Phenylindoles for the treatment of HIV

Abstract

The invention as disclosed herein is a method and composition for the treatment of HIV in humans and other host animals, that includes the administration of an effective HIV treatment amount of a phenylindole as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e., anti-HIV) activity, or are metabolized to a compound that exhibits such activity.

We claim:  
     
         1 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or its pharmaceutically acceptable salt or thereof, wherein 
 (a) R 1  is hydrogen; acyl; —C(═O)H; —C(═W)H; —C(═O)R 2 ; —C(═W)R 2 ; —C(═O)OH; —C(═W)OH; —C(═O)OR 2 ; —C(═W)OR 2 ; —C(═O)SH; —C(═W)SH; —C(═O)SR 2 ; —C(═W)SR 2 ; —C(═O)NH 2 ; —C(═W)NH 2 ; —C(═O)NHR 2 ; —C(═W)NHR 2 ; —C(═O)NR 2 R 3 ; —C(═W)NR 2 R 3 ; —C(═W)NH—(CH 2 ) p -(amino acid) or —(CH 2 ) p -(amino acid);  
 (b) R 4′ , R 5′ , R 6′ , R 7′ , R 2″ , R 3″ , R 4″ , R 5″  and R 6″  are each independently H; halo (F, Cl, Br or I); —NO 2 ; —CN; —OH; —OR 2 ; —SH; —SR 2 ; —NH 2 ; —NHR 2 ; —NR 2 R 3 ; —NHSO 2 —C 1-3 alkyl; —NR 2 SO 2 —C 1-3 alkyl; —NHCO—C 1-3 alkyl; —NR 2 CO—C 1-3 alkyl; optionally substituted or unsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and in particular CH 3 , CF 3 , vinyl bromide, —CR 2 R 2 —S(O) n —R 3 , —CR 2 R 2 NH 2 , —CR 2 R 2 NHR 2 , —CR 2 R 2 NR 2 R 3  and —CR 2 R 2 —C(═O)R 2 ); alkacyl; optionally substituted or unsubstituted acyl; —C(═O)H; —C(═W)H; —C(═O)R 2 ; —C(═W)R 2 ; —C(═O)OH; —C(═W)OH; —C(═O)OR 2 ; —C(═W)OR 2 ; —C(═O)—SH; —C(═W)SH; —C(═O)SR 2 ; —C(═W)SR 2 ; —C(═O)NH 2 ; —C(═W)NH 2 ; —C(═O)NHR 2 ; —C(═W)NHR 2 ; —C(═O)NR 2 R 3 ; —C(═W)—NR 2 R 3 , —C(═W)NH(CH 2 ) p -(amino acid), a residue of an amino acid or —(CH 2 ) p (amino acid); wherein if R 5′  is hydrogen, F, Cl, Br, —NO 2 , —CN, —OR 2 , —NR 2 R 2 , —NHSO 2 —C 1-3 alkyl or —NHCO—C 1-3 alkyl, then at least one of R 4′ , R 6′  and R 7′  is not hydrogen or alternatively, wherein at least two of R 4′ , R 5′ , R 6′ , R 7′  are not hydrogen.  
 (c) Z is optionally substituted or unsubstituted acyl, —C(═O)NH 2 ; —C(═W)—NH 2 ; —C(═O)NHR 2 ; —C(═W)NHR 2 ; —C(═O)NR 2 R 3 ; —C(═W)NR 2 R 3 ; —C(═W)NH(CH 2 ) p -(amino acid); a residue of an amino acid, —(CH 2 ) p -(amino acid); —C(═O)R 3 ; —C(═O)H; —C(═W)H; —C(═O)R 2 ; —C(═W)R 2 ; —C(═O)OR 3 ; —C(═O)OH; —C(═W)OH; —C(═O)OR 2 ; —C(═W)—OR 2 ; —C(═O)—SH; —C(═W)SH; —C(═O)SR 2 ; —C(═W)SR 2 ; optionally substituted or unsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and in particular CH 3 , CF 3 , vinyl bromide, —CR 2 R 2 —S(O) n —R 3 , —CR 2 R 2 NH 2 , —CR 2 R 2 NHR 2 , —CR 2 R 2 NR 2 R 3  and —CR 2 R 2 —C(═O)R 2 ); —CN, or halo (F, Cl, Br or I);  
 (d) Y is O, S or S(O) n ;  
 (e) each W is independently O, S, —NH 2 , —NHR 2 , —NR 2 R 2 , —N—CN, —N—NH 2 , —N—NHR 2 , —N—NR 2 R 3 , —N—OH or —N—OR 2 ;  
 (f) each R 2  is independently hydrogen or an optionally substituted or unsubstituted branched or unbranched lower alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and in particular CH 3 , CF 3 , vinyl bromide, —CR 2 R 2 —S(O) n —R 3 , —CR 2 R 2 NH 2 , —CR 2 R 2 NHR 2 , —CR 2 R 2 NR 2 R 3  and —CR 2 R 2 —C(═O)R 2 );  
 (g) each R 3  is independently hydrogen; optionally substituted or unsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and in particular CH 3 , CF 3 , vinyl bromide, —CR 2 R 2 —S(O) n —R 3 , —CR 2 R 2 NH 2 , —CR 2 R 2 NHR 2 , —CR 2 R 2 NR 2 R 3  and —CR 2 R 2 —C(═O)R 2 ); optionally substituted or unsubstituted aryl (such as phenyl); optionally substituted or unsubstituted heterocycle; optionally substituted or unsubstituted alkylaryl, optionally substituted or unsubstituted alkylhereterocycle, optionally substituted or unsubstituted aralkyl, optionally substituted or unsubstituted heterocycle-alkyl;  
 (h) each n is independently 0, 1 or 2;  
 (i) each p is independently 0, 1, 2, 3, 4 or 5; and  
 (j) wherein if one or more of the optionally substituted branched or unbranched alkyl, alkenyl, alkynyl, lower alkyl, lower alkenyl or lower alkynyl; acyl; aryl; heterocycle; alkaryl; alkheterocycle; arylalkyl or alkylheterocycle substitutents is substituted, then preferably it is substituted with one or more of halogen (F, Cl, Br or I), —OH, —OR 2 , —SH, —SR 2 , oxime (defined herein as —CH═N—OH), hydrazine (defined herein as —NH—NH 2 ), —C(═O)H, —C(═W)H, —C(═O)R 2 , —C(═W)R 2 , —C(═O)OH, —C(═W)OH, —C(═O)OR 2 , —C(═W)OR 2 , —C(═O)SH, —C(═W)SH, —C(═O)SR 2 , —C(═W)SR 2 , —C(═O)NH 2 , —C(═W)NH 2 , —C(═O)—NHR 2 , —C(═W)NHR 2 , —C(═O)NR 2 R 3 , —C(═W)—NR 2 R 3 , —NH 2 , —NHR 2 , —NR 2 R 3 , —NHSO 2 —C 1-3 alkyl, —NR 2 SO 2 —C 1-3 alkyl, —NHCO—C 1-3 alkyl, —NR 2 CO—C 1-3 alkyl, —S(O) n —R 3 , C 1-3  alkoxy, C 1-3 thioether, a residue of an amino acid such as —NH(CH 2 ) p -(amino acid) or —C(═W)NH(CH 2 ) p -(amino acid).  
 
     
     
         2 . The compound of  claim 1 , wherein Y is SO 2 .  
     
     
         3 . The compound of  claim 1 , wherein Z is an amide.  
     
     
         4 . The compound of  claim 1 , wherein R 1  is hydrogen.  
     
     
         5 . The compound of  claim 1 , wherein 
 (a) R 1  is hydrogen;    (b) R 4′ , R 5′ , R 6′  and R 7′  are independently hydrogen, halogen (F, Cl, Br or I), —NO 2 , —CN, —OR 2 , —NR 2 R 2 , —NHSO 2 —C 1-3 alkyl, —NHCO—C 1-3 alkyl, oxime, hydrazine, or C 1-3  alkyl or alkenyl optionally substituted with one or more of —OH, —SH, —C(O)H, —COOH, halogen (F, Cl, Br or I), —NR 2 R 2 , —C 1-3  alkoxy or —C 1-3  thioether; wherein if R 5′  is hydrogen, F, Cl, Br, —NO 2 , —CN, —OR 2 , —NR 2 R 2 , —NHSO 2 —C 1-3 alkyl or —NHCO—C 1-3 alkyl, then at least one of R 4′ , R 6′  and R 7′  is not hydrogen;    (c) R 2″ , R 3″ , R 4″ , R 5″  and R 6″  are independently hydrogen, halogen (F, Cl, Br or I), —NO 2 , —CN, —OH, —OR 2 , —NR 2 R 2 , —NHSO 2 —C 1-3 alkyl, —NHCO—C 1-3 alkyl, —C 1-5  alkoxy, oxime, hydrazine, —C 1-5  alkyl or alkenyl optionally substituted with one or more of —OH, —SH, —C(O)H, —COOH, halogen (F, Cl, Br or I), —NR 2 R 2 , —C 1-5  thioether or —C 1-5  alkoxy;    (d) Z is —CN, —C(═W)NR 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —CR 2 R 2 —S(O) n —R 3 , —CR 2 R 2 NHR 2 , —CR 2 R 2 —CO—R 3  or substituted or unsubstituted lower alkyl;    (e) Y is O, S, or S(O) n ;    (f) each W is independently O, S, —N—CN or —N—OR 2 ;    (g) R 2  is hydrogen or C 1-3  alkyl;    (h) R 3  is hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, —C 1-5  alkoxy, —OH, —NR 2 R 2 , or —(CH 2 ) p C(O)NR 2 R 2 ,    (i) each n is independently 0, 1 or 2; and    (j) each p is independently 0, 1, 2, 3, 4, or 5.    
     
     
         6 . the compound of  claim 1 , wherein 
 (a) R 1  is hydrogen;    (b) R 4′ , R 5′ , R 6′ , R 7′ , are independently hydrogen, halogen (F, Cl, Br or I), —NO 2 , —CN, —OR 2 , —NR 2 R 2 , —NHSO 2 —C 1-3 alkyl, —NHCO—C 1-3 alkyl, oxime (defined herein as —CH═N—OH), hydrazine (defined herein as —NH—NH 2 ), or C 1-3  alkyl or alkenyl optionally substituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR 2 R 2 , C 1-3  alkoxy, or C 1-3  thioether; wherein if R 5′  is hydrogen, F, Cl, Br, —NO 2 , —CN, —OR 2 , —NR 2 R 2 , —NHSO 2 —C 1-3 alkyl or —NHCO—C 1-3 alkyl, then at least one of R 4′ , R 6′  and R 7′  is not hydrogen;    (c) R 2″ , R 3″ , R 4″ , R 5″ , and R 6″ , are independently hydrogen, halogen (F, Cl, Br or I), —NO 2 , —CN, —OR 2 , —NHSO 2 —C 1-3 alkyl, —NHCO—C 1-3 alkyl, oxime, hydrazine, —C 1-5  alkyl or alkenyl optionally substituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR 2 R 2 , C 1-5  thioether, or C 1-5  alkoxy, —C 1-5  alkoxy, —OH, or —NR 2 R 2 ,    (d) Z is —C(W)NR 2 R 3 , or —COR 3 ,    (e) Y is —S(O) n — or —O—, in which n is 0, 1 or 2.    (f) W is O, S, —N—CN or —N—OR 2 ;    (g) R 2  is hydrogen or C 1-3  alkyl,    (h) R 3  is C 1-5  alkyl, C 1-5  alkenyl, aryl, or heterocycle, substituted with one or more of C(O)NR 2 R 2 , —NR 2 R 2 , —(CH 2 ) m C(O)NR 2 R 2 , —(CH 2 ) m C(=W)—NH(CH 2 ) p -(amino acid);    (i) each n is independently 0, 1 or 2; and    (j) each p is independently 0, 1, 2, 3, 4, or 5.    
     
     
         7 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         8 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         13 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         14 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         15 . A pharmaceutical composition comprising an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.  
     
     
         16 . A pharmaceutical composition comprising an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, in combination with one or more other anti-HIV agent, optionally with a pharmaceutically acceptable carrier or diluent.  
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the other anti-HIV agent is a reverse transcriptase inhibitor.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the reverse transcriptase inhibitor induces a mutation lysine 103→asparagine and/or tyrosine 181→cysteimie in HIV reverse transcriptase.  
     
     
         19 . A method for the treatment or prophylaxis of an HIV-infection in a host comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         20 . A method for the treatment or prophylaxis of an HIV-infection in a host comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, in combination and/or alternation with one or more other anti-HIV agent, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         21 . The method of  claim 20 , wherein the other anti-HIV agent is a reverse transcriptase inhibitor.  
     
     
         22 . The method of  claim 21 , wherein the reverse transcriptase inhibitor induces a mutation lysine 103→asparagine and/or tyrosine 181→cysteine in HIV reverse transcriptase.  
     
     
         23 . A method for the treatment or prophylaxis of an HIV-infection in a host, wherein the HIV has a mutation at lysine 103→asparagine and/or tyrosine 181→cysteine in HIV reverse transcriptase, comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         24 . A method for the treatment or prophylaxis of an HIV-infection in a host, wherein the HIV is resistant to one or more reverse transcriptase inhibitor(s), comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, in combination and/or alternation with one or more other anti-HIV agent, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         25 . A method for salvage therapy in the treatment or prophylaxis of an HIV-infection in a host, comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         26 . A method for salvage therapy in the treatment or prophylaxis of an HIV-infection in a host, comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, in combination and/or alternation with one or more other anti-HIV agent, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         27 . A method for the treatment or prophylaxis of an HIV-infection in a host, wherein the HIV is resistant to one or more reverse transcriptase inhibitor(s), comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         28 . A method for the treatment or prophylaxis of an HIV-infection in a host, wherein the HIV has a mutation at lysine 103→asparagine and/or tyrosine 181→cysteine in HIV reverse transcriptase, comprising administering to said host an effective anti-HIV treatment amount of a compound of  claim 1 , or its pharmaceutically acceptable salt thereof, in combination and/or alternation with one or more other anti-HIV agent, optionally in a pharmaceutically acceptable carrier or diluent.  
     
     
         29 . The method of any one of claims  19 - 28  wherein the host is a human.