Oxo-substituted compound

Abstract

Provided is a novel compound that has an excellent β-lactamase inhibitory effect. More specifically, provided is a compound represented by formula (1a), (1b) or (11) having an excellent β-lactamase inhibitory effect or a pharmaceutically acceptable salt thereof. By using this compound either in combination with a β-lactam drug or alone, a useful preventive or therapeutic agent for bacterial infections is provided. Also provided are useful preventive or therapeutic agents for treating various diseases with the combined use of the aforesaid compound and β-lactam drugs.

1 - 54 . (canceled) 
     
     
         55 . A compound represented by formula (11): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 R G  is a hydroxyl group, a thiol group, or —NHR a1 , 
 G is an oxygen atom, a sulfur atom, or —NR a1 —, 
 X is a hydroxyl group, an optionally substituted C 1-6  alkoxy group, or —NR a2 R b1 , R a1 , R a2 , and R b1  are the same or different, each independently
 1) a hydrogen atom, 
 2) a C 1-6  alkyl group, 
 3) a C 3-10  alicyclic group, 
 4) C 6-10  aryl 
 5) 5- or 6-membered heteroaryl, 
 6) a 4- to 10-membered non-aryl heterocycle, 
 7) a C 1-6  alkylcarbonyl group, 
 8) a C 3-10  alicyclic carbonyl group, 
 9) a C 6-10  arylcarbonyl group, 
 10) a 5- or 6-membered heteroarylcarbonyl group, 
 11) a C 1-6  alkylsulfonyl group, 
 12) a C 3-10  alicyclic sulfonyl group, 
 13) a C 6-10  arylsulfonyl group, 
 14) a 5- or 6-membered heteroarylsulfonyl group, or 
 15) —OR c1 , 
 wherein each substituent from 2) to 14) is optionally substituted, 
 wherein R a2  and R b1  together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, 
 
 R c1  is
 1) a hydrogen atom 
 2) a C 1-6  alkyl group, 
 3) a C 3-10  alicyclic group, 
 4) C 6-10  aryl, 
 5) 5- or 6-membered heteroaryl, or 
 6) a 4- to 10-membered non-aryl heterocycle, 
 wherein each substituent from 2) to 6) is optionally substituted, 
 
 L 1  is a single bond, an oxygen atom, a sulfur atom, —SO—, —SO 2 —, —NR d —, —NR d C(═O)—, or —NR d SO 2 —, 
 L 2  is a single bond or an optionally substituted C 1-6  alkylene group, 
 Z is
 1) a hydrogen atom, 
 2) a hydroxyl group, 
 3) a cyano group, 
 4) a carboxyl group, 
 5) a C 3-10  alicyclic group, 
 6) C 6-10  aryl, 
 7) 5- or 6-membered heteroaryl, 
 8) a 4- to 10-membered non-aryl heterocycle, 
 9) a C 1-6  alkoxy group, 
 10) a C 3-10  alicyclic oxy group, 
 11) a C 6-10  aryloxy group, 
 12) a 5- or 6-membered heteroaryloxy group, 
 13) a 4- to 10-membered non-aryl heterocyclyl oxy group, 
 14) a C 1-6  alkylthio group, 
 15) a C 3-10  alicyclic thio group, 
 16) a C 6-10  arylthio group, 
 17) a 5- or 6-membered heteroarylthio group, 
 18) a 4- to 10-membered non-aryl heterocyclyl thio group, 
 wherein each substituent from 5) to 18) is optionally substituted, 
 19) —SO 2 —NR e1 R f1 , 
 20) —NR e1 —C(═O)OR f1 , 
 21) —NR g1 —C(═O)NR e1 R f1 , 
 22) —NR e1 —C(═S)R f1 , 
 23) —NR e1 —C(═S)OR f1 , 
 24) —NR g1 —C(═S)NR e1 R f1 , 
 25) —NR g1 —CR e1 (═NR f1 ), 
 26) —NR g1 —CR e1 (═N—OR f1 ), 
 27) —NR h1 —C(═NR g1 )NR e1 R f1 , 
 28) —NR h1 —C(═N—OR g1 )NR e1 R f1 , 
 29) —NR i1 —C(═NR h1 )NR g1 —NR e1 R f1 , 
 30) —NR i1 —C(═N—OR h1 )NR g1 —NR e1 R f1 , 
 31) —NR e1 —SO 2 —R f1 , 
 32) —NR g1 —SO 2 —NR e1 R f1 , 
 33) —C(═O)OR e1 , 
 34) —C(═S)OR e1 , 
 35) —C(═S)NR e1 R f1 , 
 36) —C(═S)NR e1 OR f1 , 
 37) —C(═S)NR g1 —NR e1 R f1 , 
 38) —C(═NR e1 )R f1 , 
 39) —C(═N—OR e1 )R f1 , 
 40) —C(═NR h1 )NR g1 —NR e1 R f1 , 
 41) —C(°N—OR h1 )NR g1 —NR e1 R f1 , 
 42) —NR e1 R f1 , 
 43) —NR g1 —NR e1 R f1 , 
 44) —NR e1 OR f1 , 
 45) —NR e1 —C(═O)R f1 , 
 46) —C(═O)NR e1 R f1 , 
 47) —C(═O)NR e1 OR f1 , 
 48) —C(═O)NR g1 —NR e1 R f1 , 
 49) —C(═O)R e1 , 
 50) —C(═NR g1 )NR e1 R f1 , or 
 51) —C(═N—OR h1 )NR e1 R f1 , 
 
 one of R 1 , R 2 , and R 3  is a group represented by formula (2): 
 
       
         
           
           
               
               
           
         
         wherein 
         Y is an oxygen atom, a sulfur atom, or —NR j —, 
         ring A is an optionally substituted 4- to 20-membered non-aryl heterocycle, 
         L 3  is —C(═O)—, —S(═O), or —S(═O) 2 —, 
         L 4  is
 1) a single bond, 
 2) a C 1-6  alkylene group, 
 3) a C 3-10  cycloalkylene group, 
 4) a C 6-10  arylene group, 
 5) a 5- or 6-membered heteroarylene group, 
 6) a 4- to 10-membered non-aryl heterocyclylene group, or 
 7) —C(═N—OR h1 ), 
 wherein each substituent from 2) to 6) is optionally substituted, and 
 
         R 5  is
 1) a hydrogen atom 
 2) a C 1-6  alkyl group, 
 3) a C 3-10  alicyclic group, 
 4) a 4- to 10-membered non-aryl heterocycle, 
 5) C 6-10  aryl, 
 6) 5- or 6-membered heteroaryl, 
 7) a C 1-6  alkylthio group, 
 wherein each substituent from 2) to 7) is optionally substituted, or 
 8) —NR e1 OH, 
 
         the remaining two, which are without the structure of formula (2) among R 1 , R 2  and R 3 , are the same or different, each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6  alkyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted C 1-6  (alkylthio group, an optionally substituted 5- or 6-membered heteroaryl, or —NR a3 R b2 , 
         R d , R e1 , R e2 , R f1 , R f2 , R g1 , R g2 , R h1 , R h2 , R i1 , R i2  and R j  are the same or different, each independently a hydrogen atom, an optionally substituted C 1-6  alkyl group, an optionally substituted C 3-10  alicyclic group, optionally substituted C 6-10  aryl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 4- to 10-membered non-aryl heterocycle, 
         a combination of R e1  and R f1  or R e2  and R f2 , when attached to the same nitrogen atom, together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, 
         R 4  is
 1) —C(═O)R 8 , 
 2) —SO 2 -L 6 -R 8 , 
 wherein R 8  in 1) and 2) is —NR a5 R b4 , —NR a5 -L 7 -B(OR m1 ) 2 , —OR m1 , or an optionally substituted C 1-6  alkyl group, and L 6  is a single bond or —NR a6 —, 
 3) —NR a4 R b3 , 
 4) —B(OR m1 ), 
 5) —PO(OR m1 )(OR m2 ), 
 6) optionally substituted 5-membered heteroaryl, 
 7) an optionally substituted 5-membered non-aryl heterocycle, or 
 8) a bioisostere of one of 1) to 7), 
 wherein the formulas of 2), 4), 5), and 6) include a carboxylic acid isostere, and 8) may include them in duplicates, 
 
         R a3 , R a4 , R a5 , R a6 , R b2 , R b3 , and R b4  are the same or different, each independently having the same definition as R a1 , R a2 , and R b1 , wherein a combination of R a3  and R b2 , R a4  and R b3 , or R a5  and R b4 , when attached to the same nitrogen atom, together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, 
         R m1  is
 1) a hydrogen atom, 
 2) a C 1-6  alkyl group, 
 3) a C 3-10  alicyclic group, 
 4) C 6-10  aryl, 
 5) 5- or 6-membered heteroaryl, or 
 6) a 4- to 10-membered non-aryl heterocycle, 
 wherein each substituent from 2) to 6) is optionally substituted, 
 
         wherein if R m1  is attached to a boron atom via an oxygen atom, two R m1 , as C 2-4  alkylene, together with the boron atom and two oxygen atoms, may form a 5- to 7-membered non-aryl heterocycle, wherein an alkylene moiety is optionally substituted in the non-aryl heterocycle, 
         R m2  is a hydrogen atom, an optionally substituted C 1-6  alkyl group, or an optionally substituted C 3-10  alicyclic group, and 
         L 7  is an optionally substituted C 1-3  alkylene group. 
       
     
     
         56 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , wherein the compound of formula (11) is represented by formula (12): 
       
         
           
           
               
               
           
         
       
     
     
         57 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , wherein the compound of formula (12) is represented by formula (13): 
       
         
           
           
               
               
           
         
       
     
     
         58 . The compound or the pharmaceutically acceptable salt thereof according to  claim 57 , wherein X and R G  are hydroxyl groups, R 4  is a carboxyl group, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle. 
     
     
         59 . The compound or the pharmaceutically acceptable salt thereof according to  claim 58 , wherein the compound of formula (13) is represented by formula (14): 
       
         
           
           
               
               
           
         
       
     
     
         60 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , wherein R G  is a hydroxyl group or a thiol group. 
     
     
         61 . The compound or the pharmaceutically acceptable salt thereof according to  claim 60 , wherein R G  is a hydroxyl group. 
     
     
         62 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , wherein X is a hydroxyl group or a C 1-6  alkoxy group. 
     
     
         63 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , wherein X is a hydroxyl group. 
     
     
         64 . The compound or the pharmaceutically acceptable salt thereof according to  claim 63 , wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or 3. 
     
     
         65 . The compound or the pharmaceutically acceptable salt thereof according to  claim 64 , wherein m is 1, and n is 1. 
     
     
         66 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , wherein L 3  is —C(═O)—. 
     
     
         67 - 69 . (canceled) 
     
     
         70 . A medicament comprising the compound or the pharmaceutically acceptable salt thereof according to  claim 55 . 
     
     
         71 . The medicament according to  claim 70 , which is a therapeutic drug or a prophylactic drug for a bacterial infection. 
     
     
         72 . A β-lactamase inhibiting agent comprising the compound or the pharmaceutically acceptable salt thereof according to  claim 55  as an active ingredient. 
     
     
         73 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to  claim 55  and a pharmaceutically acceptable carrier. 
     
     
         74 . The pharmaceutical composition according to  claim 73 , further comprising an additional agent. 
     
     
         75 . The pharmaceutical composition according to  claim 74 , wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent. 
     
     
         76 . The pharmaceutical composition according to  claim 74 , wherein the additional agent is a β-lactam agent. 
     
     
         77 . The pharmaceutical composition according to  claim 75 , wherein the β-lactam agent is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442. 
     
     
         78 . The pharmaceutical composition according to  claim 77 , wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. 
     
     
         79 . The pharmaceutical composition according to  claim 77 , wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam. 
     
     
         80 . The pharmaceutical composition according to  claim 74 , wherein the additional agent is included in the pharmaceutical composition such that the additional agent is concomitantly administered with the compound or the pharmaceutically acceptable salt thereof. 
     
     
         81 . The pharmaceutical composition according to  claim 80 , wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent. 
     
     
         82 . The pharmaceutical composition according to  claim 81 , wherein the additional agent is a β-lactam agent. 
     
     
         83 . The pharmaceutical composition according to  claim 82 , wherein the β-lactam agent is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442. 
     
     
         84 . The pharmaceutical composition according to  claim 83 , wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. 
     
     
         85 . The pharmaceutical composition according to  claim 83 , wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam. 
     
     
         86 . The compound or the pharmaceutically acceptable salt thereof according to  claim 55 , which is suitable for treating a bacterial infection. 
     
     
         87 . The compound or the pharmaceutically acceptable salt thereof according to  claim 86 , wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved. 
     
     
         88 . The compound or the pharmaceutically acceptable salt thereof according to  claim 87 , wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, eye infection, or an odontogenic infection. 
     
     
         89 . A medicament comprising a combination of the compound or the pharmaceutically acceptable salt thereof according to  claim 55  and at least one agent selected from the group consisting of therapeutic agents for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, eye infection, and an odontogenic infection. 
     
     
         90 . (canceled) 
     
     
         91 . A method for treating a bacterial infection, comprising administering a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to  claim 55  to a patient in need thereof. 
     
     
         92 . The method according to  claim 91 , wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved. 
     
     
         93 . The method according to  claim 92 , wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection. 
     
     
         94 . The method of  claim 93 , wherein an additional agent is concomitantly administered.