Antibacterial compounds

Patent metadata

Field	Value
Publication number	US-9340556-B2
Application number	US-201214349754-A
Country	US
Kind code	B2
Filing date	Oct 4, 2012
Priority date	Oct 4, 2011
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

The present invention relates to cephalosporin antibacterial compounds of Formula (I):

or corresponding pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, compound preparation and treatment methods for bacterial infections, especially those caused by gram-negative bacteria.

First claim

What is claimed is:

1. A compound of Formula (II):

wherein:
X is N, or C—R a ;
R 1 and R 2 each are hydrogen, (C 1-6 )alkyl, or (CH 2 )p—C(O)OR b ;
R 3 and R 4 each are hydrogen, OH or OR c ;
wherein:
R a is hydrogen or halogen;
R b or R c each is H, (C 1-6 )-alkyl, an alkali metal or negative charge;

A is R 5 or —NR d C(O)R 5
wherein R d is H or (C 1-6 )-alkyl

R 5 is an optionally saturated or unsaturated monocyclic heterocyclic ring or an optionally saturated or unsaturated bi-cyclic or fused heterocyclic ring;
wherein:
each monocyclic heterocyclic ring has from 3 to 7 ring atoms and contains up to four heteroatoms;
each fused heterocyclic ring optionally includes carbocyclic rings or heterocyclic rings of up to four heteroatoms;
R 5 optionally is substituted by one or more of the following substituents selected from —H, —OH, Oxo (═O), —CN, —NO 2 , -halogen, -straight or branched C 1-6 alkyl, -straight or branched C 1-6 haloalkyl, C 3-6 -cycloalkyl, -straight or branched C 1-6 straight or branched alkoxy, —OC(O)OH, —OC(O)R e , —C(O)OR f , —O(CH 2 ) y OR g , —NR h R i , —SO 2 R j , —S(CH 2 ) q R k , —NR l C(O)R m , aryl or heteroaryl;
wherein:
hetero atoms are selected from oxygen, nitrogen or sulphur,
carbocyclic rings or heterocyclic rings for each fused heterocyclic ring systems include non-aromatic rings or aromatic rings;
monocyclic heterocyclic rings or fused heterocyclic rings include substituted aromatic and non-aromatics;
each R e , R f , R g , R h , R i , R j , R k , R l , or R m each is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;
each aryl or heteroaryl as defined above is optionally substituted with one or more of the following substituents selected from H, —OH, —CN, —NO 2 , -halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, —OC(O)OH, —OC(O)R n , —C(O)OR o , —O(CH 2 ) y— OR p , —NR q R r , —SO 2 R s , —S(CH 2 ) y —R t , —NR u C(O)R v ;
wherein:
 R n , R o , R p , R q , R r , R s , R t , R u , or R v each are selected from C 1-6 alkyl, C 1-6 -haloalkyl, or C 1-6 -alkoxy;

n, m, o, p, q or y each are 0 or an integer from 1 to 5; or
a pharmaceutically acceptable salt thereof.

2. The compound of Formula (III) according to claim 1 :

wherein:
X is N, or C—R a ;
R 1 and R 2 each are hydrogen, (C 1-6 )alkyl, or (CH 2 )p—C(O)OR b ;
R 3 and R 4 each are hydrogen, OH or OR c ;
wherein:
R a is hydrogen or halogen;
R b or R c each is H, (C 1-6 )-alkyl, an alkali metal or negative charge;

A is R 5 or —NR d C(O)R 5
wherein:
R d is H or (C 1-6 )-alkyl

R 5 is a monocyclic 3 to 7 membered heterocyclic ring or a bicyclic 10 membered heterocyclic ring;
wherein:
each 3 to 7 membered heterocyclic ring contains up to four heteroatoms or
each bicyclic 10 membered heterocyclic ring contains up to four heteroatoms;
wherein:
 hetero atoms are selected from oxygen, nitrogen or sulphur;
 carbocyclic rings or heterocyclic rings for each 10 membered heterocyclic ring systems contain non-aromatic rings or aromatic rings;

R 5 optionally is substituted by one or more of the following substituents selected from —H, —OH, Oxo (═O), —CN, —NO 2 , -halogen, -straight or branched C 1-6 alkyl, -straight or branched C 1-6 haloalkyl, C 3-6 -cycloalkyl, -straight or branched C 1-6 straight or branched alkoxy, —OC(O)OH, —OC(O)R e , —C(O)OR f , —O(CH 2 ) y OR g , —NR h R i , —SO 2 R j , —S(CH 2 ) q R k , —NR l C(O)R m , aryl or heteroaryl;
wherein:
each R e , R f , R g , R h , R i , R j , R k , R l , or R m as defined above is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;
each aryl or heteroaryl as defined above is optionally substituted with one or more of the following substituents selected from H, —OH, —CN, —NO 2 , -halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, —OC(O)OH, —OC(O)R n , —C(O)OR o , —O(CH 2 ) y— OR p , —NR q R r , —SO 2 R s , —S(CH 2 ) y— R t , —NR u C(O)R v ;
wherein:
 R n , R o , R p , R q , R r , R s , R t , R u , or R v each as defined above are selected from C 1-6 alkyl, C 1-6 -haloalkyl, or C 1-6 -alkoxy;

n, m, o, p, q or y each are 0 or an integer from 1 to 5; or
a pharmaceutically acceptable salt thereof.

3. The compound of Formula (IV):

wherein:
X is C—R a ;
R 1 and R 2 each are hydrogen, (C 1-6 )alkyl, or (CH 2 )p-C(O)OR b ;
R 3 and R 4 each are hydrogen, OH or OR c ;
wherein:
R a is hydrogen or halogen;
R b or R c each is H, (C 1-6 )-alkyl, an alkali metal or negative charge;

A is R 5 or —NR d C(O)R 5
wherein R d is H or (C 1-6 )-alkyl;

R 5 is an optionally saturated or unsaturated monocyclic heterocyclic ring or an optionally saturated or unsaturated bi-cyclic or fused heterocyclic ring;
wherein:
each monocyclic heterocyclic ring has from 3 to 7 ring atoms and contains up to four heteroatoms;
each fused heterocyclic ring optionally includes carbocyclic rings or
heterocyclic rings of up 4 heteroatoms;
R5 optionally is substituted by one or more of the following substituents selected from —H, —OH, Oxo (═O), —CN, —NO 2 , -halogen, -straight or branched C 1-6 alkyl, -straight or branched C 1-6 haloalkyl, C 3-6 cycloalkyl, -straight or branched C 1-6 straight or branched alkoxy, —OC(O)OH, —OC(O)R e , —C(O)OR f , —O(CH 2 ) y OR g , —NR h R i , —SO 2 R j , —S(CH 2 ) q R k , —NR l C(O)R m , aryl or heteroaryl;
wherein:
hetero atoms are selected from oxygen, nitrogen or sulphur,
carbocyclic rings or heterocyclic rings for each fused heterocyclic ring systems include non-aromatic rings or aromatic rings;
monocyclic heterocyclic rings or fused heterocyclic rings include substituted aromatic and non-aromatics;
each R e , R f , R g , R h , R i , R j , R k , R l , or R m each is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;
each aryl or heteroaryl as defined above is optionally substituted with one or more of the following substituents selected from H, —OH, —CN, —NO 2 , -halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, —OC(O)OH, —OC(O)R n , —C(O)OR o , —O(CH 2 ) y— OR p , —NR q R r , —SO 2 R s , —S(CH 2 ) y— R t , —NR u C(O)R v ;
wherein:
 R n , R o , R p , R q , R r , R s , R t , R u , or R v each are selected from C 1-6 alkyl, C 1-6 -haloalkyl, or C 1-6 -alkoxy;

n, m, o, p, q or y each are 0 or an integer from 1 to 5; or
a pharmaceutically acceptable salt thereof.

4. The compound of Formula (IV) according to claim 3 , wherein X is C—R a and R a is hydrogen.

5. The compound of Formula (V) according to claim 2 :

wherein:
X is C—R a ;
R 1 and R 2 each are hydrogen, (C 1-6 )alkyl, or (CH 2 )p—C(O)OR b ;
R 3 and R 4 each are hydrogen, OH or OR c ;
wherein:
R a is hydrogen or halogen;
R b or R c each is H, (C 1-6 )-alkyl, an alkali metal or negative charge;

A is R 5 or —NR d C(O)R 5
wherein:
R d is H or (C 1-6 )-alkyl

R 5 is a monocyclic 3 to 7 membered heterocyclic ring or a bicyclic 10 membered heterocyclic ring;
wherein:
each 3 to 7 membered heterocyclic ring contains up to four heteroatoms;
each bicyclic 10 membered heterocyclic ring contains up to four heteroatoms;
wherein:
each heteroatom is se

Assignees

• Glaxo Group Ltd
• Shionogi & Co

Inventors

• Liao Xiangmin
• Pearson Neil David
• Pendrak Israil
• Sano Masayuki

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

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

• C07D501/60 Primary

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

• C07D501/56 Primary

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