Cephem compounds, their production and use
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.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein in the formula (I),
(i) A is defined by the formula (Ia):
Where 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 benzene ring or a substituted 5- or 6-membered aromatic heterocyclic ring having at least one heteroatom selected from O, S and N, wherein the heteroaromatic ring includes pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and thienyl;
(vi) F is substituted amidine or substituted guanidine; and
(vii) G is hydrogen, methyl, ethyl, C 3-6 alkyl, C 3-6 cycloalkyl or a substituted 5- or 6-membered aliphatic or a substituted 5- or 6-membered aromatic heterocyclic ring, wherein the heterocyclic ring is substituted with at least 1-2 hetero atoms selected from N, O, and S (αor β).
2. A compound as recited in claim 1 , where E is selected from a substituted aryl or a 5- and 6-membered aromatic heterocyclic rings
3. A compound as recited in claim 2 , wherein the optional substituents include 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 the following organic residues
5. The compound of formula (I) as recited in claim 1 , which is selected from the following group of compounds:
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 .
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)