Treatment of Retinopathy of Prematurity (ROP)

Abstract

Disclosed herein are methods of treating retinopathy of prematurity (ROP) in a premature and/or low birth weight infant in need thereof, comprising administering to the infant an effective amount of a compound represented by Structural Formula I, Structural Formula Ia or Structural Formula II described herein, or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods of inhibiting the destruction of retinal blood vessels in a premature and/or low birth weight infant in need thereof, comprising administering to the infant an effective amount of a compound represented by Structural Formula I, Structural Formula Ia or Structural Formula II, or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods of treating hyperoxia in a premature and/or low birth weight infant in need thereof, comprising administering to the infant an effective amount of a compound represented by Structural Formula I, Structural Formula Ia or Structural Formula II, or a pharmaceutically acceptable salt thereof. By using the methods disclosed herein, particularly when an infant is hyperoxic, oxygen toxicity to the retina of the eye can be inhibited without restricting oxygen supplementation, which is often necessary to sustain the life of premature infants.

What is claimed is: 
     
         1 . A method of treating hyperoxia in a premature and/or low birth weight infant in need thereof, the method comprising administering to the infant an effective amount of a compound represented by Structural Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen, alkyl, alkoxy, amino, substituted amino, aminoacyl, aryl, halo, heteroaryl, heterocyclyl and —XR 6 ;
 X is oxygen, —S(O) n — or —NR 7 —; 
 n is 0, 1 or 2; 
 R 6  is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl; and 
 R 7  is hydrogen, alkyl or aryl; or 
 R 6  and R 7 , together with the nitrogen atom to which they are commonly bound, form a heterocyclyl; 
 
         R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, halo, hydroxy, cyano, —S(O) m —NR 8 —R 8 , —NR 8 C(O)NR 8 R 8  and —YR 8 ;
 m is 0, 1 or 2; 
 Y is oxygen, —S(O) m′ - or —NR 9 —; 
 m′ is 0, 1 or 2; 
 each R 8  is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl; and 
 R 9  is selected from the group consisting of hydrogen, alkyl and aryl; or 
 R 8  and R 9 , together with the nitrogen atom to which they are commonly bound, form a heterocyclyl; or 
 
         R 2  and R 3 , together with their intervening carbon atoms, form an aryl or heteroaryl; 
         R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, aryl, heteroaryl, and —ZR 10 ;
 Z is oxygen, —S(O) p — or —NR 11 —; 
 p is 0, 1, or 2; 
 R 10  is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclyl; and 
 R 11  is hydrogen, alkyl or aryl; or 
 R 10  and R 11 , together with the nitrogen atom to which they are commonly bound, form a heterocyclyl; 
 
         R″ is hydrogen or alkyl; and 
         R′″ is selected from the group consisting of hydroxy, alkoxy, acyloxy, cycloalkoxy, aryloxy, heteroaryloxy, aryl and —S(O) q —R 12 ;
 q is 0, 1 or 2; and 
 R 12  is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl. 
 
       
     
     
         2 . A method of inhibiting the destruction of retinal blood vessels in a premature and/or low birth weight infant in need thereof, the method comprising administering to the infant an effective amount of a compound represented by Structural Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen, alkyl, alkoxy, amino, substituted amino, aminoacyl, aryl, halo, heteroaryl, heterocyclyl and —XR 6 ;
 X is oxygen, —S(O) n — or —NR 7 —; 
 n is 0, 1 or 2; 
 R 6  is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl; and 
 R 7  is hydrogen, alkyl or aryl; or 
 R 6  and R 7 , together with the nitrogen atom to which they are commonly bound, form a heterocyclyl; 
 
         R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, halo, hydroxy, cyano, —S(O) m —NR 8 —R 8 , —NR 8 C(O)NR 8 R 8  and —YR 8 ;
 m is 0, 1 or 2; 
 Y is oxygen, —S(O) m′ — or —NR 9 —; 
 m′ is 0, 1 or 2; 
 each R 8  is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl; and 
 R 9  is selected from the group consisting of hydrogen, alkyl and aryl; or 
 R 8  and R 9 , together with the nitrogen atom to which they are commonly bound, form a heterocyclyl; or 
 
         R 2  and R 3 , together with their intervening carbon atoms, form an aryl or heteroaryl; 
         R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, aryl, heteroaryl, and —ZR 10 ;
 Z is oxygen, —S(O) p — or —NR 11 —; 
 p is 0, 1, or 2; 
 R 10  is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclyl; and 
 R 11  is hydrogen, alkyl or aryl; or 
 R 10  and R 11 , together with the nitrogen atom to which they are commonly bound, form a heterocyclyl; 
 
         R″ is hydrogen or alkyl; and 
         R′″ is selected from the group consisting of hydroxy, alkoxy, acyloxy, cycloalkoxy, aryloxy, heteroaryloxy, aryl and —S(O) q —R 12 ;
 q is 0, 1 or 2; and 
 R 12  is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl. 
 
       
     
     
         3 . The method of  claim 1 , wherein the compound is represented by Structural Formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 1 , wherein the compound is represented by Structural Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method of  claim 1 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered while the infant is in a hyperoxic state. 
     
     
         6 . The method of  claim 1 , wherein the infant is a premature infant. 
     
     
         7 . The method of  claim 1 , wherein the infant is a severely premature infant. 
     
     
         8 . The method of  claim 1 , wherein the infant is a low birth weight infant. 
     
     
         9 . The method of  claim 1 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered systemically. 
     
     
         10 . The method of  claim 9 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered intraperitoneally, intravenously or subcutaneously. 
     
     
         11 . The method of  claim 9 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered orally. 
     
     
         12 . The method of  claim 1 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered during about the first 14 to about the first 28 days of the infant's life. 
     
     
         13 . The method of  claim 12 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered during about the first 16 days of the infant's life. 
     
     
         14 . The method of  claim 12 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered during about the first 21 to about the first 28 days of the infant's life. 
     
     
         15 . The method of  claim 1 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered at about 3 to about 7 day intervals. 
     
     
         16 . The method of  claim 15 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered every four days. 
     
     
         17 . The method of  claim 15 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered every seven days. 
     
     
         18 . The method of  claim 1 , further comprising administering supplemental oxygen to the premature and/or low birth weight infant. 
     
     
         19 . The method of  claim 18 , wherein an oxygen saturation level of about 90% to about 95% is maintained in the premature and/or low birth weight infant. 
     
     
         20 . A method of treating hyperoxia in a premature and/or low birth weight infant in need thereof, the method comprising:
 administering to the infant an effective amount of a compound represented by Structural Formula II:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and
 further administering supplemental oxygen to the infant.