Integrin-mediated drug targeting

1. A conjugate having the formula (1)

CT-AA1-AA2-AA3-AA4-Sp-IA  (I)

in which

CT is camptothecin or 9-aminocamptothecin, which can be bonded to the rest of the conjugate via the C20—OH group or, in the case of 9-aminocamptothecin, via the free amino group;

AA1 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;

AA2 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of lysine, glutamate, histidine, glycine, arginine, ornithine and leucine, and can optionally carry protective groups or a radical Sp′;

AA3 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;

AA4 is absent or is a naturally occurring amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp′;

in which

Sp′ is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical;

Sp is absent, is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical or is an alkanedicarboxylic acid radical having 3 to 6 carbon atoms or is a carbonyl or a thiocarbonyl radical;

with the proviso that at least one of the radicals AA1 to AA4 and/or Sp is present,

IA is a non-peptide radical addressing an α v β 3 integrin receptor, which is a radical of the formula (m)

in which

R 7 is OH, a substituted or unsubstituted alkoxy or cycloalkoxy radical, a substituted or unsubstituted aryloxy radical or a saturated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (III) is bonded to the rest of the conjugate;

R is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkynyl radical, a hydroxyl radical or an alkoxy radical or is bonded to R 9 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R 8 is bonded and can optionally contain heteroatoms;

R 9 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkynyl radical, a hydroxyl radical or an alkoxy radical or is bonded to R 8 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R 9 is bonded and can optionally contain heteroatoms;

R 10 is —SO 2 R 10′ , —COOR 10″ , —COR 10′ , —CONR 10′ 2 or —CS—NR 10′ 2 , or represents a direct bond via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;

R 10′ independently of one another is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;

R 10″ is a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;

R 11 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical or a substituted or unsubstituted aryl radical,

R 16 is hydrogen, CN, a substituted or unsubstituted alkyl or cyclo-alkyl radical, a substituted or unsubstituted alkoxy radical or a halogen atom;

R 17 is hydrogen, CN, a substituted or unsubstituted alkyl or cyclo-alkyl radical, a substituted or unsubstituted alkoxy radical or a halogen atom;

L is —(CH 2 ) n NHSO 2 (CH 2 ) o —, —(CH 2 ) n SO 2 NH(CH 2 ) o —, —(CH 2 ) n NHCO(CH 2 ) o —, —(CH 2 ) n CONH(CH 2 ) o —, —(CH 2 ) n OCH 2 (CH 2 ) o —, —(CH 2 ) n CH 2 O(CH 2 ) n —, —(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 SOCH 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 —,

where n and o each is an integer of 0 or 1 and n+o≦1;

R 12 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R 13 , R 14 or R 15 , if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom, to which R 12 is bonded and can be saturated or unsaturated and/or can contain further hetero-atoms;

X is N, O or S;

p is 0 or 1;

R 13 is absent, is —H, a substituted or unsubstituted alkyl or cyclo-alkyl radical, —NO 2 , —CN, —COR 13′ , —COOR 13′ , or is bonded to one of R 12 , R 14 or R 15 with formation of an optionally substituted heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further hetero-atoms;

R 13 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical which can be saturated or unsaturated and/or can contain further heteroatoms;

Y is N or S;

R 14 is absent, hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R 12 , R 13 or R 15 , if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R 14 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;

R 15 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R 12 , R 13 or R 14 , if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R 15 is bonded and can be saturated or unsaturated and/or can contain further hetero-atoms, or optionally represents a direct bond via which the radical of the formula (III) is bonded to the rest of the conjugate;

or a physiologically acceptable salt or stereoisomer thereof.

2. The conjugate according to claim 1 , characterized in that

IA is a non-peptide radical of the formula (III) addressing an α v β 3 integrin receptor,

in which

R 7 is OH, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, cyclopropoxy, cyclopropylmethoxy, cyclobutoxy, cyclo-pentoxy, cyclohexoxy, phenoxy, benzyloxy, tolyloxy or a substituted derivative thereof, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (III) is bonded to the rest of the conjugate;

R 8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, —OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, benzyloxy or is bonded to R 9 with formation of an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring system, which includes the carbon atom to which R 8 is bonded and can optionally contain heteroatoms;

R 9 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, —OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy or is bonded to R 8 with formation of an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring system which includes the carbon atom to which R 9 is bonded and can optionally contain heteroatoms;

R 10′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl 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-chlorophenylmethyl, 2,4-dichloro-phenyl-methyl, 2,6-dichlorophenylmethyl, 3-aminophenyl, 4-amino-phenyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methylthiazol-5-yl, phenylethyl, 1-phenylpropyl, (S)-(+)-camphor-10-yl, (R)-(−)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluoro-phenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 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)aniline, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methylbenzothiazol-2-yl, N-meth-oxycarbonyl-piperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, ethoxy, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl;

R 10″ is a C 1-6 -alkyl radical, a C 3-7 -cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;

R 11 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl or

R 16 is hydrogen, CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, fluorine, chlorine, bromine or iodine;

R 17 is hydrogen, CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, fluorine, chlorine, bromine or iodine;

L is —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 NHCO—, —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 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C 1-4 -alkylamino- C 1-4 -alkyl, C 1-4 -dialkyl-amino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, one of the radicals (a1) to (a28) or is bonded to one of R 13 , R 14 or R 15 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 12 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;

R 13 is absent, is —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, —NO 2 , —CN, —COR 7′ , —COOR 7′ , or is connected to one of R 12 , R 14 or R 15 with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;

R 13 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof;

R 14 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, one of the radicals (a1) to (a28), or is bonded to one of R 12 , R 13 or R 15 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 14 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; and

R 15 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, one of the radicals (a1) to (a28) or is bonded to one of R 12 , R 13 or R 14 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 15 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, and or optionally represents a direct bond via which the radical of the formula (III) is bonded to the rest of the conjugate.

3. The conjugate according to claim 2 , wherein

R 7 represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (III) is bonded to the rest of the conjugate.

4. The conjugate according to claim 2 , wherein

R 15 represents a direct bond, via which the radical of the formula (III) is bonded to the rest of the conjugate.

5. The conjugate according to claim 2 , wherein the radical of the formula (III) is linked to the rest of the conjugate via a radical in the α- or β-position relative to the carboxyl group.

6. A process for the preparation of conjugates according to claim 1 , comprising

(A) reacting a compound of the formula (III) which has a free or optionally activated carboxyl function, with a compound of the formula (Ia) which has a free primary or secondary amino group

CT-AA1-AA2-AA3-AA4-Sp  (Ia)

CT is camptothecin or 9-aminocamptothecin, which can be bonded to the rest of the conjugate via the C20—OH group or, in the case of 9-aminocamptothecin, via the free amino group;

AA1 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;

AA2 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of lysine, glutamate, histidine, glycine, arginine, ornithine and leucine, and can optionally carry protective groups or a radical Sp′;

AA3 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;

AA4 is absent or is a naturally occurring amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp′;

in which

Sp′ is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical;

Sp is absent, is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical or is an alkanedicarboxylic acid radical having 3 to 6 carbon atoms or is a carbonyl or a thiocarbonyl radical;

in the presence of a base;

or

(B) reacting a compound of the formula (III) which has a free primary or secondary amino function,

with a carbonic acid derivative, if appropriate in the presence of a base,

followed by the reaction with a compound of the formula (Ia) which has a free primary or secondary amino group

CT-AA1-AA2-AA3-AA4-Sp  (Ia)

in which all radicals have the meaning indicated above, and

if appropriate removing protective groups and/or derivatizing nitrogen atoms present at preferred points of time in the preparation process and/or conversion of the compound obtained into the free acid and/or conversion of the compound obtained into one of its physiological salts by reaction with an inorganic or organic base or acid;

or

(C) reacting a cytotoxic compound or a cytostatic or a cytostatic derivative CT which contains a free primary or secondary amino group,

with a carbonic acid derivative in the presence of a base,

followed by the reaction with a compound of the formula (III) which has a free primary or secondary amino function,

and

if appropriate removing protective groups and/or derivatizing nitrogen atoms present at preferred points of time in the preparation process and/or conversion of the compound obtained into the free acid and/or conversion of the compound obtained into one of its physiological salts by reaction with an inorganic or organic base or acid;

or

(D) reacting a compound of the formula (III) which contains a free primary or secondary amino function,

with a compound of the formula (Ia) which contains a free or optionally activated carboxyl function

CT-AA1-AA2-AA3-AA4-Sp  (Ia)

in which all radicals have the meaning indicated above,

in the presence of a base;

and

if appropriate removing protective groups and/or derivatizing nitrogen atoms present at preferred points in time in the preparation process and/or conversion of the compound obtained into the free acid and/or conversion of the compound obtained into one of its physiological salts by reaction with an inorganic or organic base or acid.

7. The process according to claim 6 , characterized in that all steps of the process are carried out on a solid phase.

8. A pharmaceutical composition comprising a conjugate according to claim 1 , and a pharmaceutically acceptable carrier.

9. A method for the treatment of a carcinomatous disorder comprising administering to a host in need thereof an effective amount of a compound according to claim 1 .

10. The process of claim 6 wherein said carbonic acid derivative in (B) and (C) is phosgene, thiophosgene or a chloroformic acid ester.