“Multi-target” compounds with inhibitory activity towards histone deacetylases and tubulin polymerisation, for use in the treatment of cancer

1. A compound having the following Formula (II):

wherein:

R 3 represents a group A 1 having the following general formula:

and

B is selected from:

n represents an integer selected from 0 or 1;

L represents:

—(CH 2 ) r —;

—CH═CH—(CH 2 ) r —;

—CH═CH—CH═CH—(CH 2 ) r —;

—C═C—CH≡CH—(CH 2 ) r —;

—C≡C—(CH 2 ) r —; or

—C≡C—CH═CH—(CH 2 ) r —;

where r is an integer from 0 to 6;

Z 1 represents a hydrogen atom, or a halogen atom;

Z 2 represents an atom selected from a hydrogen and a halogen, or a group selected from a nitrile, and a group B, provided that if Z 2 ═B then the group -(L) n -B is absent from G;

the bonds mean that the double bond bearing Z 1 , respectively, Z 2 is of E or Z stereochemistry;

* is the carbon atom bearing R 2 or R 3 ;

G represents a phenyl or a heteroaryl:

When G is a phenyl, it is substituted by a group R 20 selected from OMe and SMe in the para position, relative to the position of the double bond bearing Z 1 and Z 2 ;

When G is a heteroaryl, it is selected from pyridines, indoles, 1-methylindoles, indolines, carbazoles, benzothiophenes and benzofurans;

R 2 represents an —OMe group;

E represents a hydrogen atom;

A represents an —OMe group;

R 1 represents an —OMe group;

2. The compound according to claim 1 , wherein the group A 1 is selected from the groups having the following general formulas:

where:

Z 1 and Z 2 each independently represent a hydrogen atom, a halogen atom selected from fluorine, chlorine and bromine, or a nitrile group;

R 20 , B, L and n are as defined in claim 1 , and;

the bonds mean that the double bond bearing Z 1 , respectively, Z 2 is of E or Z stereochemistry;

* is the carbon atom bearing R 3 .

3. The compound according to claim 1 , wherein the group A1 is selected from the groups having the following general formulas:

where:

Z 1 represents a hydrogen atom, a halogen atom selected from fluorine, chlorine and bromine, or a nitrile group;

R 20 , B, are as defined in claim 1 ;

R 21 represents a hydrogen atom, or a group selected from —OH, —NH 2 , F, N 3 , —C≡CH, —C≡C(CH 2 ) m OH where m is an integer between 0 and 5, (E)-CH═CHCH 2 OH, and (E)-CH═CHCOOR where R is a hydrogen atom or a (C 1 to C4)alkyl group, and;

the bonds mean that the double bond bearing Z 1 , respectively, Z 2 is of E or Z stereochemistry;

* is the carbon atom bearing R 3 .

4. The compound according to claim 1 , wherein it has the following formula:

5. The compound according to claim 1 , wherein it has the following formula:

6. A process for preparing a compound of claim 1 having the formula (II):

Wherein

R 3 represents a group A 1 having the following general formula:

wherein:

B is selected from

n represents an integer selected from 0 or 1;

L represents:

—(CH 2 ) r —;

—CH═CH—(CH 2 ) r —;

—CH═CH—CH═CH—(CH 2 ) r —;

—C=C—CH≡CH—(CH 2 ) r —;

—C≡C—(CH 2 ) r —; or

—C≡C—CH═CH—(CH 2 ) r —;

where r is an integer from 0 to 6;

Z 1 represents a hydrogen atom, or a halogen atom;

Z 2 represents an atom selected from a hydrogen and a halogen, or a group selected from a nitrile, and a group B, provided that if Z 2 ═B then the group -(L) n -B is absent from G;

the bonds mean that the double bond bearing Z 1 , respectively, Z 2 is of E or Z stereochemistry;

* is the carbon atom bearing R 2 or R 3 ;

G represents a phenyl or a heteroaryl:

When G is a phenyl, it is substituted by a group R 20 selected from OMe and SMe in the para position, relative to the position of the double bond bearing Z 1 and Z 2 ;

When G is a heteroaryl, it is selected from pyridines, indoles, 1-methylindoles, indolines, carbazoles, benzothiophenes and benzofurans;

R 2 represents an —OMe group;

E represents a hydrogen atom;

A represents an —OMe group;

R 1 represents an —OMe group;

the process comprising the following successive steps:

1. reacting a compound having the following general formula:

with tosylhydrazine to give the tosylhydrazone having the following general formula:

where X, Y, Z independently represent a carbon atom, and Z 1 , Z 2 , A, E, R 1 , R 2 , are as defined above;

2. metal-catalysed coupling the tosylhydrazone obtained in the preceding step with a compound having the general formula I-G-Hal to obtain the compound having the following general formula:

and Hal represents a halogen selected from a bromine atom and a chlorine atom, where G is as defined above;

3. metal-catalysed coupling carried out on the compound obtained in the preceding step followed by a treatment allowing the introduction of group -(L) n -B and obtaining the compound having the following general formula:

and where L, n and B are as defined above.

7. A pharmaceutical composition comprising at least one compound of formula (II) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7 , further comprising at least one other active principle, selected from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocine, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrozole, letrozole, tamoxifen, octreotide, lanreotide, (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]propionic acid, 4-((9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidol(5,4-d)(2)benzazepin-2-yl)amino)benzoic acid, 5,6-dimethylxanthenone-4-acetic acid and 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid.

9. A conjugate comprising the combination of:

an antibody, an antibody fragment or equivalent;

a linker molecule, and;

a compound according to claim 1 ;

covalently linked to each other.

10. The compound according to claim 1 , wherein B is

11. A method for treating cancer comprising administering to a person in need thereof an effective amount of a pharmaceutical composition comprising:

(i) at least one compound of formula (II) as defined in claim 1 , and

(ii) at least one other active principle

wherein the administration of said combination of products is simultaneous, separate or sequential.

12. A method for decreasing or inhibiting tubulin polymerisation and for decreasing or inhibiting HDACs comprising administering to a person in need thereof an effective amount of a compound according to claim 1 .

13. A method for treating cancer comprising administering to a person in need thereof an effective amount of a compound according to claim 1 .