Cephem compounds, their production and use

Abstract

Cephem compounds, pharmaceutically acceptable salts thereof, and methods of using same, wherein the compound has a bicyclic nitrogen-containing aromatic heterocyclic ring as the quaternary ammoniomethyl group at the 3-position and one or both of a terminal amidine residue (substituted or unsubstituted) attached to an aryl or a 5- or 6-membered heteroaryl group (substituted or unsubstituted) which is further attached through a spacer to the free N-atom of the quaternary nitrogen-containing bicyclic ring at the 3-side chain, or a terminal guanidine residue attached to an aryl or a 5- or 6-membered heteroaryl group (substituted or unsubstituted) which is further attached through a spacer to the free N-atom of the quaternary nitrogen-containing bicyclic ring at the 3-side chain.

We claim: 
     
       1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein in the formula (I), 
         (i) A is define by the formula (Ia): 
       
       
         
           
           
               
               
           
         
         Wherewhere X is N, C(H), C(F) or C(Cl); 
         (ii) B is defined as hydrogen, methyl, ethyl or represented by the formula (Ib) 
       
       
         
           
           
               
               
           
         
         wherein, R 1  and R 2  is independently hydrogen or lower alkyl; or 
         wherein R 1  and R 2  together may form a 3 to 6-membered spiro ring system; and 
         m is 0 or 1; 
         (iii) C represents a quaternized bicyclic nitrogen containing aromatic heterocyclic ring represented by the formulae (Ic) to (Iz) 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         (iv) D represents CH 2 , CH 2 CH 2  or CH 2 CO; 
         (v) E represents a substituted or unsubstituted benzene ring or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic ring having at least one heteroatom selected from the group consisting of O, S and N, wherein the heteroaromatic ring includes is pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and or thienyl; 
         (vi) F is optionally substituted amidine or optionally substituted guanidine; and 
         (vii) G is hydrogen, methyl, ethyl, C 3-6  alkyl, C 3-6  cycloalkyl or a an optionally substituted 5- or 6-membered aliphatic or a an optionally substituted 5- or 6-membered aromatic heterocyclic ring, wherein the heterocyclic ring is substituted with at least 1-2 hetero atoms selected from the group consisting of N, O, and S (αor β α or β). 
       
     
     
       2. A compound as recited in  claim 1 , where E is selected from a substituted aryl or a 5- and the group consisting of an optionally substituted benzene ring and an optionally substituted 5- or 6-membered aromatic heterocyclic rings ring, comprising: 
       
         
           
           
               
               
           
         
       
     
     
       3. A compound as recited in  claim 2 , wherein the optional substituents include on the benzene ring and the 5- or 6-membered aromatic heterocyclic rings of E are selected from the group consisting of chloro, fluoro, cyano, hydroxy, amino, carboxy, acetyl, methoxy, ethoxy, trifluoromethyl, pyrrolidinyloxy, and piperidinyloxy. 
     
     
       4. A compound as recited in  claim 1 , wherein the preferred examples of “-C-D-E-F” include comprises one of the following organic residues 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       5. The compound of formula (I) as recited in  claim 1 , which is selected from the following group of compounds consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. A method of treating a bacterial infection comprising administering to a mammal in need thereof an antibacterially effective amount of a compound as recited in  claim 1 . 
     
     
       7. A pharmaceutical composition containing as an active ingredient, at least one compound as recited in  claim 1  and at least one pharmaceutically acceptable carrier or diluent. 
     
     
       8. A method of treating a bacterial infection comprising administering to a mammal in need thereof a combination of (i) an antibacterially effective amount of a compound as recited in  claim 1 , and (ii) a therapeutically effective amount of a β-lactamase inhibitor selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. A pharmaceutical composition containing as an active ingredient at least (i) one compound as recited in  claim 1  and (ii) a therapeutically effective amount of a β-lactamase inhibitor selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       10. The method as recited in  claim 8 , wherein (i) and (ii) are administered simultaneously, sequentially, or separated in time. 
     
     
       11. The pharmaceutical composition as recited in  claim 9 , wherein the ratio of the weight of (i) to the weight of (ii) is in the range of from about 1:20 to about 20:1. 
     
     
       12. A process for preparing a compound of formula (I) as recited in  claim 1 , the process comprising one of the following processes:
 Process I wherein the intermediate VIII (q=0, Y=chloride) is coupled with intermediate (IX) to provide the intermediate (X) followed by removal of protecting groups to provide the compound of formula (I) 
 
       
         
           
           
               
               
           
         
         or 
         Process II wherein the intermediate VIII (q=1, Y=iodide) is coupled with intermediate (IX) and subsequently reducing the sulfoxide to sulfide providing the intermediate (XI) by removal of the protecting groups provides the compound of formula (I) 
       
       
         
           
           
               
               
           
         
         wherein in the formula VIII, P 1  is a suitable carboxy protecting group. 
       
     
     
       13. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein in the formula (I),
 (i) A is defined by the formula (Ia) 
 
       
         
           
           
               
               
           
         
         (ii) B is defined as hydrogen, methyl, ethyl or represented by the formula (Ib): 
       
       
         
           
           
               
               
           
         
         
           wherein, R 1  and R 2  are independently hydrogen or lower alkyl; or 
           wherein R 1  and R 2  together may form a 3 to 6 membered spiro ring system; and 
           m is 0 or 1; and 
         
         (iii) wherein “-C-D-E-F” is selected from the group consisting of one of the following organic residues: 
       
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       14. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein the compound is selected from the group consisting of the following compounds: