Novel multimeric molecules, a process for preparing the same and the use thereof for manufacturing medicinal drugs

A compound having the following formula (I):

• wherein:
• k and j represent independently from each other 0 or 1,
• Y represents a macrocycle the ring of which includes from 9 to 36 atoms, and is functionally substituted by three amine functionalities and by a carbon chain allowing binding of a Z spacer via an X bond,
• Rc represents a binding motif to a receptor belonging to the TNF superfamily, and preferably represent a ligand derived-sequence selected among the residues interfacing with the ligand receptor, which sequence may interact with the receptor, said ligand being selected among receptor ligands belonging to the TNF superfamily, namely among the following ligands:
• EDA, CD40L, FasL, OX40L, AITRL, CD30L, VEGI, LIGHT, 4-1 BBL, CD27L, LTα, TNF, LTβ, TWEAK, APRIL, BLYS, RANKL and TRAIL,
• X represents a chemical functionality which allows the Y group to be linked to the spacer and is selected among the following functional groups:
• a designating the bond to the Y group and b designating the bond to the Z group,
• Z represents a bi, tri- or tetrafunctional spacer having one of the following formulae:
• if j=k=0:
• if X represents a group of formulae (1′), (8′), (9′), (5′), (6′), (7′), (13′) and (15′), Z has one of the following formulae:
• m being an integer ranging from 1 to 40,
• n being an integer ranging from 1 to 10,
• if X represents a group of formulae (2′), (3′) and (4′), Z has one of the following formulae:
• if X represents a group of formulae (12′) and (14′), Z has one of the following formulae:
• m and n being as defined above,
• p being an integer ranging from 1 to 6,
• u being an integer ranging from 1 to 4,
• W designating a group of formula
• or a group of formula
• the W group being bound to the NH group through the dotted line bond a′
• if X represents a group of formulae (1′), (2′), (8′), (9′), (5′), (6′), (7′), (10′), (11′), (13′) and (15′), Z has one of the following formulae:
• m and n being as defined above,
• p being an integer ranging from 1 to 6,
• u being an integer ranging from 1 to 4,
• W designating a group of formula
• r being an integer ranging from 1 to 4,
• the W group being bound to the NH group via the dotted line bond a′
• if j=1 or k=1
• if X represents a group of formulae (12′) and (14′), Z has one of the following formulae:
• u being an integer ranging from 1 to 4,
• n being an integer ranging from 1 to 10,
• W designating a group of formula
• or a group of formula
• the W group being bound to the NH group through the dotted line bond a′,
• if X represents a group of formulae (1′), (2′), (8′), (9′), (5′), (6′), (7′), (10′), (11′), (13′) and (15′), Z has one of the following formulae:
• u being an integer ranging from 1 to 4,
• n being an integer ranging from 1 to 10,
• W designating a group of formula
• r being an integer ranging from 1 to 4,
• the W group being bound to the NH group via the dotted line bond a′
• Z can also represent one of the following formulae:
• wherein:
• if X represents a group of formulae (1′), (8′), (9′), (5′), (6′), (7′), (13′) and (15′):
• R represents one of the following groups:
• m ranging from 3 to 6 n ranging from 1 to 10
• m ranging from 1 to 40
• the R group being bound to the NH group via the dotted line bond a′,
• if X represents a group of formulae (2′), (3′) and (4′):
• R represents one of the following groups:
• n being an integer ranging from 1 to 10,
• u being an integer ranging from 1 to 4,
• the R group being bound to the NH group through the dotted line bond a′,
• if X represents a group of formulae (12′) and (14′):
• R represents one of the following groups:
• the R group being bound to the NH group through the dotted line bond a′,
• n being an integer ranging from 1 to 10,
• W designating a group of formula
• or a group of formula
• the W group being bound to the NH group through the dotted line bond a′
• if X represents a group of formulae (1′), (2′), (8′), (9′), (5′), (6′), (7′), (10′), (11′), (13′) and (15′):
• R represents one of the following groups:
• u and n being as specified above,
• W designating a group of formula
• r being an integer ranging from 1 to 4,
• the W group being bound to the NH group through the dotted line bond a′.

A process for preparing on a solid support a compound, said compound having the following formula (I):

• wherein:
• k and j represent independently from each other 0 or 1,
• Y represents a macrocycle the ring of which includes from 9 to 36 atoms, and is functionally substituted by three amine functionalities and by a carbon chain allowing binding of a Z spacer via an X bond,
• Rc represents a binding motif to a receptor belonging to the TNF superfamily, and preferably represents a ligand derived-sequence selected among the residues interfacing with the ligand receptor, which sequence may interact with the receptor, said ligand being selected among receptor ligands belonging to the TNF superfamily, namely among the following ligands:
• EDA, CD40L, FasL, OX40L, AITRL, CD30L, VEGI, LIGHT, 4-1 BBL, CD27L, LTα, TNF, LTβ, TWEAK, APRIL, BLYS, RANKL and TRAIL,
• X represents a chemical functionality which allows the Y group to be linked to the spacer and is selected among the following functional groups:
• a designating the bond to the Y group and b designating the bond to the Z group,
• Z represents a bi, tri- or tetrafunctional spacer having one of the following formulae:
• if j=k=0:
• if X represents a group of formulae (1′), (8′), (9′), (5′), (6′), (7′), (13′) and (15′), Z has one of the following formulae:
• m being an integer ranging from 1 to 40,
• n being an integer ranging from 1 to 10,
• if X represents a group of formulae (2′), (3′) and (4′), Z has one of the following formulae:
• if X represents a group of formulae (12′) and (14′), Z has one of the following formulae:
• m and n being as defined above,
• p being an integer ranging from 1 to 6,
• u being an integer ranging from 1 to 4,
• W designating a group of formula
• or a group of formula
• the W group being bound to the NH group through the dotted line bond a′
• if X represents a group of formulae (1′), (2′), (8′), (9′), (5′), (6′), (7′), (10′), (11′), (13′) and (15′), Z has one of the following formulae:
• m and n being as defined above,
• p being an integer ranging from 1 to 6,
• u being an integer ranging from 1 to 4,
• W designating a group of formula
• r being an integer ranging from 1 to 4,
• the W group being bound to the NH group via the dotted line bond a′
• if j=1 or k=1
• if X represents a group of formulae (12′) and (14′), Z has one of the following formulae:
• u being an integer ranging from 1 to 4,
• n being an integer ranging from 1 to 10,
• W designating a group of formula
• or a group of formula
• the W group being bound to the NH group through the dotted line bond a′,
• if X represents a group of formulae (1′), (2′), (8′), (9′), (5′), (6′), (7′), (10′), (11′), (13′) and (15′), Z has one of the following formulae:
• u being an integer ranging from 1 to 4,
• n being an integer ranging from 1 to 10,
• W designating a group of formula
• r being an integer ranging from 1 to 4,
• the W group being bound to the NH group via the dotted line bond a′
• Z can also represent one of the following formulae:
• wherein:
• if X represents a group of formulae (1′), (8′), (9′), (5′), (6′), (7′), (13′) and (15′):
• R represents one of the following groups:
• the R group being bound to the NH group via the dotted line bond a′,
• if X represents a group of formulae (2′), (3′) and (4′):
• R represents one of the following groups:
• n being an integer ranging from 1 to 10,
• u being an integer ranging from 1 to 4,
• the R group being bound to the NH group through the dotted line bond a′,
• if X represents a group of formulae (12′) and (14′):
• R represents one of the following groups:
• the R group being bound to the NH group through the dotted line bond a′,
• n being an integer ranging from 1 to 10,
• W designating a group of formula
• or a group of formula
• the W group being bound to the NH group through the dotted line bond a′
• if X represents a group of formulae (1′), (2′), (8′), (9′), (5′), (6′), (7′), (10′), (11′), (13′) and (15′):
• R represents one of the following groups:
• u and n being as specified above,
• W designating a group of formula
• r being an integer ranging from 1 to 4,
• the W group being bound to the NH group through the dotted line bond a′,
• with said process being characterized in that it comprises the following steps:
• forming a linear precursor of Y as specified above, which precursor is constituted of an amino acid sequence forming a growing peptide chain, being synthesized by successive coupling cycles of N-protected amino acid residues, three of which bear an amine type group, and the amine functionality of the growing peptide chain, and deprotecting, the first amino acid residue being bound to a solid support, said linear precursor of Y comprising at least one D-alanine residue, said D-alanine residue being substituted by a D-lysine residue the e-NH amine of which has been acylated by a carboxylic acid bearing the desired functionality corresponding to an X group as specified above,
• cyclizing the linear precursor of Y in a protected state mentioned above, in order to obtain a protected functionally substituted ring,
• reacting said protected functionally substituted ring with a Z-derived spacer as specified above, in order to obtain a dimerized protected functionally substituted ring,
• cleaving said previously mentioned protecting groups, to free said previously mentioned protected amine functionalities and obtain a dimerized deprotected functionally substituted ring,
• coupling said previously mentioned freed amine functionalities with an in situ formed or preformed peptide by successive assembly of amino acid residues corresponding to the Rc group as specified above, and
• cleaving the molecule from the solid support, after removal of all protecting groups present on functionally substituted side chains of the Rc group, in order to obtain the said compound.