CYCLIC AGONISTS AND ANTAGONISTS OF C5a RECEPTORS AND G PROTEIN-COUPLED RECEPTORS

Abstract

The present invention relates to novel cyclic or constrained acyclic compounds which modulate the activity of G protein-coupled receptors and are useful in the treatment of conditions mediated by G protein-coupled receptors, for example, inflammatory conditions.

1 - 32 . (canceled) 
     
     
         33 . A method of treating Alzheimer's disease mediated by a C5a receptor, comprising administering to a mammal in need thereof, a compound in amount effective to treat Alzheimer's disease, which compound has antagonist activity against a C5a receptor, has no agonist activity against a C5a receptor, and has the general formula II: 
       
         
           
           
               
               
           
         
         where A is H, alkyl, aryl, NH 2 , NHalkyl, N(alkyl) 2 , NHaryl or NHacyl; 
         B is an alkyl, aryl, phenyl, benzyl, naphthyl or indole group, or the side chain of a D- or L-amino acid selected from the group consisting of phenylalanine, homophenylalanine, tryptophan, homotryptophan, tyrosine, and homotyrosine; 
         C is the side chain of a D-, L- or homo-amino acid selected from the group consisting of proline, alanine, leucine, valine, isoleucine, arginine, histidine, aspartate, glutamate, glutamine, asparagine, lysine, tyrosine, phenylalanine, cyclohexylalanine, norleucine, tryptophan, cysteine and methionine; 
         D is the side chain of a D- or L-amino acid selected from the group consisting of cyclohexylalanine, homocyclohexylalanine, leucine, norleucine, homoleucine, homonorleucine and tryptophan; 
         E is the side chain of a D- or L-amino acid selected from the group consisting of tryptophan and homotryptophan; 
         F is the side chain of a D- or L-amino acid selected from the group consisting of arginine, 
         homoarginine, lysine and homolysine or is one of the following side-chains 
       
       
         
           
           
               
               
           
         
         or another mimetic of an arginine side chain, 
         where 
         X is NCN, NNO 2 , CHNO 2  or NSO 2 NH 2 ; 
         n is an integer from 1 to 4, and 
         R 1  is H or an alkyl, aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph; and 
         X 1  is —(CH 2 ) n NH— or (CH 2 ) r —S—, —(CH 2 ) 2 O—, —(CH 2 ) 3 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, or —CH 2 COCHRNH—, where R is the side chain of any common or uncommon amino acid, and 
         where n is an integer of from 1 to 4. 
       
     
     
         34 . The method according to  claim 33 , which is a compound selected from the group consisting SEQ ID NOS: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28. 
     
     
         35 . The method according to claim  32 , in which n is 2 or 3. 
     
     
         36 . The method according to claim  32 , in which F is one of the following side-chains 
       
         
           
           
               
               
           
         
         or another mimetic of an arginine side chain; 
         where 
         X is NCN, NNO 2 , CHNO 2  or NSO 2 NH 2 ; 
         n is an integer from 1 to 4, and 
         R 1  is H or an alkyl, aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph; 
         B is an indole, indole methyl, benzyl, phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative of the aromatic group; and 
         C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine, tryptophan or methionine. 
       
     
     
         37 . The method according to claim  32 , which has the formula 
       
         
           
                 
                 
                 
               
                     
                   Ac-Phe-[Lys-Pro-(dCha)-Trp-Arg] 
                     
                 
                     
                   or 
                 
                     
                     
                 
                     
                   Ac-Phe-[Orn-Pro-(dCha)-Trp-Arg]. 
                 
             
                
                
                
                
               
            
           
         
       
     
     
         38 . The method according to claim  32 , in which A is L-arginine. 
     
     
         39 . The method according to  claim 33 , in which F is a L-amino acid. 
     
     
         40 . The compound according to  claim 39 , in which F is L-arginine. 
     
     
         41 . The method according to claim  32 , wherein the compound is administered together with a pharmaceutically-acceptable carrier or excipient. 
     
     
         42 . The method according to  claim 41 , wherein the mammal is a human. 
     
     
         43 . The method according to claim  32 , wherein the mammal is a human. 
     
     
         44 . A method of treating Alzheimer's disease, comprising administering to a mammal in need thereof, a compound in amount effective to treat Alzheimer's disease, which compound is an agonist of the C5a receptor, and has the formula IV: 
       
         
           
           
               
               
           
         
         where A is any common or uncommon, basic, charged amino acid side chain which serves to position a positively charged group in this position; 
         B is a non-aromatic amino acid, and 
         C is any common or uncommon, hydrophobic amino acid side chain which serves to position any alkyl, aromatic or other group in this position; and 
         D is any common or uncommon, aromatic amino acid which serve to position an aromatic side-chain in this position, and has the structure: 
       
       
         
           
           
               
               
           
         
         where Z is indole, indole methyl, benzyl, benzene, naphthyl, naphthyl methyl, or a derivative thereof; and 
         R is H or an alkyl, aromatic, acyl or aromatic-acyl group; 
         E is any amino acid other than tryptophan and homotryptophan, and 
         F is the side chain of a D- or L-amino acid selected from the group consisting of arginine, homoarginine, lysine and homolysine. 
       
     
     
         45 . A method of  claim 44 , wherein the compound is administered together with a pharmaceutically acceptable carrier or excipient. 
     
     
         46 . The method of  claim 44 , wherein the mammal is a human. 
     
     
         47 . A method of treating Alzheimer's disease, comprising administering to a mammal in need thereof, a compound in amount effective to treat Alzheimer's disease, which compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 47 , wherein the compound is administered together with a pharmaceutically acceptable carrier or excipient. 
     
     
         49 . The method of  claim 47 , wherein the mammal is a human.