5-pyrrolidinylsulfonyl-isatin derivatives

Abstract

The present invention relates to novel 5 -pyrrolidinylsulfonyl isatin derivatives, non-peptidyl Caspase binding Radioligands (CbRs) and CbR-transporter conjugates derived from said isatin derivatives, diagnostic compositions comprising said compounds of the invention and their use for non-invasive diagnostic imaging.

1 . A method of preparing a diagnostic composition for non invasive imaging of caspase activity in vivo by Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET), comprising
 a) providing a non-peptidyl CbR or CbR-transporter conjugate according to Formula 1,   
       
         
           
           
               
               
           
         
         wherein R 1 —X—Y is methoxymethyl; 
         wherein R 2  is an optionally substituted alkyl, heteroalkyl, aralkyl, heteroarylalkyl, carboxymethyl or methyloxycarbonylmethyl group, 
         wherein the substituents are selected from F, I, Br, OH, NH 2 , methylamino, methoxy, fluoroethyloxy, fluoropropyloxy, trimethylamino, nitro, tosylate, triflate, mesylate, diazonium N 2   + , 3-fluorobenzoyl, 4-fluorobenzoyl, 4-fluorophenyl, tributylstannyl, trimethylstannyl, trimethylsilyl, 2-hydrazino-pyridin-5-carbonyl; or a metal-chelator or a metal-chelator bound to an aralkyl, aminoalkyl, hydroxyalkyl or piperazin-1-carbonylmethyl group; 
         and optionally additionally comprises a spacer, linker or molecular transporter selected from Annexin V, PEG 1-200 , an oligopeptide, polyamide, polysaccharide, —NHC(O)—((CH 2 ) n —NH—C(O)) m —, —O—((CH 2 ) n —O) m —, succinyl and 1,4-disubstituted 1,2,3-triazole units, wherein n=0-6 and m=1-200; 
         wherein R 2  can also contain an amino acid selected from histidine, lysine, tyrosine, cysteine, arginine and aspartic acid; and 
         wherein R 2  is labelled with a positron-emitting non-metal radionuclide selected from C-11, N-13, and F-18; and 
         b) formulating the non-peptidyl CbR or CbR-transporter conjugate in an isotonic or isohydric solution in an amount effective for use in non invasive imaging of caspase activity in vivo by SPECT or PET. 
       
     
     
         2 . A method for the diagnosis of disorders connected with apoptosis, comprising
 a) administering a 5-Pyrrolidinylsulfonyl isatin derivative of Formula 1 in vivo to a subject in need of diagnosis,   
       
         
           
           
               
               
           
         
         wherein, 
         R 1 —X—Y is methoxymethyl; 
         R 2  is an optionally substituted alkyl, heteroalkyl, aralkyl, heteroarylalkyl, carboxymethyl or methyloxycarbonylmethyl group, 
         wherein the substituents are selected from F, I, Br, OH, NH 2 , methylamino, methoxy, fluoroethyloxy, fluoropropyloxy, trimethylamino, nitro, tosylate, triflate, mesylate, diazonium N 2   + , 3-fluorobenzoyl, 4-fluorobenzoyl, 4-fluorophenyl, tributylstannyl, trimethylstannyl, trimethylsilyl, 2-hydrazino-pyridin-5-carbonyl; or a metal-chelator or a metal-chelator bound to an aralkyl, aminoalkyl, hydroxyalkyl or piperazin-1-carbonylmethyl group; 
         and optionally additionally comprises a spacer, linker or molecular transporter selected from Annexin V, PEG 1-200 , an oligopeptide, polyamide, polysaccharide, —NHC(O)—((CH 2 ) n —NH—C(O)) m —, —O—((CH 2 ) n —O) m —, succinyl and 1,4-disubstituted 1,2,3-triazole units, wherein n=0-6 and m=1-200 and 
         wherein R 2  can also contain an amino acid selected from histidine, lysine, tyrosine, cysteine, arginine and aspartic acid; 
         b) detecting formed enzyme-inhibitor complexes via a nuclear medicinal technique; and 
         c) determining in a clinical environment whether the apoptosis is physiological or pathological apoptosis. 
       
     
     
         3 . The method of  claim 2 , wherein the disorder to be diagnosed is selected from the group consisting of atherosclerosis, acute myocardial infarction, chronic heart failure, allograft rejection, stroke or neurodegenerative disorders. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . A method for monitoring therapeutic responses connected with apoptosis, comprising
 a) administering a 5-Pyrrolidinylsulfonyl isatin derivative of Formula 1 in vivo to a subject in need of monitoring of therapeutic responses in treatment of an already diagnosed disorder,   
       
         
           
           
               
               
           
         
         wherein, 
         R 1 —X—Y is methoxymethyl; 
         R 2  is an optionally substituted alkyl, heteroalkyl, aralkyl, heteroarylalkyl, carboxymethyl or methyloxycarbonylmethyl group, 
         wherein the substituents are selected from F, I, Br, OH, NH 2 , methylamino, methoxy, fluoroethyloxy, fluoropropyloxy, trimethylamino, nitro, tosylate, triflate, mesylate, diazonium N 2   + , 3-fluorobenzoyl, 4-fluorobenzoyl, 4-fluorophenyl, tributylstannyl, trimethylstannyl, trimethylsilyl, 2-hydrazino-pyridin-5-carbonyl; or a metal-chelator or a metal-chelator bound to an aralkyl, aminoalkyl, hydroxyalkyl or piperazin-1-carbonylmethyl group; 
         and optionally additionally comprises a spacer, linker or molecular transporter selected from Annexin V, PEG 1-200 , an oligopeptide, polyamide, polysaccharide, —NHC(O)—((CH 2 ) n —NH—C(O)) m —, —O—((CH 2 ) n —O) m —, succinyl and 1,4-disubstituted 1,2,3-triazole units, wherein n=0-6 and m=1-200 and 
         wherein R 2  can also contain an amino acid selected from histidine, lysine, tyrosine, cysteine, arginine and aspartic acid; 
         b) detecting formed enzyme-inhibitor complexes via a nuclear medicinal technique; and 
         c) monitoring therapeutic response to treatment of an already diagnosed disorder by determining apoptosis in the subject during a treatment regime in a clinical environment. 
       
     
     
         7 . The method of  claim 6 , wherein the method comprises the monitoring of induction of apoptosis in tumors. 
     
     
         8 . The method of  claim 6 , wherein the apoptosis is chemotherapy-induced or ionizing radiation-induced apoptosis.