13-Methyl erythromycin derivatives

Abstract

The invention relates to compounds of the formula and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 17 , R f , A, X, and Y are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formulas 1, methods of using the compounds of formula 1 in the treatment of infections and methods of preparing the compounds of formula 1.

What is claimed is:  
     
         1 . A compound of formula 1  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 A is H or halogen;  
 X is selected from —C(O)—, —CH(NR 8 R 9 )—, —CHR 8 NR 9 —, —NR 9 CHR 8 —, —C(═NR 8 )— and —C(═N—OR 8 )—, wherein the first dash of each of the foregoing X groups is attached to the C-10 carbon of the compound of formula 1 and the last dash of each group is attached to the C-8 carbon of the compound of formula 1;  
 Y is selected from CH 2 , C(O), CHF, CF 2 , C═C(R a R b ), CHSR 7 , CHR 7 , C═S, —C(═NR 8 )—, —C(═N—OR 8 ), CH(OR 8 ), CH(OC(O)R 8 ), CH(OC(O)Ar), CH(OC(O)NR 8 R 9 ), CH(O(CR a R b ) n Ar), CH(OC)(O)(CR a R b ) n Ar), CH(OC(O)CR a R b ) n NR 8 (CR a R b ) n Ar), CH(OC(O)NR 8 NR 8 R 9 ), CH(OC(O)NR 8 (CR a R b ) n NR 8 (CR a R b ) n Ar), CH(OC(O)NR 8 NR 8 (CR a R b ) n NR 8 (CR a R b ) n Ar), —CH(NR 8 R 9 )—, CH(NR 8 C(O)R 8 ), CH(NR 8 C(O)NR 8 R 9 ), CH(NR 8 C(O)OR 8 ), CH(S(CR a R b ) n Ar), —CH(NH(CR a R b ) n NR 8 (CR a R b ) n Ar) and CH(NH(CR a R b ) n Ar), wherein n is an integer ranging from 0 to 10;  
 or Y has the following structure:  
                     
 R 1  and R 2  can be taken separately or together;  
 when taken separately, R 1  is independently selected from OR 8 , OC(O)R 8 , OC(O)NR 8 R 9 , NR 8 R 9 , NR 8 C(O)R 8 , NR 8 C(O)NR 8 R 9 , O(CR a R b ) n Ar, S(CR a R b ) n Ar and N(CR a R b ) n Ar, wherein n is an integer ranging from 0 to 10;  
 when taken separately, R 2  is independently selected from OR 8 , O-mesyl, O-tosyl, OC(O)R 8 , OC(O)NR 8 R 9 , NR 8 R 9 , NR 8 C(O)R 8 , NR 8 C(O)NR 8 R 9 , O(CR a R b ) n Ar, S(CR a R b ) n Ar and NH(CR a R b ) n Ar, wherein n is an integer ranging from 0 to 10;  
 each of R a  and R b  is independently selected from H, halo and a C 1 -C 6  alkyl;  
 R a  and R b  together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 (CR a R b ) n  is alkylene, wherein n is an integer ranging from 0 to 10, uninterrupted or interrupted by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 when taken together, R 1  and R 2  taken with the intervening atoms form an additional ring having one of the following structures:  
                     
 B 1  is selected from O, (CR aa R bb ) m , SO 2 , O and NR 7 , wherein m is 0 or 1;  
 Z is selected from (CR aa R bb ) m , C(O), C(NR aa ), P-OR aa , P(O)OR aa , P(O)NR aa R bb , Si(R c R d ), SO, SO 2 , (CR aa R bb ) m CO and CO(CR aa R bb ) m , wherein m is 1 or 2;  
 R c  and R d  are independently selected from a C 1 -C 8  alkyl, a C 6 -C 10  aryl and a C 4 -C 10  heterocyclic;  
 R aa  and R bb  are independently selected from H and a C 1 -C 6  alkyl;  
 R aa  and R bb  together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 when B 1  is NR 7 , B 1  and R 6  together with the nitrogen to which they are attached can form a 3- to 10-membered ring wherein one or two carbons of said ring are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 when B 1  os NR 7 , B 1  and R 6  together with the nitrogen to which they are attached can form —N═C(R 7 )(R a R b ) n Ar, wherein n is an integer ranging from 0 to 10;  
 R 1 , R 2  and X can be taken together;  
 when taken together, R 1 , R 2  and X taken with the intervening atoms form an additional two rings having one of the following structures:  
                     
 each of D, E, F and G is independently selected from H, halo, a C 1 -C 12  alkyd, a C 3 -C 10  alkenyl, a C 3 -C 10  alkynyl and CH 2 (R a R b ) n Ar, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 D and E or F and G together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 each of J, J 1  and K is independently selected from C(O)R 8 , C(O)NR 8 R 9 , C(O)OR 8 , (CR a R b ) n Ar, S(CR a R b ) n Ar and NH(CR a R b ) n Ar; wherein n is an integer ranging from 0 to 10;  
 each of L, M, Q and V is independently selected from the group S substituents;  
 one or two carbons of the phenyl ring in which L, M, Q and V are attached can be replaced with nitrogen;  
 R 1  and X can be taken together;  
 when taken together, R 1  and X taken with the intervening atoms form an additional ring having one of the following structures:  
                     
 R 2  and X can be taken together;  
 when taken together, R 2  and X taken with the intervening atoms form an additional ring having one of the following structures:  
                     
 R 3  is OR 10 ;  
 R 3  and X can be taken together;  
 when taken together, R 3  and X taken with the intervening atoms form an additional ring having one of the following structures:  
                     
 R 3  and Y can be taken together;  
 when taken together, R 3  and Y taken with the intervening atoms form an additional ring having one of the following structures:  
                     
 R 4  is selected from H, a C(O)(C 1 -C 18 )alkyl, C(O)Ar, a OC(O)(C 1 -C 18 )alkyl and OC(O)Ar, wherein the alkyl moieties of the foregoing R 4  groups are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 5  is selected from H, halo, a C 1 -C 10  alkyl, a C 3 -C 10  alkenyl, a C 3 -C 10  alkynyl, —C(R a R b )—C(R a )═C(R b )—Ar, (CR a R b ) n Ar, OR 8 , O(CO)R 8 , OC(O)NR 8 R 9 , NR 8 R 9 , NR 8 C(O)R 8 , NR 8 C(O)NR 8 R 9 , O(CR a R b ) n Ar, S(CR a R b ) n Ar and NR 8 (CR a R b ) n Ar, wherein n is an interger ranging from 0 to 10, wherein one or two carbons of said alkyl, alkenyl and alkynyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 5  and Y can be taken together;  
 when taken together, R 5  and Y taken with the intervening atoms form the following structure:  
                     
 R 6  is selected from H, a C 1 -C 12  alkyl, a C 3 -C 10  alkenyl, a C 3 -C 10  alkynyl and CH 2 (R a R b ) n Ar, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 each of R 7 , R 8  and R 9  is independently selected from H and a C 1 -C 12  alkyl, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 ) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 8  and R 9  together with the nitrogen to which they are attached can form a 3- to 10-membered ring, in which one or two carbons are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 ) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 10  is selected from a C 1 -C 10  alkyl, a C 3 -C 10  alkenyl, a C 3 -C 10  alkynyl, —C(R a R b )—C(R a )═C(R b )—Ar and (CR a R b ) n Ar, wherein n is an integer ranging from 1 to 10, wherein one or two carbons of said alkyl, alkenyl and alkynyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents, provided that R 10  is not unsubstituted methyl;  
 R 11  is H or OCH 3 ;  
 R 12  and R 13  together with the carbon to which they are attached can form —C(O)—, —C(═NR 8 )— or —C(═N—OR 8 );  
 R 12  and R 13  together with the carbon to which they are attached can form a 3- to 10-membered ring, wherein one or two carbons of said ring are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 ) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 12  is selected from H, a C 1 -C 10  alkyl, a C 3 -C 10  alkenyl, a C 3 -C 10  alkynyl, —C(R a R b )—C(R a )═C(R b )—Ar and (CR a R b ) n Ar, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl, alkenyl and alkynyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 13  is selected from H, a C 1 -C 10  alkyl, a C 3 -C 10  alkenyl, a C 3 -C 10  alkynyl, OR 8 , OC(O)R 8 , OC(O)(CR a R b ) n Ar, OC(O)(CR a R b ) n NR 8 (CR a R b ) n Ar, OC(O)NR 8 R 9 , OC(O)NR 8 NR 8 NR 9 , OC(O)NR 8 (CR a R b ) n NR 8 (CR a R b ) n Ar, OC(O)NR 8 NR 8 (CR a R b ) n NR 8 (CR a R b ) n Ar, NR 8 R 9 , NR 8 (CO)R 8 , NR 8 C(O)NR 8 NR 9 , NR 8 C(O)OR 8 , O(CR a R b ) n Ar, O(CR a R b ) n NR 8 (CR a R b ) n Ar, S(CR a R b ) n Ar, NH(CR a R b ) n NR 8 (CR a R b ) n Ar and NH(CR a R b ) n Ar, wherein n is an interger ranging from 0 to 10;  
 each of R 14  and R 15  is independently selected from H, a C 1 -C 12  alkyl, an aryl-substituted C 1 -C 12  alkyl and a heteroaryl-substituted C 1 -C 12  alkyl, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 ) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 14  and R 15  together with the carbon to which they are attached can form a 3- to 10-membered ring, in which one or two carbons are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;  
 R 17  is a C 1 -C 20  alkyl, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, a —N(C 1 -C 6 )alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents, provided that R 17  is not unsubstituted ethyl;  
 R 18  is selected from the group consisting of an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl and a heterocycloalkyl;  
 each of R 19  and R 20  is independently selected from the group consisting of a C 1 -C 12  alkenyl, a C 1 -C 12  alkynyl, an aryl, a C 3 -C 8  cycloalkyl, a heterocycloalkyl and a heteroaryl, wherein said alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl are substituted or unsubstituted;  
 R 19  and R 20  together with the carbon to which they are attached can form a 3- to 10-membered heterocycloalkyl ring that may be substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, a C 1 -C 3  alkoxy, a C 1 -C 3  alkoxy-C 1 -C 3  alkoxy, oxo, a C 1 -C 3  alkyl, a halo-C 1 -C 3  alkyl and a C 1 -C 3  alkoxy-C 1 -C 3  alkyl;  
 each Ar is independently a 4- to 10-membered heterocyclic or a C 6 -C 10  aryl, wherein said heterocyclic and aryl groups are optionally substituted by one or more substituents independently selected from the group S substituents; and  
 the group S substituents are selected from the group consisting of: nitro, halogens, hydroxy, N 3 , CN, CHO, C 1 -C 10  alkoxy, C 1 -C 3  alkoxy-C 1 -C 3  alkoxy, oxo, C 1 -C 10  alkanoyl, C 1 -C 10  alkyl, C 1 -C 12  alkyl substituted with an aromatic heterocyclic, C 1 -C 6  alkyl substituted with O—SO 2 , C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, substituted C 3 -C 10  cycloalkyl, 4 to 10 membered heterocyclic, substituted heterocyclic, aryl, substituted aryl, trialkylsilyl, —C(O)R 8 , —NR 8 R 9 , —C(O)R 18 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 19 R 20 , —NHC(O)R 8 , —NHC(O)NR 8 R 9 , ═N—O—R 8 , ═N—NR 8 R 9 , ═N—NR 19 R 20 , ═N—R 8 , ═N—R 18 , ═N—NHC(O)R 8 , ═N—NHC(O)NR 8 R 9 , —C≡N, —S(O) n , wherein n is 0, 1 or 2, —S(O) n R 8 , wherein n is 0, 1 or 2, —S(O) n R 8 , wherein n is 0, 1 or 2, and —SO 2 NR 8 R 9 .  
 
     
     
         2 . The compound of  claim 1 , wherein A is H or F.  
     
     
         3 . The compound of  claim 1 , wherein X is selected from —C(O)—, —CH(NH 2 )—, —CH 2 NR 9 —, —NR 9 CH 2 — and —C(═N—OR 8 ).  
     
     
         4 . The compound of  claim 3 , wherein X is selected from —CH 2 NH—, —CH 2 N(Me)—, —N(Me)CH 2 —, —C(═N—OH)—, —C(═N—OMe)— and —C(═N—OCH 2 CH 2 OMe)—.  
     
     
         5 . The compound of  claim 1 , wherein R 1  is OH.  
     
     
         6 . The compound of  claim 1 , wherein R 2  is OH.  
     
     
         7 . The compound of  claim 1 , wherein R 1  is OH and R 2  is OH.  
     
     
         8 . The compound of  claim 1 , wherein R 1  is OH; R 2  is OH; A is H; and X is selected from —CH 2 NH—, —CH 2 N(Me)—, —N(Me)CH 2 —, —C(═N—OH)—, —C(═N—OMe)— and —C(═N—OCH 2 CH 2 OMe)—.  
     
     
         9 . The compound of  claim 1 , wherein R 1  is OH; R 2  is OH; A is F; and X is selected from —CH 2 NH—, —CH 2 N(Me)—, —N(Me)CH 2 —, —C(═N—OH)—, —C(═N—OMe)— and —C(═N—OCH 2 CH 2 OMe)—.  
     
     
         10 . The compound of  claim 1 , wherein R 1  and R 2  taken with the intervening atoms form an additional ring having one of the following structures:  
       
         
           
           
               
               
           
         
       
       wherein Z is CH 2  or C(═O); B 1  is selected from NH, NMe and CH 2 ; and R 6  is (CH 2 ) n Ar, wherein n is an integer ranging from 0 to 10.  
     
     
         11 . The compound of  claim 1 , wherein R 1  and R 2  taken with the intervening atoms form an additional ring having one of the following structures:  
       
         
           
           
               
               
           
         
       
       wherein Z is CH 2  or C(═O); B 1  is selected from NH, NMe and CH 2 ; and R 6  is (CH 2 ) 3 Ar, wherein n is an integer ranging from 0 to 10.  
     
     
         12 . The compound of  claim 11 , wherein Ar is selected from quinolin4-yl, 4-phenyl-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl and 4-pyridin-3-yl-imidazol-1-yl.  
     
     
         13 . The compound of  claim 1 , wherein R 3  is selected from an O(C 2 -C 4 )alkyl, OCH 2 CH═CH—Ar and O(CH 2 ) n Ar.  
     
     
         14 . The compound of  claim 1 , wherein Y is selected from CH 2 , C(O), C═S, CH(OR 8 ), CH(OC(O)R 8 ), CH(OC(O)Ar), CH(OC(O)NR 8 R 9 ) and CH(O(CR a R b ) n Ar), wherein n is an integer ranging from 0 to 10.  
     
     
         15 . The compound of  claim 1 , wherein R 5  is H or F.  
     
     
         16 . The compound of  claim 1 , wherein said compound has the following formula:  
       
         
           
           
               
               
           
         
         wherein B 1  is selected from NH, O and CH 2 ;  
         X is selected from —C(O)—, —CH 2 NH—, —CH 2 NMe—, —NHCH 2 —, —N(Me)CH 2 —, —CH(NH 2 )—, —C(═N—OMe)— and —C(═N—OCH 2 O(CH 2 ) 2 OMe)—;  
         R 5  is H or F; and  
         Ar is selected from quinolin-4-yl, 7-methoxy-quinolin-4-yl, 4-phenyl-imidazol-1-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 4-pyridin-3-yl-imidazol-1-yl, phenyl, imidazo(4,5-b)pyridin-3yl, 2-phenyl-thiazol-5-yl, 2-pyridin-3-yl-thiazol-4-yl and benzoimidazol-1-yl.  
       
     
     
         17 . The compound of  claim 1 , wherein said compound has the following formula:  
       
         
           
           
               
               
           
         
         Ar is selected from quinolin-4-yl, 7-methoxy-quinolin-4-yl, 4-phenyl-imidazol-1-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 4-pyridin-3-yl-imidazol-1-yl, phenyl, imidazo(4,5-b)pyridin-3-yl, 2-phenyl-thiazol-5-yl, 2-pyridin-3-yl-thiazol-4-yl and benzoimidazol-1-yl; and  
         R 5  is H or F.  
       
     
     
         18 . A pharmaceutical composition for the treatment of an infection in a mammal, fish or bird which comprises a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         19 . A method of treating an infection in a mammal, fish, or bird which comprises administering to said mammal, fish, or bird a therapeutically effective amount of a compound of  claim 1 .  
     
     
         20 . A compound selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts, prodrugs, and solvates of the above compounds.