Metallocene derivatives with anticancer activity

1. A compound of the following formula (I):

or a pharmaceutically acceptable salt or solvate thereof, a stereoisomer or a mixture of stereoisomers in any ratio, or a water-soluble derivative,

in which:

M is Fe, Ru or Os,

n is an integer comprised between 1 and 8,

R1 and R2 are, independently from each other, H, CF 3 , CN, OR 4 or NR 5 R 6 , and

R3 is CO 2 R 7 , OR 8 or NR 9 R 10 ,

wherein:

R 4 is H, (C 1 -C 6 )alkyl, —CO—(C 1 -C 6 )alkyl or —(CH 2 ) m NR 11 R 12 ,

R 5 , R 6 , R 11 and R 12 are, independently from one another, H, (C 1 -C 6 )alkyl or —CO—(C 1 -C 6 )alkyl,

R 7 is H or (C 1 -C 6 )alkyl,

R 8 is H, (C 1 -C 6 )alkyl or —CO—(C 1 -C 6 )alkyl,

R 9 and R 10 are, independently from one another, H, (C 1 -C 6 )alkyl or —CO—(C 1 -C 6 )alkyl, or

R 9 and R 10 form together with the nitrogen atom bearing them a cycle of the following formula:

in which:

represents a single or double bond,

X1 and X2 are, independently from one another, C═O, SO 2 , CH—OR 19 , CH—SR 20 , CH—NR 21 R 22 or CH—NHC(O)R 23 ,

R 13 and R 14 are, independently from one another, H or (C 1 -C 6 )alkyl, or

R 13 and R 14 form together with the carbon atoms bearing them a 5- or 6-membered hydrocarbon cycle,

R 19 , R 20 , R 21 and R 22 are, independently from one another, H or (C 1 -C 6 )alkyl, and

R 23 is a (C 1 -C 6 )alkyl group, and

m is an integer comprised between 1 and 8.

2. The compound according to claim 1 , wherein n is an integer comprised between 2 and 6.

3. The compound according to claim 1 , wherein it has the following formula (Ia):

4. The compound according to claim 1 , wherein M is Fe.

5. The compound according to claim 1 , wherein R1 and R2 are, independently from each other, H, OR 4 or NR 5 R 6 .

6. The compound according to claim 1 , wherein one of R1 and R2 is OR 4 and the other is H or OR 4 .

7. The compound according to claim 1 , wherein R3 is CO 2 R 7 , OR 8 or NR 9 R 10 with:

R 7 being a —(C 1 -C 6 )alkyl group,

R 8 being H, and

at least one of R 9 and R 10 being, independently from one another, —CO—(C 1 -C 6 )alkyl, or R 9 and R 10 forming together with the nitrogen atom bearing them a cycle of the following formula:

in which , R 13 and R 14 are as defined in claim 1 , and at least one of X1 and X2 is C═O.

8. The compound according to claim 1 , selected from the following compounds:

and pharmaceutically acceptable salts and solvates thereof.

9. A pharmaceutical composition comprising at least one compound according to claim 1 , in combination with at least one pharmaceutically acceptable vehicle.

10. The pharmaceutical composition according to claim 9 , further comprising at least one additional active ingredient.

11. The pharmaceutical composition according to claim 10 , wherein the at least one additional active ingredient is selected from 6-mercaptopurin, fludarabin, cladribin, pentostatin, cytarabin, 5-fluorouracil, gemcitabin, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethin, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustin, fotemustin, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazin, dacarbazin, bleomycin, vinblastin, vincristin, vindesin, vinorelbin, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide and lanreotide.

12. A process for preparing a compound of formula (I) according to claim 1 , in which R3 is CO 2 —(C 1 -C 6 )alkyl or OR 8 with R 8 H, comprising the following steps:

(i) McMurry coupling between a compound of the following formula (II):

wherein M and n are as defined in claim 1 and R3 is as defined above, and a compound of the following formula (III):

wherein R1 and R2 are as defined in claim 1 ,

to give a compound of formula (I) as defined above, and

(ii) optionally salification or solvatation of the compound of formula (I) obtained in step (i) to give a pharmaceutically acceptable salt or solvate thereof.

13. A process for preparing a compound of formula (I) according claim 1 , in which R3 is OR 8 , comprising the following steps:

(a) reduction of a compound of the following formula (lb):

wherein M, n, R1 and R2 are as defined in claim 1 and Alk is (C 1 -C 6 )alkyl, to give a compound of formula (I) in which R3 is OH,

(b) optionally substitution of the compound obtained in step (a) to give a compound of formula (I) in which R3 is OR 8 with R 8 H, and

(c) optionally salification or solvatation of the compound of formula (I) obtained in step (a) or (b) to give a pharmaceutically acceptable salt or solvate thereof.

14. A process for preparing a compound of formula (I) according to claim 1 , in which R3 is COOH, comprising the following steps:

(1) saponification of a compound of the following formula (Ic):

wherein M, n, R1 and R2 are as defined in claim 1 and Alk is (C 1 -C 6 )alkyl, to give a compound of formula (I) in which R3 is COOH, and

(2) optionally salification or solvatation of the compound of formula (I) obtained in step (1) to give a pharmaceutically acceptable salt or solvate thereof.

15. A process for preparing a compound of formula (I) according to claim 1 , in which R3 is NR 9 R 10 , comprising the following steps:

(A) reaction of a compound of the following formula (Id):

wherein M, n, R1 and R2 are as defined in claim 1 and Hal is a halogen atom,

with a compound of formula HNR 9 R 10 ,

to give a compound of formula (I) in which R3 is NR 9 R 10 , and

(B) optionally salification or solvatation of the compound of formula (I) obtained in step (A) to give a pharmaceutically acceptable salt or solvate thereof.

16. A method for the treatment of cancer comprising administering to a patient in need thereof an effective amount of a compound according to claim 1 .

17. The method according to claim 16 , wherein the compound is used alone or in combination, simultaneously, separately or sequentially, with ionizing or non-ionizing radiations or with at least one additional active ingredient.

18. The method according to claim 17 , wherein the at least one additional active ingredient is selected from 6-mercaptopurin, fludarabin, cladribin, pentostatin, cytarabin, 5-fluorouracil, gemcitabin, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethin, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustin, fotemustin, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazin, dacarbazin, bleomycin, vinblastin, vincristin, vindesin, vinorelbin, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide and lanreotide.