Novel cytostatic conjugates with integrin ligands

Abstract

The present invention relates to cytostatics which have a tumour-specific action as a result of linkage to α v β 3 integrin antagonists via preferred linking units which can be selectively cleaved by elastase, i.e. by an enzyme which can especially be found in tumour tissue. The preferred linking units provide sufficient stability of the conjugate of cytostatic and α v β 3 integrin antagonist in biological fluids and, at the same time, the desired intracellular action within tumour cells as a result of its specific enzymatic or hydrolytic cleavability with release of the cytostatic.

1 . Conjugates of the formula  
         CT−LI−Sp x −IA  (I)  wherein    CT denotes a monovalent radical from the group of a cytotoxic radical, a radical of a cytostatic and a radical of a cytostatic derivative, which can each additionally carry hydroxyl, carboxyl or amino group,    LI denotes a bivalent peptide radical of the formula      −AA1−AA2−AA3−AA4 q −  (III),    wherein independently of one another each of the radicals AA1 to AA4 represents an amino acid residue in the D- or L- configuration, which can each optionally carry protective groups, and    q denotes zero or 1,    Sp denotes a carbonyl or a thiocarbonyl group,    x is zero or 1,    IA denotes a monovalent non-peptide radical addressing an α v β 3  integrin receptor, which radical corresponds to the formula                          wherein the bond between radical (II) and SP (if x=1) or LI (if x=zero) is located as one of the following alternatives: 
 a) between radical (II) and LI via the carbon atom which in formula (II) is marked with a cross,  
 b) between radical (II) and SP or LI 
 (iii) via Y (possible only, if p=1),  
 (iv) (ii) via the nitrogen atom, to which R 10  is attached or preferably  
 (iii) via R 10 ,  
 
 in which formula (II)  
 R 7  denotes hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted aryloxy, or saturated or unsaturated, optionally substituted heterocyclyloxy or represents a single bond, in case the radical (II) is bonded to the rest of the conjugate directly via the carbon atom marked with a cross;  
 R 8  denotes hydrogen, hydroxyl, substituted or unsubstituted alkyl or alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, saturated or unsaturated, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkinyl, or 
 together with (i) R 9  and (ii) the carbon atom, to which R 8  is bonded, forms a substituted or unsubstituted carbocycle or heterocycle;  
 
 R 9  denotes hydrogen, hydroxyl, substituted or unsubstituted alkyl or alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkinyl, substituted or unsubstituted aryl, saturated or unsaturated, substituted or unsubstituted heterocyclyl, or 
 together with (i) R 8  and (ii) the carbon atom, to which R 9  is bonded, forms a substituted or unsubstituted carbocycle or heterocycle;  
 
 R 10  denotes 
 a) one of the monovalent groups of —SO 2 R 101 , —CO—R 101 , —CO—OR 102 , —CO—NR 101 R 103 , —CS—NR 101 R 103  in case the radical (II) is bonded to the rest of the conjugate directly via the carbon atom marked with a cross or via Y, or  
 b) one of the bivalent groups of —SO 2 R 101 , —CO—R 101 , —COOR 102 , —CO—NR 101 R 103 , —CS—NR 101 R 103  in case the radical (II) is bonded to the rest of the conjugate via R 10 , or  
 c) a single bond in case the radical (II) is bonded to the rest of the conjugate via the nitrogen atom, to which R 11  is bonded;  
 
 R 101  denotes 
 a) substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or saturated or unsaturated, substituted or unsubstituted heterocyclyl, in case the radical (II) is not bonded to the rest of the conjugate via R 101 ; or  
 b) a bivalent group selected from substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, and saturated or unsaturated, substituted or unsubstituted heterocyclo-diyl, in case the radical (II) is bonded to the rest of the conjugate via R 101 ,  
 
 R 102  denotes 
 a) a monovalent group selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or saturated or unsaturated, substituted or unsubstituted heterocyclyl, in case the radical (II) is not bonded to the rest of the conjugate via R 102 , or  
 b) a bivalent group selected from substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, or saturated or unsaturated, substituted or unsubstituted heterocyclo-diyl, in case the radical (II) is bonded to the rest of the conjugate via R 102 ;  
 
 R 103  denotes hydrogen or one of the meanings of R 101 , 
 R 11  denotes (i) hydrogen, (ii) substituted or unsubstituted alkyl, (iii) the radical of a saturated or unsaturated (non-aromatic or aromatic) cyclic compound which can contain up to 4 hetero atoms per molecule or (iv) alkyl, substituted with a radical of group (iii) above;  
 L denotes —(CH 2 ) n NHSO 2 (CH 2 ) o —, —(CH 2 ) n SO 2 NH(CH 2 ) o —, —(CH 2 ) n NH—CO(CH 2 ) o —, —(CH 2 ) n CONH(CH 2 ) o —, —(CH 2 ) n O—CH 2 (CH 2 ) o —, —(CH 2 ) n CH 2 O(CH 2 ) o —, —(CH 2 ) n COO(CH 2 ) o —, —(CH 2 ) n OOC—(CH 2 ) o —, —(CH 2 ) n CH 2 CO(CH 2 ) o —, —(CH 2 ) n —COCH 2 (CH 2 ) o —, —NHCONH—, —(CH 2 ) n SCH 2 (CH 2 ) o —, —(CH 2 ) n CH 2 S(CH 2 ) o —, —(CH 2 ) n CH 2 SO(CH 2 ) o —, —(CH 2 ) n SO—CH 2 (CH 2 ) o —, —(CH 2 ) n CH 2 —SO 2 (CH 2 ) o — or —(CH 2 ) n —SO 2 CH 2 (CH 2 ) o —, wherein n and o denote zero or 1 and wherein n+o≦1;  
 R 12  denotes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or saturated or unsaturated, substituted or unsubstituted heterocyclyl, or 
 together with (i) one of R 15  (if present), R 13  or R 14  and (ii) the nitrogen atom, to which R 12  is bonded, forms saturated or unsaturated, substituted or unsubstituted heterocyclyl which can contain further hetero atoms;  
 
 
 X denotes N, O or S;  
 y denotes zero, if X=O or S, and denotes 1, if X=N;  
 R 13  denotes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, cyano, nitro, —CO—R 104  or —CO—OR 105 , or together with (i) X and (ii) one of R 12 , R 14  or R 15  forms substituted or unsubstituted heterocyclyl which can contain further hetero atoms;  
 R 104  denotes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or saturated or unsaturated, substituted or unsubstituted heterocyclyl which can contain further hetero atoms; 
 R 105  denotes hydrogen or one of the meanings of R 104 ;  
 Y denotes N or S;  
 R 14  denotes (i) hydrogen, (ii) substituted or unsubstituted alkyl, (iii) the radical of a saturated or unsaturated (non-aromatic or aromatic) cyclic compound which can contain up to 4 hetero atoms per molecule or (iv) alkyl, substituted with a radical of group (iii) above; or 
 together with (i) Y and (ii) one of R 15  (if present), R 12  or R 13  forms a saturated or unsaturated, substituted or unsubstituted heterocyclyl which can contain further hetero atoms;  
 
 z denotes zero, if Y S, and denotes 1, if Y=N;  
 p denotes zero or 1;  
 R 15  denotes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or saturated or unsaturated, substituted or unsubstituted heterocyclyl or 
 together with (i) Y and (ii) one of R 14  (if p=z=1), R 12 , or R 13  forms saturated or unsaturated, substituted or unsubstituted heterocyclyl which can contain further hetero atoms, or represents a single bond in case the radical (II) is bonded to the rest of the conjugate via Y;  
 
 R 16  to R 19  independently from each other denote cyano, halogen, substituted or unsubstituted alkyl or alkoxy, or substituted or unsubstituted cycloalkyl; and  
 g, h, i, and k independently from each other denote zero or 1;  
 
   and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         2 . Conjugates according to  claim 1 , wherein 
 LI is a group of formula -AA1-AA2-AA3-AA4 q - (III), wherein 
 AA1 denotes the residue of a naturally occurring amino acid in the D- or L-configuration selected from glycine, alanine, valine, leucine, isoleucine, histidine, glutamate, aspartate, serine, lysine, ornithine and phenylalanine,  
 AA2 denotes the residue of a naturally occurring amino acid in the D- or L-configuration selected from alanine, valine, phenylalanine, tyrosine, threonine, serine, isoleucine, lysine, glutamate, histidine, glycine, arginine, asparagine, glutamine, S-methyl cysteine, methionine, aspartate, tryptophane, proline, ornithine and leucine,  
 AA3 and AA4 (if q=1) independently from each other denote the residues of a naturally occurring amino acid in the D- or L-configuration selected from alanine, valine, phenylalanine, tyrosine, serine, isoleucine, lysine, glutamate, glutamine, histidine, glycine, arginine, asparagine, aspartate, tryptophane, proline, ornithine, methionine, S-methyl cysteine, norvaline and leucine,  
   q denotes zero or 1,    and the radicals CT, Sp and IA are as defined in  claim 1 ,    and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         3 . Conjugates according to  claim 1 , wherein 
 Li is a group of formula -AA 1-AA2-AA3-AA4 q - (III), wherein 
 AA1 denotes a bivalent residue of valine, leucine or isoleucine;  
 AA2 denotes a bivalent proline residue,  
 AA3/AA4 independently from one another denote a bivalent residue of alanine, norvaline, histidine, glycine, asparagine or aspartate,  
 q denotes zero or 1,  
   and the radicals CT, Sp and IA are as defined in  claim 1 , and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         4 . Conjugates according to one of  claims 1  to  3 , wherein 
 CT denotes the radical of camptothecin or a camptothecin derivative, which is formally formed by the abstraction of the hydrogen atom from the hydroxyl group at its C 20 -carbon atom or from a functional group present in the molecule such as an amino or a hydroxy group;    LI and Sp are as defined in  claim 1;  and    IA is a non-peptide radical of the formula (II) addressing an α v β 3  integrin receptor, wherein 
 R 7  denotes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, cyclopropoxy, cyclopropylmethoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, phenoxy, tolyloxy, benzyloxy, or a substituted derivative thereof or, preferably, 
 hydroxyl or a single bond (in case the radical (II) is bonded to the rest of the conjugate via the carbon atom marked with a cross);  
 
 R 8  denotes hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, tolyl, benzyl, benzyl-oxy, or a substituted derivative thereof, or 
 together with (i) R 9  and (ii) the carbon atom, to which R 8  is bonded, forms a substituted or unsubstituted 3- to 6-membered carbocycle or heterocycle;  
 
 R 9  denotes hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, tolyl, benzyl, or a substituted derivative thereof, or 
 together with (i) R 8  and (ii) the carbon atom, to which R 9  is bonded, forms a substituted or unsubstituted 3- to 6-membered carbocycle or heterocycle;  
 
 R 10  is as defined in  claim 1;   
 R 101  denotes a monovalent radical selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, phenyl, tolyl, benzyl, or a substituted derivative thereof, —C 6 H 2 (CH 3 ) 3 , —C 6 (CH 3 ) 5 , —CH 2 —C 6 H 2 (CH 3 ) 3 , 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenyl-methyl, 2,4-di-chlorophenyl-methyl, 2,6-dichlorophenyl-methyl, 3-aminophenyl, 4-aminophenyl, 4-carboxyphenyl, 2-methoxycarbonylphenyl-methyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5-bis(trifluoromethyl)-phenyl, 4-trifluoromethoxyphenyl, benzyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, 1-phenyl-propyl, (S)-(+)-camphor-10-yl, (R)-(−)-camphor-10-yl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxy-phenyl, 3-methylphenyl, 4-methyl-phenyl, 4-tert.-butyl-phenyl, 4-propylphenyl, 2,5-dimethyl-phenyl, 2-meth-oxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methyl-phenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)-anilino, 4-acetamidophenyl, 2,2,2-trifluoro-ethyl, 5-chloro-3 methyl-benzothiazol-2-yl, N-methoxycarbonyl-piperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, ethoxy, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methyl-isoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triaza-indolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl, or 
 a bivalent radical formally obtained by abstraction of a hydrogen from the above monovalent R 101  radicals, via which (bivalent radical) the radical (II) can be bonded to the rest of the conjugate;  
 
 R 102  denotes a monovalent radical selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl; phenyl, tolyl, benzyl, or a substituted derivative thereof; —C 6 H 2 (CH 3 ) 3 , —C 6 (CH 3 ) 5 , —CH 2 C 6 H 2  (CH 3 ) 3 , 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichloro-phenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3-aminophenyl, 4-aminophenyl, 4-chloro-phenyl-methyl, 2,4-dichlorophenyl-methyl, 2,6-dichlorophenyl-methyl, 2-methoxycarbonylphenyl-methyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)-phenyl, 4-trifluoromethoxyphenyl, 2-acetamido-4-methylthiazol-5-yl, phenyl-ethyl, 1-phenyl-propyl, (S)-(+)-camphor-10-yl, (R)-(−)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-tert.-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkyl-sulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)-aniline, 4-acetamidophenyl, 2,2,2-trifluoro-ethyl, 5-chloro-3-methyl-benzothiazol-2-yl, N-methoxycarbonyl-piperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, ethoxy, 2-chloro-pyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methyl-isoxazol-3-yl, 1-adamantyl, 4-chloro-phenoxy-methyl, 2,2-dimethylethenyl, 2-chloropyridin-5-methyl, 5,7-dimethyl-1,3; 4-triaza-indolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl, or 
 a bivalent radical formally obtained by abstraction of a hydrogen from the above monovalent R 102  radicals, via which (bivalent radical) the radical (II) can be bonded to the rest of the conjugate;  
 
 R 103  denotes hydrogen or one of the meanings of R 101 , via which radical R 103 , if it is bivalent, the radical (II) can be bonded to the rest of the conjugate;  
 R 11  denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, cyclopropylmethyl, 5-methyl-hex-2-yl, amino-C 1-4 -alkyl, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl or C 1-4 -alkoxy-C 1-4 -alkyl, phenyl, tolyl, benzyl, or a substituted derivative thereof, or one of the following radicals:  
                                                         
 L denotes —NHSO 2 —, —CH 2 NHSO 2 —, —NHSO 2 CH 2 —, —SO 2 —NH—, —CH 2 SO 2 NH—, —SO 2 NHCH 2 —, —NHCO—, —CH 2 NH—CO—, —NHCOCH 2 —, —CONH—, —CH 2 CONH—, —CONHCH 2 —, —OCH 2 —, —CH 2 OCH 2 , —OCH 2 CH 2 —, —CH 2 O— or —CH 2 CH 2 O—;  
 R 12  denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, cyclopropylmethyl, 5-methyl-hex-2-yl, C 1-4 -alkoxy-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, phenyl, tolyl, benzyl, or a substituted derivative thereof, or one of the radicals (a1) to (a28) or together with (i) one of R 15  (if present), R 13  or R 14 , and (ii) the nitrogen atom, to which R 12  is bonded, forms a substituted or unsubstituted, saturated or unsaturated 4- to 6-membered heterocyclic residue which can contain further hetero atoms;  
 X denotes N, O or S;  
 p denotes zero or 1;  
 R 13  denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, nitro, cyano, —COR 104 , —CO—OR 105  or  
 together with (i) X and (ii) one of R 12 , R 14  or R 15  forms a substituted or unsubstituted 4- to 6-membered heterocycle which can contain further hetero atoms;  
 R 104  denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, tolyl, benzyl, or a substituted derivative thereof;  
 R 105  denotes hydrogen or one of the meanings of R 104 ,  
 Y denotes N or S;  
 R 14  denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, cyclopropylmethyl, 5-methyl-hex-2-yl, phenyl, tolyl, benzyl, or a substituted derivative thereof, C 1-4 -alkoxy-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, one of the radicals (a1) to (a28), or 
 together with (i) Y and (ii) one of R 15  (if present), R 12 , or R 13  forms a saturated or unsaturated, substituted or unsubstituted 4- to 6-membered heterocyclic residue which can contain further hetero atoms; and  
 
 R 15  denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, cyclopropylmethyl, 5-methyl-hex-2-yl, C 1-4 -alkoxy-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, phenyl, tolyl, benzyl, or a substituted derivative thereof, 
 one of the radicals (a1) to (a28) or  
 together with (i) Y and (ii) one of R 14  (if p=z=1), R 12 , or R 13  forms a saturated or unsaturated, substituted or unsubstituted 4- to 6-membered heterocyclic residue which can contain further hetero atoms, or  
 represents a single bond in case the radical (II) is bonded to the rest of the conjugate via Y,  
 and the other radicals are as defined in one of  claims 1  to  3 ,  
 
   and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         5 . Conjugates according to  claim 4 , wherein 
 R 7  represents a single bond and 
 the radical (II) is bonded to the rest of the conjugate directly via the carbon atom marked with a cross,  
 and the other radicals of formula (II) are as defined in  claim 4 ,  
 and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.  
   
     
     
         6 . Conjugates according to  claim 4 , wherein 
 R 15  represents a single bond via which the radical (II) is bonded to the rest of the conjugate,    and the other radicals of formula (II) are as defined in  claim 4 ,    and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         7 . Conjugates according to  claim 4 , wherein the radical (II) is bonded to the rest of the conjugate via R 10 , 
 and the other radicals of formula (II) are as defined in  claim 4 ,    and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         8 . Conjugates according to  claim 4 , wherein 
 CT denotes the radical of camptothecin or a camptothecin derivative, which is formally formed by the abstraction of the hydrogen atom from the hydroxyl group at its C 20 -carbon atom or from a functional group present in the molecule such as an amino or a hydroxy group;    LI is as defined in  claim 3 ,    Sp is a carbonyl or a thiocarbonyl group,    IA is radical (II) wherein 
 R 7  is hydroxyl,  
 R 8 , R 9 , R 12 , R 14 , and R 16 R to R 19  are hydrogen,  
 R 10  is —CO—NH-Ph-*NH— wherein the radical (II) is bonded to the rest of the conjugate via the nitrogen atom marked with a star,  
   L is —NH—SO 2  linked to the adjacent phenylene units A and B such that each of these phenylene units is 1,3-substituted,    and the other radicals of formula (II) are as defined in  claim 4 ,    and their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.    
     
     
         9 . Conjugate selected from the compounds of Examples 1 to 12, their stereoisomers, their hydrates, their physiologically acceptable salts and the hydrates of these salts.  
     
     
         10 . A process for preparing the conjugates according to one of  claims 1  to  9  comprising 
 [A] (for conjugates (I) wherein x=zero) the reaction of a moiety comprising radical (II) which has a free or an activated carboxyl function, with a moiety comprising the unit CT-LI— which has a free primary or secondary amino group, or    [B] the reaction of a moiety comprising radical (II) which has a free primary or secondary amino function, 
 with a carbonic acid derivative such as, for example, phosgene, thio-phosgene or a chloroformic acid ester,  
 followed by the reaction with a moiety comprising the unit CT-LI— which has a free primary or secondary amino group, or  
   [C] the reaction of a moiety comprising radical (II) which contains a free primary or secondary amino function, 
 with a moiety comprising the unit CT-LI— which contains a free or activated carboxyl function,  
 wherein all radicals throughout [A] to [C] have the meanings of formula (I) in  claim 1 .  
   
     
     
         11 . A method for the treatment of cancer comprising administering to a host in need thereof an effective amount of a conjugate according to one of  claims 1  to  9 .  
     
     
         12 . A pharmaceutical composition comprising as an active ingredient an effective amount of at least one of the conjugates according to one of  claims 1  to  9  and at least one pharmacologically acceptable formulating agent.  
     
     
         13 . A method of manufacturing a pharmaceutical composition by combining at least one of the conjugates according to one of  claims 1  to  9  with at least one pharmacologically acceptable formulating agent.  
     
     
         14 . A pharmaceutical composition comprising as an active ingredient an effective amount of at least one of the conjugates according to one of  claims 1  to  9  and at least one pharmaceutical active ingredient which is different from the conjugates according to  claims 1  to  9 .  
     
     
         15 . A pharmaceutical composition in dosage unit form comprising an effective amount of a conjugate according to one of  claims 1  to  9  and an inert pharmaceutical carrier.  
     
     
         16 . A method of treating cancer in mammals comprising the administration of an effective amount of at least one conjugate according to one of  claims 1  to  9  either alone or in admixture with a diluent or pharmaceutical carrier.