Novel Dyes for Organ Function Monitoring

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 composition comprising a compound of formula  
       
         
           
           
               
               
           
         
       
       wherein R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57  and R 58 , Y 6 , and Z 6  are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, glucose derivatives of R groups, 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 ) b PO 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 NHCONH(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, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) n —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, wherein R a  and R b  are defined in the same manner as Y 6 ; W 6  and X 6  are selected from the group consisting of —CR c R d  wherein R c  and R d  are defined in the same manner as Y 6  with the proviso that CR c R d  is not —C(CH 2 OH) 2 , —O—, —NR c  wherein R c , is defined in the same manner as Y 6 , —S—, and —Se; V 6  is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; D 6  is a single or a double bond; A 6 , B 6  and E 6  may be the same or different and are selected from the group consisting of —O—, —S—, —Se—, —P—, —NR a , —CR c R d , CR c , alkyl, and —C═O wherein R a , R c , and R d  are defined in the same manner as Y 6 ; A 6 , B 6 , D 6 , and E 6  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 atoms; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a 6  and b 6  vary from 0 to 5; and T is either H or a negative charge.  
     
     
         2 . The composition of  claim 1  wherein R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , and R 58 , Y 6 , and Z 6  are independently selected from the group consisting of —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 ) n —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; W 6  is selected from the group consisting of —NR c  and —Se; and X 6  is selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 6  is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; D 6  is a single or a double bond; A 6 , B 6  and E 6  are independently selected from the group consisting of —O—, —S—, —NR a , —CR c R d , CR c , and alkyl; A 6 , B 6 , D 6 , and E 6  may 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 atom; a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k independently vary from 1-50; a 5  and b 5  independently vary from 0 to 5; wherein R a , R b , R c , and R d  are defined in the same manner as Y 6 ; and T is a negative charge.  
     
     
         3 . The composition of  claim 1  further comprising a contrast agent.  
     
     
         4 . The composition of  claim 1  wherein the compound comprises a radioactive halogen.  
     
     
         5 . The composition of  claim 1  further comprising a radioactive metal ion or a paramagnetic metal ion.  
     
     
         6 . A method for performing an imaging procedure comprising administering to a mammal an effective amount of a compound of formula  
       
         
           
           
               
               
           
         
       
       wherein R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , and R 58 , Y 6 , and Z 6  are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, glucose derivatives of R groups, 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 ) b PO 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 NHCONH(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, wherein R a  and R b  are defined in the same manner as Y 6 ; W 6  and X 6  are selected from the group consisting of —CR c R d  wherein R c  and R d  are defined in the same manner as Y 6 , —O—, —NR c  wherein R c  is defined in the same manner as Y 6 , —S—, and —Se with the proviso that W 6  is not NR c  when X 6  is CR c R d ; V 6  is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; D 6  is a single or a double bond; A 6 , B 6  and E 6  may be the same or different and are selected from the group consisting of —O—, —S—, —Se—, —P—, —NR a , —CR c R d , CR c , alkyl, and —C═O wherein R a , R c , and R d  are defined in the same manner as Y 6 ; A 6 , B 6 , D 6 , and E 6  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; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a 6  and b 6  vary from 0 to 5; and T is either H or a negative charge, and thereafter performing the imaging procedure.  
     
     
         7 . The method of  claim 6  comprising administering an effective amount of the composition wherein R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , and R 58 , Y 6 , and Z 6  are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 olyalkoxyalkyl, 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 ) n —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 wherein R a  and R b  are defined in the same manner as Y 6 ; W 6  and X 6  are selected from the group consisting of —CR c R d  wherein R c , and R d  are defined in the same manner as Y 6  with the proviso that CR c R d  is not —C(CH 2 OH) 2 , —O—, —NR c  wherein R c  is defined in the same manner as Y 6 , —S—, and —Se; V 6  is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a  wherein R a  is defined in the same manner as Y 6 ; D 6  is a single or a double bond; A 6 , B 6  and E 6  are independently selected from the group consisting of —O—, —S—, —NR a , —CR c R d , CR c , and alkyl CO 2 T wherein R a , R c , and R d  are defined in the same manner as Y 6 ; A 6 , B 6 , D 6 , and E 6  may 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 atom; a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k independently vary from 1-50; a 5  and b 5  independently vary from 0 to 5; and T is a negative charge.  
     
     
         8 . The method of  claim 6  comprising administering an effective amount of the composition wherein each of R 46 , R 48 , R 50  to R 53 , R 55 , and R 57  is H; each of 7, R 49 , R 54 , and R 56  is SO 3 T; R 58  is glucose; each of Y 5  and Z 6  is —(CH 2 ) 3 SO 3 T; each of W 6  and X 6  is NR c ; D 6  is a double bond; each of B 6  and E 6  is —CH—; A 6  is —CH 2 —; each of a 6  and b 6  is 1; V 5  is a single bond; and T is a negative charge.  
     
     
         9 . The method of  claim 6  wherein the procedure uses light of wavelength in the region of 350-1300 nm.  
     
     
         10 . The method of  claim 6  wherein the procedure comprises monitoring a blood clearance profile by at least one of fluorescence or absorbance using light of wavelength in the region of 350 to 1300 nm.  
     
     
         11 . The method of  claim 6  wherein the composition further comprises a non-optical contrast agent or a non-optical contrast agent is further administered, and imaging includes at least one of magnetic resonance, ultrasound, x-ray, positron emission tomography, computed tomography, and single photon emission computed tomography.  
     
     
         12 . The method of  claim 6  wherein the procedure is for physiological function monitoring.  
     
     
         13 . The method of  claim 6  wherein the procedure is for determining organ perfusion in vivo.  
     
     
         14 . The method of  claim 6  further comprising optically imaging the mammal.  
     
     
         15 . The method of  claim 6  wherein the compound contains a radioactive halogen and imaging the mammal by at least one of optical imaging or nuclear imaging.  
     
     
         16 . The method of  claim 6  wherein the compound administered further comprises a radioactive metal ion or a paramagnetic metal ion.  
     
     
         17 . The method of  claim 16  further comprising imaging by at least one of optical imaging, nuclear imaging, or magnetic resonance imaging.  
     
     
         18 . A method of imaging a patient comprising administering a non-optical contrast agent composition further comprising the compound of  claim 1  and performing at least one of an optical imaging procedure or a non-optical imaging procedure.  
     
     
         19 . The method of  claim 18  wherein the non-optical contrast agent composition is a magnetic resonance composition, a computed tomography composition, an x-ray composition, a nuclear imaging composition, a positron emission tomography composition, a single photon emission computed tomography composition, or an ultrasound composition.  
     
     
         20 . The method of  claim 18  wherein the compound stabilizes or buffers the non-optical contrast agent composition.