Bicyclo[3.1.0]hexane containing oxazolidinone antibiotics and derivatives thereof

Abstract

Oxazolidinones having a bicyclic[3.1.0]hexane containing moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species. The compounds are represented by structural formula I: its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof, and wherein the variables R 1 , R 2 , R 3 , R 4 , R 4a , A, Ar, HAr, n, r, and s are as defined herein.

1 . A compound of the following formula I:  
       
         
           
           
               
               
           
         
       
       its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein: 
 A represents C (when --- is present), CH, or N (when --- is not present); — 
 ---- represents a bond;  
 R represents hydrogen, or C 1-6  alkyl;  
 R 1  and R 2  independently represent  
 i) hydrogen,  
 ii) NR 5 R 6 ,  
 iii) CR 7 R 8 R 9 , C(R) 2 OR 14  CH 2 NH 14 ,  
 iv) C(═O)R 13 , C(═NOH)H, C(═NOR 13 )H, C(═NOR 13 )R 13 , C(═NOH)R 13 , C(═O)N(R 13 ) 2 , C(═NOH)N(R 13 ) 2 , NHC(═X 1 )N(R 13 ) 2 , (C═NH)R 7 , N(R 13 )C(═X 1 )N(R 13 ) 2 , COOR 13 , SO 2 R 14 , N(R 13 )SO 2 R 14 , N(R 13 )COR 14 , or (C 1-6 alkyl)CN, CN, CH═C(R) 2 , OH, C(═O)CHR 13 , C(═NR 13 )R 13 , NHC(═X 1 )R 13 ;  
 v)  
                     
 vi) C 5-10  heterocycle optionally substituted with 1-3 groups of R 7 , which may be attached through either a carbon or a heteroatom;  
                     
 represents heterocycle, heterocyclyl or heterocyclic,  
 Rx represents hydrogen or C 1-6  alkyl;  
 R 3  represent  
 i) NH(C═X 2 )R 12 ,  
 ii) NHSO 2 R 14 ,  
 iii) NH(CH 2 ) 0-4 aryl,  
 iv) NH(CH 2 ) 0-4 heteroaryl,  
 v) S(CH 2 ) 0-4 aryl,  
 vi) S(CH 2 ) 0-4 heteroaryl,  
 vii) O(CH 2 ) 0-4 aryl, or  
 viii) O(CH 2 ) 0-4 heteroaryl;  
 R 4  and R 4a  independently represent  
 i) hydrogen,  
 ii) halogen,  
 iii) C 1-6  alkoxy, or  
 iv) C 1-6  alkyl  
 r and s independently are 1-3, with the provision that when (R 4a ) s  and (R 4 ) r  are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4;  
 R 5  and R 6  independently represent  
 i) hydrogen,  
 ii) C 1-6  alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C 1-6  alkoxy, amino, imino, hydroxyamino, alkoxyamino, C 1-6  acyloxy, C 1-6  alkylsulfenyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, aminosulfonyl, C 1-6  alkylaminosulfonyl, C 1-6  dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF 3 , C 1-6  alkyl or C 1-6  alkoxy;  
 iii) C 1-6  acyl optionally substituted with 1-3 groups of halogen, OH, SH, C 1-6  alkoxy, naphthalenoxy, phenoxy, amino, C 1-6  acylamino, hydroxylamino, alkoxylamino, C 1-6  acyloxy, aralkyloxy, phenyl, pyridine, C 1-6  alkylcarbonyl, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-6  hydroxyacyloxy, C 1-6  alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3-groups of halo, OH, CN, C 1-6  alkoxy, amino, C 1-6  acylamino, CF 3  or C 1-6  alkyl;  
 iv) C 1-6  alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C 1-6  alkoxy, amino, hydroxylamino, alkoxylamino, C 1-6  acyloxy, or phenyl; said phenyl optionally substituted with 1-3 groups of halo, OH, C 1-6  alkoxy, amino, C 1-6  acylamino, CF 3  or C 1-6  alkyl;  
 v) arylsulfonyl optionally substituted with 1-3 of halogen, C 1-6  alkoxy, OH or C 1-6  alkyl;  
 vi) C 1-6  alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C 1-6  alkoxy, C 1-6  acyloxy, or phenyl, said phenyl optionally substituted with 1-3 groups of halo, OH, C 1-6  alkoxy, amino, C 1-6  acylamino, CF 3  or C 1-6  alkyl;  
 vii) aminocarbonyl, C 1-6  alkylaminocarbonyl or C 1-6  dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C 1-6  alkoxy or phenyl;  
 viii) five to six membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C 1-6  acylamino, C 1-6  alkylsulfonylamino, C 1-6  alkoxycarbonylamino, C 1-6  alkoxy, C 1-6  acyloxy or C 1-6  alkyl, said alkyl optionally substituted with 1-3 groups of halogen, or C 1-6  alkoxy;  
 ix) C 3-6  cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C 1-6  alkoxy or CN;  
 x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C 1-6  alkoxy, C 1-6  alkyl, CF 3 , C 1-6  alkanoyl, amino or C 1-6  acylamino;  
 xi) pyrrolylcarbonyl optionally substituted with 1-3 of C 1-6  alkyl;  
 xii) C 1-2  acyloxyacetyl where the acyl is optionally substituted with amino, C 1-6  alkylamino, C 1-6  dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl; or  
 R 5  and R 6  taken together with any intervening atoms can form a 3 to 7 membered heterocyclic ring containing 1-2 heteroatoms independently chosen from O, S, SO, SO 2 , N, or NR 8 ;  
 R 7  represent  
 i) hydrogen, halogen, OH, C 1-6  alkoxy, C 1-6  alkyl, alkenyl,  
 ii) amino, C 1-6  alkylamino, C 1-6  dialkylamino, hydroxylamino or C 1-2  alkoxyamino all of which can be optionally substituted on the nitrogen with C 1-6  acyl, C 1-6  alkylsulfonyl or C 1-6  alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH;  
 R 8  and R 9  independently represents  
 i) H, CN,  
 ii) C 1-6  alkyl optionally substituted with 1-3 halogen, CN, OH, C 1-6  alkoxy, C 1-6  acyloxy, or amino,  
 iii) phenyl optionally substituted with 1-3 groups of halogen, OH, C 1-6  alkoxy; or  
 R 7  and R 8  taken together can form a 3-7 membered ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO 2 , NH, and NR 8 ;  
 X 1  represents O, S or NR 13 , NCN, or NSO 2 R 14 ;  
 X 2  represents O, S, NH or NSO 2 R 14 ;  
 R 10  represents hydrogen, C 1-6  alkyl or CO 2 R 15 ;  
 R 11  represents hydrogen, C 1-6  alkyl, C 1-6  alkanoyl, halogen, amino, C 1-6  acylamino, C 1-6  alkoxy, OH or CF 3 , NHC 1-6  alkyl, or N(C 1-6  alkyl) 2 , where said alkyl may be substituted with 1-3 groups of halo, OH or C 1-6  alkoxy;  
 R 12  represents hydrogen, C 1-6  alkyl, NH 2 , C 1-6  alkylamino, C 1-6  alkoxy or C 1-6  dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, OH or C 1-6  alkoxy;  
 Each R 13  represents independently hydrogen, C 1-6  alkyl, NR 5 R 6 , SR 8 , S(O)R 8 , S(O) 2 R 8 , CN, C 1-6  alkylS(O)R, C 1-6  alkoxycarbonyl, hydroxycarbonyl, C 1-6  acyl, C 3-7  membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO 2 , NH and NR 8  where said C 1-6  alkyl or C 1-6  acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R) 2 , CO 2 R, C 6-10 aryl, C 5-10 heteroaryl, or C 1-6 alkoxy groups;  
 When two R 13  groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3-7 membered ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO 2 , NH, and NR 8 ;  
 R 14  represents amino, C 1-6  alkyl, C 1-6  haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C 1-6  alkoxy, C 1-6  acylamino, or C 1-6  alkyl, hydroxy and/or amino, s aid amino and hydroxy optionally protected with an amino or hydroxy protecting group;  
 R 15  is C 1-6  alkyl or benzyl said benzyl optionally substituted with 1-3 groups of halo, OH, C 1-6  alkoxy, amino, C 1-6  acylamino, or C 1-6  alkyl; and  
 m, n, and q represents 0-1.  
 
     
     
         2 . A compound according to  claim 1  wherein A is CH.  
     
     
         3 . A compound according to  claim 1  wherein A is C and --- is present.  
     
     
         4 . A compound according to  claim 1  wherein A is N.  
     
     
         5 . A compound according to  claim 1  wherein R 1  and R 2  independently represent H, NR 5 R 6 , CN, OH, C(R) 2 OR 14 , NHC(═X1)N(R 13 ) 2 , C(═NOH)N(R 13 ) 2 , or CR 7 R 8 R 9 .  
     
     
         6 . A compound according to  claim 1  wherein  
       
         
           
           
               
               
           
         
       
       is pyridine, pyrimidine, or piperidine.  
     
     
         7 . A compound according to  claim 5  wherein one of R 1  and R 2  is H and the other is NR 5 R 6 .  
     
     
         8 . A compound according to  claim 5  wherein one of R 1  and R 2  is H and the other is CN.  
     
     
         9 . A compound according to  claim 1  wherein R 5  and R 6  independently are: 
 i) hydrogen,    ii) C 1-6  alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C 1-6  alkoxy, amino, imino, hydroxyamino, alkoxyamino, C 1-6  acyloxy, C 1-6  alkylsulfenyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, aminosulfonyl, C 1-6  alkylaminosulfonyl, C 1-6  dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethyenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF 3 , C 1-6  alkyl or C 1-6  alkoxy;    iii) C 1-6  acyl optionally substituted with 1-3 groups of halogen, OH, SH, C 1-6  alkoxy, naphthalenoxy, phenoxy, amino, C 1-6  acylamino, hydroxylamino, alkoxylamino, C 1-6  acyloxy, aralkyloxy, phenyl, pyridine, C 1-6  alkylcarbonyl, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-6  hydroxyacyloxy, C 1-6  alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C 1-6  alkoxy, amino, C 1-6  acylamino, CF 3  or C 1-6  alkyl;    iv) benzoyl optionally substituted with 1-3 groups of halogen, OH, C 1-6  alkoxy, C 1-6  alkyl, CF 3 , C 1-6  alkanoyl, amino or C 1-6  acylamino.    
     
     
         10 . A compound according to  claim 1  wherein X 1  represents O.  
     
     
         11 . A compound according to  claim 1  wherein one of R 1  or R 2  is hydrogen and the other is:  
       
         
           
           
               
               
           
         
       
       wherein R 10 , X 1 , m, q, and R 11  are as described in  claim 1 .  
     
     
         12 - 19 . (canceled)  
     
     
         20 . A compound according to  claim 1  of the structural formula IIIa or IIIb:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 4a , and Rx are as described in  claim 1  and A is N.  
     
     
         21 . A compound according to  claim 20  wherein R 1  and R 2  independently represent H, NR 5 R 6 , CN, OH, C(R) 2 OR 14 , NHC(═X1)N(R 13 ) 2 , C(═NOH)N(R 13 ) 2 , or CR 7 R 8 R 9   
       
         
           
           
               
               
           
         
       
     
     
         22 . A compound according to  claim 21  wherein one of R 1  and R 2  is H and the other is NR 5 R 6 .  
     
     
         23 . A compound according to  claim 21  wherein one of R 1  and R 2  is H and the other is CN.  
     
     
         24 . A compound according to  claim 1  of the structural formula IIIa or IIIb:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 4a , and Rx are as described herein and A is C wherein --- is present.  
     
     
         25 . A compound according to  claim 24  wherein R 1  and R 2  independently represent H, NR 5 R 6 , CN, OH, C(R) 2 OR 14 , NHC(═X1)N(R 13 ) 2 , C(═NOH)N(R 13 ) 2 , or CR 7 R 8 R 9   
       
         
           
           
               
               
           
         
       
     
     
         26 . A compound according to  claim 25  wherein one of R 1  and R 2  is H and the other is NR 5 R 6 .  
     
     
         27 . A compound according to  claim 25  wherein one of R 1  and R 2  is H and the other is CN.  
     
     
         28 - 31 . (canceled)  
     
     
         32 . A pharmaceutical composition comprised of a compound in accordance with  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         32 . (canceled)  
     
     
         33 . A pharmaceutical composition produced by combining a compound in accordance with  claim 1  with a pharmaceutically acceptable carrier.  
     
     
         34 . A method of treating or preventing a bacterial infection in a mammalian patient in need thereof, comprising administering to said patient an effective amount of a compound of  claim 1 .  
     
     
         35 . A method for the preparation of a compound of  claim 1 , wherein A is a nitrogen atom and the 3-azabicyclo[3.1.0]hexane has a 6-amino substituent, the method comprising: 
 1) reacting a 6-amino-3-azabicyclo[3.1.0]hexane having a protected 6-amino substituent with a heteroaryl compound bearing a nitro group and a leaving group;    2) reducing the product from step 1) to the corresponding amino compound, and protecting the resulting amino group;    3) reacting the protected amino heteroaryl product from step 2) with a strong base and then condensing with a glycidyl ester to form a 5-hydroxymethyloxazolidinone as a product;    4) converting the 5-hydroxymethyloxaxolidinone from step 3) to a 5-aminomethyloxazolidinone by first converting the hydroxy group to an activated leaving group, displacing the leaving group with sodium azide, and then reducing the resulting 5-azidooxazolidinone to the amine; and    5) acylating the 5-aminooxazolidinone from step 4) and converting the amino substituent to R 3 .    
     
     
         36 . A method according to  claim 35 , wherein the product from step 5) is further subjected to reductive alkylation, or acylation.  
     
     
         37 . A method according to  claim 35 , wherein the protected amino heteroaryl product from step 2), after reaction with a strong base, is reacted with a racemic glycidyl ester to prepare a racemic oxazolidinone.  
     
     
         38 . A method according to  claim 35 , wherein the protected amino heteroaryl product from step 2), after reaction with a strong base, is reacted with a chiral glycidyl ester to prepare chiral oxazolidinone.  
     
     
         39 . A method according to  claim 38 , wherein the chiral glycidylester is an R-glycidylester.  
     
     
         40 . A method according to  claim 38 , wherein the chiral glycidylester is an S-glycidylester.  
     
     
         41 . A method for the preparation of a compound of  claim 1 , wherein A is a nitrogen atom and the 3-azabicyclo[3.1.0]hexane has a 6-carbon substituent, the method comprising: 
 1) reacting a 6-amino-3-azabicyclo[3.1.0]hexane having a protected 6-hydroxyl or 6-alkyl substituent with a heteroaryl compound bearing a nitro group and a leaving group;    2) reducing the product from step 1) to the corresponding amino compound, and protecting the resulting amino group;    3) reacting the protected amino heteroaryl product from step 2) with a strong base and then condensing with a glycidyl ester to form a 5-hydroxymethyloxazolidinone as a product;    4) converting the 5-hydroxymethyloxazolidinone from step 3) to a 5-aminomethyloxazolidinone by first converting the hydroxy group to an activated leaving group, displacing the leaving group with sodium azide, and then reducing the resulting 5-azidooxazolidinone to the amine; and    5) acylating the 5-aminooxazolidinone from step 4) and converting the amino substituent to R 3 .    
     
     
         42 . A method according to  claim 41 , wherein the protected amino heteroaryl product from step 2), after reaction with a strong base, is reacted with a racemic glycidyl ester to prepare a racemic oxazolidinone.  
     
     
         43 . A method according to  claim 41 , wherein the protected amino heteroaryl product from step 2), after reaction with strong base, is reacted with a chiral glycidyl ester to prepare a chiral oxazolidinone.  
     
     
         44 . A method according to  claim 43 , wherein the chiral glycidylester is an R-glycidylester.  
     
     
         45 . A method according to  claim 43 , wherein the chiral glycidylester is an S-glycidylester.  
     
     
         46 . A method for preparation of a compound of  claim 1 , wherein the 3-azabicyclo[3.1.0]hexane has a protected hydroxyl group in the 6-position, the method comprising: 
 1) removing the protecting group to provide the free hydroxyl group;    2) activating the hydroxy group displacement with a nucleophilic substituent by converting the hydroxyl group to a leaving group; and    3) reacting the product from step 2) to replace the leaving group with a nucleophilic group.    
     
     
         47 . A method for preparation of a compound of  claim 1 , wherein the 3-azabicyclo-[3.1.0]hexane has a protected hydroxyl group in the 6-position, the method comprising: 
 1) removing the protecting group to provide the free hydroxyl group;    2) oxidizing the hydroxyl group to the aldehyde;    3) further oxidizing the aldehyde group to the carboxylic acid; and    4) converting the carboxylic acid to a leaving group and treating with a nucleophile to introduce a nucleophilic group into the 6-position.    
     
     
         48 . A method for the preparation of a compound of  claim 1 , wherein A contains a carbon atom and the 3-azabicyclo[3.1.0]hexane has a 6-amino substituent, the method comprising: 
 1) reacting a protected 3-trifluoromethanesulfonyl-6-amino-bicyclo[3.1.0]hexene with a substituted 2-oxo-3-(4-trimethylstannylphenyl)-5-substituted oxazolidinone to produce a cross-coupled product; and    2) reducing the double bond by hydrogenation to produce the bicylo[3.1.0]hexane.