Neurotensin receptor ligands

Abstract

The present invention is related to a compound of formula (I) wherein R1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylmethyl, halogen, nitro and trifluoromethyl; ALK is (C2-C5)alkylidene; R3, R4 and R5 are each and independently selected from the group consisting of hydrogen and (C1-C4)alkyl under the proviso that one of R3, R4 and R5 is of the formula (II) wherein ALK′ is (C2-C5)alkylidene; R6 is selected from the group consisting of hydrogen and (C1-C4)alkyl; and R7 is selected from the group consisting of H and an Effector moiety; or a pharmacologically acceptable salt, solvate or hydrate thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; 
         AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; 
         R 2  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylmethyl, halogen, nitro and trifluoromethyl; 
         ALK is (C 2 -C 5 )alkylidene; 
         R 3 , R 4  and R 5  are each and independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl under the proviso that one of R 3 , R 4  and R 5  is of the following formula (II) 
       
       
         
           
           
               
               
           
         
         wherein 
         ALK′ is (C 2 -C 5 )alkylidene; 
         R 6  is selected from the group consisting of hydrogel and (C 1 -C 4 )alkyl; and 
         R 7  is selected from the group consisting of H and an Effector moiety; 
         or a pharmacologically acceptable salt, solvate or hydrate thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein the Effector moiety is comprising or capable of comprising an Effector, wherein the Effector is selected from the group consisting of a diagnostically active agent, a therapeutically active agent and a combination thereof. 
     
     
         3 . The compound of any of  claims 1  to  2 , wherein the Effector moiety is selected from the group consisting of Acceptor, -[Acceptor-Effector], -[Linker-Acceptor], and -[Linker-Acceptor-Effector], wherein
 Acceptor is a moiety which mediates linking of an Effector to the N atom of formula (II) or which mediates linking of the Effector to the Linker, 
 Effector is selected from the group comprising a diagnostically active agent and a therapeutically active agent, 
 Linker is a moiety which links the Acceptor to the N atom of formula (II), 
 -[Acceptor-Effector] is a moiety where the Effector is complexed or covalently bound to the Acceptor, 
 -[Linker-Acceptor] is a moiety where the Linker is conjugated to the Acceptor, and 
 -[Linker-Acceptor-Effector] is a moiety where the Linker is conjugated to the Acceptor, whereby the Effector is complexed or covalently bound to the Acceptor. 
 
     
     
         4 . The compound of any one of  claims 1 ,  2  and  3 , wherein R 1  is methyl. 
     
     
         5 . The compound of any one of  claims 1 ,  2 ,  3  and  4 , wherein AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid and cyclohexylglycine. 
     
     
         6 . The compound of any one of  claims 1 ,  2 ,  3 ,  4  and  5 , preferably any one of  claims 1 ,  2  and  3 , wherein R 2  is isopropyl. 
     
     
         7 . The compound of any one of  claims 1 ,  2 ,  3 ,  4 ,  5  and  6 , preferably any one of  claims 1 ,  2  and  3 , wherein R 3 , R 4  and R 5  are each and independently selected from the group consisting of hydrogen and methyl under the proviso that one of R 3 , R 4  and R 5  is of the following formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         ALK′ is (C 2 -C 5 )alkylidene; 
         R 6  is selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl. 
       
     
     
         8 . The compound of  claim 7 , wherein R 6  is selected from the group consisting of hydrogen and methyl. 
     
     
         9 . The compound of any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7  and  8  preferably any one of  claims 1 ,  2  and  3 , wherein R 7  is H. 
     
     
         10 . The compound of any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7  and  8 , wherein Effector is a diagnostically active nuclide, preferably a diagnostically active radionuclide, or a therapeutically active nuclide, preferably a therapeutically active radionuclide. 
     
     
         11 . The compound of any one of  claims 1 , 2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8  and  10 , wherein Acceptor is a chelator or an aromate, wherein the animate is preferably an electron rich aromate. 
     
     
         12 . The compound of any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10  and  11 , wherein the compound is selected from the group consisting of a compound of formula (III), a compound of formula (IIIa), a compound of formula (IIIb), a compound of formula (IIIc), a compound of formula (IIId), a compound of formula (IIIe), a compound of formula (IIIf), a compound of formula (IIIg), a compound of formula (IV), a compound of formula (IVa), a compound of formula (IVb), a compound of formula (V), a compound of formula (Va) and a compound of formula (Vb), wherein
 the compound of formula (III) is 
 
       
         
           
           
               
               
           
         
         the compound of formula (IIIa) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IIIb) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IIIc) is 
       
       
         
           
           
               
               
           
         
         (IIIc); 
         the compound of formula (IIId) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IIIe) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IIIf) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IIIg) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IV) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IVa) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (IVb) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (V) is 
       
       
         
           
           
               
               
           
         
         the compound of formula (Va) is 
       
       
         
           
           
               
               
           
         
         and the compound of formula (Vb) is 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , wherein the compound is a compound of formula (IIIa) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (IIIa); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         14 . The compound of  claim 12 , wherein the compound is a compound of formula (IIIb) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (IIIb); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         15 . The compound of  claim 12 , wherein the compound is a compound of formula (IIIc) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (IIIb); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         16 . The compound of  claim 12 , wherein the compound is a compound of formula (IVa) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (IVa); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         17 . The compound of  claim 12 , wherein the compound is a compound of formula (IVb) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (IVb); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         18 . The compound of  claim 12 , wherein the compound is a compound of formula (Va) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (Va); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         19 . The compound of  claim 12 , wherein the compound is a compound of formula (Vb) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (Vb); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  111 In,  177 Lu,  67 Ga,  68 Ga,  64 Cu and  90 Y. 
     
     
         20 . The compound of  claim 12 , wherein the compound is a compound of formula (IIId) and the diagnostically active radionuclide and the therapeutically active radionuclide is chelated by the chelator of formula (IIId); preferably the diagnostically active radionuclide and the therapeutically active radionuclide is selected from the group comprising  67 Ga and  68 Ga. 
     
     
         21 . The compound of  claim 12 , wherein the compound is a compound of formula (IIIe) and the diagnostically active radionuclide is chelated by the chelator of formula (IIIe); preferably the diagnostically active radionuclide is selected from the group comprising  67 Ga and  68 Ga. 
     
     
         22 . The compound of  claim 12 , wherein the compound is a compound of formula (IIIf) and the diagnostically active radionuclide is chelated by the chelator of formula (IIIf); preferably the diagnostically active radionuclide is  89 Zr. 
     
     
         23 . The compound of  claim 12 , wherein the compound is a compound of formula (IIIg) and the diagnostically active radionuclide is  18 F, wherein said  18 F is replacing the F atom at the fluorobenzoic acid moiety of the compound of formula (IIIg). 
     
     
         24 . The compound of any one of  claims 1  to  24 , for use in a method for the diagnosis of a disease. 
     
     
         25 . The compound of any one of  claims 1  to  23 , for use in a method for the treatment of a disease. 
     
     
         26 . The compound of any one of  claims 1  to  23 , for use in a method for the identification of a subject, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method for the identification of a subject comprises carrying out a method of diagnosis using the compound of any one of  claims 1  to  23 , preferably a method for the diagnosis of a disease as described in  claim 24 . 
     
     
         27 . The compound of any one of  claims 1  to  23 , for use in a method for the stratification of a group of subjects into subjects which are likely to respond to a treatment of a disease, and into subjects which are not likely to respond to a treatment of a disease, wherein the method for the stratification of a group of subjects comprises carrying out a method of diagnosis using the compound of any one of  claims 1  to  23 , preferably a method for the diagnosis of a disease as described in  claim 24 . 
     
     
         28 . The compound of any one of  claims 24 ,  25 ,  26  and  27 , wherein the disease is a disease involving neurotensin receptor, preferably the disease is a disease involving neurotensin receptor 1, and more preferably the disease is selected from the group comprising tumors and hematological malignancies. 
     
     
         29 . A composition, preferably a pharmaceutical composition, wherein the composition comprises a compound according to any one of  claims 1  to  23  and a pharmaceutically acceptable excipient. 
     
     
         30 . A kit comprising a compound according to any one of  claims 1  to  23 , one or more optional excipient(s) and optionally one or more device(s), whereby the device(s) is/are selected from the group comprising a labeling device, a purification device, a handling device, a radioprotection device, an analytical device or an administration device.