US2015030618A1PendingUtilityA1
Novel binder-drug conjugates (adcs) and use thereof
Est. expiryApr 21, 2031(~4.8 yrs left)· nominal 20-yr term from priority
Inventors:Hans-Georg LerchenLars LindenSherif El SheikhJörg WilludaCharlotte Christine KopitzJoachim SchuhmacherSimone GrevenChristoph MahlertBeatrix Stelte-LudwigSven GolfierRudolf BeierIring HeislerAxel HarrengaKarl-Heinz ThierauchSandra BruderHeike PetrulHannah JörissenSandra Borkowski
A61P 35/00A61P 43/00A61P 35/02A61P 9/00C07K 5/06A61K 31/404A61K 31/536C07K 7/06A61K 47/6859A61K 31/537A61K 31/4025C07K 5/0207C07K 16/28A61K 31/4245A61K 47/542C07K 16/30C07K 7/02C07K 5/06034C07K 5/06052A61K 38/00A61K 31/5355C07K 2317/565C07K 5/0205C07K 16/2863C07K 2317/76C07K 16/2812A61K 31/422C07K 2317/24A61K 31/40C07K 16/18A61K 39/3955A61K 45/06A61K 47/50C07K 5/0606C07K 2317/21A61K 31/5377A61K 47/6851A61K 47/6869A61K 47/6889A61K 47/68031A61K 47/48723
61
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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 C4.4a, 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 . (canceled)
2 . Binder-drug conjugates of the general formula (Ia)
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 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 benzyl-oxycarbonyl,
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 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 C4.4a 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 C4.4a 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 - 6 . (canceled)
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, or 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 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 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 )-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.
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 to via a carbon atom of the succinimide, 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,
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 A ,
## 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 claim 7 , 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 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, or 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 claim 10 , 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)
selected from the group consisting of:
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 . (canceled)
15 . Binder-drug conjugates of the general formula (Ia) according to claim 2 ,
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 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
R 35 is methyl,
and also their salts, solvates and solvates of the salts.
16 . (canceled)
17 . Binder-drug conjugates of the general formula (Ia) according to claim 15 , 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 C4.4a 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 C4.4a 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 . (canceled)
19 . Process for preparing the compounds of the general formula (Ia) according to claim 15 , 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 claim 15 ,
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 claim 15 ,
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 claim 15 ,
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 claim 15 .
20 . (canceled)
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 )-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 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 )-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 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 claim 2 , where the binder binds to a cancer target molecule
24 - 28 . (canceled)
29 . Binder-drug conjugate according to claim 2 , where the binder is an antibody or an antigen-binding antibody fragment thereof or an antibody mimetic.
30 . Binder-drug conjugate according to claim 29 , where the antibody is a monoclonal antibody.
31 . (canceled)
32 . Binder-drug conjugate according to claim 29 , where the antibody is an intact or a modified intact antibody and wherein the antibody is a human, humanized or chimeric antibody.
33 . Binder-drug conjugate according to claim 29 , where the antibody is an antibody of the IgG class.
34 - 49 . (canceled)
50 . Process for preparing the compounds of the general formula (Ia) according to claim 2 , 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 claim 2 ,
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 claim 2 ,
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 claim 2 ,
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 claim 2 .
51 . Binder-drug conjugate according to claim 2 selected from the following compounds:
in which
n is a number 2 to 8,
and
AK 1 is a binder which is bonded via a cysteine residue to the toxophor-linker unit,
AK 2 is a binder which is bonded via a lysine residue to the toxophor-linker unit.
52 . (canceled)
53 . A medicament comprising the binder-drug conjugate of claim 2 in combination with a pharmaceutically acceptable excipient.
54 . The medicament of claim 53 , further comprising one or more anti-hyperproliferative, cytostatic, or cytotoxic substances.
55 . A method for the treatment of cancer in a human or animal subject comprising administering to said subject the binder-drug conjugate of claim 2 .
56 . A method for the treatment of cancer in a human or animal subject comprising administering to said subject the medicament of claim 54 .Cited by (0)
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