US2014127240A1PendingUtilityA1
Novel Binder-Drug Conjugates (ADCs) and Use of Same
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 Brokowski
A61P 35/00A61P 43/00A61P 35/02A61P 9/00C07K 7/02A61K 31/537C07K 5/0207A61K 47/6869A61K 47/6889A61K 31/404C07K 5/06052C07K 16/30A61K 31/422A61K 31/4245C07K 5/0205C07K 16/2812A61K 47/50C07K 16/2863A61K 45/06C07K 7/06C07K 5/06A61K 47/6851A61K 31/5377C07K 5/06034A61K 38/00C07K 16/18A61K 31/40A61K 31/536A61K 47/6859A61K 31/5355C07K 2317/565C07K 16/28A61K 39/3955C07K 2317/24C07K 5/0606A61K 47/542C07K 2317/21C07K 2317/76A61K 31/4025A61K 47/68031A61K 47/48415
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Claims
Abstract
The present patent application relates to novel binder-drug conjugates (ADCs) of N,N-dialkylauristatins directed against the target epidermal growth factor receptor (EGFR, gene ID 1956), effective metabolites of these ADCs, methods for producing these ADCs, use of these ADCs for treatment and or prevention of diseases as well as the use of these ADCs to produce pharmaceutical drugs for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic diseases such as cancer, for example. Such treatments may be administered as monotherapy or in combination with other pharmaceutical drugs or other therapeutic measures.
Claims
exact text as granted — not AI-modified1 . Binder-drug ingredient conjugates of 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,
wherein
§ denotes the linkage site to the group AK and
§§denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site with the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
2 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 1 to 50, AK is AK 1 or AK 2
wherein
AK 1 is a binder which is bound to the group G by a sulfur atom of the binder,
AK 2 is a binder which is bound to the group G by a nitrogen atom of the binder,
G for the case when AK=AK 1 , is a group of the formula
wherein
# 1 denotes the linkage site to the sulfur atom of the binder,
# 2 denotes the linkage site to the group L 1 ,
or
for the case when AK=AK 2 , G is carbonyl,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl, or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
L 1A is linear (C 2 -C 10 )-alkanediyl,
B 1 is a group of the formula
wherein
## 5 denotes the linkage site to the group L 1A ,
## 6 denotes the linkage site to the group L 1B ,
L 5 is a bond or (C 2 -C 4 )-alkanediyl,
L 6 is a bond or a group with the formula
wherein
## 7 denotes the linkage site to the carbonyl group,
## 8 denotes the linkage site to 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 bound form a five- or six-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 bound form a five- or six-membered heterocycle,
L 1B is linear (C 2 -C 10 )-alkanediyl,
and
wherein (C 1 -C 10 )-alkanediyl may be substituted with one to four substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally situated between them, to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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
wherein
*** denotes the linkage site to the carbonyl group,
**** denotes the linkage site to 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 four- to seven-membered heterocycle,
Q 2 is a three- to seven-membered carbocycle or a four- to seven-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 bound form a five- or six-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 bound form a five- or six-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 its homologs 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 bound 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 bound form a three- to seven-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 bound form a pyrrolidine ring,
L 2 is linear (C 2 -C 10 )-alkanediyl or for a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally present between them to form a (C 3 -C 6 ) cycloalkyl ring or a phenyl ring,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O grouping contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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, di-phenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
3 - 6 . (canceled)
7 . Compounds of formula (XXXa)
in which
Cys is a cysteine radical which is bound to a carbon atom of the succinimide via the sulfur atom of the side chain,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl, or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
L 1A is linear (C 2 -C 10 )-alkanediyl,
B 1 is a group of the formula
wherein
## 5 denotes the linkage site to the group L 1A ,
## 6 denotes the linkage site to 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 bound form a five- or six-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 bound form a five- or six-membered heterocycle,
L 1B is linear (C 2 -C 10 )-alkanediyl,
and
wherein (C 1 -C 10 )-alkanediyl may be substituted with one to four substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally situated between them, to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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 four- to seven-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 bound form a five- or six-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 bound form a five- or six-membered heterocycle,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
L 2 is linear (C 2 -C 10 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally present between them to form a (C 3 -C 6 ) cycloalkyl ring or a phenyl ring,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
8 . Compounds of the formula (XXXa) according to claim 7 , wherein
Cys is a cysteine radical which is bound to a carbon atom of the succinimide via the sulfur atom of the side chain, L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, or a group of formula
wherein
m is a number from 2 to 3,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
L 1A is linear (C 2 -C 6 )-alkanediyl,
B 1 is a group of the formula
wherein
## 5 denotes the linkage site to the group L 1A ,
## 6 denotes the linkage site to 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
wherein (C 2 -C 6 )-alkanediyl may be substituted with one to two methyl substituents,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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 bound form a piperazinyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 3,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 1 and R 2 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 3 and R 4 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHCH 2 phenyl,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
9 . Compounds of the formula (XXXa) according to claim 7 , wherein
Cys is a cysteine radical which is bound to a carbon atom of the succinimide via the sulfur atom of the side chain, L 1 is a bond or linear (C 2 -C 6 )-alkanediyl, B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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 a group of the formula
wherein
p is a number from 2 to 3,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 or —C(═O)—NR 8 R 9 ,
wherein
R 7 is hydrogen,
R 8 is hydrogen,
R 9 is hydrogen, and
R 35 is methyl,
as well as their salts, solvates, and solvates of the salts.
10 . Compounds of formula (XXXI)
in which
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl, or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
L 1A is linear (C 2 -C 10 )-alkanediyl,
B 1 is a group of the formula
wherein
## 5 denotes the linkage site to the group L 1A ,
## 6 denotes the linkage site to 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 bound form a five- or six-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 bound form a five- or six-membered heterocycle,
L 1B is linear (C 2 -C 10 )-alkanediyl,
and
wherein (C 1 -C 10 )-alkanediyl may be substituted with one to four substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally situated between them, to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to L 2 ,
P is O or NH,
Q 1 is a four- to seven-membered heterocycle,
Q 2 is a three- to seven-membered carbocycle or a four- to seven-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 its homologs 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 bound 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 bound form a three- to seven-membered carbocycle,
R 27 is hydrogen or (C 1 -C 4 )-alkyl,
L 2 is linear (C 2 -C 10 )-alkanediyl or for a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally present between them to form a (C 3 -C 6 ) cycloalkyl ring or a phenyl ring,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
11 . Compounds of the formula (XXXI) according to claim 10 , wherein
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
m is a number from 2 to 3,
##1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
wherein (C 2 -C 6 )-alkanediyl may be substituted with one or two methyl substituents,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to L 2 ,
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 (C 1 -C 4 )-alkyl,
or
R 19 and R 20 together with the atoms to which they are bound 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 bound form a cyclopropyl ring,
R 27 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 3,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with one or two methyl substituents,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,4-relation to one another, including the carbon atoms optionally present between them to form a phenyl ring,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 1 and R 2 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 3 and R 4 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHCH 2 phenyl,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
12 . Compounds of the formula (XXXI) according to claim 10 , wherein
L 1 is a bond, B is a bond, L 2 is linear (C 2 -C 6 )-alkanediyl or for a group of the formula
wherein
p is a number from 2 to 3,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to the group T 1 ,
T 1 is a group of the formula —C(═O)—OR 7 or —C(═O)—NR 8 R 9 ,
wherein
R 7 is hydrogen,
R 8 is hydrogen,
R 9 is hydrogen, and
R 35 is methyl,
as well as their salts, solvates, and solvates of the salts.
13 . A compound of formula (XXXa) or (XXXI) selected from the group consisting of:
N-[6-(3-{[(2R)-2-amino-2-carboxyethyl]sulfanyl}-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]sulfanyl}-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, and 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,
as well as their salts, solvates, and solvates of the salts.
14 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein R 35 is methyl, thereby providing a binder-drug conjugate of 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,
wherein
§ denotes the linkage site to the group AK and
§§ denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl, and
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
as well as their salts, solvates, and solvates of the salts.
15 . 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
wherein
AK 1 is a binder bound to the group G via a sulfur atom of the binder,
AK 2 is a binder bound to the group G via a nitrogen atom of the binder,
G for the case when AK=AK 1 , is a group of the formula
wherein
# 1 denotes the linkage site to the sulfur atom of the binder,
# 2 denotes the linkage site to the group L 1 ,
or
for the case when AK=AK 2 , G is carbonyl,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
wherein (C 1 -C 10 )-alkanediyl may be substituted with 1 to 4 methyl substituents,
and
wherein two carbon atoms of the alkanediyl chain in 1,2-, 1,3- or 1,4-relation to one another may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring including the carbon atoms optionally situated between them,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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
wherein
*** denotes the linkage site to the carbonyl group,
**** denotes the linkage site to L 2 ,
R 25 is hydrogen or methyl,
Q 1 is a four- to seven-membered heterocycle,
Q 2 is a three- to seven-membered carbocycle or a four- to seven-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 bound form a five- or six-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 bound form a five- or six-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 its homologs 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 bound 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 bound form a three- to seven-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 a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with 1 to 4 methyl substituents,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally present between them to form a (C 3 -C 6 ) cycloalkyl ring or a phenyl ring, and
D has the meaning as described in claim 14 ,
as well as 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
wherein
AK 1 is an antibody or an antigen-binding antibody fragment and is bound to the group G via a sulfur atom,
AK 2 is an antibody or an antigen-binding antibody fragment and is bound to the group G via a nitrogen atom, and
n, G, L 1 , B, L 2 , and D have the meanings given in claim 14 ,
as well as their salts, solvates, and solvates of the salts.
17 - 18 . (canceled)
19 . Method for production of compounds of formula (I) as defined in claim 14 , the method comprising
[A] mixing a solution of binder in a buffer with a reducing agent selected from the group consisting of dithiothreitol and tris-(2-carboxyethyl)phosphine hydrochloride, and then reacting the resulting solution with a compound of formula (II)
in which D, L 1 , B and L 2 each have the meanings given in claim 14 ,
to form a compound of formula (I-A)
in which n, AK 1 , D, L 1 , B and L 2 each have the meanings given in claim 14 ,
or
[B] mixing a solution of binder in a buffer with a reducing agent selected from the group consisting of dithiothreitol and tris-(2-carboxyethyl)phosphine hydrochloride, and then reacting the resulting solution with a compound of formula (III)
in which D, L 1 , B and L 2 each have the meanings given in claim 14 ,
to form a compound of formula (I-B)
in which n, AK 2 , D, L 1 , B and L 2 each have the meanings given in claim 14 .
20 . (canceled)
21 . Compounds of the general formula (XXXa) according to claim 7 , wherein R 35 is methyl, thereby providing a compound of the general formula (XXX)
in which
Cys is a cysteine radical which is bound to a carbon atom of the succinimide via the sulfur atom of the side chain,
L 1 is a bond, linear (C 1 -C 10 )-alkanediyl or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
wherein (C 1 -C 10 )-alkanediyl may be substituted with 1 to 4 methyl substituents,
and
wherein two carbon atoms of the alkanediyl chain in 1,2-, 1,3- or 1,4-relation to one another may be bridged to form a (C 3 -C 6 )-cycloalkyl ring or a phenyl ring including the carbon atoms optionally situated between them,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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
wherein
*** denotes the linkage site to the carbonyl group,
**** denotes the linkage site to L 2 ,
R 25 is hydrogen or methyl,
Q 1 is a three- to seven-membered carbocycle or a four- to seven-membered azaheterocycle,
Q 2 is a three- to seven-membered carbocycle or a four- to seven-membered azaheterocycle,
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 bound form a five- or six-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 bound form a five- or six-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 its homologs 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 bound 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 bound form a three- to seven-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 a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with 1 to 4 methyl substituents,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally present between them to form a (C 3 -C 6 ) cycloalkyl ring or a phenyl ring,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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-Ro or —CH 2 —O—R 11 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl, and
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
as well as their salts, solvates, and solvates of the salts.
22 . Compounds of the formula (XXX) according to claim 21 , wherein
Cys is a cysteine radical which is bound to a carbon atom of the succinimide via the sulfur atom of the side chain, L 1 is a bond, linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
wherein (C 2 -C 6 )-alkanediyl may be substituted with one or two methyl substituents,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to 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 bound form a piperazinyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
L 2 is linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 3,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to the group T,
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 ,
wherein
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 with methoxycarbonyl or carboxyl,
R 5 is hydrogen or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )phenyl,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH, and
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
as well as their salts, solvates, and solvates of the salts.
23 - 44 . (canceled)
45 . Pharmaceutical drug containing a binder-drug conjugate according to claim 1 , in combination with an inert nontoxic pharmaceutically suitable excipient.
46 . Pharmaceutical drug containing a binder-drug conjugate according to claim 1 , in combination with one or more antihyperproliferative, cytostatic or cytotoxic substances.
47 . (canceled)
48 . Method for treatment or prevention of hyperproliferative or angiogenic diseases in humans and animals, the method comprising administering an effective amount of at least one binder-drug conjugate according to claim 1 .
49 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 1 to 20, AK is AK 1 or AK 2
wherein
AK 1 is a binder bound to the group G via a sulfur atom of the binder,
AK 2 is a binder bound to the group G via a nitrogen atom of the binder,
G for the case when AK=AK 1 , is a group of the formula
wherein
# 1 denotes the linkage site to the cysteine radical of the binder,
# 2 denotes the linkage site to the group L 1 ,
or
for the case when AK=AK 2 , G is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, or a group of the formula
wherein
m is a number from 2 to 6,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
L 1A is linear (C 2 -C 6 )-alkanediyl,
B 1 is a group of the formula
wherein
## 5 denotes the linkage site to the group L 1A ,
## 6 denotes the linkage site to the group L 1B ,
L 5 is a bond,
L 6 is a bond or a group with the formula
wherein
## 7 denotes the linkage site to the carbonyl group,
## 8 denotes the linkage site to 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 10 )-alkanediyl,
and
wherein (C 2 -C 6 )-alkanediyl may be substituted with one to two methyl substituents,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
wherein
*** denotes the linkage site to the carbonyl group,
**** denotes the linkage site to L 2 ,
R 25 is hydrogen or methyl,
R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl,
Q 1 is a four- to seven-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 bound 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 bound 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 bound form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen or methyl,
R 27 is hydrogen,
L 2 is linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with one or two methyl substituents,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 1 and R 2 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl or benzyloxy,
R 3 is hydrogen,
R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 3 and R 4 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
50 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 1 to 10, AK is AK 1 or AK 2
wherein
AK 1 is a binder bound to the group G via a sulfur atom of the binder,
AK 2 is a binder bound to the group G via a nitrogen atom of the binder,
G for the case when AK=AK 1 , is a group of the formula
wherein
# 1 denotes the linkage site to the cysteine radical of the binder,
# 2 denotes the linkage site to the group L 1 ,
or
for the case when AK=AK 2 , G is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, or a group of the formula
wherein
m is a number from 2 to 3,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
wherein (C 2 -C 6 )-alkanediyl may be substituted with one or two methyl substituents,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
wherein
*** denotes the linkage site to the carbonyl group,
**** denotes the linkage site to 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 bound 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 bound form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen,
L 2 is linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 6,
## 3 is linkage site to the group B,
## 4 is linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 1-hydroxyethyl, benzyl, 1-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl,
or
R 1 and R 2 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl or benzyloxy,
R 3 is hydrogen,
R 4 is benzyl, 1-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R 3 and R 4 together with the carbon atom to which they are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHCH 2 phenyl,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
51 . Method for producing compounds of the general formula (Ia) as defined in claim 1 , the method comprising
[A] mixing a solution of binder in a buffer with a reducing agent selected from the group consisting of dithiothreitol and tris-(2-carboxyethyl)phosphine hydrochloride and then reacting the resulting solution with a compound of formula (IIa)
in which D, L 1 , B, L 2 and R 35 each have the meanings given in claim 1 ,
to form a compound of formula (Ia-A)
in which n, AK 1 , D, L 1 , B, L 2 and R 35 each have the meanings given in claim 1 ,
or
[B] mixing a solution of binder in a buffer with a reducing agent selected from the group consisting of dithiothreitol and tris-(2-carboxyethyl)phosphine hydrochloride and then reacting the resulting solution with a compound of formula (IIIa)
in which D, L 1 , B, L 2 and R 35 each have the meanings given in claim 1 ,
to form a compound of formula (Ia-B)
in which n, AK 2 , D, L 1 , B, L 2 and R 35 each have the meanings given in claim 1 .
52 . (canceled)
53 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 1 to 50, AK is a bond, the group §-G-L 1 -B-§§ is a linker,
wherein
§ denotes the linkage site to the group AK and
§§ denotes the linkage site to the nitrogen atom,
L 2 is linear (C 2 -C 10 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
wherein (C 2 -C 10 )-alkanediyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of methyl, hydroxyl and benzyl,
and
wherein two carbon atoms of the alkanediyl chain may be bridged in 1,2-, 1,3- or 1,4-relation to one another, including the carbon atoms optionally present between them to form a (C 3 -C 6 ) cycloalkyl ring or a phenyl ring,
D is a group of the formula
wherein
# 3 denotes the linkage site to 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 4 denotes the linkage site to the vicinal nitrogen atom,
# 5 denotes the linkage site to the carbonyl group,
the ring A with the N—O group contained in it is a mono- or bicyclic, optionally substituted heterocycle of the formula
wherein
# 6 denotes the linkage site to the carbonyl group,
R 6 is hydrogen, hydroxyl 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 attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
wherein
# 7 denotes the linkage site to the vicinal nitrogen atom,
# 8 denotes the linkage site to 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 ,
wherein
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 bound form a four- to seven-membered heterocycle,
R 10 is benzoyl,
R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl,
R 5 is hydrogen, methyl or a group of the formula
wherein
# 9 denotes the linkage site to —CHC(R 26 )-T 2 ,
R 12 is phenyl, which may be substituted with methoxycarbonyl, carboxyl or a group of the formula —S(O) 2 OH,
R 13 is phenyl, which may be substituted with methoxycarbonyl or carboxyl,
R 26 is hydrogen or hydroxyl,
T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and
R 35 is methyl or hydroxyl,
as well as their salts, solvates, and solvates of the salts.
54 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 2 to 8, AK is AK 1 or AK 2 ,
wherein
AK 1 is a binder that is bound to the group G via a sulfur atom of the cysteine radical of the binder,
AK 2 is a binder that is bound to the group G via a nitrogen atom of the lysine radical of the binder,
G for the case when AK=AK 1 , is a group of the formula
wherein
# 1 denotes the linkage site to the cysteine radical of the binder,
# 2 denotes the linkage site to the group L 1 ,
or
for the case when AK=AK 2 , G is carbonyl,
L 1 is a bond, linear (C 2 -C 6 )-alkanediyl, or a group of the formula
wherein
m is a number from 2 to 3,
## 1 denotes the linkage site to the group G,
## 2 denotes the linkage site to the group B,
wherein (C 2 -C 6 )-alkanediyl may be substituted with one or two methyl substituents,
B is a bond or a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to L 2 ,
L 3 is a bond or ethane-1,2-diyl,
L 4 is a bond or a group of the formula
wherein
*** denotes the linkage site to the carbonyl group,
**** denotes the linkage site to 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 bound 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 bound form a cyclopropyl ring,
R 23 is methyl,
R 24 is hydrogen,
L 2 is linear (C 2 -C 6 )-alkanediyl or a group of the formula
wherein
p is a number from 2 to 6,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
the ring A with the N—O group contained therein is
wherein
# 6 denotes the linkage site to the carbonyl group,
R 3 is hydrogen,
R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
T 1 is a group of the formula —C(═O)—NR 8 R 9 ,
wherein
R 8 is hydrogen or methyl,
R 9 is hydrogen, methyl or ethyl, and
R 35 is methyl,
as well as their salts, solvates, and solvates of the salts.
55 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 2 to 8, AK is AK 1 ,
wherein
AK 1 is binder that is bound to the group G via a sulfur atom of the cysteine radical of the binder,
G is a group of the formula
wherein
# 1 denotes the linkage site to the cysteine radical of the binder,
# 2 denotes the linkage site to the group L 1 ,
L 1 is pentane-1,5-diyl,
B is a group of the formula
wherein
* denotes the linkage site to L 1 ,
** denotes the linkage site to L 2 ,
L 3 is a bond,
L 4 is a bond,
R 16 is hydrogen,
R 17 is hydrogen,
L 2 is propane-1,3-diyl,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
the ring A with the N—O group contained therein is
wherein
# 6 denotes the linkage site to the carbonyl group,
R 3 is hydrogen,
R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
T 1 is a group of the formula —C(═O)—NR 8 R 9 ,
wherein
R 8 is hydrogen,
R 9 is hydrogen, and
R 35 is methyl,
as well as their salts, solvates, and solvates of the salts.
56 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 2 to 8, AK is AK 1 ,
wherein
AK 1 is a binder that is bound to the group G via a sulfur atom of the cysteine radical of the binder,
G is a group of the formula
wherein
# 1 denotes the linkage site to the cysteine radical of the binder,
# 2 denotes the linkage site to the group L 1 ,
L 1 is a bond,
B is a bond,
L 2 is hexane-1,6-diyl,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
the ring A with the N—O group contained therein is
wherein
# 6 denotes the linkage site to the carbonyl group,
R 3 is hydrogen,
R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
T 1 is a group of the formula —C(═O)—NR 8 R 9 ,
wherein
R 8 is hydrogen, and
R 9 is hydrogen,
as well as their salts, solvates, and solvates of the salts.
57 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 2 to 8, AK is AK 2 ,
wherein
AK 2 is a binder that is bound to the group G via a nitrogen atom of the binder,
G is carbonyl, L 1 is a bond, B is a bond, L 2 is pentane-1,5-diyl, D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
the ring A with the N—O group contained therein is
wherein
# 6 denotes the linkage site to the carbonyl group,
R 3 is hydrogen,
R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
T 1 is a group of the formula —C(═O)—NR 8 R 9 ,
wherein
R 8 is hydrogen,
R 9 is hydrogen, and
R 35 is methyl,
as well as their salts, solvates, and solvates of the salts.
58 . Binder-drug conjugates of the general formula (Ia) according to claim 1 , wherein
n is a number from 2 to 8, AK is AK 2 ,
wherein
AK 2 is a binder that is bound to the group G via a nitrogen atom of the lysine radical of the binder,
G is carbonyl, L 1 is a bond, B is a bond, L 2 is a group of the formula
wherein
p is the number 3,
## 3 denotes the linkage site to the group B,
## 4 denotes the linkage site to the nitrogen atom,
D is a group of the formula
wherein
# 3 denotes the linkage site to the nitrogen atom,
R 1 is hydrogen,
R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
the ring A with the N—O group contained therein is
wherein
# 6 denotes the linkage site to the carbonyl group,
R 3 is hydrogen,
R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl,
T 1 is a group of the formula —C(═O)—NR 8 R 9 ,
wherein
R 8 is hydrogen, and
R 9 is hydrogen,
as well as their salts, solvates, and solvates of the salts.Cited by (0)
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