Aminopiperidine derivatives as antibacterials

Abstract

Aminopiperidine derivatives of Formula (I) and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man:

1 . A compound of formula (I) or a pharmaceutically acceptable derivative thereof:  
     
       
         
         
             
             
         
       
       wherein:  
       Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each CH;  
       R 1  is hydroxy; (C 1-6 )alkoxy optionally substituted by (C 1-6 )alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C 1-6 )alkyl, acyl or (C 1-6 )alkylsulphonyl groups, CONH 2 , hydroxy, thiol, (C 1-6 )alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C 1-6 )alkylsulphonyloxy; (C 1-6 )alkoxy-substituted (C 1-6 )alkyl; halogen; (C 1-6 )alkyl; (C 1-6 )alkylthio; nitro; azido; acyl; acyloxy; (C 1-6 )alkylsulphonyl; (C 1-6 )alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C 1-6 )alkyl, acyl or (C 1-6 )alkylsulphonyl groups;  
       R 2  is hydrogen, or (C 1-4 )alkyl or (C 1-4 )alkenyl optionally substituted with 1 to 3 groups selected from:  
       amino optionally substituted by one or two (C 1-4 )alkyl groups; carboxy; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 2-4 )alkenyloxycarbonyl; (C 2-4 )alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, aminocarbonyl(C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )alkylsulphonyl, trifluoromethylsulphonyl, (C 1-4 )alkenylsulphonyl, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylcarbonyl, (C 2-4 )alkenyloxycarbonyl or (C 2-4 )alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R 10 ; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted by R 10 ; 5-oxo-1,2,4-oxadiazol-3-yl; thiol; halogen; (C 1-4 )alkylthio; trifluoromethyl; azido; hydroxy optionally substituted by (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylcarbonyl, (C 2-4 )alkenyloxycarbonyl, (C 2-4 )alkenylcarbonyl; oxo; (C 1-4 )alkylsulphonyl; (C 2-4 )alkenylsulphonyl; or (C 1-4 )aminosulphonyl wherein the amino group is optionally substituted by (C 1-4 )alkyl or (C 2-4 )alkenyl;  
       R 3  is hydrogen; or  
       R 3  is in the 2-, 3- or 4-position and is:  
       carboxy; (C 1-6 )alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, aminocarbonyl(C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )alkylsulphonyl, trifluoromethylsulphonyl, (C 1-6 )alkenylsulphonyl, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkylcarbonyl, (C 2-6 )alkenyloxycarbonyl or (C 2-6 )alkenylcarbonyl and optionally further substituted by (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, aminocarbonyl(C 1-6 )alkyl or (C 2-6 )alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R 10 ; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted by R 10 ; or 5-oxo-1,2,4-oxadiazol-3-yl; or  
       (C 1-4 )alkyl or ethenyl substituted with any of the substituents listed above for R 3  and up to 3 groups R 12  independently selected from:  
       thiol; halogen; (C 1-6 )alkylthio; trifluoromethyl; azido; (C 1-6 )alkoxycarbonyl; (C 1-6 )alkylcarbonyl; (C 2-6 )alkenyloxycarbonyl; (C 2-6 )alkenylcarbonyl; hydroxy optionally substituted by (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkylcarbonyl, (C 2-6 )alkenyloxycarbonyl, (C 2-6 )alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )alkylcarbonyl or (C 2-6 )alkenylcarbonyl; amino optionally mono- or disubstituted by (C 1-16 )alkoxycarbonyl, (C 1-6 )alkylcarbonyl, (C 2-6 )alkenyloxycarbonyl, (C 2-6 )alkenylcarbonyl, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )alkylsulphonyl, (C 2-6 )alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C 1-6 )alkyl or (C 2-6 )alkenyl; aminocarbonyl wherein the amino group is optionally substituted by (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, aminocarbonyl(C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkylcarbonyl, (C 2-6 )alkenyloxycarbonyl or (C 2-6 )alkenylcarbonyl and optionally further substituted by (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, aminocarbonyl(C 1-6 )alkyl or (C 2-6 )alkenyl; oxo; (C 1-6 )alkylsulphonyl; (C 2-6 )alkenylsulphonyl; or (C 1-6 )aminosulphonyl wherein the amino group is optionally substituted by (C 1-6 )alkyl or (C 2-6 )alkenyl;  
       in addition when R 3  is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a cyclic ester or amide linkage, respectively; or  
       when R 3  is in the 3- or 4-position it may with R 2  or R 4  form a C 3-5  alkylene group optionally substituted by a group R 5  selected from:  
       (C 1-12 )alkyl; hydroxy(C 1-12 )alkyl; (C 1-12 )alkoxy(C 1-12 )alkyl; (C 1-12 )alkanoyloxy(C 1-12 )alkyl; (C 3-6 )cycloalkyl; hydroxy(C 3-6 )cycloalkyl; (C 1-12 )alkoxy(C 3-6 )cycloalkyl; (C 1-12 )alkanoyloxy(C 3-6 )cycloalkyl; (C 3-6 )cycloalkyl(C 1-12 )alkyl; hydroxy-, (C 1-12 )alkoxy- or (C 1-12 )alkanoyloxy-(C 3-6 )cycloalkyl(C 1-12 )alkyl; cyano; cyano(C 1-12 )alkyl; (C 2-12 )alkenyl; (C 2-12 )aynyl; tetrahydrofuryl; mono- or di-(C 1-12 )alkylamino(C 1-12 )alkyl; acylamino(C 1-12 )alkyl; (C 1-12 )alkyl- or acyl-aminocarbonyl(C 1-12 )alkyl; mono- or di- (C 1-12 )alkylamino(hydroxy) (C 1-12 )alkyl; optionally substituted phenyl(C 1-12 )alkyl, phenoxy(C 1-12 )alkyl or phenyl(hydroxy)(C 1-12 )alkyl; optionally substituted diphenyl(C 1-12 )alkyl; optionally substituted phenyl(C 2-12 )alkenyl; optionally substituted benzoyl or benzoyl(C 1-12 )alkyl; optionally substituted heteroaryl or heteroaryl(C 1-12 )alkyl; and optionally substituted heteroaroyl or heteroaroyl(C 1-12 )alkyl;  
       R 4  forms a group with R 3  as above defined, or is a group —CH 2 —R 5  where R 5  is as defined above:  
       n is 0, 1 or 2;  
       A is NR 11  or CR 6 R 7  and B is NR 11 , O, SO 2  or CR 8 R 9  and wherein:  
       each of R 6 , R 7 , R 8  and R 9  is independently selected from: hydrogen; (C 1-6 )alkylthio; halo; trifluoromethyl; azido; (C 1-6 )alkyl; (C 2-6 )alkenyl; (C 1-6 )alkoxycarbonyl; (C 1-6 )alkylcarbonyl; (C 2-6 )alkenyloxycarbonyl; (C 2-6 )alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R 3 ; (C 1-6 )alkylsulphonyl; (C 2-6 )alkenylsulphonyl; or (C 1-6 )aminosulphonyl wherein the amino group is optionally substituted by (C 1-6 )alkyl or (C 1-6 )alkenyl;  
       or R 6  and R 8  together represent a bond and R 7  and R 9  are as above defined;  
       or R 6  and R 7  or R 8  and R 9  together represent oxo;  
       provided that:  
       when A is NR 11 , B is not NR 11 , O or SO 2 ;  
       when A is CO, B is not CO, O or SO 2 ;  
       when n is 0 and A is NR 11 , CR 8 R 9  can only be CO;  
       when A is CR 6 R 7  and B is SO 2 , n is 0;  
       when n is 0, B is not NR 11  or O; and  
       when A-B is CR 7 ═CR 9 , n is 1 or 2;  
       R 10  is selected from (C 1-4 )alkyl; (C 2-4 )alkenyl and aryl any of which may be optionally substituted by a group R 12  as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )alkylsulphonyl, trifluoromethylsulphonyl, (C 1-6 )alkenylsulphonyl, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkylcarbonyl, (C 2-6 )alkenyloxycarbonyl or (C 2-6 )alkenylcarbonyl and optionally further substituted by (C 1-6 )alkyl or (C 2-6 )alkenyl; (C 1-6 )alkylsulphonyl; trifluoromethylsulphonyl; (C 1-6 )alkenylsulphonyl; (C 1-6 )alkoxycarbonyl; (C 1-6 )alkylcarbonyl; (C 2-6 )alkenyloxycarbonyl; and (C 2-6 )alkenylcarbonyl;  
       R 11  is hydrogen; trifluoromethyl, (C 1-6 )alkyl; (C 1-6 )alkenyl; (C 1-6 )alkoxycarbonyl; (C 1-6 )alkylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by (C 1-6 )alkoxycarbonyl, (C 1-6 )alkylcarbonyl, (C 1-6 )alkenyloxycarbonyl, (C 2-6 )alkenylcarbonyl, (C 1-6 )alkyl or (C 1-6 )alkenyl and optionally further substituted by (C 1-6 )alkyl or (C 1-6 )alkenyl.  
     
   
   
       2 . A compound according to  claim 1  wherein R 1  is methoxy, amino(C 3-5 )alkyloxy, guanidino(C 3-5 )alkyloxy, piperidyl(C 3-5 )alkyloxy, nitro or fluoro.  
   
   
       3 . A compound according to  claim 1  wherein R 3  is hydrogen; optionally substituted aminocarbonyl; optionally substituted (C 1-6 )alkyl; carboxy(C 1-4 )alkyl; optionally substituted aminocarbonyl(C 1-4 )alkyl; cyano(C 1-4 )alkyl; optionally substituted 2-oxo-oxazolidinyl or optionally substituted 2-oxo-oxazolidinyl(C 1-4 alkyl).  
   
   
       4 . A compound according to  claim 1  wherein R 3  is in the 3-position and the substitutents at the 3- and 4-position of the piperidine ring are cis.  
   
   
       5 . A compound according to  claim 1  wherein A is NH and B is CO, or A is CHOH and B is CH 2 .  
   
   
       6 . A compound according to  claim 1  wherein R 11  is hydrogen.  
   
   
       7 . A compound according to  claim 1  wherein R 4  is (C 5-12 )alkyl, optionally substituted phenyl(C 2-3 )alkyl or optionally substituted phenyl(C 3-4 )alkenyl.  
   
   
       8 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.  
   
   
       9 . A method of treatment of bacterial infections in mammals which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable derivative thereof.