4"-substituted-9-deoxo-9A-AZA-9A-homoerythromycin a derivatives

Abstract

The invention relates to compounds of the formula and to pharmaceutically acceptable salts thereof. The compounds of formula 1 are antibacterial agents that may be used to treat various bacterial and protozoa infections. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of treating bacterial protozoa infections by administering the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1 and to intermediates useful in such preparation.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is H, hydroxy or methoxy;  
 R 2  is hydroxy;  
 R 3  is C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, cyano, —CH 2 S(O) n R 8  wherein n is an integer ranging from 0 to 2, —CH 2 OR 8 , —CH 2 N(OR 9 )R 8 , —CH 2 NR 8 R 15 , —(CH 2 ) m (C 6 -C 10  aryl), or —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 3  groups are optionally substituted by 1 to 3 R 16  groups;  
 or R 2  and R 3  are taken together to form an oxazolyl ring as shown below  
                     
 R 4  is H, C(O)R 9,  —C(O)OR 9 , —C(O)NR 9 R 10  or a hydroxy protecting group;  
 R 5  is —SR 8 , —(CH 2 ) n C(O)R 8  wherein n is 0 or 1, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(CH 2 ) m (C 6 -C 10  aryl), or —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 5  groups are optionally substituted by 1 to 3 R 16  groups;  
 each R 6  and R 7  is independently H, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(CH 2 ) m (C 6 -C 10  aryl), or —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;  
 each R 8  is independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(CH 2 ) q CR 11 R 12 (CH 2 ) r NR 13 R 14  wherein q and r are each independently an integer ranging from 0 to 3 except q and r are not both 0, —(CH 2 ) m (C 6 -C 10  aryl), or —CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 8  groups, except H, are optionally substituted by 1 to 3 R 16  groups;  
 or where R 8  is as —CH 2 NR 8 R 15 , R 15  and R 8  may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R 8 )—, in addition to the nitrogen to which R 15  and R 8  are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R 16  groups;  
 each R 9  and R 10  is independently H or C 1 -C 6  alkyl;  
 each R 11 , R 12 , R 13  and R 14  is independently selected from H, C 1 -C 10  alkyl, —CH 2 ) m (C 6 -C 10  aryl), and —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 11 , R 12 , R 13  and R 14  groups, except H, are optionally substituted by 1 to 3 R 16  groups;  
 or R 11  and R 13  are taken together to form —(CH 2 ) p — wherein p is an integer ranging from 0 to 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds;  
 or R 13  and R 14  are taken together to form a 4-10 membered monocydic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R 5 )—, in addition to the nitrogen to which R 13  and R 14  are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R 16  groups;  
 R 15  is H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl, wherein the foregoing R 15  groups are optionally substituted by 1 to 3 substituents independently selected from halo and —OR 9 ;  
 each R 16  is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R 17 , —C(O)OR 17 , —C(O)OR 17 , —OC(O)OR 17,  —NR 6 C(O)R 7,  —C(O)NR 6 R 7 , —NR 6 R 7 , hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —(CH 2 ) m (C 6 -C 10  aryl), and —CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein said aryl and heteroaryl subsituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R 17 , —C(O)OR 17 , —C(O)OR 17 , —C(O)OR 17 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , hydroxy, C 1 -C 6  alkyl, and C 1 -C 6  alkoxy;  
 each R 17  is independently selected from H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(CH 2 ) m (C 6 -C 10  aryl), and —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;  
 with the proviso that R 8  is not H where R 3  is —CH 2 S(O) n R 8.    
 
     
     
         2 . The compound of  claim 1  wherein R 4  is H, acetyl, or benzyloxycarbonyl.  
     
     
         3 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, R 3  is —CH 2 NR 15 R 8  or —CH 2 SR 8 .  
     
     
         4 . The compound of  claim 3  wherein R 3  is —CH 2 NR 15 R 8  and R 15  and R 8  are independently selected from H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, and C 2 -C 10  alkynyl, wherein the foregoing R 15  and R 8  groups, except H, are optionally substituted by 1 or 2 substituents independently selected from hydroxy, halo and C 1 -C 6  alkoxy.  
     
     
         5 . The compound of  claim 4  wherein R 15  and R 8  are each independently selected from H, methyl, ethyl, allyl, n-butyl, isobutyl, 2-methoxyethyl, cyclopentyl, 3-methoxypropyl, 3-ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-propynyl, sec-butyl, tert-butyl, and n-hexyl.  
     
     
         6 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, R 3  is —CH 2 NHR 8 , and R 8  is —(CH 2 ),(C 6 -C 10 aryl) wherein m is an integer ranging from 0 to 4.  
     
     
         7 . The compound of  claim 6  wherein R 8  is phenyl or benzyl.  
     
     
         8 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, R 3  is —CH 2 NR 15 R 8 , and R 15  and R 8  are taken together to form a 4-10 membered saturated ring.  
     
     
         9 . The compound of  claim 8  wherein R 15  and R 8  are taken together to form a piperidino, trimethyleneimino, or morpholino ring.  
     
     
         10 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, R 3  is —CH 2 NR 5 R 8 , and R 15  and R 8  are taken together to form a 5-10 membered heteroaryl ring optionally substituted by 1 or 2 C 1 -C 6  alkyl groups.  
     
     
         11 . The compound of  claim 10  wherein R 15  and R 8  are taken together to form a pyrrolidino, triazolyl, or imidazolyl ring wherein said heteroaryl groups are optionally substituted by 1 or 2 methyl groups.  
     
     
         12 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, R 3  is —CH 2 SR 8 , and R 8  is selected from C 1 -C 10  alkyl, C 2 -C 10  alkenyl, and C 2 -C 10  alkynyl, wherein said R 8  groups are optionally substituted by 1 or 2 substituents independently selected from hydroxy, halo and C 1 -C 6  alkoxy.  
     
     
         13 . The compound of  claim 12  wherein R 8  is methyl, ethyl, or 2-hydroxyethyl.  
     
     
         14 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, and R 3  is selected from C 1 -C 10  alkyl, C 2 -C 10  alkenyl, and C 2 -C 10  alkynyl, wherein said R 3  groups are optionally substituted by 1 or 2 substituents independently selected from hydroxy, —C(O)R 17 , —NR 6 R 7 , halo, cyano, azido, 5-10 membered heteroaryl, and C 1 -C 6  alkoxy.  
     
     
         15 . The compound of  claim 14  wherein R 3  is methyl, allyl, vinyl, ethynyl, 1-methyl-1-propenyl, 3-methoxy-1-propynyl, 3-dimethylamino-1-propynyl, 2-pyridylethynyl, 1-propynyl, 3-hydroxy-1-propynyl, 3-hydroxy-1-propenyl, 3-hydroxypropyl, 3-methoxy-1-propenyl, 3-methoxypropyl, 1-propynyl, n-butyl, ethyl, propyl, 2-hydroxyethyl, azidomethyl, formylmethyl, 6-cyano-1-pentynyl, 3-dimethylamino-1-propenyl, or 3-dimethylaminopropyl.  
     
     
         16 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, and R 3  is —(CH 2 ) m (5-10 membered heteroaryl) wherein m is an integer ranging from 0 to 4.  
     
     
         17 . The compound of  claim 16  wherein R 3  is 2-thienyl, 2-pyridyl, 1-methyl-2-imidazolyl, 2-furyl, or 1-methyl-2-pyrrolyl.  
     
     
         18 . The compound of  claim 2  wherein R 1  is hydroxy, R 2  is hydroxy, and R 3  is —CH 2 ) m (C 6 -C 10  aryl) wherein m is an integer ranging from 0 to 4.  
     
     
         19 . The compound of  claim 18  wherein R 3  is phenyl.  
     
     
         20 . The compound of  claim 2  wherein R 2  and R 3  are taken together to form an oxazolyl ring as shown below  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 2  wherein R 3  is selected from the following:  
       
         
           
           
               
               
           
         
         wherein X 3  is O, S or —N(R 15 )—, R 9  and R 15  are as defined in  claim 1 , and the —OR 9  group may be attached at any available carbon on the phenyl group.  
       
     
     
         22 . A pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         23 . A method of treating a bacterial infection or a protozoa 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 .  
     
     
         24 . A method of preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is H, hydroxy or methoxy;  
 R 2  is hydroxy;  
 R 3  is C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, cyano, —CH 2 S(O) n R 8  wherein n is an integer ranging from 0 to 2, —CH 2 OR 8 , —CH 2 N(OR 9 )R 8 , —CH 2 NR 8 R 15 , —(CH 2 ) m (C 6 -C 10  aryl), or —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 3  groups are optionally substituted by 1 to 3 R 16  groups;  
 or R 2  and R 3  are taken together to form an oxazolyl ring as shown below  
                     
 R 4  is H, —C(O)R 9 , —C(O)OR 9 , —C(O)NR 9 R 10  or a hydroxy protecting group;  
 R 5  is —SR 8 , —CH 2 ) n C(O)R 8  wherein n is 0 or 1, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —CH 2 ) m (C 6 -C 10  aryl), or —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 5  groups are optionally substituted by 1 to 3 R 16  groups;  
 each R 6  and R 7  is independently H, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —CH 2 ) m (C 6 -C 10  aryl), or —(CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;  
 each R 8  is independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(CH 2 ) q CR 11 R 12 (CH 2 ) r NR 13 R 14  wherein q and r are each independently an integer ranging from 0 to 3 except q and r are not both 0, —(CH 2 ) m (C 6 -C 10  aryl), or —CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 8  groups, except H, are optionally substituted by 1 to 3 R 16  groups;  
 or where R 8  is as —CH 2 NR 8 R 15 , R 15  and R 8  may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R 8 )—, in addition to the nitrogen to which R 15  and R 8  are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R 16  groups;  
 each R 9  and R 10  is independently H or C 1 -C 6  alkyl;  
 each R 11 , R 12 , R 13  and R 14  is independently selected from H, C 1 -C 10  alkyl, —(CH 2 ) m (C 6 -C 10  aryl), and —CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R 11 , R 12 , R 13  and R 14  groups, except H, are optionally substituted by 1 to 3 R 16  groups;  
 or R 11  and R 13  are taken together to form —CH 2 ) p — wherein p is an integer ranging from 0 to 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds;  
 or R 13  and R 14  are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R 8 )—, in addition to the nitrogen to which R 13  and R 14  are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R 16  groups;  
 R 15  is H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl, wherein the foregoing R 15  groups are optionally substituted by 1 to 3 substituents independently selected from halo and —OR 9 ;  
 each R 16  is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R 17 , —C(O)OR 17 , —C(O)OR 17 , —OC(O)OR 17 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —CH 2 ) m (C 6 -C 10  aryl), and —CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein said aryl and heteroaryl subsituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R 17 , —C(O)OR 17 , —C(O)OR 17 , —OC(O)OR 17 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7,  —NR 6 R 7 , hydroxy, C 1 -C 6  alkyl, and C 1 -C 6  alkoxy;  
 each R 17  is independently selected from H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(CH 2 ) m (C 6 -C 10  aryl), and —CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;  
 with the proviso that R 8  is not H where R 3  is —CH 2 S(O) n R 8 ; which comprises treating a compound of the formula  
                     
 wherein R 1  and R 4  are as defined above, with a compound of the formula HOR 8 , HSR 8  or HNR 15 R 8 , wherein n, R 15  and R 8  are as defined above, wherein if said compound of formula HSR 8  is used the resulting R 3  group of formula —CH 2 SR 8  is optionally oxidised to CH 2 S(O)R 8  or —CH 2 S(O) 2 R 8 .  
 
     
     
         25 . The method of  claim 24  wherein the compound of formula 5 is prepared by treating a compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 1  and R 4  are as defined in  claim 24 , with (CH 3 ) 3 S(O) n X 2 , wherein n is 0 or 1 and X 2  is halo, —BF 4  or —PF 6 , in the presence of a base.  
       
     
     
         26 . The method of  claim 25  wherein X 2  is iodo or BF 4  and said base is selected from potassium tert-butoxide, sodium tertbutoxide, sodium ethoxide, sodium hydride, 1,1,3,3-tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicylo[4.3.0]non-5-ene, potassium hexamethyldisilazide (KHMDS), potassium ethoxide, and sodium methoxide.  
     
     
         27 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is H, hydroxy or methoxy; and,  
 R 4  is H, —C(O)R 9 , —C(O)OR 9 , C(O)NR 9 R 10  or a hydroxy protecting group; and,  
 each R 9  and R 10  is independently H or C 1 -C 6  alkyl.  
 
     
     
         28 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is H, hydroxy or methoxy; and,  
 R 4  is H, —C(O)R 9 , —C(O)OR 9 , —C(O)NR 9 R 10  or a hydroxy protecting group; and,  
 each R 9  and R 10  is independently H or C 1 -C 8  alkyl.