US2013122024A1PendingUtilityA1
New binder-drug conjugates (adcs) and use thereof
Est. expiryApr 21, 2031(~4.8 yrs left)· nominal 20-yr term from priority
Inventors:Hans-Georg LerchenBeatrix Stelte-LudwigSven GolfierCharlotte Christine KopitzRudolf BeierSherif El SheikhIring HeislerAxel HarrengaKarl-Heinz ThierauchJoachim SchuhmacherSandra BruderSimone GrevenLars LindenJörg WilludaChristoph MahlertHeike PetrulHannah JörißenSandra Borkowski
A61P 43/00A61P 9/00A61P 35/00A61P 35/02C07K 5/0207C07K 7/02C07K 5/0205A61K 45/06C07K 16/2863C07K 5/06052A61K 31/5377C07K 2317/76A61K 47/50C07K 5/06034A61K 31/5355C07K 16/2812A61K 38/00A61K 31/4245A61K 47/6869C07K 16/30A61K 31/40C07K 16/18A61K 31/537A61K 31/404A61K 31/536C07K 16/28A61K 47/542A61K 47/6889A61K 39/3955A61K 31/422C07K 5/0606C07K 2317/24C07K 7/06C07K 5/06C07K 2317/21A61K 31/4025A61K 47/6859A61K 47/6851C07K 2317/565A61K 47/68031
57
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Claims
Abstract
The present application relates to new binder-drug conjugates (ADCs) of N,N-dialkylauristatins that are directed against the target mesothelin, to active metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for treating and/or preventing illnesses, and also to the use of these ADCs for producing medicaments for treating and/or preventing illnesses, more particularly hyperproliferative and/or angiogenic diseases such as, for example, cancer diseases. Such treatments may be practised as a monotherapy or else in combination with other medicaments or further therapeutic measures.
Claims
exact text as granted — not AI-modified1 . Binder-drug conjugates of the general formula (Ia)
in which
n is a number from 1 to 50,
AK is a binder,
the group §-G-L 1 -B-L 2 -§§ is a linker,
where
§ marks the linkage site with the group AK and
§§ marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen or methyl,
R 2 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen or methyl,
R 4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
2 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , in which
n is a number from 1 to 50, AK is AK 1 or AK 2 where
AK 1 is a binder which is bonded via a sulphur atom of the binder to the group G,
AK 2 is a binder which is bonded via a nitrogen atom of the binder to the group G,
G when AK=AK 1 , is a group of the formula
where
# 1 marks the linkage site with the sulphur atom of the binder,
# 2 marks the linkage site with the group L 1 ,
or
when AK=AK 2 , is carbonyl,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl, a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
L 1A is linear (C 2 -C 10 )-alkanediyl,
B 1 is a group of the formula
in which
## 5 marks the linkage site with the group L 1A ,
## 6 marks the linkage site with the group L 1B ,
L 5 is a bond or (C 2 -C 4 )-alkanediyl,
L 6 is a bond or a group of the formula
in which
## 7 marks the linkage site with the carbonyl group,
## 8 marks the linkage site with L 1B ,
R 33 is hydrogen, (C 1 -C 4 )-alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
R 34 is hydrogen or methyl,
R 29 is hydrogen or (C 1 -C 4 )-alkyl,
R 30 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 29 and R 30 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 31 is hydrogen or (C 1 -C 4 )-alkyl,
R 32 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 31 and R 32 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
L 1B is linear (C 2 -C 10 )-alkanediyl,
and
where (C 1 -C 10 )-alkanediyl may be substituted by 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxy and benzyl,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
P is O or NH,
L 3 is a bond or (C 2 -C 4 )-alkanediyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is hydrogen or methyl,
R 28 is hydrogen, (C 1 -C 4 )-alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
Q 1 is a 4- to 7-membered heterocycle,
Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,
R 14 is hydrogen or (C 1 -C 4 )-alkyl,
R 15 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 14 and R 15 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 16 is hydrogen or (C 1 -C 4 )-alkyl,
R 17 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 18 is hydrogen or (C 1 -C 4 )-alkyl,
R 19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R 20 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or (C 1 -C 4 )-alkyl,
R 22 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R 23 is (C 1 -C 4 )-alkyl,
R 24 is hydrogen or (C 1 -C 4 )-alkyl,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
R 36 is hydrogen, (C 1 -C 4 )-alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
R 37 is hydrogen or methyl,
or
R 36 and R 37 together with the atoms to which they are bonded form a pyrrolidine ring,
L 2 is linear (C 2 -C 10 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxy and benzyl,
and
where two carbon atoms of the alkanediyl chain in 1,2-, 1,3- or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
D is a group of the formula
in which
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen or methyl,
R 2 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen or methyl,
R 4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
3 . Binder-drug conjugates of the general formula (Ia) according to claim 1 or 2 , in which
n is a number from 1 to 20,
AK is AK 1 or AK 2
where
AK 1 is an antibody or an antigen-binding antibody fragment which binds to mesothelin and is bonded via the sulphur atom of a cysteine residue of the binder to the group G,
AK 2 is an antibody or an antigen-binding antibody fragment which binds to mesothelin and is bonded via the NH side group of a lysine residue of the binder to the group G,
G when AK=AK 1 , is a group of the formula
in which
# 1 marks the linkage site with the cysteine residue of the binder,
# 2 marks the linkage site with the group L 1 ,
or
when AK=AK 2 , is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
L 1A is linear (C 2 -C 6 )-alkanediyl,
B 1 is a group of the formula
in which
## 5 marks the linkage site with the group L 1A ,
## 6 marks the linkage site with the group L 1B ,
L 5 is a bond,
L 6 is a bond or a group of the formula
in which
## 7 marks the linkage site with the carbonyl group,
## 8 marks the linkage site with L 1B ,
R 33 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
R 34 is hydrogen or methyl,
R 29 is hydrogen,
R 30 is hydrogen,
R 31 is hydrogen or methyl,
R 32 is hydrogen or methyl,
L 1B is linear (C 2 -C 6 )-alkanediyl,
and
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is hydrogen or methyl,
R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
Q 1 is a 4- to 7-membered heterocycle,
R 14 is hydrogen,
R 15 is hydrogen,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a piperazinyl ring,
R 18 is hydrogen,
R 19 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
R 20 is hydrogen or methyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or methyl,
R 22 is hydrogen or methyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
R 27 is hydrogen,
R 36 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
R 37 is hydrogen or methyl,
or
R 36 and R 37 together with the atoms to which they are bonded form a pyrrolidine ring,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
4 . Binder-drug conjugates of the general formula (Ia) according to any of claims 1 to 3 , in which
n is a number from 1 to 10,
AK is AK 1 or AK 2
where
AK 1 is an antibody which comprises the six CDR sequences of the antibody MF-Ta, the variable light and variable heavy chain of the antibody MF-Ta or the light and heavy chain of the antibody MF-Ta, and is bonded via the sulphur atom of a cysteine residue of the binder to the group G,
AK 2 is an antibody which comprises the six CDR sequences of the antibody B01-3, B01-10, M31-B01 or D02-6, the variable light and variable heavy chain of the antibody B01-3, B01-10, M31-B01 or D02-6 or the light and heavy chain of the antibody B01-3, B01-10, M31-B01 or D02-6, and is bonded via the NH side group of a lysine residue of the binder to the group G,
G when AK=AK 1 , is a group of the formula
in which
# 1 marks the linkage site with the cysteine residue of the binder,
# 2 marks the linkage site with the group L 1 ,
or
when AK=AK 2 , is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, a group of the formula
where
m is a number 2 or 3,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is methyl,
R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
Q 1 is piperidine-1,4-diyl,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a piperazinyl ring,
R 21 is hydrogen or methyl,
R 22 is hydrogen or methyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen,
R 36 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
R 37 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHCH 2 phenyl,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
5 . Binder-drug conjugates of the general formula (Ia) according to any of claims 1 to 4 , in which
n is a number from 1 to 10,
AK is AK 2
where
AK 2 is an antibody which comprises the six CDR sequences of the antibody MF-Ta, the variable light and variable heavy chain of the antibody MF-Ta or the light and heavy chain of the antibody MF-Ta, and is bonded via the NH side group of a lysine residue of the binder to the group G,
G is carbonyl,
L 1 is a bond,
B is a bond,
L 2 is linear (C 3 -C 6 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 3 is hydrogen,
R 4 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 or —C(═O)—NR 8 R 9
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen,
R 9 is hydrogen or benzyl,
R 35 is methyl,
and also their salts, solvates and solvates of the salts.
6 . Binder-drug conjugates of the general formula (Ia) according to any of claims 1 to 4 , in which
n is a number from 1 to 10,
AK is AK 1 ,
where
AK 1 is an antibody which comprises the six CDR sequences of the antibody MF-Ta, the variable light and variable heavy chain of the antibody MF-Ta or the light and heavy chain of the antibody MF-Ta, and is bonded via the sulphur atom of a cysteine residue of the binder to the group G,
G is a group of the formula
where
# 1 marks the linkage site with the cysteine residue of the binder,
# 2 marks the linkage site with the group L 1 ,
L 1 is a bond, linear (C 3 -C 5 )-alkanediyl or a group of the formula
where
m is a number 2 or 3,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 3 -C 5 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is methyl,
R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a piperazinyl ring,
L 2 is linear (C 3 -C 5 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 3 is hydrogen,
R 4 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 or —C(═O)—NR 8 R 9 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen,
R 9 is hydrogen or benzyl,
R 35 is methyl,
and also their salts, solvates and solvates of the salts.
7 . Compounds of the formula (XXXa)
in which
Cys is a cysteine residue which is bonded via the sulphur atom of the side chain to a carbon atom of the succinimide,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl, a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
L 1A is linear (C 2 -C 10 )-alkanediyl,
B 1 is a group of the formula
in which
## 5 marks the linkage site with the group L 1A ,
## 6 marks the linkage site with the group L 1B ,
L 5 is a bond or (C 2 -C 4 )-alkanediyl,
L 6 is a bond,
R 29 is hydrogen or (C 1 -C 4 )-alkyl,
R 30 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 29 and R 30 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 31 is hydrogen or (C 1 -C 4 )-alkyl,
R 32 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 31 and R 32 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
L 1B is linear (C 2 -C 10 )-alkanediyl,
and
where (C 1 -C 10 )-alkanediyl may be substituted by 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxy and benzyl,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
P is O or NH,
L 3 is a bond or (C 2 -C 4 )-alkanediyl,
L 4 is a bond,
Q 1 is a 4- to 7-membered heterocycle,
Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,
R 14 is hydrogen or (C 1 -C 4 )-alkyl,
R 15 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 14 and R 15 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 16 is hydrogen or (C 1 -C 4 )-alkyl,
R 17 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 18 is hydrogen or (C 1 -C 4 )-alkyl,
R 19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R 20 hydrogen or (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or (C 1 -C 4 )-alkyl,
R 22 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R 23 is (C 1 -C 4 )-alkyl,
R 24 is hydrogen or (C 1 -C 4 )-alkyl,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
L 2 is linear (C 2 -C 10 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxy and benzyl,
and
where two carbon atoms of the alkanediyl chain in 1,2-, 1,3- or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen or methyl,
R 2 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen or methyl,
R 4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T2,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
8 . Compounds of the formula (XXXa) according to claim 7 , in which
Cys is a cysteine residue which is bonded via the sulphur atom of the side chain via a carbon atom of the succinimide, L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, a group of the formula
where
m is a number 2 or 3,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
L 1A is linear (C 2 -C 6 )-alkanediyl,
B 1 is a group of the formula
in which
## 5 marks the linkage site with the group L 1A ,
## 6 marks the linkage site with the group L 1B ,
L 5 is a bond,
L 6 is a bond,
R 29 is hydrogen,
R 30 is hydrogen,
R 31 is hydrogen or methyl,
R 32 is hydrogen or methyl,
L 1B is linear (C 2 -C 6 )-alkanediyl,
and
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond,
R 14 is hydrogen,
R 15 is hydrogen,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form piperazinyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site to —CHCH 2 phenyl,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
9 . Compounds of the formula (XXXa) according to either of claim 7 or 8 , in which
Cys is a cysteine residue which is bonded via the sulphur atom of the side chain via a carbon atom of the succinimide,
L 1 is a bond or linear (C 2 -C 6 )-alkanediyl,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond,
L 4 is a bond,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is benzyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 3 is hydrogen,
R 4 is benzyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 or —C(═O)—NR 8 R 9 ,
in which
R 7 is hydrogen,
R 8 is hydrogen,
R 9 is hydrogen,
R 35 is methyl,
and also their salts, solvates and solvates of the salts.
10 . Compounds of the formula (XXXI)
in which
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl, a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
L 1A is linear (C 2 -C 10 )-alkanediyl,
B 1 is a group of the formula
in which
## 5 marks the linkage site with the group L 1A ,
## 6 marks the linkage site with the group L 1B ,
L 5 is a bond or (C 2 -C 4 )-alkanediyl,
L 6 is a bond,
R 29 is hydrogen or (C 1 -C 4 )-alkyl,
R 30 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 29 and R 30 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 31 is hydrogen or (C 1 -C 4 )-alkyl,
R 32 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 31 and R 32 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
L 1B is linear (C 2 -C 10 )-alkanediyl,
and
where (C 1 -C 10 )-alkanediyl may be substituted by 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxy and benzyl,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
P is O or NH,
Q 1 is a 4- to 7-membered heterocycle,
Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,
R 18 is hydrogen or (C 1 -C 4 )-alkyl,
R 19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R 20 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or (C 1 -C 4 )-alkyl,
R 22 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
L 2 is linear (C 2 -C 10 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxy and benzyl,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
D is a group of the formula
in which
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen or methyl,
R 2 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen or methyl,
R 4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
11 . Compounds of the formula (XXXI) according to claim 10 , in which
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl or a group of the formula
where
m is a number 2 or 3,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
R 18 is hydrogen,
R 19 is methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
R 20 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or methyl,
R 22 is hydrogen or methyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a cyclopropyl ring,
R 27 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
and
where two carbon atoms of the alkanediyl chain in 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a phenyl ring,
D is a group of the formula
in which
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, 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 bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atoms to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHCH 2 phenyl,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.
12 . Compounds of the formula (XXXI) according to either of claim 10 or 11 , in which
L 1 is a bond,
B is a bond,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is benzyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is benzyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 or —C(═O)—NR 8 R 9 ,
in which
R 7 is hydrogen,
R 8 is hydrogen,
R 9 is hydrogen,
R 35 is methyl,
and also their salts, solvates and solvates of the salts.
13 . Compounds of the formulae (XXXa) and (XXXI) selected from the following group:
N-[6-(3-{[(2R)-2-amino-2-carboxyethyl]sulphanyl}-2,5-dioxopyrrolidin-1-yl)hexyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide, N-[6-(3-{[(2R)-2-amino-2-carboxyethyl]sulphanyl}-2,5-dioxopyrrolidin-1-yl)hexyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide, N-(6-{[(5S)-5-amino-5-carboxypentyl]amino}-6-oxohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate, N-(6-{[(5S)-5-amino-5-carboxypentyl]amino}-6-oxohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide, and also their salts, solvates and solvates of the salts.
14 . Binder-drug conjugates of the general formula (I)
in which
n is a number from 1 to 50,
AK is a binder,
the group §-G-L 1 -B-L 2 -§§ is a linker,
where
§ marks the linkage site with the group AK and
§§ marks the linkage site with the nitrogen atom,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
and also their salts, solvates and solvates of the salts.
15 . Binder-drug conjugates according to claim 14 with the general formula (I),
in which
n is a number from 1 to 50,
AK is AK 1 or AK 2
where
AK 1 is a binder which is bonded via a sulphur atom of the binder to the group G,
AK 2 is a binder which is bonded via a nitrogen atom of the binder to the group G,
G when AK=AK 1 , is a group of the formula
where
# 1 marks the linkage site with the sulphur atom of the binder,
# 2 marks the linkage site with the group L 1 ,
or
when AK=AK 2 , is carbonyl,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl or is a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 1 -C 10 )-alkanediyl may be substituted by 1 to 4 methyl substituents,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
P is O or NH,
L 3 is a bond or (C 2 -C 4 )-alkanediyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is hydrogen or methyl,
Q 1 is a 4- to 7-membered heterocycle,
Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,
R 14 is hydrogen or (C 1 -C 4 )-alkyl,
R 15 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 14 and R 15 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 16 is hydrogen or (C 1 -C 4 )-alkyl,
R 17 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 18 is hydrogen or (C 1 -C 4 )-alkyl,
R 19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R 20 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or (C 1 -C 4 )-alkyl,
R 22 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R 23 is (C 1 -C 4 )-alkyl,
R 24 is hydrogen or (C 1 -C 4 )-alkyl,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
L 2 is linear (C 2 -C 10 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 to 4 methyl substituents, and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
D has the definitions indicated in claim 14 ,
and also their salts, solvates and solvates of the salts.
16 . Binder-drug conjugates according to claim 14 or 15 of the general formula (I),
in which
n is a number from 1 to 50,
AK is AK 1 or AK 2
where
AK 1 is an antibody or an antigen-binding antibody fragment and are bonded via a sulphur atom to the group G,
AK 2 is an antibody or an antigen-binding antibody fragment and are bonded via a nitrogen atom to the group G,
G, L 1 , B, L 2 and D have the definitions indicated in the claim 14 or 15 ,
and also their salts, solvates and solvates of the salts.
17 . Binder-drug conjugates according to any of claims 14 to 16 of the general formula (I), in which
n is a number from 1 to 20,
AK is AK 1 or AK 2
where
AK 1 is an antibody or an antigen-binding antibody fragment which binds to mesothelin and is bonded via the sulphur atom of a cysteine residue of the binder to the group G,
AK 2 is an antibody or an antigen-binding antibody fragment which binds to mesothelin and is bonded via the NH side group of a lysine residue of the binder to the group G,
G when AK=AK 1 , is a group of the formula
in which
# 1 marks the linkage site with the cysteine residue of the binder,
# 2 marks the linkage site with the group L 1 ,
or
when AK=AK 2 , is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is methyl,
Q 1 is a 4- to 6-membered carbocycle or piperidine-1,4-diyl,
R 14 is hydrogen,
R 15 is hydrogen,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a piperazinyl ring,
R 18 is hydrogen,
R 19 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
R 20 is hydrogen or methyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or methyl,
R 22 is hydrogen or methyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
and also their salts, solvates and solvates of the salts.
18 . Binder-drug conjugates according to any of claims 14 to 17 of the general formula (I)
in which
n is a number from 1 to 10,
AK is AK 1 or AK 2
where
AK 1 is an antibody which comprises the six CDR sequences of the antibody MF-Ta, the variable light and variable heavy chain of the antibody MF-Ta or the light and heavy chain of the antibody MF-Ta, and is bonded via the sulphur atom of a cysteine residue of the binder to the group G,
AK 2 is an antibody which comprises the six CDR sequences of the antibody MF-Ta, the variable light and variable heavy chain of the antibody MF-Ta or the light and heavy chain of the antibody MF-Ta, and is bonded via the NH side group of a lysine residue of the binder to the group G,
G when AK=AK 1 , is a group of the formula
in which
# 1 marks the linkage site with the cysteine residue of the binder,
# 2 marks the linkage site with the group L 1 ,
or
when AK=AK 2 , is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
m is a number 2 or 3,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 2 -C 6 )-alkanediyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is methyl,
Q 1 is piperidine-1,4-diyl,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a piperazinyl ring,
R 21 is hydrogen or methyl,
R 22 is hydrogen or methyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen,
L 2 is linear (C 2 -C 6 )-alkanediyl,
D is a group of the formula
where
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )phenyl,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
and also their salts, solvates and solvates of the salts.
19 . Process for preparing the compounds of the invention according to any of claims 14 to 18 , of the general formula (I), characterized in that a solution of the binder in a buffer
[A] is admixed with a suitable reducing agent, such as, for example, dithiothreitol or tris(2-carboxyethyl)phosphine hydrochloride, and is subsequently reacted with a compound of the formula (II)
in which D, L 1 , B and L 2 each have the definitions indicated in claims 1 to 5 ,
to give a compound of the formula (I-A)
in which n, AK 1 , D, L 1 , B and L 2 each have the definitions indicated in claims 1 to 5 ,
or
[B] is reacted with a compound of the formula (III)
in which D, L 1 , B and L 2 each have the definitions indicated in claims 1 to 5 ,
to give a compound of the formula (I-B)
in which n, AK 2 , D, L 1 , B and L 2 each have the definitions indicated in claims 1 to 5 .
20 . Compounds prepared by the process according to claim 19 or 54 , where AK 1 and AK 2 is an antibody which comprises the six CDR sequences of the antibody MF-Ta, the variable light and variable heavy chain of the antibody MF-Ta or the light and heavy chain of the antibody MF-Ta,
and also their salts, solvates and solvates of the salts.
21 . Compounds of the formula (XXX)
in which
Cys is a cysteine residue which is bonded via the sulphur atom of the side chain to a carbon atom of the succinimide,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl or is a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 1 -C 10 )-alkandiyl may be substituted by 1 to 4 methyl substituents,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
P is O or NH,
L 3 is a bond or (C 2 -C 4 )-alkanediyl,
L 4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L 2 ,
R 25 is hydrogen or methyl,
Q 1 is a 3- to 7-membered carbocycle or a 4- to 7-membered aza heterocycle,
Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered aza heterocycle,
R 14 is hydrogen or (C 1 -C 4 )-alkyl,
R 15 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 14 and R 15 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 16 is hydrogen or (C 1 -C 4 )-alkyl,
R 17 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R 18 is hydrogen or (C 1 -C 4 )-alkyl,
R 19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R 20 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R 21 is hydrogen or (C 1 -C 4 )-alkyl,
R 22 is hydrogen or (C 1 -C 4 )-alkyl,
or
R 21 and R 22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R 23 is (C 1 -C 4 )-alkyl,
R 24 is hydrogen or (C 1 -C 4 )-alkyl,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
L 2 is linear (C 2 -C 10 )-alkanediyl or is a group of the formula
where
p is a number from 2 to 6,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
where (C 2 -C 10 )-alkanediyl may be substituted by 1 to 4 methyl substituents,
and
where two carbon atoms of the alkanediyl chain in 1,2, 1,3 or 1,4 relation to one another, with inclusion of any carbon atoms situated between them, may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
D is a group of the formula
in which
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R 10 is benzoyl
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )-T 2 ,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxy,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
and also their salts, solvates and solvates of the salts.
22 . Compounds of the formula (XXX) according to claim 21 , in which
Cys is a cysteine residue which is bonded via the sulphur atom of the side chain to a carbon atom of the succinimide, L 1 is a bond, linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
m is a number from 2 to 6,
## 1 marks the linkage site with the group G,
## 2 marks the linkage site with the group B,
where (C 2 -C 6 )-alkandiyl may be substituted by 1 or 2 methyl substituents,
B is a bond or a group of the formula
where
* marks the linkage site with L 1 ,
** marks the linkage site with L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond,
R 14 is hydrogen,
R 15 is hydrogen,
R 16 is hydrogen or methyl,
R 17 is hydrogen or methyl,
or
R 16 and R 17 together with the atoms to which they are bonded form a piperazinyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or is a group of the formula
where
p is a number 2 or 3,
## 3 marks the linkage site with the group B,
## 4 marks the linkage site with the nitrogen atom,
D is a group of the formula
in which
# 3 marks the linkage site with the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 4 marks the linkage site with the adjacent nitrogen atom,
# 5 marks the linkage site with the carbonyl group,
the ring A with the N—O moiety present therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
# 6 marks the linkage site with the carbonyl group,
R 6 is hydrogen, hydroxy or benzyloxy,
R 3 is hydrogen,
R 4 is benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
# 7 marks the linkage site with the adjacent nitrogen atom,
# 8 marks the linkage site with the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10 or —CH 2 —O—R 11 ,
in which
R 7 is hydrogen, methyl, ethyl, n-propyl, benzyl or adamantylmethyl,
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R 5 is hydrogen or a group of the formula
in which
# 9 marks the linkage site with —CHC(R 26 )phenyl,
R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
and also their salts, solvates and solvates of the salts.
23 . Binder-drug conjugate according to any of claims 1 to 6 or 14 to 18 where the binder binds to a cancer target molecule.
24 . Binder-drug conjugate according to any of claim 1 to 6 , 14 to 18 or 23 , where the binder binds to an extracellular target molecule.
25 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 24 , where the binder binds to an extracellular cancer target molecule.
26 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 25 , where the target molecule, extracellular target molecule, cancer target molecule or extracellular cancer target molecule is a protein.
27 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 26 , where the binder after binding to the extracellular target molecule is internalized by the cell expressing the target molecule.
28 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 27 , where the binder is a binder protein.
29 . Binder-drug conjugate according to any of claims 1 , 2 , 14 , 15 , 20 or 23 to 28 , where the binder is an antibody or an antigen-binding antibody fragment thereof or an antibody mimetic.
30 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 29 , 10 where the antibody is a monoclonal antibody.
31 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 and 23 to 30 , where the antibody is a human, humanized or chimeric antibody.
32 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 31 , where the antibody is an intact or a modified intact antibody.
33 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 32 , where the antibody is an antibody of the IgG class.
34 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 33 , where the binder binds to an extracellular cancer target molecule which is selected from the group consisting of EGF receptor (NP — 005219.2), mesothelin (Q13421-3), C4.4a (NP — 055215.2) and carboanhydrase IX (CA IX; NP — 001207.2).
35 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 34 , where the binder binds specifically to an extracellular cancer target molecule which is selected from the group consisting of EGF receptor (NP — 005219.2), mesothelin (Q13421-3), C4.4a (NP — 055215.2) and carboanhydrase IX (CA IX; NP — 001207.2).
36 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 35 , where the antibody binds to C4.4a.
37 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 36 , where the antibody binds to mesothelin and exhibits invariant binding.
38 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 37 , where the antibody binds specifically to mesothelin.
39 . Binder-drug conjugate according to any of claims 1 to 6 , 14 to 18 or 23 to 38 , where the binder is an anti-mesothelin antibody or antigen-binding antibody fragment which comprises the amino acid sequences of the three CDR regions of the light chain and the amino acid sequences of the three CDR regions of the heavy chain of an antibody described in WO 2009068204-A1 (Table 7; pages 61-63).
40 . Binder-drug conjugate according to any of claims 1 to 3 , 14 to 17 or 23 to 39 , where the antimesothelin antibody or antigen-binding antibody fragment is selected from the group consisting of
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MF-Ta,
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MF-J,
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MOR06640,
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MF-226, and
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MOR06626.
41 . Binder-drug conjugate according to any of claims 1 to 3 , 14 to 17 or 23 to 40 , where the antimesothelin antibody or antigen-binding antibody fragment is selected from the group consisting of
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MF-Ta,
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MF-J,
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MOR06640,
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MF-226, and
anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MOR06626.
42 . Antibodies or antigen-binding antibody fragments which bind to mesothelin, where the antibody sequence comprises the amino acid sequence of the variable heavy chain represented by the sequences SEQ ID NO:404 and the amino acid sequence of the variable light chain represented by the sequence SEQ ID NO:405.
43 . Antibodies or antigen-binding antibody fragments which bind to mesothelin, where the antibody sequence comprises the amino acid sequence of the variable heavy chain which is encoded by the nucleic acid sequence SEQ ID NO:406, and the amino acid sequence of the variable light chain which is encoded by the nucleic acid sequence SEQ ID NO:407.
44 . Antibodies which bind to mesothelin, where the antibody sequence comprises the amino acid sequence of the heavy chain represented by the sequences SEQ ID NO:408 and the amino acid sequence of the light chain represented by the sequence SEQ ID NO:409.
45 . Antibodies or antigen-binding antibody fragments according to any of claims 42 to 44 , which bind specifically to mesothelin.
46 . Binder-drug conjugate according to any of claims 1 to 3 , 14 to 17 or 23 to 38 , where the anti-mesothelin antibody comprises the amino acid sequence of the heavy chain represented by the sequences SEQ ID NO:408 and the amino acid sequence of the light chain represented by the sequence SEQ ID NO:409.
47 . Binder-drug conjugate or compounds according to any of claim 1 to 18 , 21 to 41 or 46 for the treatment and/or prophylaxis of illnesses.
48 . Binder-drug conjugate or a compound according to any of claim 1 to 18 , 21 to 41 or 46 for use in a method for the treatment and/or prophylaxis of hyperproliferative and/or angiogenic diseases.
49 . Binder-drug conjugate or a compound according to any of claim 1 to 18 , 21 to 41 or 46 for producing a medicament for the treatment and/or prophylaxis of hyperproliferative and/or angiogenic diseases.
50 . Medicament comprising a binder-drug conjugate or a compound according to any of claims 1 to 18 , 21 to 41 or 46 to 48 , in combination with an inert, non-toxic, pharmaceutically suitable excipient.
51 . Medicament comprising a binder-drug conjugate or a compound according to any of claims 1 to 18 , 21 to 41 or 46 to 48 , in combination with one or more anti-hyperproliferative, cytostatic or cytotoxic substances.
52 . Medicament according to claim 50 or 51 for the treatment and/or prophylaxis of hyperproliferative and/or angiogenic diseases.
53 . Method for the treatment and/or prophylaxis of hyperproliferative and/or angiogenic diseases in humans and animals, using an effective amount of at least one binder-drug conjugate or a compound according to any of claims 1 to 18 or 21 to 41 , or of a medicament as defined in either of claims 50 and 51 .
54 . Process for preparing the compounds of the invention according to any of claims 1 to 6 , of the general formula (Ia), characterized in that a solution of the binder in a buffer
[A] is admixed with a suitable reducing agent, such as, for example, dithiothreitol or tris(2-carboxyethyl)phosphine hydrochloride, and is subsequently reacted with a compound of the formula (IIa)
in which D, L 1 , B, L 2 and R 35 each have the definitions indicated in claims 1 to 6 ,
to give a compound of the formula (Ia-A)
in which n, AK 1 , D, L 1 , B, L 2 and R 35 each have the definitions indicated in claims 1 to 6 .
or
[B] is reacted with a compound of the formula (IIIa)
in which D, L 1 , B, L 2 and R 35 each have the definitions indicated in claims 1 to 6 ,
to give a compound of the formula (Ia-B)
in which n, AK 2 , D, L 1 , B, L 2 and R 35 each have the definitions indicated in claims 1 to 6 .
55 . Binder-drug conjugates selected from the following compounds:
where in each case
n is a number from 2 to 8, preferably 2 to 5,
AK 1 is a human or humanized antibody or an antigen-binding antibody fragment which binds to mesothelin and is bonded via the sulphur atom of a cysteine residue of the binder to the group G,
AK 2 is a human or humanized antibody or an antigen-binding antibody fragment which binds to mesothelin and is bonded via the NH side group of a lysine residue of the binder to the group G.Cited by (0)
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