US2016193359A1PendingUtilityA1
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 LerchenLars LindenSherif El SheikhJörg WilludaCharlotte Christine KopitzJoachim SchuhmacherSimone GrevenChristoph MahlertBeatrix Stelte-LudwigSven GolfierRudolf BeierIring HeislerAxel HarrengaKarl-Heinz ThierauchSandra BruderHeike PetrulHannah JörißenSandra Borkowski
A61P 35/02A61P 43/00A61P 9/00A61P 35/00A61K 31/4025A61K 38/00C07K 5/0606A61K 31/5355C07K 16/30A61K 31/536C07K 7/06C07K 16/2863A61K 47/6889C07K 16/2812A61K 45/06C07K 16/18C07K 5/06034C07K 16/28C07K 5/06A61K 31/404A61K 31/40A61K 31/422A61K 31/4245C07K 5/0207A61K 47/50C07K 7/02A61K 47/6869A61K 31/537C07K 2317/565A61K 31/5377C07K 5/06052C07K 5/0205A61K 47/6851C07K 2317/76A61K 47/6859C07K 2317/21A61K 47/542A61K 39/3955C07K 2317/24A61K 47/48715A61K 47/48569A61K 47/68031
56
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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 . 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 5 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 , 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 1 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 claim 1 , 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 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 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
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,
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 claim 1 , 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 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 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 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 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 claim 1 , 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 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 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 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 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 # 8
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 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: or 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 (CZ-Cln)-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 (1 S,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 (1 S,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; or
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 1 -C 5 )-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 1 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 (1 S,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 (1 S,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 2 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.
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 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 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 . (canceled)
11 . Compounds of the formula (XXXI) according to claim 7 , 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 7 , 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,
## 1 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) according to claim 7 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 according to claim 1 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 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 claim 14 ,
and also their salts, solvates and solvates of the salts.
17 . Binder-drug conjugates according to claim 14 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 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 2 )-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 claim 14 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 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 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 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,
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 # 8
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 - 21 . (canceled)
22 . Compounds of the formula (XXX) 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, 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 1 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 - 28 . (canceled)
29 . Binder-drug conjugate according to claim 1 , where the binder is an antibody or an antigen-binding antibody fragment thereof or an antibody mimetic.
30 - 37 . (canceled)
38 . Binder-drug conjugate according to claim 29 , where the antibody binds specifically to C4.4a.
39 - 41 . (canceled)
42 . Binder-drug conjugate according to claim 38 , where the C4.4a antibody or antigen-binding antibody fragment is selected from the group consisting of
antibody which comprises the amino acid sequence of the light chain represented by SEQ ID NO: 346 and which comprises the amino acid sequence of the heavy chain represented by SEQ ID NO: 347 (M31-B01), antibody which comprises the amino acid sequence of the light chain represented by SEQ ID NO: 352 and which comprises the amino acid sequence of the heavy chain represented by SEQ ID NO: 353 (B01-3), antibody which comprises the amino acid sequence of the light chain represented by SEQ ID NO: 364 and which comprises the amino acid sequence of the heavy chain represented by SEQ ID NO: 365 (B01-10), and antibody which comprises the amino acid sequence of the light chain represented by SEQ ID NO: 382 and which comprises the amino acid sequence of the heavy chain represented by SEQ ID NO: 383 (D02-6).
43 - 49 . (canceled)
50 . Process for preparing the compounds of the invention according to claim 1 , 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 claim 1 ,
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 1 ;
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 1 ,
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 1 .
51 . Binder-drug conjugate according to claim 1 selected from the following compounds:
in which
n is a number 2 to 8, preferably 2 to 5,
and
AK 1 is a human or humanized antibody or an antigen-binding antibody fragment which binds to C4.4a and is bonded via a cysteine residue to the toxophor-linker unit,
AK 2 is a human or humanized antibody or an antigen-binding antibody fragment which binds to C4.4a and is bonded via a lysine residue to the toxophor-linker unit.
52 . Binder-drug conjugate according to claim 1 selected from the following compounds:
n is a number 2 to 8, preferably 2 to 5,
and
AK 1B and AK 2B is B01-3.
53 . Binder-drug conjugate according to claim 1 wherein D is
wherein the asterisk marks the linkage site with the nitrogen atom.
54 . A method for the treatment of cancer in a human comprising administering to a human the binder-drug conjugation of claim 1 .
55 . An anti-C4.4a antibody or anti-mesothelin antibody or anti-carboanhydrase IX antibody or antigen-binding antibody fragment, wherein the anti-C4.4a antibody comprises at least one, two, or three of the CDR amino acid sequences given in Table 1 or Table 2, the anti-mesothelin antibody (MF-Ta) comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO:398 (HCDR1), SEQ ID NO:399 (HCDR2), and SEQ ID NO:400 (HCDR3) and the CDR sequences of the variable light chain represented by the sequences SEQ ID NO:401 (LCDR1), SEQ ID NO:402 (LCDR2), and SEQ ID NO:403 (LCDR3), and the anti-carboanhydrase IX antibody comprises the heavy chain and light chain sequence of a 3ee9-IgG1 antibody.
56 . The anti-C4.4 antibody of claim 55 which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 75-77 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 78-80 (B01-10), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 5, 9 and 13 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 17, 21 and 25 (M31-B01), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 6, 10 and 14 an which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 18, 22 and 26 (M20-D02-S-A), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 7, 11 and 15 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 19, 23 and 27 (M60-G03), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 8, 12 and 16 and which comprise the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 20, 24 and 28 (36-H02), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 45-47 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 48-50 (B01-3), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 55-57 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 58-60 (B01-5), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 65-67 and which comprises the CDR sequences of variable light chain represented by the sequences SEQ ID NO: 68-70 (B01-7), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 85-87 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 88-90 (B01-12), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 95-97 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 98-100 (D02-4), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 105-107 and which comprises CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 108-110 (D02-6), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 115-117 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 118-120 (D02-7), antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 125-127 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 128-130 (D02-11), and antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 135-137 which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 138-140 (D02-13).Cited by (0)
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