Drug conjugate comprising quinoline derivatives

1. A compound having the formula (I):

wherein:

R 1 represents a group: —NH 2 , —NHCOR a , —NHCOOR b , —(C 2 -C 6 )alkenylene-CO—NH—OH, —(C 2 -C 6 )alkynylene-CO—NH—OH or —OH;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R 3 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR c ;

R 4 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR d ;

R a represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R b represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R c represents a group: —(C 1 -C 5 )alkyl or —CF 3 ; and

R d represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

in the following state: base or acid, or salts of acids or salts of bases; or in the form of a hydrate or a solvate.

2. The compound according to claim 1 , wherein R 3 represents a hydrogen atom.

3. The compound according to claim 1 , wherein R 4 represents a hydrogen atom.

4. The compound according to claim 1 , having the formula (Ia):

wherein:

R 1 represents a group: —NH 2 , —NHCOR a , —NHCOOR b , —(C 2 -C 6 )alkenylene-CO—NH—OH, —(C 2 -C 6 )alkynylene-CO—NH—OH or —OH;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R a represents a group: —(C 1 -C 5 )alkyl or —CF 3 ; and

R b represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

in the following state: base or acid, or salts of acids or salts of bases; or in the form of a hydrate or a solvate.

5. The compound according to claim 1 , wherein R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , or —OCHF 2 .

6. The compound according to claim 1 , wherein R 1 represents a group: —NH 2 , —NHCOR a , —NHCOOR b , or —OH.

7. The compound according to claim 1 , selected from:

8. The compound according to claim 1 , having the formula (Ib):

wherein:

R 5 represents a hydrogen atom, a group: —COR a , or —COOR b ;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R 3 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR c ;

R 4 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR d ;

R a represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R b represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R c represents a group: —(C 1 -C 5 )alkyl or —CF 3 ; and

R d represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

in the following state: base or acid, or salts of acids or salts of bases; or in the form of a hydrate or a solvate.

9. The compound according to claim 1 , wherein R 1 represents a group: —(C 2 -C 6 )alkenylene-CO—NH—OH or —(C 2 -C 6 )alkynylene-CO—NH—OH.

10. The compound according to claim 1 , having the formula (Ic):

wherein:

W represents —CH═CH— or —C≡C—;

n is 0, 1, 2, 3 or 4;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R 3 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR c ;

R 4 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR d ;

R c represents a group: —(C 1 -C 5 )alkyl or —CF 3 ; and

R d represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

in the following state: base or acid, or salts of acids or salts of bases; or in the form of a hydrate or a solvate.

11. The compound according to claim 10 , selected from:

12. A preparation method for preparing a compound according to claim 1 , wherein R 1 represents an —NH 2 or —OH group, wherein:

a compound having the formula (B):

wherein R 2 is as defined according to claim 1 and R 9 represents a —NO 2 or —O-Benzoyl group; is brought into contact with a compound having the formula (D):

wherein R 3 and R 4 are as defined according to claim 1 ;

so as to form, by an aromatic nucleophilic substitution reaction, or by a coupling reaction in the presence of a catalyst, the compound having the formula (E):

wherein R 3 , R 4 and R 2 are as defined according to claim 1 , and R 10 represents a —NO 2 or —O-Benzoyl group;

the compound having the formula (E) is subjected to a methylation reaction, then to a reduction or deprotection reaction so as to form the compound having the formula (I):

wherein R 3 , R 4 and R 2 are as defined according to claim 1 , and R 1 represents an —NH 2 or —OH group, with R a and R b being as defined according to claim 1 .

13. A preparation method for preparing the compound (Ic) according to claim 10 , wherein:

the compound having the formula (N):

wherein R 3 and R 4 are as defined according to claim 10 ; is brought into contact with a compound having the formula (O):

wherein R 2 is as defined according to claim 10 , so as to form, by an aromatic nucleophilic substitution reaction, followed by a methylation reaction, the compound having the formula (P):

wherein R 3 , R 4 and R 2 are as defined according to claim 10 ;

the compound having the formula (P) is subjected to an organometallic coupling reaction with a group: —(C 2 -C 6 )alkenylene-CO—NH—O-(2-tetrahydropyranyl) or —C 2 -C 6 -alkynylene-CO—NH—O-(2-tetrahydropyranyl), then to a deprotection reaction, so as to form the compound having the formula (Ic):

wherein,

n·R 3 , R 4 , and R 2 are as defined according to claim 10 .

14. An intermediate compound, selected from:

15. A compound having the formula (II):

wherein:

Y 1 represents —O—, —NH—, —NHCO—, —NHCOR a —, —NHCOO—, —NHCOOR b —, —(C 2 -C 6 )alkenylene-CO—NH—O— or —(C 2 -C 6 )alkenylene-CO—NH—O—;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R 3 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR c ;

R 4 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR d ;

R a represents a group: —(C 1 -C 5 )alkylene- or —CF 2 —;

R b represents a group: —(C 1 -C 5 )alkylene- or —CF 2 —;

R c represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R d represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

L represents a linking agent (linker);

RM* is selected from RM and RM′, wherein RM is a reactive functional group that is able to form a covalent bond with a targeting agent moiety, and wherein RM′ is an RM moiety carrying at least one protecting group;

in the following state: base or salts of bases; or in the form of a hydrate or a solvate.

16. The compound according to claim 15 , wherein the L-RM* group is selected from among:

17. The compound according to claim 15 , selected from among:

18. An antibody-drug conjugate having the formula (III):

wherein:

Y 1 represents —O—, —NH—, —NHCO—, —NHCOR a —, —NHCOO—, —NHCOOR b —, —(C 2 -C 6 )alkenylene-CO—NH—O— or —(C 2 -C 6 )alkenylene-CO—NH—O—;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R 3 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR c ;

R 4 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR d ;

R a represents a group: —(C 1 -C 5 )alkylene- or —CF 2 —;

R b represents a group: —(C 1 -C 5 )alkylene- or —CF 2 —;

R c represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R d represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

L represents a linking agent (linker);

AC represents a targeting agent moiety; and

wherein the DAR (drug-to-antibody [targeting agent] ratio) varies between 1 and 8.

19. A preparation method for preparing a compound having the formula (II)

wherein

Y 1 represents —O—, —NH—, —NHCO—, —NHCOR a —, —NHCOO—, —NHCOOR b —, —(C 2 -C 6 )alkenylene-CO—NH—O— or —(C 2 -C 6 )alkenylene-CO—NH—O—;

R 2 represents a group: —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 or —OCHF 2 ;

R 3 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR c ;

R 4 represents a hydrogen atom or a group: —CH 3 , —CN, —F, —Cl or —OR d ;

R a represents a group: —(C 1 -C 5 )alkylene- or —CF 2 —;

R b represents a group: —(C 1 -C 5 )alkylene- or —CF 2 —;

R c represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

R d represents a group: —(C 1 -C 5 )alkyl or —CF 3 ;

L represents a linking agent (linker);

RM* is selected from RM and RM′, wherein RM is a reactive functional group that is able to form a covalent bond with a targeting agent moiety, and wherein RM′ is an RM moiety carrying at least one protecting group;

in the following state: base or salts of bases: or in the form of a hydrate or a solvate;

the method comprising a reaction step of reacting a compound having the formula (I) according to claim 1 , with a compound having the formula X-L″-RM* wherein:

X represents a group that is capable of reacting with an R 1 group as defined according to claim 1 ;

L represents a linking agent (linker);

RM* is selected from RM and RM′, wherein RM is a reactive functional group that is able to form a covalent bond with a targeting agent moiety, and wherein RM′ is an RM moiety carrying at least one protecting group;

wherein the reaction between the —R 1 moiety of the compound having the formula (I) and the compound having the formula X-L″-RM* results in the formation of a —Y 1 -L-RM* moiety.

20. The A preparation method according to claim 19 , wherein RM* is RM, the method further comprising a deprotection step of deprotecting an RM′ moiety resulting in an RM group.

21. A pharmaceutical composition comprising an antibody-drug conjugate according to claim 18 , in association with a pharmaceutically acceptable carrier.

22. A method of therapeutic treatment, wherein said method comprises administering to a subject in need thereof an antibody-drug conjugate according to claim 18 .

23. The method according to claim 22 , wherein the therapeutic treatment is killing or inhibiting cell growth.

24. The method according to claim 22 , wherein the therapeutic treatment is treatment of cancer.