N-carboxyalkylauristatins and use thereof

1. A compound of formula (I)

or a salt or solvate thereof, in which

L is linear (C 1 -C 12 )-alkanediyl, which may be substituted with methyl up to four times and in which (a) two carbon atoms in 1,2-, 1,3- or 1,4-relation to one another are optionally bridged by including the carbon atoms optionally between them to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring, or (b) up to three CH 2 groups not vicinal to one another are optionally replaced by —O—,

and

T is a group of the formula

wherein

* denotes the linkage site to the nitrogen atom,

R 1 is phenyl or 1H-indol-3-yl,

and

R 2 is hydrogen or a group of the formula

wherein

** denotes the respective linkage site to the radical of the respective group T,

A is linear (C 1 -C 4 )-alkanediyl or linear (C 2 -C 4 )-alkenediyl,

R 3 is phenyl that is optionally substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl,

n is the number 0, 1 or 2,

R 4 is phenyl, benzyl or 2-phenylethyl which is optionally substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl in the phenyl group

Het is a divalent 5-membered heteroaryl ring with up to three ring heteroatoms from the series N, O and/or S,

and

R 5 is (C 3 -C 6 )-cycloalkyl, phenyl or (C 1 -C 4 )-alkyl, which is optionally substituted with phenyl, wherein the aforementioned phenyl groups are optionally substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl.

2. The compound of claim 1 or a salt or solvate thereof, wherein

L is linear (C 1 -C 8 )-alkanediyl, in which (a) two carbon atoms in 1,3- or 1,4-relation to one another are optionally bridged by including one or two of the carbon atoms between them to form a phenyl ring, or (b) up to two CH 2 groups not vicinal to one another are optionally replaced by —O—,

and

T is a group of the formula

wherein

* denotes the linkage site to the nitrogen atom,

R 1 is phenyl or 1H-indol-3-yl,

and

R 2 is hydrogen or a group of the formula

wherein

** denotes the linkage site to the radical of the respective group T,

A is ethene-1,2-diyl or propene-1,3-diyl,

R 3 is phenyl, which is optionally substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl,

Het is a divalent 5-membered heteroaryl ring selected from the series of pyrazolyl, imidazolyl, 1,3-oxazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl,

and

R 5 is a phenyl, which is optionally may be substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl.

3. The compound of claim 1 or a salt or solvate thereof, wherein

L is linear (C 1 -C 6 )-alkanediyl,

and

T is a group of the formula

wherein

* denotes the linkage site to the nitrogen atom,

and

R 2 is hydrogen or a group of the formula

wherein

** denotes the linkage site to the radical of the respective group T,

A is ethene-1,2-diyl,

R 3 is phenyl, which is optionally substituted with methoxycarbonyl or carboxyl,

Het is 1,3,4-oxadiazol-2,5-yl,

and

R 5 is a phenyl, which is optionally substituted with methoxycarbonyl or carboxyl.

4. A method for preparing a compound of claim 1 or a salt or solvate thereof, the method comprising providing a compound of formula (II)

in which T has the meaning given in claim 1 ,

and reacting the compound of formula (II) in an inert solvent, either

[A] by base-induced alkylation with a compound of formula (III)

in which L has the meaning given in claim 1 ,

E 1 is hydrogen, (C 1 -C 4 )-alkyl or benzyl,

and

X is a leaving group selected from the group consisting of chloride, bromide, iodide, mesylate, triflate, and tosylate,

to form a compound of formula (IV)

in which L and T have the meanings given in claim 1 ,

and E 1 is hydrogen, (C 1 -C 4 )-alkyl or benzyl, wherein, when E 1 is (C 1 -C 4 )-alkyl or benzyl, the ester radical is removed, thereby producing a hydrogen at E 1 in formula (III), thus producing the carboxylic acid of formula (I);

or

[B] with a compound of formula (V)

wherein

E 1 is hydrogen, (C 1 -C 4 )-alkyl or benzyl,

and

L A has the meaning of L given in claim 1 , but is shortened by one CH 2 unit in the alkyl chain length,

in the presence of a suitable reducing agent to produce a compound of formula (VI)

in which L A has the meaning of L given in claim 1 , but is shortened by one CH 2 unit in the alkyl chain length,

T has the meaning given in claim 1 , and

E 1 is hydrogen, (C 1 -C 4 )-alkyl or benzyl, wherein, when E 1 stands for (C 1 -C 4 )-alkyl or benzyl, the ester radical is removed, thereby producing a hydrogen at E 1 in formula (V),

thus producing the carboxylic acid of formula (I-A)

in which L A has the meaning of L given in claim 1 , but is shortened by one CH 2 unit in the alkyl chain length, and T has the meaning given in claim 1 .

5. A pharmaceutical composition comprising a compound as defined in claim 1 or a salt or solvate thereof, and further comprising one or more inert, non-toxic, pharmaceutically suitable excipients.

6. The pharmaceutical composition of claim 5 , further comprising one or more additional active ingredients.

7. A method for the treatment of cancer or tumor conditions in humans or animals, said method comprising administering to a subject an effective amount of at least one compound as defined in claim 1 .

8. A method for treatment of cancer or tumor diseases in humans or animals, said method comprising administering to a subject an effective amount of at least one pharmaceutical composition of claim 5 .

9. The compound of claim 1 , wherein said compound is selected from the group consisting of:

10. An antiproliferative conjugate in which a compound of claim 1 is connected with a protein.

11. The antiproliferative conjugate according to claim 10 , wherein the protein is an antibody.

12. An antiproliferative conjugate in which a compound of claim 8 is connected with a protein.

13. The antiproliferative conjugate according to claim 12 , wherein the protein is an antibody.