Cytotoxic agents comprising new tomaymycin derivatives and their therapeutic use

1. A compound of formula (I):

wherein:

represents an optional single bond;

represents either a single bond or a double bond;

provided that when represents a single bond, U and U′, the same or different, independently represent H, and W and W′, the same or different, are independently selected from the group consisting of —OH, —OR, —OCOR, —COOR, —OCOOR, —OCONRR′, —NRCONRR′, —OCSNHR, —SH, —SR, —SOR, —SOOR, —SO 3 − , —NRSOOR′, —NRR′, —NROR′, —NRCOR′, —N 3 , —CN, Hal, a trialkyl, triarylphosphonium and a cyclic carbamate, a cyclic thiocarbamate or a cyclic amine where U and W and/or U′ and W′ taken together with the nitrogen and carbon atoms to which they are attached form the cyclic carbamate, the cyclic thiocarbarmate or the cyclic amine;

and when represents a double bond, U and U′ are absent and W and W′ represent H;

R1, R2, R1′, R2′ are the same or different and independently chosen from H, halide or alkyl optionally substituted by one or more Hal, CN, NRR′, CF 3 , OR, aryl, Het, or S(O) q R, or R1 and R2 and R1′ and R2′ form together a double bond containing group ═B and ═B′ respectively;

B and B′ are the same or different and independently chosen from Alkenyl being optionally substituted by one or more Hal, CN, NRR′, CF 3 , OR, SR, SOR, SO 2 R, Aryl, Het, or B and B′ represent an oxygen atom;

X, X′ are —O—;

A, A′ are the same or different and independently chosen from Alkyl or Alkenyl, each being optionally substituted by one or more Hal, CN, NRR′, CF 3 , OR, SR, SOR, SO 2 R, Aryl, Het, Alkyl, Alkenyl;

Y, Y′ are the same or different and independently chosen from H, OR;

T is —NR— or a 4 to 10-membered aryl, cycloalkyl, heterocyclic, heteroaryl or a linear or branched alkyl, each being substituted by one or more non-cleavable linker(s) and optionally substituted by one or more of Hal, CN, NRR′, CF 3 , R, OR, SOR or SO 2 R;

n, n′, equal or different, are 0 or 1;

q is 0, 1 or 2; and

R, R′ are equal or different and independently chosen from H, Alkyl, Aryl, each being optionally substituted by Hal, CN, COOH, COOR, CONHR, CONRR′, NRR′, CF 3 , R, OR, SOR, SO 2 R, Aryl, Het;

wherein the linker:

(A) is of formula -G-D-(Z) p C(═O)—Z′R″ wherein:

G is a single, a double or a triple bond, —O—, —S— or —NR—;

D is a single bond or -E-, -E-NR—F—, -E-O—, -E-O—F—, -E-NR—CO—, -E-CONR—, -E-NR—CO—F—, -E-CO—NR—F—, -E-CO—, —CO-E-, -E-CO—F, -E-S—, -E-S—F—, -E-NR—CS—, -E-CS—NR—, -E-NR—CS—F—, -E-CS—NR—F—;

E and F are the same or different and are independently chosen from linear or branched —(OCH 2 CH 2 ) i Alkyl(OCH 2 CH 2 ) j —, -Alkyl(OCH 2 CH 2 ) i -Alkyl-, —(OCH 2 CH 2 ) j —, —(OCH 2 CH 2 ) i Cycloalkyl(OCH 2 CH 2 ) j —, —(OCH 2 CH 2 ) i Heterocyclic(OCH 2 CH 2 ) j —, —(OCH 2 CH 2 ) i Aryl(OCH 2 CH 2 ) j —, —(OCH 2 CH 2 ) i Heteroaryl(OCH 2 CH 2 ) j —, -Alkyl-(OCH 2 CH 2 ) i Alkyl(OCH 2 CH 2 ) j —, -Alkyl-(OCH 2 CH 2 ) i —, -Alkyl-(OCH 2 CH 2 ) i Cycloalkyl(OCH 2 CH 2 ) j —, -Alkyl(OCH 2 CH 2 ) i Heterocyclic(OCH 2 CH 2 ) j —, -Alkyl-(OCH 2 CH 2 ) i Aryl(OCH 2 CH 2 ) j —, -Alkyl(OCH 2 CH 2 ) i Heteroaryl(OCH 2 CH 2 ) j —, -Cycloalkyl-Alkyl-, -Alkyl-Cycloalkyl-, -Heterocyclic-Alkyl-, -Alkyl-Heterocyclic-, -Alkyl-Aryl-, -Aryl-Alkyl-, -Alkyl-Heteroaryl-, -Heteroaryl-Alkyl-;

i and j, identical or different are integers and independently chosen from 0, 1 to 2000 ;

Z is a linear or branched Alkyl, cycloalkyl, Aryl, heteroaryl, heterocyclyl, aralkyl, cycloalkyl, heteroaralkyl, or heterocyclylalkyl, optionally substituted by solubilizing functions such as amino, ether, sulfonic and carboxylic groups;

p is 0 or 1; and

(B) is selected from the group consisting of:

—(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—(CR 13 R 14 ) t (OCH 2 CH 2 ) y O(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—(CR 13 R 14 ) t (NR 19 CO)(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—(CR 13 R 14 ) t (OCO)(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—(CR 13 R 14 ) t (CO)(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—(CR 13 R 14 ) t (CONR 19 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—(CR 13 R 14 ) t -phenyl-CO(CR 15 R 16 ) u COZ′R″, —(CR 13 R 14 ) t -furyl-CO(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t -oxazolyl-CO(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t -thiazolyl-CO(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t -thienyl-CO(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t -imidazolyl-CO(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t piperazino-CO(CR 15 R 16 ) u COZ′R″,

—(CR 13 R 14 ) t -phenyl-QCOZ′R″,

—(CR 13 R 14 ) t -furyl-QCOZ′R″, —(CR 13 R 14 ) t -oxazolyl-QCOZ′R″,

—(CR 13 R 14 ) t -thiazolyl-QCOZ′R″, —(CR 13 R 14 ) t -thienyl-QCOZ′R″,

—(CR 13 R 14 ) t -imidazolyl-QCOZ′R″, —(CR 13 R 14 ) t -piperazino-QCOZ′R″,

—(C≡C)—(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—O(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—O(CR 13 R 14 ) t (NR 19 CO)(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—O(CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—O-phenyl-QCOZ′R″, —O-furyl-QCOZ′R″, —O-oxazolyl-QCOZ′R″,

—O-thiazolyl-Q COZ′R″, —O-thienyl-QCOZ′R″, —O-imidazolyl-QSCOZ′R″,

—O-morpholino-QCOZ′R″, —O-piperazino-QCOZ′R″,

—OCO(CR 13 R 14 ) t (NR 19 CO)(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—OCO—(CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—OCONR 12 (CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—OCO-phenyl-QCOZ′R″, —OCO-furyl-QCOZ′R″, —OCO-oxazolyl-QCOZ′R″,

—OCO-thiazolyl-QCOZ′R″, —OCO-thienyl-QCOZ′R″, —OCO-imidazolyl-QCOZ′R″,

—OCO-piperazino-QCOZ′R″, or

—CO(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—CO—(CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—CONR 12 (CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—CO-phenyl-QCOZ′R″, —CO-furyl-QCOZ′R″-CO-oxazolyl-QCOZ′R″,

—CO-thiazolyl-QCOZ′R″, —CO-thienyl-QCOZ′R″, —CO-imidazolyl-QCOZ′R″,

—CO-piperazino-QCOZ′R″, —CO-piperidino-QCOZ′R″,

—NR 19 (CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—NR 19 CO(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—NR 19 (CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—NR 19 CO(CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—NR 19 CONR 12 (CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—NR 19 CONR 12 (CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—NR 19 CO-phenyl-QCOZ′R″, —NR 19 CO-furyl-QCOZ′R″, —NR 19 CO-oxazolyl-QCOZ′R″,

—NR 19 CO-thiazolyl-QCOZ′R″, —NR 19 CO-thienyl-QCOZ′R″,

—NR 19 CO-imidazolyl-QCOZ′R″, —NR 19 CO-morpholino-QCOZ′R″,

—NR 19 CO-piperazino-QCOZ′R″, —NR 19 CO-piperidino-QCOZ′R″,

—NR 19 -phenyl-QCOZ′R″, —NR 19 -furyl-QCOZ′R″, —NR 19 -oxazolyl-QCOZ′R″,

—NR 19 -thiazolyl-QCOZ′R″, —NR 19 -thienyl-QCOZ′R″, —NR 19 -imidazolyl-QCOZ′R″,

—NR 19 -piperazino-QCOZ′R″, —NR 19 -piperidino-QCOZ′R″,

—NR 19 CO—NR 12 -phenyl-QCOZ′R″, —NR 19 CO—NR 12 -oxazolyl-QCOZ′R″,

—NR 19 CO—NR 12 -thiazolyl-QCOZ′R″, —NR 19 CO—NR 12 -thienyl-QCOZ′R″,

—NR 19 CO—NR 12 -piperidino-QCOZ′R″,

—S(O) q (CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—S(O) q (CR 13 R 14 ) t (CR 17 ═CR 18 )(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″,

—SCONR 12 (CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″, —SCO-piperazino-QCOZ′R″, and —SCO-piperidino-QCOZ′R″,

wherein:

Q is a direct link or a linear alkyl or branched alkyl having from 1-10 carbon atoms or a polyethylene glycol spacer with 2 to 20 repeating ethyleneoxy units;

R 19 and R 12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having from 1 to 10 carbon atoms, or simple or substituted aryl or heterocyclic, and R 12 can in addition be H ;

R 13 , R 14 , R 15 and R 16 are the same or different and are H or a linear or branched alkyl having from 1 to 4 carbon atoms ;

R 17 and R 18 are H or alkyl ;

q is 0, 1 or 2 ;

u is an integer from 1 to 10 and can also be 0 ;

t is an integer from 1 to 10 and can also be 0 ;

y is an integer from 1 to 20 and can also be 0; and

(C) —C(═O)—Z′R″ is a carbonyl containing function wherein Z′ represents a single bond or —O—, —S—, —NR— and R″ represents H, Alkyl, Cycloalkyl, Aryl, heteroaryl or heterocyclic, each being optionally substituted by one or more Hal, CN, NRR′, CF 3 , R, OR, SOR, SO 2 R, Aryl, Het;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

2. The compound according to claim 1 wherein W and W′ are the same or different and are —OH, —OMe, —OEt, —NHCONH 2 , or —SMe;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

3. The compound according to claim 1 having the following formula (II):

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

4. The compound according to claim 1 , having formula:

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

5. The compound according to claim 1 wherein A=A′;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

6. The compound according to claim 1 wherein A=A′=linear unsubstituted alkyl;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

7. The compound according to claim 1 wherein Y═Y′;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

8. The compound according claim 2 wherein Y═Y′═OAlkyl;

or a pharmaceutically acceptable salt, optical isomer, racemate, diastereomer or enantiomer of said compound.

9. The compound according to claim 1 wherein T is a 4 to 10-membered aryl or heteroaryl;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

10. The compound according to claim 1 wherein T is a phenyl or pyridyl group;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

11. The compound according to claim 1 , wherein G is a single bond or —O—;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

12. The compound according to claim 1 , wherein D is a single bond or -E- or -E-O—;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

13. The compound according claim 1 , wherein D is -E-;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

14. The compound according to claim 13 wherein E is linear or branched -Alkyl- or -Alk(OCH 2 CH 2 ) i —;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

15. The compound according to claim 1 , wherein Z is linear or branched -Alkyl-;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

16. The compound according claim 1 wherein p is 0;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

17. The compound according to claim 1 wherein Z′ is a single bond or O;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

18. The compound according to claim 1 wherein Z′ is O;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

19. The compound according to claim 1 wherein R″ is H or linear or branched -Alkyl- or optionally substituted heterocyclic;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

20. The compound according to claim 1 wherein R″ is H or alkyl or a succinimide group

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

21. The compound according claim 1 wherein —Z′R″ is —OH, —Oalkyl or

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

22. The compound according to claim 1 wherein said linker is selected from the group consisting of:

—(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″;

—(CR 13 R 14 ) t (OCH 2 CH 2 ) y O(CR 15 R 16 ) u COZ′R″;

—O(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″;

—O(CR 13 R 14 ) t (NR 19 CO)(CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″;

—(C≡C)—(CR 13 R 14 ) t (CR 15 R 16 ) u (OCH 2 CH 2 ) y COZ′R″;

—O(CR 13 R 14 ) t COZ′R″;

—(OCH 2 CH 2 ) y COZ′R″;

—(C≡C)—(CR 13 R 14 ) t COZ′R″;

—O(CR 13 R 14 ) t (NR 19 CO)(CR 15 R 16 ) u COZ′R″; and

—(CR 13 R 14 ) t (OCH 2 CH 2 ) y COZ′R″;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

23. A compound of formula:

wherein:

-G-D-(Z) p —C(═O)—Z′R″ is as defined in claim 1 ;

M represents CH or N; and

Y═Y′═OMe;

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

24. A compound selected from the group consisting of:

4-(3,5-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4]benzodiazepin-5-one-8-yloxymethyl]-phenoxy)-butyric acid;

4-(3,5-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4]benzodiazepin-5-one-8-yloxymethyl]-phenoxy)-acetic acid;

3-(2-{2-[2-(3,5-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4]benzodiazepin-5-one-8-yloxymethyl]-phenoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid;

6-(3,5-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4] benzodiazepin-5-one-8-yloxymethyl]-phenyl)-hex-5-ynoic acid;

3-(2-{2-[2-(2,6-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4]benzodiazepin-5-one-8-yloxymethyl]-pyridin-4-yloxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid;

4-(2,6-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4]benzodiazepin-5-one-8-yloxymethyl]-pyridin-4-yloxy)-butyric acid;

N-[2-(3,5-Bis-[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1c][1,4]benzodiazepin-5-one-8-yloxymethyl]-phenoxy)-ethyl]-N-methyl-succinamic acid;

4-(3,5-Bis-[(S)-2-methylidene-7-methoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1 c][1,4] benzodiazepin-5-one-8-yloxymethyl]-phenyl)-propanoic acid;

(2-{2-[2-(2-{3-[3,5-Bis-(7-methoxy-2-methylene-5-oxo-2,3 ,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yloxymethyl)-phenyl]-propoxy}-ethoxy)ethoxy]-ethoxy}-ethoxy)-acetic acid; and

(3-{2-[2-(2-{3-[3,5-Bis-(7-methoxy-2-methylene-5-oxo-2,3 ,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yloxymethyl)-phenyl]-propoxy}-ethoxy)ethoxy]-ethoxy}-ethoxy)-propanoic acid;

and the corresponding N-hydroxysuccinimidyl esters thereof,

or a pharmaceutically acceptable salt thereof;

or optical isomers, racemates, diastereomers or enantiomers of said compound.

25. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier.

26. The compound of claim 1 , wherein Y═Y′═OMe.

27. The compound of claim 1 , wherein n=n′=1.

28. The compound of claim 1 , wherein B═B′=═CH 2 or ═CH—CH 3 .