US 2013/0095123 A1Published application

New binder-drug conjugates (ADCs) and use thereof

AssigneesBayer Pharma AG, Seattle Genetics, Inc., Bayer Intellectual Property GmbH

InventorsHans-Georg Lerchen, Lars Linden, Sherif El Sheikh, Willuda Willuda, Charlotte Christine Kopitz, Joachim Schuhmacher, Simone Greven, Christoph Mahlert, Beatrix Stelte-Ludwig, Sven Golfier, Rudolf Beier, Iring Heisler, Axel Harrenga, Karl-Heinz Thierauch, Sandra Bruder, Heike Petrul, Hannah Jörißen, Sandra Borkowski

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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.

Claims52

Dependent claims

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-L1-B-L2-§§ 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,
R1 is hydrogen or methyl,
R2 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
R1 and R2 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,
R6 is hydrogen, hydroxy or benzyloxy,
R3 is hydrogen or methyl,
R4 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
R3 and R4 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 T1,
T1 is a group of the formula —C(═O)—OR7, —C(═O)—NR8R9, —C(═O)—NH—NH—R10 or —CH2—O—R11,
in which
R7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R8 is hydrogen or methyl,
R9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R8 and R9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R10 is benzoyl,
R11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R5 is hydrogen, methyl or a group of the formula
in which
#9 marks the linkage site with —CHC(R26)-T2,
R12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O)2OH,
R13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R26 is hydrogen or hydroxy,
T2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.

43 more elements

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,
L1 is a bond, linear (C1-C10)-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,
L1A is linear (C2-C10)-alkanediyl,
B1 is a group of the formula
in which
##5 marks the linkage site with the group L1A,
##6 marks the linkage site with the group L1B,
L5 is a bond or (C2-C4)-alkanediyl,
L6 is a bond,
R29 is hydrogen or (C1-C4)-alkyl,
R30 is hydrogen or (C1-C4)-alkyl,
or
R29 and R30 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R31 is hydrogen or (C1-C4)-alkyl,
R32 is hydrogen or (C1-C4)-alkyl,
or
R−and R32 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
L1B is linear (C2-C10)-alkanediyl,
and
where (C1-C10)-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 (C3-C6)-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L1,
** marks the linkage site with L2,
P is O or NH,
L3 is a bond or (C2-C4)-alkanediyl,
L4 is a bond,
Q1 is a 4- to 7-membered heterocycle,
Q2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,
R14 is hydrogen or (C1-C4)-alkyl,
R15 is hydrogen or (C1-C4)-alkyl,
or
R14 and R15 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R16 is hydrogen or (C1-C4)-alkyl,
R17 is hydrogen or (C1-C4)-alkyl,
or
R16 and R17 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R18 is hydrogen or (C1-C4)-alkyl,
R19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R20 is hydrogen or (C1-C4)-alkyl,
or
R19 and R20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R21 is hydrogen or (C1-C4)-alkyl,
R22 is hydrogen or (C1-C4)-alkyl,
or
R21 and R22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R23 is (C1-C4)-alkyl,
R24 is hydrogen or (C1-C4)-alkyl,
R27 is hydrogen or (C1-C4)-alkyl,
L2 is linear (C2-C10)-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 (C2-C10)-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 (C3-C6)-cycloalkyl ring or a phenyl ring,
D is a group of the formula
where
#3 marks the linkage site with the nitrogen atom,
R1 is hydrogen or methyl,
R2 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
R1 and R2 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,
R6 is hydrogen, hydroxy or benzyloxy,
R3 is hydrogen or methyl,
R4 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
R3 and R4 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 T1,
T1 is a group of the formula —C(═O)—OR7, —C(═O)—NR8R9, —C(═O)—NH—NH—R10 or —CH2—O—R11,
in which
R7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R8 is hydrogen or methyl,
R9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R8 and R9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R10 is benzoyl,
R11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R5 is hydrogen, methyl or a group of the formula
in which
#9 marks the linkage site with —CHC(R26)-T2,
R12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O)2OH,
R13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R26 is hydrogen or hydroxy,
T2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.

100 more elements

Compounds of the formula (XXXI)

in which
L1 is a bond, linear (C1-C10)-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,
L1A is linear (C2-C10)-alkanediyl,
B1 is a group of the formula
in which
##5 marks the linkage site with the group L1A,
##6 marks the linkage site with the group L1B,
L5 is a bond or (C2-C4)-alkanediyl,
L6 is a bond,
R29 is hydrogen or (C1-C4)-alkyl,
R30 is hydrogen or (C1-C4)-alkyl,
or
R29 and R30 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R31 is hydrogen or (C1-C4)-alkyl,
R32 is hydrogen or (C1-C4)-alkyl,
or
R31 and R32 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
L1B is linear (C2-C10)-alkanediyl,
and
where (C1-C10)-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 (C3-C6)-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L1,
** marks the linkage site with L2,
P is O or NH,
Q1 is a 4- to 7-membered heterocycle,
Q2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,
R18 is hydrogen or (C1-C4)-alkyl,
R19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R20 is hydrogen or (C1-C4)-alkyl,
or
R19 and R20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R21 is hydrogen or (C1-C4)-alkyl,
R22 is hydrogen or (C1-C4)-alkyl,
or
R21 and R22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R27 is hydrogen or (C1-C4)-alkyl,
L2 is linear (C2-C10)-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 (C2-C10)-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 (C3-C6)-cycloalkyl ring or a phenyl ring,
D is a group of the formula
in which
#3 marks the linkage site with the nitrogen atom,
R1 is hydrogen or methyl,
R2 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
R1 and R2 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,
R6 is hydrogen, hydroxy or benzyloxy,
R3 is hydrogen or methyl,
R4 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
R3 and R4 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 T1,
T1 is a group of the formula —C(═O)—OR7, —C(═O)—NR8R9, —C(═O)—NH—NH—R10 or —CH2—O—R11,
in which
R7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R8 is hydrogen or methyl,
R9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R8 and R9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R10 is benzoyl,
R11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R5 is hydrogen, methyl or a group of the formula
#9 marks the linkage site with —CHC(R26)-T2,
R12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O)2OH,
R13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R26 is hydrogen or hydroxy,
T2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
R35 is methyl or hydroxy,
and also their salts, solvates and solvates of the salts.

86 more elements

Binder-drug conjugates of the general formula (I)

in which
n is a number from 1 to 50,
AK is a binder,
the group §-G-L1-B-L2-§§ 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,
R1 is hydrogen,
R2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R1 and R2 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,
R6 is hydrogen, hydroxy or benzyloxy,
R3 is hydrogen,
R4 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 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 T1,
T1 is a group of the formula —C(═O)—OR7, —C(═O)—NR8R9, —C(═O)—NH—NH—R10 or —CH2—O—R11,
in which
R7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R8 is hydrogen or methyl,
R9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R8 and R9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R10 is benzoyl,
R11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R5 is hydrogen, methyl or a group of the formula
in which
#9 marks the linkage site with —CHC(R26)-T2,
R12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O)2OH,
R13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R26 is hydrogen or hydroxy,
T2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
and also their salts, solvates and solvates of the salts.

42 more elements

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,
L1 is a bond, linear (C1-C10)-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 (C1-C10)-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 (C3-C6)-cycloalkyl ring or a phenyl ring,
B is a bond or a group of the formula
where
* marks the linkage site with L1,
** marks the linkage site with L2,
P is O or NH,
L3 is a bond or (C2-C4)-alkanediyl,
L4 is a bond or a group of the formula
in which
*** marks the linkage site with the carbonyl group,
**** marks the linkage site with L2,
R25 is hydrogen or methyl,
Q1 is a 3- to 7-membered carbocycle or a 4- to 7-membered aza heterocycle,
Q2 is a 3- to 7-membered carbocycle or a 4- to 7-membered aza heterocycle,
R14 is hydrogen or (C1-C4)-alkyl,
R15 is hydrogen or (C1-C4)-alkyl,
or
R14 and R15 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R16 is hydrogen or (C1-C4)-alkyl,
R17 is hydrogen or (C1-C4)-alkyl,
or
R16 and R17 together with the atoms to which they are bonded form a 5- or 6-membered heterocycle,
R18 is hydrogen or (C1-C4)-alkyl,
R19 is hydrogen or the side group of a natural α-amino acid or of its homologues or isomers,
R20 is hydrogen or (C1-C4)-alkyl,
or
R19 and R20 together with the atoms to which they are bonded form a pyrrolidinyl ring,
R21 is hydrogen or (C1-C4)-alkyl,
R22 is hydrogen or (C1-C4)-alkyl,
or
R21 and R22 together with the atoms to which they are bonded form a 3- to 7-membered carbocycle,
R23 is (C1-C4)-alkyl,
R24 is hydrogen or (C1-C4)-alkyl,
R27 is hydrogen or (C1-C4)-alkyl,
L2 is linear (C2-C10)-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 (C2-C10)-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 (C3-C6)-cycloalkyl ring or a phenyl ring,
D is a group of the formula
in which
#3 marks the linkage site with the nitrogen atom,
R1 is hydrogen,
R2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R1 and R2 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,
R6 is hydrogen, hydroxy or benzyloxy,
R3 is hydrogen,
R4 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 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 T1,
T1 is a group of the formula —C(═O)—OR7, —C(═O)—NR8R9, —C(═O)—NH—NH—R10 or —CH2—O—R11,
in which
R7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl,
R8 is hydrogen or methyl,
R9 is hydrogen, methyl, ethyl, n-propyl or benzyl,
or
R8 and R9 together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle,
R10 is benzoyl,
R11 is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
R5 is hydrogen, methyl or a group of the formula
in which
#9 marks the linkage site with —CHC(R26)-T2,
R12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O)2OH,
R13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
R26 is hydrogen or hydroxy,
T2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
and also their salts, solvates and solvates of the salts.

86 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/656,681Filed 20 Oct 2012
Priority: EP 11163467.121 Apr 2011
Published: 18 Apr 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification41 codes

A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…
A61K 31/4025
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: not condensed and…
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings

Family

Application13/656,681Continuation in part
US 8,992,932 B2Related patent
US 2013/0095123 A1This patent

From the US filing history. Foreign family members aren’t listed.

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