compound analysis were performed on a DIONEX Ultimate 3000 HPLC system equipped with a quad-wavelength UV detector and a DIONEX Acclain® 120 column (C18, 5 µm, 120 Å) in a temperature-controlled compartment at 30°C. Chromatograms were recorded at 220 and 254 nm. Integration was performed using Chromeleon software version 6.80 SP1 Build 2238. The eluents consisted of A (H₂O + TFA 0.2%) and B (CH₃CN). Example 2 Evaluation of the therapeutic efficacy of the formula (III) conjugate in vivo on a murine model of human pancreatic cancer 1) Materials and Methods a) Animals used

[0141] The therapeutic efficacy of the formula conjugate (III), as synthesized according to the reaction protocol described in Example 1, was evaluated in 6-week-old female Swiss Nude mice (Charles River Laboratories, L'Arbresle, France). The animals were acclimated for 7 days in the laboratory prior to the experiment. The mice were housed in plastic cages equipped with filtering lids (HEPA filter), within a ventilated rack, at a temperature of 20 ± 2°C with a 12 / 12-hour light / dark cycle, and with free access to water and food. ad libitum. b) Human pancreatic tumor of the Mia Paca type transplanted orthotopically

[0142] The Mia Paca 2 cells were derived from a 65-year-old man with pancreatic adenocarcinoma. The Mia Paca 2 pancreatic cancer cell line was provided by the American Type Culture Collection (Rockville, MD). These cells were chosen because they can generate hypoxic tumors, reflecting the clinical pathological situation.

[0143] These cells were modified to express the luciferase gene (Mia PaCa 2-Luc). The cells were cultured in 75 cm³ flasks and maintained in a humidified incubator at 37°C in 5% CO2 with Dulbecco Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum, 2.5% horse serum, 1% L-glutamine and 1% penicillin and streptomycin.

[0144] For implantation, the abdomens of the mice were disinfected with povidone-iodine solution (Betadine®, ASTA Medica, Belgium). A 1-cm incision was made in the upper left quadrant of the abdomen. The tip of the pancreatic tail was grasped, and the pancreas and spleen were gently externalized laterally for full exposure. The needle was inserted into the pancreatic tail and advanced to the region of the pancreatic head. Two × 10⁶ < cells Mia PaCa 2-Luc in 50 µL of PBS were slowly injected using a 27-gauge needle. The spleen was then repositioned within the abdomen, and the skin and peritoneum were sutured with 5-0 absorbable suture material. The animals' pain was managed with an opioid analgesic (Skenan LP 10 mg micro-granules, Bristol-Myers Squibb). c) Processing methods

[0145] Mice (6 animals per group) received treatment 7 days after tumor implantation. Intravenous injections were administered once weekly for 2 weeks with doses of 2 mg / kg and 4 mg / kg of bifunctionalized MMAE (formula (III) conjugate, days 7 and 14). Control groups were treated either with MMAE alone at a dose of 0.3 mg / kg or with the excipient consisting of a mixture of DMSO and PBS (5% / 95%; control).

[0146] The evolution of the tumor volume was monitored by ultrasound. Measurements were performed using the VisualSonics Vevo™ 2100 imaging system. in vivo high resolution (VisualSonics™ Inc., Toronto, Canada) on days 3, 7, 9, 11, 14, 16, 18, 21, 23, 28, 38, 52, 66 and 78. 2) Results

[0147] There Figure 2This illustrates the evolution of tumor volume over a period of 70 days. A significant increase in tumor volume is observed from day 35 onwards for both the control and non-functionalized MMAE. Thus, non-functionalized MMAE is not suitable for the treatment of pancreatic tumors. When mice receive two injections (days 7 and 14) of 2 mg / kg of bi-functionalized MMAE, i.e., a formula (III) conjugate, the progression of tumor volume is slower than with the control or non-functionalized MMAE. Conversely, the administration of two injections (days 7 and 14) of a dose of 4 mg / kg results in a complete absence of tumor growth. Example 3 Evaluation of the therapeutic efficacy of the formula (III) conjugate in vivo on a murine model of human pancreatic cancer 1) Materials and Methods a) Animals used

[0148] The therapeutic efficacy of the formula conjugate (III), as synthesized according to the reaction protocol described in Example 1, was evaluated on 6-week-old female Balb / c Nude mice (Laboratoires Charles River France - L'Arbresle) as previously indicated in Example 2. b) Human pancreatic tumor of the Mia Paca type transplanted orthotopically

[0149] The human Mia Paca type pancreatic tumor grafted orthotopically is such as that described in example 2. c) Processing methods

[0150] The mice (5 animals per group) received treatment when tumor volumes reached a size between 2.5 and 3.5 cm³, volumes representative of the situation in humans where pancreatic cancers are detected late in most cases. Intravenous injections of the bifunctionalized MMAE conjugate, i.e., the formula (III) conjugate (synthesized according to the reaction protocol described in Example 1), were administered once a week for 9 weeks at a dose of 4 mg / kg. The control group was treated with the excipient consisting of a mixture of DMSO and PBS (5% / 95%). Tumor volume changes were monitored by ultrasound, as described in Example 2. 2) Results

[0151] There Figure 3 illustrates the evolution of the volume of a MIA-PaCa type pancreatic tumor grafted orthotopically followed by ultrasound for 80 days.

[0152] Tumor volume regression of 92 to 100% can be observed in mice treated with formula (III) conjugate (panel A), whereas animals not treated with formula (III) conjugate (vehicle, corresponding to excipient DMSO / PBS; panel B) all succumbed within twenty days of the start of the therapeutic protocol. Example 4 Evaluation of the therapeutic efficacy of the formula (III) conjugate in vivo on a murine model of human breast cancer 1) Materials and Methods a) Animals used

[0153] The therapeutic efficacy of the formula conjugate (III), as synthesized according to the reaction protocol described in Example 1, was evaluated on 6-week-old female Balb / c Nude mice (Laboratoires Charles River France - L'Arbresle) as shown in Example 3. b) Human breast tumor type MDA-MB-231 grafted orthotopically

[0154] The MDA-MB-231 cells were derived from a breast adenocarcinoma in a 51-year-old woman. The MDA-MB-231 breast cancer cell line was provided by Caliper LifeSciences (Roissy, France). These cells were chosen because they can generate hypoxic tumors, reflecting the clinical pathological situation.

[0155] These cells are modified to express the luciferase gene. The cells were cultured in 75 cm³ flasks and maintained in a humidified incubator at 37°C under an atmosphere consisting of air with Eagle's Minimal Essential Medium (EMEM) supplemented with 10% fetal bovine serum, 1% L-Glutamine, 1% sodium pyruvate, 1% non-essential amino acids, 2% sodium bicarbonate and 1% penicillin and streptomycin.

[0156] For implantation, the abdomens of the mice were disinfected with povidone-iodine solution (Betadine®, ASTA Medica, Belgium). The needle was inserted into the subcutaneous space at the level of the lower left mammary gland. The 2 x 10⁶ MDA-MB-231-Luc cells, in 100 µL of PBS, were slowly injected using a 27-gauge needle. The needle was then slowly withdrawn. The mice were anesthetized for this procedure by inhalation of isoflurane (2% in air). c) Processing methods

[0157] Mice (6 animals per group) received treatment 15 days after tumor implantation. Intravenous injections were administered once weekly for 5 weeks with doses of 4 mg / kg conjugated with formula (III) (days 15, 22, 29, 36, and 43). Control groups were treated either with MMAE alone at a dose of 0.3 mg / kg or with the excipient consisting of a mixture of DMSO and PBS (5% / 95%).

[0158] The evolution of the tumor volume was monitored by 3D ultrasound. Measurements were taken as described in example 2, on days 7, 11, 15, 19, 22, 25, 27, 29, 32, 34, 36, 39, 43 and 50. 2) Results

[0159] There figure 4 illustrates the evolution of the volume of a human breast tumor of type MDA-MB-231 grafted orthotopically monitored by ultrasound for 50 days.

[0160] Complete and sustained tumor regression was observed in animals treated with the formula (III) conjugate (4 mg / kg) (panel C), whereas free MMAE (panel B) resulted in only very modest antitumor activity compared to control animals (panel A). These results were obtained without any visible side effects in the group of mice receiving the formula (III) conjugate. REFERENCES Patent-type documents

[0161] US 7,829,531 WO 2011 / 145068 Non-patent type documents

[0162] Kolb et al. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, vol 40(11), 2004-2021. Kratz et al. Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound. J. Med. Chem. 2002, vol 45, 5523-5533. Legigan et al. The first generation of β-galactosidase-responsive prodrugs designed for the selective treatment of solid tumors in prodrug monotherapy. Angew. Chem. Int. Ed. 2012, vol 51, 11606-11610. Legigan et al. Synthesis and antitumor efficacy of a β-glucuronidase-responsive albumin-binding prodrug of doxorubicin. J. Med. Chem. 2012, vol 55, 4516-4520. Legigan et al. Synthesis and biological evaluations of monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy. Eur. J. Med. Chem. 2013, vol 67, 75-80. Teming et al.Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels. Bioconjugate Chem. 2006, vol 17, 1385-1394. Tranoy-Opalinski et al. β-glucuronidase-responsive prodrugs for selective cancer chemoterapy : an update. Eur. J. Med. Chem., 2014, vol 74, 302-313.

Claims

1. Conjugate of general formula (I): in which: - A represents a radical from the dolastatin family or one of its derivatives, - L represents a radical capable of reacting with an amino, hydroxyl, or thiol function, and preferably a thiol function, - G comprises and preferably represents a glucuronyl radical or one of its derivatives, - Y represents H, or an electron-withdrawing radical, in particular chosen from NO2, CF3, and a halogen, - R 1 and R 2 represent, independently of each other, H or an alkyl radical in C1 to C 10 , linear or branched, saturated or unsaturated, - Z represents a hydrocarbon spacer radical comprising covalent bonding functions at each of its ends, - X represents -O- or -NR 3 COO-, with R 3 which can represent a hydrogen atom or an alkyl radical in C1 to C 10, linear or branched, saturated or unsaturated, the bond with the G radical being ensured by the oxygen atom (-O), one of its isomers and / or one of its pharmaceutically acceptable salts.

2. Conjugated according to claim 1, wherein Y represents NO2 in position ortho of X, and R 1 and R 2 represent H.

3. Conjugated according to any one of claims 1 or 2, wherein A represents a radical derived from dolastatin 10, auristatin PE, auristatin E, monomethyl auristatin E and their derivatives, preferably a radical derived from monomethyl auristatin E or one of its derivatives.

4. Conjugated according to any one of claims 1 to 3, wherein L comprises a motif capable of reacting with a free amino, hydroxy or thiol function carried by a macromolecule, preferably a free thiol function.

5. Conjugated according to any one of claims 1 to 4, wherein L represents a maleimidocaproyl type motif.

6. Conjugated according to any one of claims 1 to 5, in which Z represents a radical Z 1 -Z 2 -(Z 3 ) m , in which: - m represents 0 or 1 - Z 1 represents an L-click bonding function between the carbon bearing the R functions 1 and R 2 and the Z function 2 , - Z 2 represents an alkylene group, linear or branched, saturated or unsaturated, in C1-C 10 , optionally interrupted by one or more heteroatoms chosen from O or N, a glycosyl radical, an O-(CHR) radical 4 -CHR 5 -O-) p or N-(CHR 4 -CHR 5 -O-) p in which p is a natural number ranging from 1 to 20, and R 4 and R 5 H or CH3 appear independently of each other, provided that R4 and R 5 do not simultaneously include CH3, a group derived from an amino acid or peptide, or a combination of these groups, a Z end 2 forming a covalent bond with L, either directly via an ether function, or indirectly via a Z function 3 , - Z 3 represents a function of the ester, amide, ether, carbamate or carbonate type established between the Z function 2 and the radical L.

7. Conjugated according to any one of claims 1 to 6, of the following formula (III): one of its isomers and / or one of its pharmaceutically acceptable salts.

8. Pro-drug comprising at least one molecule of the conjugate according to any one of claims 1 to 7, said molecule of the conjugate being covalently linked to a molecule of albumin or one of its fragments or derivatives.

9. Pro-drug according to claim 8, wherein the covalent bond is established with the thiol function of cysteine ​​at position 34 of endogenous albumin.

10. Prodrug according to any one of claims 8 and 9, which has the following formula (VII): one of its isomers and / or one of its pharmaceutically acceptable salts.

11. Pharmaceutical composition comprising at least an effective amount of at least one conjugate as defined in any one of claims 1 to 7 or a prodrug as defined in any one of claims 8 to 10.

12. Conjugated according to any one of claims 1 to 7, for its use in the prevention and / or treatment of cancer and / or inflammatory disease.

13. Prodrug according to any one of claims 8 to 10, or for its use in the prevention and / or treatment of cancer and / or inflammatory disease.

14. Composition according to claim 11, for its use in the prevention and / or treatment of cancer and / or inflammatory disease.