6-11 Bicyclic Ketolide Derivatives

Abstract

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

1 - 23 . (canceled) 
   
   
       24 . A compound represented by the formula: 
     
       
         
         
             
             
         
       
       or a racemate, enantiomer, regioisomer, salt, ester or prodrug thereof, wherein A and B, taken together with the carbon atom to which they are attached, is C═N—O—Ar 1 -M-Ar 2 , wherein —Ar 1 -M-Ar 2  is 
     
     
       
         
         
             
             
         
       
       one of X and Y is hydrogen and the other is selected from:
 a) hydrogen; 
 b) deuterium; 
 c) —OH; 
 d) —OR p , where R p  is as previously defined; 
 e) —NR 4 R 5 , where R 4  and R 5  are each independently selected from:
 (1) hydrogen; 
 (2) C 1 -C 12  alkyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; or 
 (3) R 4  and R 5 , taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl moiety; 
 
 
       alternatively, X and Y taken together with the carbon atom to which they are attached are selected from:
 a) C═O; 
 b) C═N-Q, wherein Q is selected from:
 (1) —R 11 , where R 11  is as previously defined; 
 (2) amino protecting group; 
 (3) —C(O)R 11 , where R 11  is as previously defined; 
 (4) —OR 6 , where R 6  is independently selected from:
 a. hydrogen; 
 b. —CH 2 O (CH 2 ) 2 OCH 3 ; 
 c. —CH 2 O(CH 2 O) n CH 3 , where n is as previously defined; 
 d. —C 1 -C 12  alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; 
 e. —C 3 -C 12  cycloalkyl; 
 f. —C(O)—C 1 -C 12  alkyl; 
 g. —C(O)—C 3 -C 12  cycloalkyl; 
 h. —C(O)—R 1 , where R 1  is as previously defined; or 
 i. —Si(R a )(R b )(R c ), wherein R a , R b  and R c  are each independently selected from C 1 -C 12  alkyl, aryl or substituted aryl; or 
 
 (5) O—C(R 7 )(R 8 )—O—R 6 , where R 6  is as previously defined, provided that R 6  is not C(O)—C 1 -C 12  alkyl, C(O)—C 3 -C 12  cycloalkyl, or C(O)—R 1 , and R 7  and R 8  taken together with the carbon atom to which they are attached form a C 3 -C 12  cycloalkyl group or each independently is selected from:
 a. hydrogen; or 
 b. C 1 -C 12  alkyl; 
 
 
 
       L is selected from:
 a) —CH 3 ; 
 b) —CH 2 CH 3 ; 
 c) —CH(OH)CH 3 ; 
 d) —(CH 2 ) n NHC(O)—R 11 , wherein n and R 11  are as previously defined; 
 e) C 1 -C 6  alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; 
 f) C 2 -C 6  alkenyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; or 
 g) C 2 -C 6  alkynyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; 
 
       W is —NR 20 R 21 , where R 20  and R 21  are each independently selected from:
 a) hydrogen; 
 b) C 1 -C 12  alkyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; 
 c) C 2 -C 12  alkenyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; 
 d) C 2 -C 12  alkynyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; or 
 e) R 20  and R 21 , taken together with the nitrogen atom to which they are attached form a heterocycloalkyl moiety; or 
 
       Z is selected from:
 a) hydrogen; 
 b) methyl; or 
 c) halogen; and 
 
       R 2 ′ is hydrogen or R p , where R p , is as previously defined. 
     
   
   
       25 . A compound according to  claim 24  wherein the compound is a pharmaceutically acceptable salt. 
   
   
       26 . A compound according to  claim 24  wherein the compound is a free base. 
   
   
       27 . A compound according to  claim 24  wherein the compound is an ester or prodrug. 
   
   
       28 . A compound according to  claim 24  wherein the compound is a Z oxime isomer. 
   
   
       29 . A compound according to  claim 24  wherein the compound is an E oxime isomer. 
   
   
       30 . A compound of  claim 24 , wherein X and Y taken together with the carbon atom to which they are attached are C═N—Ac. 
   
   
       31 . A compound of  claim 24 , wherein L is —CH 2 CH 3 . 
   
   
       32 . A compound of  claim 24 , wherein W is —N(CH 3 ) 2 . 
   
   
       33 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 24  or a pharmaceutically-acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier. 
   
   
       34 . A method for treating a bacterial infection in a subject in need of such treatment, comprising administering to said subject a therapeutically-effective amount of a pharmaceutical composition according to  claim 28 . 
   
   
       35 . The method according to  claim 34  wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. 
   
   
       36 . The method according to  claim 34  wherein the compound is administered orally or by injection. 
   
   
       37 . The method according to  claim 34  wherein the subject is a human. 
   
   
       38 . The method according to  claim 34  wherein the compound is administered in combination with one or more antibiotics. 
   
   
       39 . The method according to  claim 34  wherein the infection or disorder is selected from the group consisting of pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection by  Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,  or  Peptostreptococcus  spp.  Pseudomas  spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by  Streptococcus pyogenes,  Groups C and G streptococci,  Clostridium diptheriae,  or  Actinobacillus haemolyticum;  respiratory tract infections related to infection by  Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae,  or  Chlamydia pneumoniae;  uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by  Staphylococcus aureus,  coagulase-positive staphylococci,  S. pyogenes, S. agalactiae,  Streptococcal groups C-F,  viridans  streptococci,  Corynebacterium  spp.,  Clostridium  spp., or  Bartonella henselae;  uncomplicated acute urinary tract infections related to infection by  S. saprophyticus  or  Enterococcus  spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by  Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum,  or  Nesseria gonorrheae;  toxin diseases related to infection by  S. aureus,  or Groups A, S, and C streptococci; ulcers related to infection by  Helicobacter pylori;  systemic febrile syndromes related to infection by  Borrelia recurrentis;  Lyme disease related to infection by  Borrelia burgdorferi;  conjunctivitis, keratitis, and dacrocystitis related to infection by  C. trachmatis, N. gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae,  or  Listeria  spp.; disseminated  Mycobacterium  avium complex (MAC) disease related to infection by  Mycobacterium  avium, or  Mycobacterium intracellulare;  gastroenteritis related to infection by  Campylobacter jejuni;  intestinal protozoa related to infection by  Cryptosporidium  spp. odontogenic infection related to infection by  viridans  streptococci; persistent cough related to infection by  Bordetella pertussis;  gas gangrene related to infection by  Clostridium perfringens  or  Bacteroides  spp.; Skin infection by  S. aureus, Propionbacterium  acne; atherosclerosis related to infection by  Helicobacter pylori  and  Chlamydia pneumoniae.    
   
   
       40 . The method according to  claim 34  wherein the infection is selected from the group consisting of pneumonia, otitis-media, sinusitis, bronchitis, tonsillitis,  Propionbacterium  acne and skin and soft tissue infection. 
   
   
       41 . The method according to  claim 34  wherein the infection or disorder is selected from the group consisting of bovine respiratory disease related to infection by  P. haemolytica, P. multocida, Mycoplasma bovis,  or  Bordetella  spp.; cow enteric disease related to infection by  E. coli  or protozoa, dairy cow mastitis related to infection by  S. aureus, S. uberis, agalactiae, S. dysgalactiae, Klebsiella  spp.,  Corynebacterium,  or  Enterococcus  spp.; swine respiratory disease related to infection by  A. pleuropneumoniae, P. multocida,  or  Mycoplasma  spp.; swine enteric disease related to infection by  E. coli, Lawsonia intracellularis, Salmonella  spp., or  Serpulina hyodyisinteriae;  cow footrot related to infection by  Fusobacterium  spp.; cow metritis related to infection by  E. coli;  cow hairy warts related to Infection by  Fusobacterium necrophorum  or  Bacteroides nodosus;  cow pink-eye related to infection by  Moraxella boxis,  cow premature abortion related to infection by protozoa; urinary tract infection in dogs and cats related to infection by  E. coli;  skin and soft tissue infections in dogs and cats related to infection by  S. epidermidis, S. intermedius,  coagulase neg.  Staphylococcus  or  P. multocida;  and dental or mouth infections in dogs and cats related to infection by  Alcaligenes  spp.,  Bacteroides  spp.,  Clostridium  spp.,  Enterobacter  spp.,  Eubacterium  spp.,  Peptostreptococcus  spp.,  Porphfyromonas  spp.,  Campylobacter  spp.,  Actinomyces  spp.,  Erysipelothrix  spp.,  Rhodococcus  spp.,  Trypanosoma  spp.,  Plasmodium  spp.,  Babesia  spp.,  Toxoplasma  spp.,  Pneumocysitis  spp.,  Leishmania  spp., and  Trichomonas  spp. and  Prevotella  spp. 
   
   
       42 . A method for controlling a bacterial infection in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to  claim 33 .