Pyrazine derivatives with extended conjugation and methods of using the same in optical applications

Abstract

The present invention relates to pyrazine derivatives capable of absorbing and emanating spectral energy in the visible and/or near infrared spectrum. Pyrazine derivatives of the invention may be administered to a patient in the form of a pharmaceutically acceptable composition and utilized in medical (e.g., diagnostic imaging) procedures.

1 - 97 . (canceled) 
     
     
         98 . A compound of Formula (2), or a pharmaceutically acceptable salt thereof, for optically assessing a physiological function in a patient in need thereof; 
       
         
           
           
               
               
           
         
         wherein 
         EWG is an electron withdrawing group; 
         EDG is an electron donating group; 
         x and y are each independently from the other 1, 2 or 3, and the sum of x and y is 3 or 4; and 
         at least one of EWG and EDG is conjugated to the pyrazine ring through a chemically unsaturated linking group. 
       
     
     
         99 . The compound according to  claim 98 , wherein the compound of Formula (2) absorbs and emits spectral energy in the visible and/or near infrared spectrum when exposed to non-ionizing radiation. 
     
     
         100 . The compound according to  claim 98 , wherein the compound of Formula (2) further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of diluents, carriers, adjuvants, preservatives, solubilizers, emulsifiers, tonicity modifiers, buffers and combinations thereof. 
     
     
         101 . The compound according to  claim 98 , wherein the compound of Formula (2) is selected from the group consisting of Formula (2d), Formula (2e), Formula (2h) and Formula (2i), 
       
         
           
           
               
               
           
         
         wherein 
         each EWG is independently selected from the group consisting of —CN, CO 2 R 1 , —CONR 2 R 3 , COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 , and —PO 3 R 8 R 9 ; 
         each EDG is independently selected from the group consisting of —OR 10 , —SR 11 , —NR 12 R 13 , —N(R 14 )COR 15 , and —P(R 16 ); 
         R 1 -R 9  are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl, aryl, heteroaryl, —(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   — , —(CH 2 ) a OSO 3 H, —(CH 2 ) a OSO 3   — , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   — , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H — , —(CH 2 ) a PO 3   ═ , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a PO 3 H and —(CH 2 ) a OPO 3 ; 
         R 10 -R 16  are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl, aryl, heteroaryl, —(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   — , —(CH 2 ) a OSO 3 H, —(CH 2 ) a OSO 3   — , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   — , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H — , —(CH 2 ) a PO 3   ═ , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a OPO 3 H —  and —(CH 2 ) a OPO 3 ; and 
         a is an integer from 1 to 10. 
       
     
     
         102 . The compound according to  claim 101 , wherein each EWG is independently selected from the group consisting of —CN, —CO 2 R 1 , —CONR 2 R 3 , —NO 2 , and —SO 2 R 6 ; and
 each EDG is independently selected from the group consisting of —OR 10 , —SR 11 , —NR 12 R 13 , and —N(R 14 )COR 15 . 
 
     
     
         103 . The compound according to  claim 101 , wherein the compound of Formula (2) is the compound of Formula (2d). 
     
     
         104 . The compound according to  claim 101 , wherein the compound of Formula (2) is the compound of Formula (2e). 
     
     
         105 . The compound according to  claim 101 , wherein the compound of Formula (2) is the compound of Formula (2h). 
     
     
         106 . The compound according to  claim 101 , wherein the compound of Formula (2) is the compound of Formula (2i). 
     
     
         107 . The compound according to  claim 98 , wherein the compound of Formula (2) is selected from the group consisting of Formula (2f), Formula (2j), Formula (2l), Formula (2m), and Formula (2n), 
       
         
           
           
               
               
           
         
         wherein 
         each EWG is independently selected from the group consisting of CN, CO 2 R 1 , —CONR 2 R 3 , COR 4 , NO 2 , SOR 5 , SO 2 R 6 , SO 2 OR 7 , and PO 3 R 8 R 9 ; 
         each EDG is independently selected from the group consisting of —OR 10 , —SR 11 , —NR 12 R 13 , N(R 14 )COR 15 , and —P(R 16 ); 
         R 1 -R 9  are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl, aryl, heteroaryl, —(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   — , —(CH 2 ) a OSO 3 H, —(CH 2 ) a OSO 3   — , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   — , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H — , —(CH 2 ) a PO 3   ═ , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a PO 3 H and —(CH 2 ) a OPO 3 ; 
         R 10 -R 16  are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl, aryl, heteroaryl, —(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   — , —(CH 2 ) a OSO 3 H, —(CH 2 ) a OSO 3   — , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   — , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H — , —(CH 2 ) a PO 3   ═ , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a OPO 3 H —  and —(CH 2 ) a OPO 3 ; and 
         a is an integer from 1 to 10. 
       
     
     
         108 . The compound according to  claim 107 , wherein the compound of Formula (2) is the compound of Formula (2f). 
     
     
         109 . The compound according to  claim 107 , wherein the compound of Formula (2) is the compound of Formula (2j). 
     
     
         110 . The compound according to  claim 107 , wherein the compound of Formula (2) is the compound of Formula (2l). 
     
     
         111 . The compound according to  claim 107 , wherein the compound of Formula (2) is the compound of Formula (2m). 
     
     
         112 . The compound according to  claim 107 , wherein the compound of Formula (2) is the compound of Formula (2n). 
     
     
         113 . The compound according to  claim 107 , wherein the compound of Formula (2) absorbs and emits spectral energy in the visible and/or near infrared spectrum when exposed to non-ionizing radiation. 
     
     
         114 . A pharmaceutical formulation for optically assessing a physiological function in a patient in need thereof; the formulation comprising:
 a compound according to Formula (2), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;   
       
         
           
           
               
               
           
         
         wherein 
         EWG is an electron withdrawing group; 
         EDG is an electron donating group; 
         x and y are each independently from the other 1, 2 or 3, and the sum of x and y is 3 or 4; and 
         at least one of EWG and EDG is conjugated to the pyrazine ring through a chemically unsaturated linking group. 
       
     
     
         115 . The pharmaceutical formulation according to  claim 114 , wherein the compound of Formula (2) is selected from the group consisting of Formula (2d), Formula (2e), Formula (2f), Formula (2h) Formula (2i), Formula (2j), Formula (2l), Formula (2m), and Formula (2n), 
       
         
           
           
               
               
           
         
         wherein 
         each EWG is independently selected from the group consisting of —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 , and —PO 3 R 8 R 9 ; 
         each EDG is independently selected from the group consisting of —OR 10 , —SR 11 , —NR 12 R 13 , —N(R 14 )COR 15 , and —P(R 16 ); 
         R 1 -R 9  are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl, aryl, heteroaryl, —(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   — , —(CH 2 ) a OSO 3 H, —(CH 2 ) a OSO 3   — , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   — , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H — , —(CH 2 ) a PO 3   ═ , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a PO 3 H and —(CH 2 ) a OPO 3 ; 
         R 10 -R 16  are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl, aryl, heteroaryl, —(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   — , —(CH 2 ) a OSO 3 H, —(CH 2 ) a OSO 3   — , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   — , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H — , —(CH 2 ) a PO 3   ═ , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a OPO 3 H —  and —(CH 2 ) a OPO 3 ; and 
         a is an integer from 1 to 10. 
       
     
     
         116 . The pharmaceutical formulation according to  claim 114 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of diluents, carriers, adjuvants, preservatives, solubilizers, emulsifiers, tonicity modifiers, buffers and combinations thereof. 
     
     
         117 . The pharmaceutical formulation according to  claim 114 , wherein the pharmaceutically formulation is configured for intravenous administration to the patient.