Peptide deformylase activated prodrugs

Abstract

This invention provides compounds and methods for using them to inhibit the growth of microorganism that expresses Peptide Deformylase, the compounds having the general formula:

1 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen or CH 3 ;  
 R 4  is selected from the group consisting of a substituted or unsubstituted aryl group, a substituted or unsubstituted, saturated or unsaturated C 1 -C 6  alkyl group and  
 —CH 2 CH 2 XCH 3 , wherein X is selected from the group consisting of oxygen, sulfur and CH 2 ;  
 R 5  and R 6  are independently selected from the group consisting of hydrogen, a substituted or unsubstituted C 5 -C 14  aryl group and a substituted or unsubstituted, saturated or unsaturated C 1 -C 6  alkyl group;  
 =A 1  is either absent, in which case the carbon to which it was attached becomes a CH 2  group, or A 1  is selected from the group consisting of oxygen, sulfur, NH, NOH, NR 8 , and CR 9 R 10 , wherein R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl;  
 =A 2  is either absent, in which case the carbon to which it was attached becomes a CH 2  group, or A 2  is selected from the group consisting of oxygen, sulfur, NH, NOH and NR 11  wherein R 11  is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;  
 B 1  is either absent or is selected from the group consisting of oxygen, sulfur, NR 12  and  
 CR 13 R 14 , wherein R 12 R 13  and R 14  are independently selected from the group consisting of hydrogen and a substituted or unsubstituted saturated or unsaturated alkyl;  
 B 2  is selected from the group consisting of carbon, oxygen and nitrogen, wherein, when B 2  is oxygen, R 5  and R 6  are absent and when B 2  is nitrogen, one of R 5  or R 6  is absent;  
 B 1  may be joined through R 12 , R 13  or R 14  to R 5  or R 6  to form a saturated or unsaturated, substituted or unsubstituted ring which may contain 0-3 nitrogen atoms and/or 0-1 oxygen or sulfur atoms;  
 B 3  and B 4  are independently absent or selected from the group consisting of oxygen, sulfur, NH, CH 2 , NR 17 , CHR 18 , CR 21 R 22  and, when either linker 1 -B 5 -Toxin 1  or linker 2 -B 6 -Toxin 2  is absent, OR 15 , SR 16 , NR 19 R 20  and CR 23 R 24 R 25 , wherein R 15 —R 25  are independently selected from the group consisting of hydrogen, substituted or unsubstituted, saturated or unsaturated alkyl and substituted or unsubstituted aryl;  
 B 3  or B 4  may be joined through one of R 15 —R 25  to B 1 , R 5  or R 6  to form a saturated or unsaturated, substituted or unsubstituted ring which contains one phosphorus atom and which may contain 0-3 nitrogen atoms and/or 0-1 oxygen or sulfur atoms;  
 B 5  and B 6  are independently absent or selected from the group consisting of oxygen, sulfur, OC(═O), SC(═S), OC(═O)NH, SC(═S)NH, OC(═S)NH, N(R 26 ) and C(R 27 )(R 28 ), wherein R 26 , R 27  and R 28  are independently selected from the group consisting of hydrogen and a substituted or unsubstituted, saturated or unsaturated alkyl;  
 Linker 1  and Linker 2  are independently absent or present and if present are traceless; and, one of Toxin 1  or Toxin 2  may be absent.  
 
     
     
         2 . The compound of  claim 1 , wherein: 
 R 1  is hydrogen; and,    R 4  is CH 2 CH 2 XCH 3 , wherein X is selected from the group consisting of CH 2 , sulfur and oxygen.    
     
     
         3 . The compound of  claim 2 , wherein X is sulfur.  
     
     
         4 . The compound of  claim 3 , wherein A 1  and A 2  are both oxygen.  
     
     
         5 . The compound of  claim 4 , wherein Linker 1 -B 5 -Toxin 1  is absent.  
     
     
         6 . The compound of  claim 5 , wherein B 1  is absent.  
     
     
         7 . The compound of  claim 5 , wherein B 2  is carbon.  
     
     
         8 . The compound of  claim 5 , wherein B 2  is nitrogen.  
     
     
         9 . The compound of  claim 5 , wherein B 3  is selected from the group consisting of OH, OCH 3 , OCH 2 CH 3  and OC 6 H 5 .  
     
     
         10 . The compound of  claim 5 , wherein Linker 2  is selected from the group consisting of 
 substituted or unsubstituted allyl;    substituted or unsubstituted benzyl,    C 6 H 4 CH 2 X 1 C(═X 2 ), wherein X 1  and X 2  are independently selected from the group consisting of oxygen, sulfur and N(R 29 ), wherein R 29  is hydrogen or C 1 -C 6  alkyl; and,    (CH 2 ) n N(R)C(═O), wherein n is 2 or 3 and R is hydrogen or C 1 -C 6  alkyl.    
     
     
         11 . The compound of  claim 10 , wherein B 6  is absent.  
     
     
         12 . The compound of  claim 1 , wherein Toxin 1  and Toxin 2  are independently selected from the group consisting of aminoglycosides, mitomycin, CC-1065, ducarmycin, cyclopropyl indole, cyclopropyl benzoindole analogs, anthracyclins, vinca alkaloids, mitomycins, bleomycins, penicillins, cephalosporins, oxacillins, carbopenems, tetracyclins, chloramphenicols, macrolides, cycloserines, fluoroquinolones (including, but not limited to, ciprofloxacin and norfloxacin), glycopeptides, aminoglycosides, peptide antibiotics, oxazolidinones, quinolones, sulfonamides, cytotoxic nucleosides, pteridine family, nitrogen mustards, polyhalogenated biaryl ethers, diynenes, podophillotoxins, taxoids, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 6-mercaptopurine, cytosine arabinoside, podophillotoxin, etoposide, etoposide phosphate, melphalan, vindesine, vinblastine, vincristine, leurosidine, leurosine, bis-(2-chloroethyl)amine, trichlorcarban, trichlorocarbanilide, triclosan, tribromosalicylanilide, sulphamethoxazole, chloramphenicol, cycloserine, trimethoprim, chlorhexidine, hexachlorophene, fentichlor, 5-chloro-2-(2,4-dichlorophenoxy)phenol, 4-chloro-2-(2,4-dichlorophenoxy)phenol, 3-chloro-2-(2,4-dichlorophenoxy)phenol, 6-chloro-2-(2,4-dichlorophenoxy)phenol, 5-chloro-2-(3,4-dichlorophenoxy)phenol, 5-chloro-2-(2,5-dichlorophenoxy)phenol, 5-chloro-2-(3,5-dichlorophenoxy)phenol, 2,2′-dihydroxy biphenyl ether, halogenated 2-hydroxybenzophenones, 2-mercaptopyridine-N-oxide, combretastatin, camptothesin, apoptolidene, cisplatin, epothilone, halichondrin, hemiasterlin, methioprim, thapsigargin, chloroquine, 4-hydroxycyclophosphamide, etoposide, colchicine, melphalan, quercetin, genistein, erbstatin, N-(4-aminobutyl)-5-chloro-2-naphtalen-sulfonamide, pyridinyloxazol-2-one, isoquinolyloxazolone-2-one, verapamil, quinine, quinidine, and chloroquine.  
     
     
         13 . The compound of  claim 11 , wherein Toxin 2  is selected from the group consisting of aminoglycosides, mitomycin, CC-1065, ducarmycin, cyclopropyl indole, cyclopropyl benzoindole analogs, anthracyclins, vinca alkaloids, mitomycins, bleomycins, penicillins, cephalosporins, oxacillins, carbopenems, tetracyclins, chloramphenicols, macrolides, cycloserines, fluoroquinolones (including, but not limited to, ciprofloxacin and norfloxacin), glycopeptides, aminoglycosides, peptide antibiotics, oxazolidinones, quinolones, sulfonamides, cytotoxic nucleosides, pteridine family, nitrogen mustards, polyhalogenated biaryl ethers, diynenes, podophillotoxins, taxoids, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 6-mercaptopurine, cytosine arabinoside, podophillotoxin, etoposide, etoposide phosphate, melphalan, vindesine, vinblastine, vincristine, leurosidine, leurosine, bis-(2-chloroethyl)amine, trichlorcarban, trichlorocarbanilide, triclosan, tribromosalicylanilide, sulphamethoxazole, chloramphenicol, cycloserine, trimethoprim, chlorhexidine, hexachlorophene, fentichlor, 5-chloro-2-(2,4-dichlorophenoxy)phenol, 4-chloro-2-(2,4-dichlorophenoxy)phenol, 3-chloro-2-(2,4-dichlorophenoxy)phenol, 6-chloro-2-(2,4-dichlorophenoxy)phenol, 5-chloro-2-(3,4-dichlorophenoxy)phenol, 5-chloro-2-(2,5-dichlorophenoxy)phenol, 5-chloro-2-(3,5-dichlorophenoxy)phenol, 2,2′-dihydroxy biphenyl ether, halogenated 2-hydroxybenzophenones, 2-mercaptopyridine-N-oxide, combretastatin, camptothesin, apoptolidene, cisplatin, epothilone, halichondrin, hemiasterlin, methioprim, thapsigargin, chloroquine, 4-hydroxycyclophosphamide, etoposide, colchicine, melphalan, quercetin, genistein, erbstatin, N-(4-aminobutyl)-5-chloro-2-naphtalen-sulfonamide, pyridinyloxazol-2-one, isoquinolyloxazolone-2-one, verapamil, quinine, quinidine, and chloroquine.  
     
     
         14 . The compound of  claim 13 , wherein Toxin 2  is a quinolone.  
     
     
         15 . The compound of  claim 13 , wherein Toxin 2  is selected from the group consisting of triclosan, cyclopropylindole, cyclopropylbenzoindole and derivatives thereof.  
     
     
         16 . The compound of  claim 5 , wherein B 1  is joined to R 5  or R 6  to form a ring.  
     
     
         17 . (canceled)  
     
     
         18 . (canceled)  
     
     
         19 . A method for the treatment of a disease caused by a microorganism expressing a peptide deformylase enzyme (PDF), comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 .  
     
     
         20 . A method for inhibiting the growth of a microorganism that expresses a peptide deformylase enzyme (PDF), comprising contacting the microorganism with an effective amount of a compound of  claim 1 .  
     
     
         21 . A method for alleviating the symptoms of an infection in a subject in need thereof wherein the symptoms are caused by a microorganism that expresses a peptide deformylase enzyme (PDF), comprising administering to the subject an effective amount of a compound of  claim 1 .  
     
     
         22 . The method of any of  claims 19  to  21 , wherein the microorganism expressing PDF is selected from the group consisting of  S. aureus, S. epidermidis, K. pneumoniae, E. aerogenes, E. cloacae, M. catarrhalis, E. coli, E. faecalis, H. influenzae  and  P. aeruginosa.    
     
     
         23 . The method of  claim 19 , wherein the disease is selected from the group consisting of acute colitis, acute enteritis, bacteremia, endocarditis, epiglottitis, lymphagitis, pneumonia, meningitis, neonatal sepsis, osteomyelitis, otitis media, perihepatitis and sinusitis.  
     
     
         24 . The method of  claim 21 , wherein the infection is selected from the group consisting of central nervous system infections, enteric infections, genital infections, lower respiratory tract infections, neonatal sepsis and urinary tract infection.  
     
     
         25 . The method of  claim 20 , wherein the contacting is in vitro or ex vivo.  
     
     
         26 . The method of any of  claims 19  to  21 , further comprising administering an effective amount of an antibiotic.  
     
     
         27 . The method of any of  claim 26 , wherein the compound is administered with a pharmaceutically acceptable carrier.  
     
     
         28 . The method of  claim 21 , wherein the subject is selected from a fish or an animal.  
     
     
         29 . The method of  claim 28 , wherein the subject is a fish.  
     
     
         30 . The method of any of  claims 19  to  21 , wherein the compound has the structure: