Minimally invasive physiological function monitoring agents

Abstract

Highly hydrophilic indole and benzoindole derivatives that absorb and fluoresce in the visible region of light are disclosed. These compounds are useful for physiological and organ function monitoring. Particularly, the molecules of the invention are useful for optical diagnosis of renal and cardiac diseases and for estimation of blood volume in vivo.

1 . A compound having the formula 
     
       
         
         
             
             
         
       
     
     wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44  and R 45 , Y 5 , and Z 5  are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C5-C20 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 )bPO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 HT, —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCON H(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c -CH 2 —OH, —(CH 2 ) d -CO 2 T, —CH 2 -(CH 2 —O—CH 2 ) e -CH 2 -CO 2 T, —(CH 2 ) f -NH 2 , —CH 2 -(CH 2 —O—CH 2 ) g -CH 2 -NH 2 , —(CH 2 ) h -N(R a )-(CH 2 ) i -CO 2 T, and —(CH 2 ) j -N(R b )-CH 2  -(CH 2 —O—CH 2 ) k -CH 2 -CO 2 T;
 each of W 5  and X 5  is independently selected from the group consisting of —NR c , —Se, and —S—; 
 V 5  is a single bond or is selected from —O—, —S—, —Se—, and —NR a ; 
 D 5  is a single or a double bond; 
 each of A 5  and B 5  is independently —O—, —S—, —Se—, —P—, —NR a , —CR c R d , alkyl, and —C=O; 
 E 5  is selected from the group consisting of —S—, —Se—, —P—, —NR a , CR c R d , —CR c , alkyl, and —C=O; 
 A 5 , B 5 , D 5 , and E 5  may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom; 
 each of a, b, d, f, h, i, and j independently vary from 1-10; 
 each of c, e, g, and k independently vary from 1-100; 
 each of a 5  and b 5  vary from 0 to 5; 
 each of R a , R b , R c , and R d  is defined in the same manner as Y 5 ; and 
 T is either H or a negative charge. 
 
   
   
       2 . The compound of claim I wherein each of W 5  and X 5  is —S—. 
   
   
       3 . The compound of  claim 1  wherein each of W 5  and X 5  is —NR c . 
   
   
       4 . The compound of  claim 1  wherein each of W 5  and X 5  is —Se—. 
   
   
       5 . The compound of  claim 1  wherein each of R 37  R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44  and R 45 , Y 5 , and Z 5  is independently selected from —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C5-C20 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c , —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g  —CH 2 —NH 2 , —(CH 2 ) h —N(Ra)—(CH 2 ) i —CO 2 T, or —(CH 2 ) j —N(Rb)—cH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T. 
   
   
       6 . The compound of  claim 5  wherein each of R 37 , R 39 , R 42 , and R 44  is H. 
   
   
       7 . The compound of  claim 5  wherein each of R 38 , R 40 , R 41 , and R 43  is SO 3 T. 
   
   
       8 . The compound of  claim 1  wherein R 45  is glucose. 
   
   
       9 . The compound of  claim 5  wherein each of Y 5  and Z 5  is —(CH 2 ) 3 SO 3 T. 
   
   
       10 . The compound of  claim 1  wherein V 5  is a single bond or is selected from —O—, —S—, or —NR a . 
   
   
       11 . The compound of  claim 1  wherein V 5  is a single bond. 
   
   
       12 . The compound of  claim 1  wherein D 5  is a double bond. 
   
   
       13 . The compound of  claim 1  wherein each of A 5  and B 5  is independently selected from —O—, —S—, —CR c R d , or alkyl. 
   
   
       14 . The compound of  claim 1  wherein A 5 , B 5 , D 5 , and E 5  together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom. 
   
   
       15 . The compound of  claim 1  wherein A 5  B 5 , D 5 , and E 5  together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or two oxygen, nitrogen, or sulfur atoms. 
   
   
       16 . The compound of  claim 1  wherein each of B 5  and E 5  is —CH—. 
   
   
       17 . The compound of  claim 1  wherein A 5  is —CH 2 —. 
   
   
       18 . The compound of  claim 1  wherein each of a, b, d, f, h, i, and j independently vary from 1-5. 
   
   
       19 . The compound of  claim 1  wherein each of c, e, g, and k independently vary from 1-50. 
   
   
       20 . The compound of  claim 1  wherein each of a 5  and b 5  is 1. 
   
   
       21 . The compound of  claim 1  wherein T is a negative charge. 
   
   
       22 . The compound of  claim 1  comprising a radioactive halogen. 
   
   
       23 . The compound of  claim 1  wherein at least one R group is replaced by EDTA, DPTA, or DOTA. 
   
   
       24 . The compound of  claim 23  further comprising a radioactive metal ion or a paramagnetic metal ion. 
   
   
       25 . A biocompatible composition comprising
 the compound of  claim 1 , and   at least one biocompatible excipient.   
   
   
       26 . The composition of  claim 25  further comprising a contrast agent. 
   
   
       27 . The composition of  claim 25  formulated as at least one of a liposome, a micelle, a microcapsule, or a microparticle. 
   
   
       28 . Use of the compound of  claim 1  in a medical phototherapy procedure. 
   
   
       29 . The use of  claim 28 , wherein the medical phototherapy procedure comprises exposing the compound to visible and/or near infrared light while the compound is on and/or in the body of a patient. 
   
   
       30 . Use of the compound of  claim 1  in a diagnostic procedure. 
   
   
       31 . The use of  claim 30  wherein the diagnostic procedure comprises monitoring a blood clearance profile by fluorescence using light of wavelength in the region of 350 nm to 1300 nm. 
   
   
       32 . The use of  claim 30  wherein the diagnostic procedure comprises monitoring a blood clearance profile by absorption using light of wavelength in the region of 350 to 1300 nm. 
   
   
       33 . The use  claim 30  wherein the procedure further comprises administering a non-optical contrast agent and imaging by at least one of magnetic resonance, ultrasound, X-ray, positron emission tomography, computed tomography, and single photon emission computed tomography. 
   
   
       34 . The use of  claim 30  wherein the diagnostic procedure comprises monitoring physiological function. 
   
   
       35 . The use of  claim 30  wherein the diagnostic procedure comprises monitoring renal function. 
   
   
       36 . The use of  claim 30  wherein the diagnostic procedure comprises monitoring cardiac function. 
   
   
       37 . The use of  claim 30  wherein the diagnostic procedure comprises monitoring hepatic function. 
   
   
       38 . The use of  claim 30  wherein the diagnostic procedure comprises determining organ perfusion in vivo.