N-carboxyalkyl-auristatin and the use thereof

1. A compound of formula (I)

or a salt or solvate thereof, wherein

L is a straight-chain (C 1 -C 12 )-alkandiyl, optionally substituted with methyl up to four times and in which (a) two carbon atoms is optionally connected to each other in 1,2-, 1,3-, or 1,4 relation, if necessary including carbon atoms that are located between them to form a (C 3 -C 6 )-cycloalkyl-ring or a phenyl ring or (b) up to three CH 2 groups not adjacent to each other are optionally substituted for an O,

R 1 is hydrogen or methyl,

R 2 is isopropyl, isobutyl, sec.-butyl, tert.-butyl, 1-hydroxyethyl, phenyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl, or 1H-indol-3-ylmethyl,

or

R 1 and R 2 , together with the carbon atom to which they are both connected, form a 2-phenylcyclopropan-1,1-diyl group of the formula

wherein

# marks the points of attachment with other parts of the molecule,

and

T is a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6 , or —CH 2 —O—R 7 in which

R 3 is hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 10 )-cycloalkyl, wherein (C 1 -C 6 )-alkyl is optionally substituted with phenyl, naphthyl, or (C 3 -C 10 )-cycloalkyl,

R 4 is hydrogen or (C 1 -C 6 )-alkyl,

R 5 is hydrogen, (C 1 -C 6 )-alkyl, or (C 3 -C 10 )-cycloalkyl, wherein (C 1 -C 6 )-alkyl is optionally substituted with phenyl,

or

R 4 and R 5 are connected to each other and, together with the nitrogen atom they are attached to, form a 5- to 7-membered, saturated aza-heterocyclic compound, which may optionally contain a further ring-heteroatom selected from the group consisting of >N—H, >N—CH 3 , or —O—; and wherein said further ring-heteroatom is located either at the 1,3- or 1,4-location in relation to the aforementioned nitrogen atom,

R 6 is (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylcarbonyl, phenyl, or benzoyl, and

R 7 is (C 1 -C 6 )-alkyl, optionally substituted with phenyl, where phenyl is optionally substituted with (C 1 -C 6 )-alkoxycarbonyl or carboxyl.

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

L is a straight-chain (C 1 -C 8 )-alkandiyl, in which (a) two carbon atoms are optionally linked to each other in 1,3 or 1,4 relation including one or two carbon atoms located between them to form a phenyl ring or (b) up to two CH 2 groups not adjacent to each other which is optionally substituted for an O,

R 1 is hydrogen,

R 2 is benzyl, 4-hydroxybenzyl, 1-phenylethyl, or 1H-indol-3-ylmethyl,

or

R 1 and R 2 , together with the carbon atom to which they are both connected, form a 2-phenylcyclopropan-1,1-diyl group of the formula

wherein

# marks the points of attachment with other parts of the molecule,

and

T is a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6 , or —CH 2 —O—R 7 in which

R 3 is hydrogen or (C 1 -C 4 )-alkyl, which is optionally substituted with phenyl, naphthyl, or (C 3 -C 10 )-cycloalkyl,

R 4 is hydrogen or methyl,

R 5 is hydrogen or (C 1 -C 4 )-alkyl, which is optionally substituted with phenyl,

or

R 4 and R 5 are connected to each other and together with the nitrogen atom they are attached to, form a piperidine- or morpholine ring,

R 6 is (C 1 -C 4 )-alkylcarbonyl or benzoyl,

and

R 7 is (C 1 -C 4 )-alkyl or benzyl, which, in the phenyl group, is optionally substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl.

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

L is a straight-chain (C 1 -C 6 )-alkandiyl,

R 1 is hydrogen,

R 2 is benzyl, 1-phenylethyl or 1-H-indol-3-ylmethyl,

or

R 1 and R 2 , together with the carbon atom they are both attached to, form a (1S,2R)-2-phenylcyclopropan-1,1-diyl group of the formula

wherein

#1 marks the point of attachment with the adjacent nitrogen atom

and

#2 marks the point of attachment of group T,

and

T is a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6 , or —CH 2 —O—R 7 in which

R 3 is hydrogen, methyl, ethyl, n-propyl, benzyl, or adamantylmethyl,

R 4 is hydrogen or methyl,

R 5 is hydrogen, methyl, ethyl, n-propyl, or benzyl,

R 6 is benzoyl,

and

R 7 is benzyl, which is optionally substituted with methoxycarbonyl or carboxyl in the phenyl group.

4. The compound of claim 1 or a salt or solvate thereof, wherein said compound has the formula (IA)

wherein L, R 1 , R 2 , and T have the meaning indicated in claim 1 , and the radicals R 1 and R 2 supporting C X -carbon atom has the pictured configuration.

5. A method for producing the compound of claim 1 , the method comprising providing a compound of formula (II)

wherein R 1 , R 2 , and T have the meaning indicated in claim 1 ;

and coupling in an inert solvent the compound of formula (II) either by

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

wherein

L has the meaning indicated 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 produce a compound of formula (IV)

wherein E 1 , L, R 1 , R 2 , and T are defined as above,

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

or

[B] treatment with a compound of formula (V)

wherein

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

and

L A has the meaning indicated in claim 1 , however, with the alkyl chain-length shortened by one CH 2 -unit,

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

wherein E 1 , L A , R 1 , R 2 , and T are defined as above,

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

in which L A , R 1 , R 2 , and T are defined as above.

6. A pharmaceutical composition comprising a compound as defined in claim 1 , and further comprising one or more inert, non-toxic, pharmaceutically suitable agents.

7. The pharmaceutical composition of claim 6 , further comprising one or more additional cytostatic or cytotoxic agents.

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 compound of claim 1 .

9. 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 6 .

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

or a salt or solvate thereof.

11. The compound of claim 10 , wherein said compound is selected from the group consisting of:

or a salt or solvate thereof.

12. The compound of claim 10 , wherein said compound is selected from the group consisting of:

or a salt or solvate thereof.

13. The compound of claim 10 , wherein said compound is selected from the group consisting of:

or a salt or solvate thereof.

14. The compound of claim 10 , wherein said compound is selected from the group consisting of:

or a salt or solvate thereof.

15. The compound of claim 10 , wherein said compound is selected from the group consisting of:

or a salt or solvate thereof.

16. The compound of claim 14 , wherein the compound is

or a salt or solvate thereof.