Peptoid compounds

Abstract

The invention relates to new peptoid compounds of formula (I), as well as their use in the treatment of bacterial infections, such as those caused by vancomycin resistant microorganisms, and to compositions thereof.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is an aromatic or heteroaromatic ring system or partially or fully reduced derivatives thereof; 
         Q is hydrogen, C 1 -C 12  straight chain, branched or cyclic alkyl substituted with one or more hydroxy groups, or a mono- or di-saccharide moiety; 
         Z is —CR 10 R 11 —, —NR 12 —, —C(O)O—, —C(O)NR 12 — or —O—, where R 10  and R 11  are independently selected from hydrogen, hydroxy, C 1 -C 6  alkyl, C 6 -C 10  aryl, C 1 -C 6  alkoxy and —N(R 13 ) 2  and where each R 13  is independently selected from hydrogen and C 1 -C 6  alkyl, and where R 12  is selected from hydrogen and C 1 -C 6  alkyl; 
         R 1  is selected from hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —N(R 13 ) 2  and —N(R 12 )—COR 14 ; where R 12  and R 13  are as defined above, and where R 14  is selected from hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and —NR 12 ; 
         R 2  is selected from hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —N(R 13 ) 2  and —N(R 12 )—COCHR 2a R 2b ; where R 2a  and R 2b  are selected from hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —N(R 13 ) 2  and —N(R 12 )—COR 14 ; where R 12 , R 13  and R 14  are as defined above; 
         R 3 , R 4  and R 5  are independently selected from hydrogen, C 1 -C 6  alkyl and a side chains of α-amino acids or their enantiomers or their derivatives; 
         R 6  is —CO 2 R 15 , —CONHR 16 , —CONHOR 16 , —CONHNHR 16 , —SO 2 N(R 16 ) 2 , —SO 2 R 17  or —P(O)(OR 18 )(OR 18 ) where each R 15 , R 16 , R 17  and R 18  is independently selected from hydrogen, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl and C 7 -C 10  arylalkyl; 
         B is an α-amino acid residue, a β-amino acid residue or an α,α-disubstituted amino acid residue, such residue forming amide linkages with the adjacent molecules; 
         W is —O— or CR 10 R 11  where R 10  and R 11  are as defined above; 
         Y is an optionally substituted amino group, a moiety containing an optionally substituted amino group or a salt thereof; 
            is a single or double bond; 
         R 7  and R 8a  are hydrogen or are absent if   is a double bond; and 
         R 8b  and R 9  are hydrogen, and X is selected from (CR 10 R 11 ) u , —(CR 10 R 11 ) u —CH═CH—, —NR 12 (CR 10 R 11 ) u —, —(CR 10 R 11 ) u NR 12 —, —O(CR 10 R 11 ) u —, —(CR 10 R 11 ) u O— or —O(CR 10 R 11 )CH═CH— where R 10 , R 11  and R 12  are as defined above; or 
         R 8b  and R 9  together form a covalent bond between X and the carbon to which R 8b  is attached, and X is selected from (CR 10 R 11 ) x NR 12 (CR 10 R 11 ) x NR 12 —, —O(CR 10 R 11 ) x — or —(CR 10 R 11 ) x O—, where R 10 , R 11  and R 12  are as defined above; 
         n, m, r and t are independently selected from 0 or 1; 
         s is an integer selected from 0 to 3; 
         p is an integer selected from 0 to 6, provided that when W is —O—, p is at least 1; and 
         u, x and q are independently selected from 0 to 4; 
         and salts and pharmaceutically acceptable derivatives thereof. 
       
     
     
         2 . A compound according to  claim 1  having the formula (IA): 
       
         
           
           
               
               
           
         
         wherein A, Q, Z, R 2a , R 2b , R 3 , B, R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 , X, r, s, n, m, p, q and t are as defined above. 
       
     
     
         3 . A compound according to  claim 1  wherein A is an optionally substituted monoaryl group or an optionally substituted fused di- or poly aryl or heteroaryl group wherein the optional substituents are selected from one or more of C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 1 -C 6  dialkylamino, halo, C 1 -C 6  haloalkyl (for example trifluoromethyl) nitro, nitrile, sulfonylsulfonamide, alkylsulfonyl, arylsulfonyl, or carboxy groups. 
     
     
         4 . A compound according to  claim 3  wherein A is optionally substituted phenyl, fluorene, phenanthrene, indole, indazole, benzimidazole, carbazole, quinoline, isoquinoline, dibenzazepine and dibenzazocine. 
     
     
         5 . A compound according to  claim 4  wherein A is optionally substituted 1,4-linked phenyl, 1,3-linked fluorene or 3,6-linked 9H carbazole. 
     
     
         6 . A compound according to  claim 1  wherein A is an optionally substituted bridged or bonded di- or poly aryl or heteroaryl group or their atropisomers wherein the optional substituents are selected from one or more of C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 1 -C 6  dialkylamino, halo, C 1 -C 6  haloalkyl (for example trifluoromethyl) nitro, nitrile, sulfonylsulfonamide, alkylsulfonyl, arylsulfonyl, or carboxy groups. 
     
     
         7 . A compound according to  claim 6  wherein A is optionally substituted bi-phenyl or bi-naphthyl or their atropisomers. 
     
     
         8 . A compound according to  claim 7  wherein A is a 3,3′-linked 2,2′-dimethoxy-1,1′-binaphthyl group or a 2,2′-linked 1,1′-binaphthyl group. 
     
     
         9 . A compound according to  claim 1  wherein Q is hydrogen. 
     
     
         10 . A compound according to  claim 1  wherein Z is —CH 2 — or —O—. 
     
     
         11 . A compound according to  claim 1  wherein s is 0, 1 or. 2 and each R 1  is independently selected from hydrogen or hydroxy. 
     
     
         12 . A compound according to  claim 1  wherein R 2  is hydrogen, hydroxy or N(R 12 )COR 2a R 2b . 
     
     
         13 . A compound according to  claim 1  wherein R 3  is hydrogen. 
     
     
         14 . A compound according to  claim 1  wherein B is absent or a D- or L-alanyl residue, a D-lysinyl residue, a D-arginyl residue or a D-homoarginyl residue. 
     
     
         15 . A compound according to  claim 1  wherein Y is selected from a group consisting of: —N(R 13 ) 2 , —N(R 12 )—COR 14 , —NR 13 C(═NR 13 )N(R 13 ) 2 , —C(═NR 13 )N(R 13 ) 2 , —NR 13 C(═O)N(R 13 ) 2 , —N═NC(═NR 13 )N(R 13 ) 2 , NR 13 NR 13 C(═O)NHN(R 13 ) 2 ) —NR 13 C(═)NHN(R 13 ) 2 , wherein R 12  and each R 13  is independently selected from hydrogen and C 1 -C 6  alkyl and R 14  is selected from hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 5  alkoxy and NR 12 ; and a 3-8-membered N-containing cyclogroup. 
     
     
         16 . A compound according to  claim 15  wherein Y is an unsubstituted amino group or a guanidino group, or their hydrochloride salts. 
     
     
         17 . A compound according to  claim 1  wherein R 6  is CO 2 R 15  where R 15  is C 1 -C 6 alkyl or C 7 -C 10 arylalkyl. 
     
     
         18 . A compound according to  claim 17  wherein R 15  is methyl or benzyl. 
     
     
         19 . A compound according to  claim 1  wherein R 8b  and R 9  are hydrogen and X is —(CR 10 R 11 ) u —, —O(CH 2 ) u —, —CH═CH—, —O(CR 10 R 11 )CH═CH— or —CR 10 R 11 —CH═CH— where R 10  and R 11  are hydrogen and u is an integer selected from 2 or 3. 
     
     
         20 . A compound according to  claim 1  wherein R 8b  and R 9  together form a covalent bond between X and the carbon to which R 8b  is attached and X is —(CR 10 R 11 ) x -or —O(CH 2 ) x — wherein R 10  and R 11  are hydrogen and x is an integer from 1 to 4. 
     
     
         21 . A compound according to  claim 1  selected from
 benzyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononanoate 
 (aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene hydrochloride 
 (aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane hydrochloride 
 (aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-butoxy)carbonyl]amino}butyl)-1(1,3),2 (1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene 
 methyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoate hydrochloride 
 (aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene hydrochloride 
 (aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene hydrochloride 
 (aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane hydrochloride 
 Methyl (2S,5S,8R/S)-8-acetamido-2-allyl-9-[6-allyl-9-tert-butoxycarbonyl-9H-carbazol-3-yl]-3,6-diaza-5-{3-[(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-guanidino]propyl}-4,7-dioxononanoate 
 6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) 
 6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) 
 6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) 
 6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-ene-12-methoxycarbonyl-7,10-dioxo-[1,2](3,6)-1H-carbazolophane HCl (9S,12S) 
 6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) 
 Methyl (2S,5S,8R/S)-8-Acetamido-5-(4-aminobutyl)-3,6-diaza-9-{9-[(4-methoxyphenyl)methyl]-6-propyl-9H-carbazol-3-yl}-4,7-dioxo-2-propylnonanoate hydrochloride 
 6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) 
 methyl(aR/S,2S,5R)-2-allyl-5-12-({[(2′-allyloxy-1,1′-binaphthoxymethyl)carbonyl}amino)-3-aza-9-guanidino-4-oxononanoate hydrochloride 
 (aR,S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-ene hydrochloride 
 methyl(aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxodecanoate hydrochloride 
 methyl(aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-3,6-diaza-5-(4-guanidinobutyl)-4,7-dioxodecanoate hydrochloride 
 (aR/S,9R,128)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2 (1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-ene hydrochloride 
 
     
     
         22 . A composition comprising a compound of formula (I), salts or pharmaceutically acceptable derivatives thereof according to  claim 1  together with one or more pharmaceutically acceptable carriers or adjuvants. 
     
     
         23 . A method of treating a bacterial infection in a mammal comprising administering an effective amount of a compound of formula (I), salts or pharmaceutically acceptable derivatives thereof according to  claim 1 . 
     
     
         24 . A method according to  claim 24  where the mammal is a human. 
     
     
         25 . A method according to  claim 24  wherein the bacterial infection is caused by Gram positive bacteria. 
     
     
         26 . A method according to  claim 26  wherein the bacterial infection is caused by vancomycin resistant  Staphylococcus aureas.    
     
     
         27 . The use of a compound of formula (I) according to  claim 1  in the manufacture of a medicament for treating bacterial infections.