Gram-positive carbapenem antibacterials and processes for their preparation

Abstract

The present invention provides β-methyl carbapenem compounds and pharmaceutical compositions useful in the treatment of bacterial infections and methods for treating such infections using such compounds and/or compositions. The invention includes administering an effective amount of a carbapenem compound or salt and/or prodrug thereof to a host in need of such a treatment. The present invention is also in the field of synthetic organic chemistry and is specifically provides an improved method of synthesis of β-methyl carbapenems which are useful as antibacterial agents.

1 . A carbapenem compound of the formula [(I),] (II), (III) or
 (IV):   
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
       R 1  is either H or alkyl; 
       CO 2 M is independently a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; 
       P is independently hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; 
       X is independently O, S, S(O) x , wherein x is 0, 1 or 2, phosphate, carbonyl, thiocarbonyl, iminyl, P(O) 2 , P(O) 3 , C(O), C(O)O, OC(O), C(O)NH, C(O)NR, NHC(O), NRC(O), amine, NH, or NR; 
       each R is independently H or alkyl; 
       each 
     
     
       
         
         
             
             
         
       
     
     is independently a 5- or 6-membered monocyclic aromatic or heteroaromatic ring;
 Z is selected from the group consisting of a bond, C═CR 2 , C═CY 1 , O, S, carbonyl, 
 thiocarbonyl, iminyl, C(O), C(O)O, OC(O), C(O)NH, C(O)NR, NHC(O), NRC(O), N(A-(CH 2 ) n -Q)C(O), CON(A-(CH 2 ) n -Q), C(═NH), C(═NR), C(═N-A-(CH 2 ) n -Q), amine, NH, NR, or N(A-(CH 2 ) n -Q); 
 each Y 1  and Y 2  is independently selected from the group consisting of hydrogen; halo; —CN; —NO 2 ; —NR a R b ; —OR c ; —SR c ; —C(O)NR a R b ; —C(O)OR h ; S(O)R c ; —SO 2 R c ; —SO 2 NR a R b ; —NR a SO 2 R b ; —C(O)R a ; —OC(O)R a ; OC(O)NR a R b ; —NR a C(O)NR b R c ; —NR a CO 2 R h ; —OCO 2 R h ; NR a C(O)R b ; —C 1-6  straight- or branched-chain alkyl, —C 2-6  straight- or branched-chain alkenyl, or —C 2-6  straight- or branched-chain alkynyl, unsubstituted or substituted with 1 to 4 R d  groups; -A-(CH 2 ) n -Q; —(CH 2 ) n A-Q; —[(CH 2 ) n A] m (CH 2 ) p -Q; —CH 2 N-Q; and —C 3-7  cycloalkyl, unsubstituted or substituted with one to four R d  groups; 
 A is O, S, NH, NCH 3 , NR, or —CH 2 —; 
 each m, n, and p is independently 0, 1, 2 or 3; 
 each R a , R b  and R c  is independently selected from hydrogen, —C 1-6  straight- or branched-chain alkyl, unsubstituted or substituted with one to four R d  groups, or —C 3-7  cycloalkyl, unsubstituted or substituted with one to four R d  groups; 
 or R a  and R b  taken together with any intervening atoms form a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR c , or —C(O)—, said ring being unsubstituted or substituted with one to four R i  groups; 
 or R b  and Re taken together with any intervening atoms form a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR a , or —C(O)—, said ring being unsubstituted or substituted with one to four R i  groups; 
 each R d  is independently selected from the group consisting of halo; —CN; —NO 2 ; —NR e R f ; —OR g ; —SR g ; —CONR e R f ; —COOR g ; —SOR g ; —SO 2 R g ; —SO 2 NR e R f ; —NR e SO 2 R f ; —COR e ; —NR e COR f ; —OCOR e ; —OCONR e R f ; NR e CONR f R g ; —NR e CO 2 R h ; —OCO 2 R h ; —C(NR e )NR f R g ; NR e C(NH)NR f R g  or —NR e C(NR f )R g ; 
 each R e , R f  and R g  is independently selected from hydrogen; —R; —C 1-6  straight- or branched-chain alkyl unsubstituted or substituted with one to four R i  groups; 
 or R e  and R f  taken together with any intervening atoms form a 4-6 membered saturated ring 
 optionally interrupted by one to three of O, S, —C(O)— or NR g , said ring being unsubstituted or substituted with one to four R i  groups; 
 each R i  is independently selected from halo; —CN; —NO 2 ; phenyl; —NHSO 2 R h ; —OR h , —SR h ; —N(R h ) 2 ; —N + (R h ) 3 ; —C(O)N(R h ) 2 ; SO 2 N(R h )2; heteroaryl; heteroarylium; —CO 2 R h ; —C(O)R h ; —OCOR h ; NHCOR h ; guanidinyl; carbamimidoyl or ureido; 
 each R h  is independently selected from hydrogen, a —C 1-6  straight or branched-chain alkyl 
 group, a —C 3 -C 6  cycloalkyl group or phenyl, or when two R h  groups are present, said R h  groups can form a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO 2 , —C(O)—, NH and NCH 3 ; 
 each Q is selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
       wherein: 
       a and b are 1, 2 or 3; 
       L −  is a pharmaceutically acceptable counterion; 
       α is O, S or NR s ; 
       β, δ, λ, μ and σ are independently selected from CR t , N or N + R s , provided that no more than one of β, δ, λ, μ, and σ is N + R s ; 
       each R s  is independently selected from hydrogen; phenyl or C 1-6  straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i  groups; 
       each R t  is independently selected from hydrogen; halo; phenyl; —CN; —NO 2 ; —NR u R v ; —OR u ; —SR u ; —CONR u R v ; —COOR h ; —SOR u ; —SO 2 R u ; —SO 2 NR u R v ; —NR u SO 2 R v ; —COR u ; —NR u COR v ; —OCOR u ; —OCONR u R v ; —NR u CO 2 R v ; —NR u CONR v R w ; —OCO 2 R v ; —C 1-6  straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i  groups; 
       each R u  and R v  is independently hydrogen or —C 1-6  straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i  groups; 
       or R u  and R v  together with any intervening atoms form a 4-6 membered saturated ring 
       optionally interrupted by one or more of O, S, NRW or —C(O)—, said ring being unsubstituted or substituted with one to four R i  groups; 
       each R w  is independently hydrogen; —C 1-6  straight- or branched-chain alkyl, unsubstituted or 
       substituted with one to four R i  groups; C 3-6  cycloalkyl optionally substituted with one to four R i  groups; phenyl optionally substituted with one to four R i  groups, or heteroaryl optionally substituted with 1-4 R i  groups; or R h  and R w  taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO 2 , NH or NCH 3 ; 
       R x  is independently hydrogen or a C 1-8  straight- or branched chain alkyl, optionally 
       interrupted by one or two of O, S, SO, SO 2 , NR w , N + R h R w , or —C(O)—, said chain being unsubstituted or substituted with one to four of halo, CN, NO 2 , OR w , SR w , SOR w , SO 2 R w , NR h R w , N + (R h ) 2 R w , —C(O)—R w , C(O)NR h R w , SO 2 NR h R w , CO 2 R w , OC(O)R w , OC(O)NR h R w , NR h C(O)R w , NR h C(O)NR h R w , or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R i  groups or with one to two C 1-3  straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i  groups; 
       R y  and R z  are independently hydrogen; phenyl; —C 1-6  straight or branched chain alkyl, unsubstituted or substituted with one to four R i  groups, and optionally interrupted by O, S, NR w , N + R h R w  or —C(O)—; 
       or R x  and R y  together with any intervening atoms form a 4-6 membered saturated ring optionally interrupted by O, S, SO 2 , NR w , N + R h R w  or —C(O)—, unsubstituted or substituted with 1-4 R i  groups, 
       and when R x  and R y  together form a 4-6 membered ring, R z  is as defined above or R z  represents an additional saturated 4-6 membered ring fused to the ring represented by R x  and R y  taken together, optionally interrupted by O, S, NR w  or —C(O)—, said rings being unsubstituted or substituted with one to four R i  groups; 
       wherein if the compound is of formula (III), X is O and R is CH 3 , then the substituent 
     
     
       
         
         
             
             
         
       
     
   
   
       2 . (canceled) 
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . (canceled) 
   
   
       6 . (canceled) 
   
   
       7 . (canceled) 
   
   
       8 . (Canceled) 
   
   
       9 . The compound of  claim 1  wherein at least one of Y 1  and Y 2  is not hydrogen. 
   
   
       10 . The compound of  claim 9  wherein Y 1  is hydrogen and Y 2  is not hydrogen. 
   
   
       11 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . (canceled) 
   
   
       14 . (canceled) 
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . (canceled) 
   
   
       18 . (canceled) 
   
   
       19 . (canceled) 
   
   
       20 . (canceled) 
   
   
       21 . (canceled) 
   
   
       22 . (canceled) 
   
   
       23 . (canceled) 
   
   
       24 . (canceled) 
   
   
       25 . (canceled) 
   
   
       26 . The compound of  claim 1  wherein the carbapenem is of the formula (VI): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt and/or prodrug thereof. 
       X is O or NH; and 
       Y 1  is —(CH 2 ) n -Q wherein n=1-3 and Q is selected from the group consisting of —NH—C(═NR 3 )—N(R 3 ) 2 , —S—C(═NR 3 )—N(R 3 ) 2  and —S—O—N(R 3 ) 2 , wherein R 3  is independently C 1 -C 4  alkyl or H. 
     
   
   
       27 . (canceled) 
   
   
       28 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       29 . The composition of  claim 28  wherein X is O. 
   
   
       30 . (canceled) 
   
   
       31 . (canceled) 
   
   
       32 . (canceled) 
   
   
       33 . (canceled) 
   
   
       34 . (canceled) 
   
   
       35 . (canceled) 
   
   
       36 . The composition of  claim 28  wherein the composition is suitable for intravenous administration. 
   
   
       37 . The composition of  claim 28  wherein the composition further comprises at least one additional antibacterial agent. 
   
   
       38 . A method of preventing or treating an infection by a gram positive bacteria, in a host comprising administering to the host a therapeutic amount of a compound of  claim 1 , optionally in a pharmaceutically acceptable carrier. 
   
   
       39 . The method of  claim 38  wherein X is O. 
   
   
       40 . (canceled) 
   
   
       41 . (canceled) 
   
   
       42 . (canceled) 
   
   
       43 . (Canceled) 
   
   
       44 . (canceled) 
   
   
       45 . (canceled) 
   
   
       46 . The method of  claim 38  wherein the host is a human. 
   
   
       47 . The method of  claim 38  wherein the infection is by a drug resistant
 bacterial strain.   
   
   
       48 . The method of  claim 38  wherein the infection is by a multiple-drug resistant strain. 
   
   
       49 . The method of  claim 47  or  48  wherein the strain is selected from a methicillin resistant  Staphylococcus aureus  (MRSA), a methicillin resistant  Staphylococcus epidermidis  (MRSE), a methicillin resistant coagulase negative  Staphylococci  (MRCNS), a vancomycin resistant  Enterococcus faecalis,  and vancomycin resistant  Enterococcus faecium.    
   
   
       50 . The method of  claim 38  wherein the compound is administered in combination or alternation with at least one other antimicrobial agent. 
   
   
       51 . The method of  claim 38  wherein the compound is administered in combination with a β-lactamase inhibiting agent. 
   
   
       52 . The method of  claim 48  wherein the strain is selected from a methicillin resistant  Staphylococcus aureus  (MRSA), a methicillin resistant  Staphylococcus epidermidis  (MRSE), a methicillin resistant coagulase negative  Staphylococci  (MRCNS), a vancomycin resistant  Enterococcus faecalis,  and vancomycin resistant  Enterococcus faecium.