Tubulysin analogues

1. Tubulysin compounds having the general formula (II)

wherein:

W is a group selected from OR 13 or NR 14 R 15 ,

X is a substituted five- or six-membered aromatic (arylene) or heteroaromatic ring (hetero-arylene),

Y is H, —CH 2 —, NH, NMe, a sulfur atom or an oxygen atom,

Z is a group selected from the group consisting of OR 16 , NR 17 R 18 ,

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 23 , R 24 and R 25 each independently represents H, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroalkyl, and where R 1 and R 3 or R 1 and R 2 may be linked to form together with the nitrogen atom a five-membered pyrrolidine ring or a six-membered piperidine ring,

R 12 is H, H an acyl group (C(O)R), a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl, with R being a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl,

R 19 represents H, halogen, nitro, amine, monoalkylamine or dialkylamine group, hydroxyl, alkyloxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroalkyl; in positions 2 and/or 3 and/or 4, and/or 5, and/or 6, or in any combination thereof,

R 22 represents OH, NH 2 , alkyloxy, alkylamino or dialkylamino group, or a linker,

V is a sulfur or oxygen atom, —CH 2 —, NH or NH-alkyl group,

and pharmaceutical acceptable salts, hydrates, solvates, prodrugs, metabolites, stereoisomers, stereoisomeric mixtures, and polymorphs thereof.

2. The tubulysin compounds according to claim 1 , wherein Y is an oxygen atom and X is a thiazole or an oxazole.

3. The tubulysin compounds according to claim 1 , wherein R 1 and R 3 are linked to form a piperidine moiety.

4. The tubulysin compounds according to claim 1 , wherein Z is tubuphenylalanyl (Tup).

5. The tubulysin compounds according to claim 1 , wherein W is NR 14 R 15 .

6. The tubulysin compounds according to claim 1 having the general formula (III):

wherein:

R′ is H or a methyl group,

R 14 , R 15 and Z are defined as above.

7. The tubulysin compounds according to claim 1 , wherein the compounds are selected from the group consisting of

8. The tubulysin compounds according to claim 1 , wherein the compounds are conjugated to

(i) biomolecules for the target-oriented delivery, or

(ii) molecular moieties, which can improve their solubility, penetration, detection, release or selectivity.

9. The tubulysin compounds according to claim 8 , wherein the biomolecule is a peptide, functional protein, enzyme, antigen, antibody, (oligo)saccharide, (poly)saccharide, nucleic acid, hormone or hormone receptor binder, or vitamin.

10. The tubulysin compounds according to claim 8 , wherein the molecular moieties are selected from polyethyleneglycols, polyamines, polyguanidines, dyes, receptor ligands, or polymers.

11. A pharmaceutical formulation comprising one or more of the tubulysin compounds according to claim 1 and one or more pharmaceutically acceptable carriers, adjuvants and/or diluents.

12. A method for the treatment of proliferative disorders comprising administering a tubulysin compounds according to claim 1 .

13. A method of producing compounds having the general formula (IV) by an Ugi-type reaction for the generation of the tertiary amide bond, as shown below

wherein:

X is a substituted five- or six-membered aromatic (arylene) or heteroaromatic ring (heteroarylene),

Y is H, —CH 2 —, NH, NMe, a sulfur atom or an oxygen atom,

Z is a group selected from the group consisting of OR 16 , NR 17 R 18 ,

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 17 , R 18 , R 20 , R 21 , R 23 , R 24 and R 25 each independently represents H, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroalkyl, and where R 1 and R 3 or R 1 and R 2 may be linked to form together with the nitrogen atom a five-membered pyrrolidine ring or a six-membered piperidine ring,

R 12 is H, H an acyl group (C(O)R), a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl, with R being a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl,

R 14 , R 16 is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroalkyl, or a usual O-protective group,

R 19 represents H, halogen, nitro, amine, monoalkylamine or dialkylamine group, hydroxyl, alkyloxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroalkyl; in positions 2 and/or 3 and/or 4, and/or 5, and/or 6; or in any combination thereof,

R 22 represents NH 2 , alkyloxy, alkylamino or dialkylamino group, or a linker, and

V is a sulfur or oxygen atom, —CH 2 —, NH or NH-alkyl group.