Chemokine receptor antagonists

Abstract

The instant invention is a series of compounds which are MCP-1 receptor antagonists of Formula I Also included in the invention are intermediates and processes for the preparation of the compounds as well as methods of using the compounds as agents for the treatment of atherosclerosis, chronic and acute inflammatory disease, chronic and acute immune disorders and transplant rejection as well as for preventing infection by HIV, treating infection by TIV, delaying the onset of AIDS, or treating AIDS.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH 2 ) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 3  is lower alkyl, lower alkenyl, benzyl, or aryl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle with the proviso that R 3  is not methyl when R 4  is hydrogen, R 5  is hydroxy, and R 6  is phenyl.  
 
     
     
         2 . A compound according to  claim 1  of formula  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is hydrogen, bromine, or nitro;  
         R 3  is methyl, n-propyl, n-butyl, or allyl;  
         R 4  is hydrogen or methyl;  
         R 5  is hydroxy, NOH, or NH 2 ;  
         R 7  is hydrogen, 3,4-methoxy, 3-methoxy, 3,5-methoxy, 3,4-chloro, 4-phenyl, or 4 
         
           
             
             
                 
                 
             
           
         
         phenyl with the proviso that R 3  is not methyl when R4 and R 7  are hydrogen, and R 5  is hydroxy  
       
     
     
         3 . A method of inhibiting the binding of MCP-1 to its receptor comprising administering a therapeutically effective amount of compound according to  claim 1  to a mammal in need thereof.  
     
     
         4 . A compound according to  claim 1  and selected from: 
 [2S-(2α,4aα,13β,14αβ)]-13b-Allyl-3-benzylidene-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol;  
 [2S-(2α,4aα,13β,14αβ)]-3-Benzylidine-13b-propyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2S-(2α,4aα,13β,14αβ)]-3-Benzylidine-13b-butyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα, 13bβ,14aβ]]-3-Benzylidine-10-bromo-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα,13bβ,14aβ]]-3-Benzylidine-13b-methyl-10-nitro-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα,13bβ,14aβ]]-3-Benzylidine-13b-methyl-12-nitro-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα,13bβ,14aβ]]-3-(3,4-Dimethoxy-benzylidene)-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2α,3α:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα,13bβ,14aβ]]-3-(3-Methoxy-benzylidene)-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα, 13bβ,14aβ]]-3-(3,5-Dimethoxy-benzylidene)-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [2R-[2α(E),4aα,13bβ,14aβ]]-3-(3,4-Dichloro-benzylidene)-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-ol;  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-Benzylidene-13b-methyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one oxime;  
 3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ylamine;  
 [1R-[1α,2β(E),4aβ,13bα,14aβ]]1,13b-Dimethyl-3-(4-styryl-benzylidene)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido] 1,2-b]isoquinolin-2-ol;  
 [1R-[1α,2β(E),4aβ,13bα,14aβ]]3-Benzylidene-1,13b-dimethyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido]1,2-b]isoquinolin-3-ol;  
 [1R-[1α,2β(E),4aβ,13bα,14aβ]]3-Biphenyl-4-ylmethylene-1,13b-dimethyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido] 1,2-b]isoquinolin-2-ol;  
 [4aS-(2E,4aα,13bβ,14aβ)]-13b-Allyl-3-benzylidene-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-one;  
 [4aS-(2E,4aα,13β,14aβ)]-3-Benzylidine-13b-propyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-one;  
 [4aS-(2E,4aα,13β,14aβ)]-3-Benzylidine-13b-butyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-one;  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-Benzylidine-10-bromo-13b-methyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one;  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-Benzylidine-13b-methyl-10-nitro-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one and [4aR-[(E),4aα,13bβ, 14aβ]]-3-Benzylidine-13b-methyl-12-nitro-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one;  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-(3,4-Dimethoxy-benzylidene)-13b-methyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one;  
 [4aR-[(E),4aα,13bβ,14aβ]]3-(3-Methoxy-benzylidene)-13b-methyl-3,4,4a,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-one;  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-(3,5-Dimethoxy-benzylidene) 13b-methyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one;  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-(3,4-Dichloro-benzylidene)-13b-methyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one; and  
 [4aR-[(E),4aα,13bβ,14aβ]]-3-Benzylidene-13b-methyl-3,4,4a,5,7,8,13,13b,14,14a-decahydro-1H-indolo[2′,3′:3,4]pyrido[1,2-b]-isoquinolin-2-one.  
 
     
     
         5 . A method of treating inflammation in a mammal in need thereof comprising administering to said mammal an effective anti-inflammatory amount of a compound of  claim 1 .  
     
     
         6 . A method of treating inflammation in a mammal in need thereof comprising administering to said mammal an effective anti-inflammatory amount of a compound of  claim 2 .  
     
     
         7 . A method of treating atherosclerosis in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         8 . A method of treating pain in a mammal in need thereof comprising administering to said mammal an effective analgesic amount of a compound of  claim 1 .  
     
     
         9 . A method of treating restenosis in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         10 . A method of treating immune disorders in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         11 . A method of treating transplant rejection in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         12 . A method of treating a virus in a mammal in need thereof comprising administering to said mammal an antivirally effective amount of a compound of  claim 1 .  
     
     
         13 . A method for preventing infection by HIV, treating infection by HIV, delaying the onset of AIDS, or treating ADS comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         14  A method for preventing infection by HIV, treating infection by HIV, delaying the onset of AIDS, or treating AIDS comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to  claim 2  or a pharmaceutically acceptable salt thereof.  
     
     
         15 . A method for modulation of the CCR-5 chemokine receptor activity in a mammal comprising administering an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         16 . A pharmaceutical composition comprising a compound according to  claim 1  in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.  
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 2  in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.  
     
     
         18 . A method of treating atherosclerosis in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8, 13,13b,14,14adodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH2) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONSR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         19 . A method of treating pain in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH2) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         20 . A method of treating restenosis in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH 2 ) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         21 . A method of treating immune disorders in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH2) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         22 . A method of treating transplant rejection in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH 2 ) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONER wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         23  A method of treating virus in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα, 13bβ, 14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH 2 ) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen,;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, -COOR, -CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         24 . A method for preventing infection by HIV, treating infection by HIV, delaying the onset of AIDS, or treating AIDS in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH 2 ) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.  
 
     
     
         25 . A method for modulation of the CCR-5 chemokine receptor activity in a mammal in need thereof comprising administering a compound of Formula II  
       
         
           
           
               
               
           
         
       
       or the compound [2R[2α(E),4aα,13bβ,14aβ]]3-Benzylidene-13b-methyl-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydro-indolo[2′,3′:3,4]pyrido[1,2-b]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof wherein: 
 the --- means a double bond is possible;  
 R 1  is hydrogen, lower alkyl, lower alkenyl, alkoxy, hydroxy, halogen, CH 2 OH, trifluoromethyl, nitro, cyano, amino, substituted amino, or (CH 2 ) m —COOR wherein m is an integer of from 0 to 2 and R is alkyl or hydrogen;  
 R 2  is hydrogen or lower alkyl;  
 R 4  is hydrogen, lower alkyl, —COOR, —CONHR wherein R is hydrogen, alkyl, or aryl;  
 R 5  is hydroxyl, amino, or carbonyl; and  
 R 6  is phenyl, substituted phenyl, naphthyl, or a heterocycle.