US 2015/0030618 A1 · NOVEL BINDER-DRUG CONJUGATES (ADCS) AND USE THEREOF

Novel binder-drug conjugates (adcs) and use thereof

AssigneeSeattle Genetics, Inc.

InventorsHans-Georg LERCHEN, Lars Linden, Sherif El Sheikh, Jörg Willuda, Charlotte C. 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.

Claims35

Dependent claims

(canceled)

Binder-drug conjugates of the general formula (Ia)

in which
n is a number from 1 to 50,
AK is AK1 or AK2
where
AK1 is a binder which is bonded via a sulphur atom of the binder to the group G,
AK2 is a binder which is bonded via a nitrogen atom of the binder to the group G,
G when AK=AK1, 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 L1,
or
when AK=AK2, is carbonyl,
L1 is a bond, linear (C1-C10)-alkanediyl, or a group of the formula
where
m is a number from 2 to 6,
##1 marks the linkage site with the group G,
##2 marks the linkage site with the group B,
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 or a group of the formula
in which
##7 marks the linkage site with the carbonyl group,
##8 marks the linkage site with L1B,
R33 is hydrogen, (C1-C4)-alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
R34 is hydrogen or methyl,
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,
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,
R28 is hydrogen, (C1-C4)-alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
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,
R36 is hydrogen, (C1-C4)-alkylcarbonyl, tert-butyloxycarbonyl or benzyl-oxycarbonyl,
R37 is hydrogen or methyl,
or
R36 and R37 together with the atoms to which they are bonded form a pyrrolidine ring,
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
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.

124 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, or a group of the formula
where
m is a number from 2 to 6,
##1 marks the linkage site with the group G,
##2 marks the linkage site with the group B,
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,
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, or a group of the formula
where
m is a number from 2 to 6,
##1 marks the linkage site with the group G,
##2 marks the linkage site with the group B,
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

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)-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,
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.

85 more elements

Dependencies are inferred from the claim text.