Cephem compound having catechol or pseudo-catechol structure

Patent metadata

Field	Value
Publication number	US-9334289-B2
Application number	US-201214113459-A
Country	US
Kind code	B2
Filing date	Apr 25, 2012
Priority date	Apr 28, 2011
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

The present invention provides a novel compound which has a wide antimicrobial spectrum, and in particular exhibits potent antimicrobial activity against beta-lactamase producing Gram negative bacteria. Specifically, the present invention provides a compound of the formula (I):

wherein each symbol is as defined in the specification, or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.

First claim

The invention claimed is:

1. A compound of the formula:

or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof,
wherein
W is —CH 2 —, —S— or —O—;
a) U is —CH 2 —, —S—, —S(═O)— or —O— when W is —CH 2 —; or
b) U is —CH 2 — when W is —S— or —O—;
L is —CH 2 —, —CH═CH—, —CH 2 —CH═CH— or —CH═CH—CH 2 —;
R 1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
with regard to R 2A and R 2B ,
a) R 2A is a hydrogen atom, a substituted or unsubstituted amino group, —SO 3 H, a substituted or unsubstituted amino sulfonyl group, carboxyl group, a substituted or unsubstituted (lower alkyl)oxycarbonyl group, a substituted or unsubstituted carbamoyl group, hydroxyl group, or a substituted carbonyloxy group; and R 2B is a hydrogen atom, or
b) R 2A and R 2B are taken together to form a substituted or unsubstituted methylidene group or a substituted or unsubstituted hydroxyimino group;
R 3 is a hydrogen atom, —OCH 3 or —NH—CH(═O);
R 11 is

E is a group selected from the following formulae which are substituted or unsubstituted on the ring:

wherein the bond to the quaternary nitrogen atom binds to L, and the other bond binds to R 10 ; p is an integer from 1 to 3; n is an integer of 1 or 2; R X is an optionally substituted lower alkyl group;
R 10 is R 12 or a group represented by the formula:

wherein ring A is a benzene ring, or a 6-membered aromatic heterocyclic group having 1-3 nitrogen atoms;
k is an integer from 2 to 5;
each R 4 is independently a hydrogen atom, halogen, hydroxyl group, —CN, —C(═O)—R 5 , —C(═O)—OH, —C(═O)—OR 5 , or —OR 5 ;
R 5 is a lower alkyl group or halo(lower)alkyl group; and
G is a single bond, a substituted or unsubstituted lower alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;
B is a single bond or a 5- or 6-membered heterocyclic group containing at least 1-3 nitrogen atoms;
D is a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR 6 —, —NR 6 —C(═O)—, —C(═O)—NR 6 —, —NR 6 —C(═O)—NR 6 —, —O—, —S—, —S(═O)—, —S(═O) 2 —NR 6 —, —NR 6 —S(═O) 2 —, —NR 6 —CH 2 —, —CH 2 —NR 6 — or —S(═O) 2 —;
each R 6 is independently a hydrogen atom or a substituted or unsubstituted lower alkyl group;
R 12 is a hydrogen atom, halogen, hydroxyl group, —SO 3 H, a substituted or unsubstituted amino group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted amino sulfonyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.

2. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 10 is a group represented by the formula:

3. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 10 is R 12 wherein R 12 is as defined in claim 1 .

4. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein G is a single bond, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —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 i Pr is isopropyl group and Ph is phenyl group.

5. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein B is a single bond or a group represented by the formula:

wherein the bond of the left side is attached to G and the bond of the right side is attached to D.

6. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein D is a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR 6 —, —NR 6 —C(═O)—NR 6 —, —NR 6 —C(═O)— or —C(═O)—NR 6 — wherein R 6 is as defined in claim 1 .

7. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the formula:

wherein each R 4 is independently hydrogen, halogen, hydroxyl group, —CN, —C(═O)—R 5 , C(═O)—OH, —C(═O)—OR 5 or —OR 5 ; and R 5 is as defined in claim 1 .

8. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 7 , wherein the formula:

9. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 7 , wherein the formula:

10. The compound or an amino-protected compound when the amino group is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein E is selected from the group consisting of the formulae (1) to (7), (10) to (12), (14), (25) to (29), (31), (42) to (44), (47), (50), (52), (53), (64) and (73).

11. The compound or an amino-protected compound

Assignees

• Nishitani Yasuhiro
• Aoki Toshiaki
• Sato Jun
• Yamawaki Kenji
• Yokoo Katsuki
• Sano Masayuki
• Shionogi & Co

Inventors

• Nishitani Yasuhiro
• Aoki Toshiaki
• Sato Jun
• Yamawaki Kenji
• Yokoo Katsuki
• Sano Masayuki

Classifications

• C07D501/46 Primary

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

• C07D501/18

  7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids · 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

• C07D501/60 Primary

  with a double bond between positions 3 and 4 · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title