Methods for Treating Systemic Lupus Erythematosus

Abstract

Methods for treating systemic lupus erythematosus (SLE) are disclosed, based on administering to a subject with SLE an amount effective to treat the subject of a polypeptide including antiogensin 1-7 (A(1-7)), Nle3A1-7, or a compound according to general formula 1.

We claim: 
     
         1 . A method of treating a subject with systemic lupus erythematosus (SLE) administering to the subject in need thereof an effective amount of a compound having the general formula 1 including salts thereof: 
       
         
           
           
               
               
           
         
         wherein:
 ring A is a five-membered or six-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms; 
 ring B is a five-membered or six-membered heteroaryl ring that contains at least one nitrogen atom; 
 A 1 , A 2 , A 3 , A 4  are independently selected from a group consisting of ═N—, —C(═O)—, —C(R a )═, ═C(R b )—, —C(R c )(R d )—N(R e )—, —C(R e )(R d )—O—, and —[C(R c )(R d )] n —, wherein n is 1 or 2; 
 X 1 —X 2  is —(R 6 )C—N—, —N—C(R 6 )—, —N—N—, —N—O—, —O—N—, —N—S— or —S—N—; 
 X 3  is —(R 7 )C=C(R 8 )—, —O—, —S—, or —N(R 9 )—; 
 Z is —O—, —N(H)— or a bond to R 5 ; 
 R a and R b  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, 
 or R a  and R b  can also join to form a ring of up to 6 atoms; 
 R c  and R d  are independently selected from a group consisting of hydrogen, alkyl, aryl, or heteroaryl, provided that R c  and R d , together with the atoms to which they are attached, form a ring of up to 6 atoms; 
 R e  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; 
 R 1 , R 3 , R 4 , R 6 , R 7 , and R 8  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyland aryloxyalkyl; 
 R 2  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; 
 R 5  is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; and 
 R 9  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl. 
 
       
     
     
         2 . The method of  claim 1 , wherein ring A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein:
 R 10  and R 11  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, or R 10  and R 11 , together with ring A to which they are attached, form a carbocyclic, heterocyclic, aryl or hetoaryl ring; 
 R 12  is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; 
 R 13  is hydrogen, alkyl, aryl or heteroaryl; 
 R 14  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and 
 R f , R g , R h , and R i , are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; 
 or a salt thereof. 
 
       
     
     
         3 . The method of  claim 1  or  2 , wherein ring B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein groups R 6 , R 7 , R 8  and R 9  are defined as in general formula 1; 
         or a salt thereof. 
       
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2 , R 3 , R 4  R 5,  R 6 , R 7 , R 8 , R 9 , R a , R b , R c , R d  and Z are defined as in general formula 1; 
 R 10  and R 11  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy 
 or R 10  and R 11 , together with ring A to which they are attached, form a carbocyclic, heterocyclic, aryl or hetoaryl ring; 
 R 12  is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; 
 R 13  is hydrogen, alkyl, aryl or heteroaryl; 
 R 14  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and 
 R f , R g , R h , and R i , are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, chloro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl; 
 or a salt thereof. 
 
       
     
     
         5 . The method of any one of  claims 1 - 4 , wherein R 2  is trifluoromethoxy. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein Z is —O— or —N(H)—. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the compound has the general formula 4a or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 Z is —O— or —N(H)—; 
 R 10  and R 11  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, 
 or R 10  and R 11 , together with ring A to which they are attached, form a carbocyclic, heterocyclic, aryl or hetoaryl ring; 
 R 12  is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; 
 R 15  is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and 
 R 16  is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino. 
 
       
     
     
         8 . The method of any one of  claims 1 - 6 , wherein the compound has the general formula 4a or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 Z is —O— or —N(H)—; 
 R 10 , R 11  and R 12  are hydrogen; 
 R 15  is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and 
 R 16  is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino. 
 
       
     
     
         9 . The method of any one of  claims 1 - 6 , wherein the compound has the general formula 4a or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 Z is —O— or —N(H)—; 
 R 10  and R 11  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, 
 or R 10  and R 11 , together with ring A to which they are attached, form a carbocyclic, heterocyclic, aryl or hetoaryl ring; 
 R 12  is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; 
 R 15  is trifluoromethyl and R 16  is ethyl. 
 
       
     
     
         10 . The method of any one of  claims 9 , wherein the compound has the formula 7 
       
         
           
           
               
               
           
         
       
     
     
         11 . A method for treating SLE, comprising administering to a subject having SLE an amount effective of a polypeptide comprising or consisting of A(1-7) (Asp-Arg-Val-Tyr-Ile-His-Pro) (SEQ ID NO:1), Nle3 A(1-7) (Asp-Arg-Nle-Tyr-Ile-His-Pro) (SEQ ID NO:2), or a pharmaceutically acceptable salt thereof, effective to treat the SLE. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein the provided compound or pharmaceutically acceptable salt thereof, or polypeptide or pharmaceutically acceptable salt thereof is provided as a composition comprising the compound or pharmaceutically acceptable salt thereof, or polypeptide or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier suitable for oral, parenteral, or topical administration. 
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the treating comprises limiting one or more of the following in the subject: lymph node swelling, rash, proteinuria, nephropathy, and antibodies against single and double stranded DNA. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the subject is a human female. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the compound or pharmaceutically acceptable salt thereof, or polypeptide or pharmaceutically acceptable salt thereof is administered in combination with one or more of belimumab, a corticosteroid, and/or hydroxychloroquine.