Cephalosporin having catechol group

Patent metadata

Field	Value
Publication number	US-9238657-B2
Application number	US-200913063878-A
Country	US
Kind code	B2
Filing date	Oct 27, 2009
Priority date	Oct 31, 2008
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

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.

First claim

The invention claimed is:

1. A compound of the formula:

wherein,
X is N, CH or C—Cl;
T is S, S═O, CH 2 or O;
A is lower alkylene, lower alkenylene or lower alkynylene;
G is optionally present, and when present is, —CH 2 —CH(CH 3 )—, —CH 2 —CH( i Pr)—, 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—, —NR 7 —, —NR 7 —CO—, —CO—NR 7 —, —NR 7 —CO—NR 7 —, —O—, —S—, —SO—, —SO 2 —NR 7 —, —NR 7 —SO 2 —, —CH 2 —NR 7 —CO— or —SO 2 —;
E is of the formula:

wherein R 1 and R 2 are each independently hydrogen, halogen, lower alkyl optionally substituted with carbamoyl, lower alkylthio, or phenyl, R 11 and R 12 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;
R 3 and R 4 are —OR 8 ;
R 5 and R 6 each is independently hydrogen, halogen, nitrile, or —OR 8 ;
R 7 each is independently hydrogen or lower alkyl;
R 8 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, R 10 is halogen, hydroxy, lower alkyl, halo(lower)alkyl, lower alkoxy, or halo(lower)alkoxy, provided that R 10 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 R 10 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 R 5 , R 6 and R 8 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 —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH═CH—, —CH═CH—CH 2 — or —CH 2 —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—CH 2 —, —CH 2 —CH═CH—, —CH 2 —CH(CH 3 )—, —CH 2 —CH( i Pr)— or —CH 2 —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—, —NR 7 —, —NR 7 —CO—NR 7 —, —NR 7 —CO— or —CO—NR 7 —, wherein R 7 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—, —NR 7 —CO—NR 7 —, —NR 7 —CO— or —CO—NR 7 —, wherein R 7 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

Assignees

• Nishitani Yasuhiro
• Yamawaki Kenji
• Takeoka Yusuke
• Sugimoto Hideki
• Hisakawa Shinya
• Aoki Toshiaki
• Shionogi & Co

Inventors

• Nishitani Yasuhiro
• Yamawaki Kenji
• Takeoka Yusuke
• Sugimoto Hideki
• Hisakawa Shinya
• Aoki Toshiaki

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D505/24

  further substituted by doubly-bound nitrogen atoms · CPC title

• C07D519/06

  containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system · CPC title

• C07D501/46 Primary

  with the 7-amino radical acylated by carboxylic acids containing hetero rings · CPC title