Claims for Patent: 9,238,657

Summary for Patent: 9,238,657

Title:	Cephalosporin having catechol group
Abstract:	The present disclosure describes Cephem compounds of the formula: wherein, X is N, CH or C—Cl; T is S or the like; A and G are lower alkylene or the like; B is a single bond or the like; D is optionally present, and when present is, —NR7—, —CO—, —CO—NR7—, —NR7—CO—, —NR7—CO—NR7—, or the like; F is optionally present, and when present is or phenylene; R3 and R4 are —OR8; R5 and R6 each is independently hydrogen, halogen, nitrile, or —OR8; or an ester at the carboxyl at the 7-position side chain or at the 4-position, a compound protected at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof, which have a wide antimicrobial spectrum and have potent antimicrobial activity against beta-lactamase producing Gram negative bacteria.
Inventor(s):	Yasuhiro Nishitani, Kenji Yamawaki, Yusuke Takeoka, Hideki Sugimoto, Shinya Hisakawa, Toshiaki Aoki
Assignee:	Shionogi and Co Ltd
Application Number:	US13/063,878
Patent Claims:	1. A compound of the formula: wherein, X is N, CH or C—Cl; T is S, S═O, CH2 or O; A is lower alkylene, lower alkenylene or lower alkynylene; G is optionally present, and when present is, —CH2—CH(CH3)—, —CH2—CH(iPr)—, lower alkylene optionally substituted with a carbocyclic group, lower alkenylene, or lower alkynylene; B is optionally present, and when present B is a 5- or 6-membered heterocyclic group containing at least 1 N atom(s); D is optionally present, and when present D is, —CO—, —O—CO—, —CO—O—, —NR7—, —NR7—CO—, —CO—NR7—, —NR7—CO—NR7—, —O—, —S—, —SO—, —SO2—NR7—, —NR7—SO2—, —CH2—NR7—CO— or —SO2—; E is of the formula: wherein R1 and R2 are each independently hydrogen, halogen, lower alkyl optionally substituted with carbamoyl, lower alkylthio, or phenyl, R11 and R12 are each independently hydrogen, lower alkyl optionally substituted with carbamoyl or carboxyl, carboxyl, or a carbamoyl, and m refers to an integer of 1 to 5; F is optionally present, and when present F is phenylene; R3 and R4 are —OR8; R5 and R6 each is independently hydrogen, halogen, nitrile, or —OR8; R7 each is independently hydrogen or lower alkyl; R8 each is independently hydrogen, lower alkyl, halo(lower)alkyl, lower alkylcarbonyl or carbamoyl; the formula: is an optionally substituted, saturated or unsaturated, monocyclic or condensed cyclic quaternary ammonium group containing one or more N atom(s); wherein the substituents are at least one selected from the group consisting of halogen, hydroxy, lower alkyl, halo(lower)alkyl, lower alkoxy, and halo(lower)alkoxy; the broken line represents the presence or absence of a bond between the cationic N atom and a ring-forming atom; provided that when G bonds to the cationic N atom, the broken line is absent; when G does not bond to the cationic N atom, the broken line represents a single bond between the cationic N atom and a neighboring atom or represents lower alkylene between the cationic N atom and a ring-forming atom other than the neighboring atom; and when G and B are not present, and D is —NH—CO— or —S—, then a group of the formula: is not a group of the formula: wherein a hydrogen atom(s) on the quaternary ring is(are) optionally substituted; or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof. 2. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein said formula is the following formula: wherein n is an integer from 0 to 5, k is an integer from 0 to 5, q is an integer from 0 to 3, R10 is halogen, hydroxy, lower alkyl, halo(lower)alkyl, lower alkoxy, or halo(lower)alkoxy, provided that R10 may be identical or different at k or q occurrences, and A and G are as defined in claim 1. 3. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein said formula is the formula: wherein n, k, q and R10 are as defined in claim 2, and A and G are as defined in claim 1. 4. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein the formula is the formula: wherein R5, R6 and R8 are as defined in claim 1. 5. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein the formula: is the formula 6. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein A is —CH2—, —CH2—CH2—, —CH2—CH2—CH2—CH═CH—, —CH═CH—CH2— or —CH2—CH═CH—. 7. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein G is optionally present, and when present is —CH═CH—, —CH═CH—CH2—, —CH2—CH═CH—, —CH2—CH(CH3)—, —CH2—CH(iPr)— or —CH2—CH(Ph)-, wherein iPr refers to isopropyl group, and Ph refers to a phenyl group. 8. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein B is optionally present, and when present is the formula: 9. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein D is absent, —CO—, —O—CO—, —CO—O—, —NR7—, —NR7—CO—NR7—, —NR7—CO— or —CO—NR7—, wherein R7 is as defined in claim 1. 10. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein D is optionally present, and when present is —CO—, —NR7—CO—NR7—, —NR7—CO— or —CO—NR7—, wherein R7 is as defined in claim 1. 11. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein R8 is hydrogen or a lower alkyl. 12. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein X is N. 13. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein X is CH or C—Cl. 14. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein T is S. 15. The compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein X is N, CH or C—Cl; T is S; A is a lower alkylene; G is optionally present, and when present is a lower alkylene; the formula: is the formula: B is absent; n is an integer of 0-3; D is —NH—CO— or —CO—NH—; E is the formula: wherein Me refers to a methyl group; F is absent; R3 and R4 are —OH, and R5 is hydrogen or Cl, and R6 is hydrogen. 16. A pharmaceutical composition comprising the compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1. 17. The pharmaceutical composition according to claim 16, which has an antimicrobial activity. 18. The compound according to claim 1, which is selected from the group consisting of: or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof. 19. The compound according to claim 1, which is of the formula: or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof. 20. The compound according to claim 1, which is of the formula: or a pharmaceutically acceptable salt, or a solvate thereof. 21. A method for treating a bacterial infection, comprising administering to a subject in need thereof the compound, or an ester at the carboxyl at the 7-position side chain or at the 4-position, a protected compound at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1.