Use of reversible inhibitors of s-adenosyl-l-homocysteine hydrolase for treating lupus

Abstract

The present invention provides compositions and methods for reversibly inhibiting S-adenosyl-L-homocysteine (SAH) hydrolase. The compounds of the present invention can be used in combination with an anti-hemorrhagic viral infection agent, an immunosuppressant, a homocysteine lowering agent, or an anti-neoplasm agent. The compositions and methods of the present invention can be used for the prevention and treatment of lupus, hemorrhagic virus infection, autoimmune diseases, autograft rejection, neoplasm, hyperhomocysteineuria, cardiovascular disease, stroke, Alzheimer's disease, or diabetes.

1 . A method for treating lupus in a mammal, comprising administering to a mammal having lupus an effective amount of a compound or a pharmaceutically acceptable salt thereof, having the formula (I): 
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of carbon and nitrogen, 
         R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl. 
       
     
     
         2 . The method of  claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is of the formula (IA) 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl. 
       
     
     
         3 . The method of  claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is of the formula (IB) 
       
         
           
           
               
               
           
         
         where R5 is cycloalkyl, alkenyl or heteroaryl; 
         R6 is acetyl, alkenyl or heteroaryl; 
         R7 and R8 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         V is oxygen, nitrogen or sulfur; and 
         W is H 1 , C 1-10  alkyl, alkenyl, vinyl aryl, or heteroaryl. 
       
     
     
         4 . The method of  claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is 
       
         
           
           
               
               
           
         
         wherein W is H or methoxy. 
       
     
     
         5 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         6 . A method for treating lupus in a mammal, comprising administering an effective amount of a combination, wherein the combination comprises:
 a) an effective amount of a compound or a pharmaceutically acceptable salt thereof, having the formula (I):   
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of carbon and nitrogen, 
         R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl; and 
         b) an effective amount of an immunosuppressant. 
       
     
     
         7 . The method of  claim 6 , wherein said compound or pharmaceutically acceptable salt thereof is of the formula (IA) 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl. 
       
     
     
         8 . The method of  claim 6 , wherein said compound or pharmaceutically acceptable salt thereof is of the formula (IB) 
       
         
           
           
               
               
           
         
         where R5 is cycloalkyl, alkenyl or heteroaryl; 
         R6 is acetyl, alkenyl or heteroaryl; 
         R7 and R8 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         V is oxygen, nitrogen or sulfur; and 
         W is H 1 , C 1-10  alkyl, alkenyl, vinyl aryl, or heteroaryl. 
       
     
     
         9 . The method of  claim 6 , wherein said compound or pharmaceutically acceptable salt thereof is 
       
         
           
           
               
               
           
         
         wherein W is H or methoxy. 
       
     
     
         10 . The method of  claim 6 , wherein the mammal is a human. 
     
     
         11 . A method for preventing or treating lupus in a mammal, which method comprises administering to a mammal, to which such treatment or prevention is needed or desired, an effective amount of a reversible inhibitor of a SAH hydrolase, whereby lupus is prevented or treated in said mammal. 
     
     
         12 . The method of  claim 11 , wherein the mammal is a human. 
     
     
         13 . The method of  claim 11 , wherein the reversible inhibitor of a SAH hydrolase is not (4-adenine-9-yl)-2-hydroxybutanoic acid. 
     
     
         14 . The method of  claim 11 , wherein the reversible inhibitor of a SAH hydrolase comprises a compound or a pharmaceutically acceptable salt thereof, having the formula (I): 
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of carbon and nitrogen, 
         R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl. 
       
     
     
         15 . The method of  claim 11 , wherein the reversible inhibitor of a SAH hydrolase comprises a compound or a pharmaceutically acceptable salt thereof, having the formula (IA) 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl. 
       
     
     
         16 . The method of  claim 11 , wherein the reversible inhibitor of a SAH hydrolase comprises a compound or a pharmaceutically acceptable salt thereof, having the formula (IB) 
       
         
           
           
               
               
           
         
         where R5 is cycloalkyl, alkenyl or heteroaryl; 
         R6 is acetyl, alkenyl or heteroaryl; 
         R7 and R8 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         V is oxygen, nitrogen or sulfur; and 
         W is H 1 , C 1-10  alkyl, alkenyl, vinyl aryl, or heteroaryl. 
       
     
     
         17 . The method of  claim 11 , wherein the reversible inhibitor of a SAH hydrolase comprises a compound or a pharmaceutically acceptable salt thereof, having the formula 
       
         
           
           
               
               
           
         
         wherein W is H or methoxy. 
       
     
     
         18 . A kit comprising an effective amount of a compound or a pharmaceutically effective amount thereof, having the formula (I): 
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of carbon and nitrogen, 
         R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl, 
         and an instruction means for administering said compound or pharmaceutically acceptable salt thereof to a mammal at risk for developing or suspected of having lupus. 
       
     
     
         19 . The kit of  claim 18 , wherein said compound or pharmaceutically acceptable salt thereof is of the formula (IA) 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl. 
       
     
     
         20 . The kit of  claim 18 , wherein said compound or pharmaceutically acceptable salt thereof is of the formula (IB) 
       
         
           
           
               
               
           
         
         where R5 is cycloalkyl, alkenyl or heteroaryl; 
         R6 is acetyl, alkenyl or heteroaryl; 
         R7 and R8 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         V is oxygen, nitrogen or sulfur; and 
         W is H 1 , C 1-10  alkyl, alkenyl, vinyl aryl, or heteroaryl. 
       
     
     
         21 . The kit of  claim 18 , wherein said compound or pharmaceutically acceptable salt thereof is 
       
         
           
           
               
               
           
         
         wherein W is H or methoxy. 
       
     
     
         22 . The kit of  claim 18 , further comprising an effective amount of an immunosuppressant.