Antimicrobial agents

Patent metadata

Field	Value
Publication number	US-9227966-B2
Application number	US-201414186516-A
Country	US
Kind code	B2
Filing date	Feb 21, 2014
Priority date	Apr 30, 2009
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The invention provides a compound of formula I:

or a salt or prodrug thereof, wherein Y, W, Z, Z 1 , Z 2 , Z 3 , Z 4 , and R 1 -R 12 have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful as antibacterial agents.

First claim

What is claimed is:

1. A compound of formula I:

wherein:
the dashed line between Y and W represents a single or double bond;
when Y is —CR 2 —, Z is —(CR 13 2 ) 2 — or —CR 14 ═CR 14 — and R 12 is a bond; W is N or (NR a ) + X − ;
when Y is —C═, Z is —(CR 13 2 ) 2 — or —CR 14 ═CR 14 — and R 12 is a bond; W is N + X − ; or
X − is a pharmaceutically suitable counterion;
Z 1 , Z 2 , Z 3 and Z 4 are each independently O, S or NR e ; or R 8 —Z 1 —, R 9 —Z 2 —, R 10 —Z 3 —, and R 11 —Z 4 — can each independently be H, optionally substituted aryl or optionally substituted heteroaryl;
R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryloxy or arylthio; and R 2 is H or (C 1 -C 6 )alkyl, wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkylthio of R 1 and R 2 is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i , and wherein any aryloxy, or arylthio of R 1 and R 2 is optionally substituted with one or more groups selected from halo, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i ;
at least one of R 3 , R 4 , R 5 , R 6 and R 7 is aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkanoyl or heteroaryl(C 1 -C 6 )alkanoyl and the remainder of R 3 , R 4 , R 5 , R 6 and R 7 are independently H, halo, nitro, sulfo, —S(O) 2 NR n R p , —N(R n )S(O) 2 R p , —NR h R i optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 3 is —Z 13 R 13′ wherein Z 13 is O, S or NR e and R 13′ is (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl or —C(═O)NR f R g or R 13′ and R 9 together with the atoms to which they are attached form a 5 to 7 membered ring; or R 6 and R 7 together with the atoms to which they are attached form a 5 to 6 membered heterocycle wherein the heterocycle is optionally fused with an optionally substituted aryl;
R 8 and R 9 are each independently, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl or —C(═O)NR f R g or R 8 and R 9 together with the atoms to which they are attached form a 5 to 7 membered ring; or R 8 —Z 1 — and R 9 —Z 2 — can each independently be H;
R 10 and R 11 are each independently, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl or —C(═O)NR f R g or R 10 and R 11 together with the atoms to which they are attached form a 5 to 7 membered ring; or R 10 —Z 3 —, and R 11 —Z 4 — can each independently be H;
each R 13 is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryloxy or arylthio wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkylthio of R 13 is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i , and wherein any aryloxy, or arylthio of R 13 is optionally substituted with one or more groups selected from halo, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i ;
each R 14 is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryloxy or arylthio wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkylthio of R 14 is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i , and wherein any aryloxy, or arylthio of R 14 is optionally substituted with one or more groups selected from halo, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i ;
R a is (C 1 -C 6 )alkyl wherein (C 1 -C 6 )alkyl is optionally substituted with one or more groups independently selected from halo, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i ;
each R e is independently H or (C 1 -C 6 )alkyl wherein (C 1 -C 6 )alkyl is optionally substituted with one or more halo;
R f and R g are each independently H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 ) alkyl or heteroaryl(C 1 -C 6 ) alkyl; or R f and R g together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino;
R h and R i are each independently H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 ) alkyl or heteroaryl(C 1 -C 6 ) alkyl; or R h and R i together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and
wherein R n and R p may be the same or different and are chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
or a salt or prodrug thereof, which is a compound of the following formula:

or a salt thereof.

2. A compound of formula I:

wherein:
the dashed line between Y and W represents a single or double bond;
when Y is —CR 2 —, Z is —(CR 13 2 ) 2 — or —CR 14 ═CR 14 — and R 12 is a bond; W is N or (NR a ) + X − ;
when Y is —C═, Z is —(CR 13 2 ) 2 — or —CR 14 ═CR 14 — and R 12 is a bond; W is N + X − ; or
X − is a pharmaceutically suitable counterion;

Z 1 , Z 2 , Z 3 and Z 4 are each independently O, S or NR e ; or R 8 —Z 1 —, R 9 —Z 2 —, R 10 —Z 3 —, and R 11 —Z 4 — can each independently be H, optionally substituted aryl or optionally substituted heteroaryl;
R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryloxy or arylthio; and R 2 is H or (C 1 -C 6 )alkyl, wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkylthio of R 1 and R 2 is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i , and wherein any aryloxy, or arylthio of R 1 and R 2 is optionally substituted with one or more groups selected from halo, cyano, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, carboxy, NO 2 , hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR h R i ;
at least one of R 3 , R 4 , R 5 , R 6 and R 7 is aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkanoyl or heteroaryl(C 1 -C 6 )alkanoyl and the remainder of R 3 , R 4 , R 5 , R 6 and R 7 are independently H, halo, nitro, sulfo, —S(O) 2 NR n R p , —N(R n )S(O) 2 R p , —NR h R i optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, or optionally substituted

Assignees

• Univ Rutgers

Inventors

• Lavoie Edmond J
• Pilch Daniel S
• Parhi Ajit
• Kaul Malvika

Classifications

• C07D455/03 Primary

  containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine · CPC title

• C07D217/02

  with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines · CPC title

• C07D217/10

  Quaternary compounds · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D217/12

  with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring · CPC title