Tricyclic oxazolidinone antibiotic compounds

Patent metadata

Field	Value
Publication number	US-9822114-B2
Application number	US-201615135352-A
Country	US
Kind code	B2
Filing date	Apr 21, 2016
Priority date	Oct 7, 2008
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

The invention relates to compounds of formula I

wherein is a bond or is absent, V is CH, CR 6 or N; R 0 is H or, if is a bond, may also be alkoxy; R 1 is H or halogen; U is CH or N when is a bond, or, if is absent, U is CH 2 , NH or NR 9 ; R 2 is H, alkylcarbonyl or —CH 2 —R 3 ; R 3 is H, alkyl or hydroxyalkyl; R 4 is H or, if n is not 0 and R 5 is H, may also be OH; R 5 is H, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, carboxy or alkoxycarbonyl; R 6 is hydroxyalkyl, carboxy, alkoxycarbonyl or —(CH 2 ) q —NR 7 R 8 , q being 1, 2 or 3 and each of R 7 and R 8 independently being H or alkyl or R 7 and R 8 forming with the N atom bearing them a ring; R 9 is alkyl or hydroxyalkyl; A is —(CH 2 ) p —, —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—; G is substituted phenyl or G 1 or G 2

wherein Q is O or S and X is CH or N; and Y 1 , Y 2 and Y 3 may each be CH or N; and n is 0 when A is —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—, and n is 0, 1 or 2 when A is —(CH 2 ) p —, p being 1, 2, 3 or 4, with the proviso that the sum of n and p is then 2, 3 or 4; and to salts thereof.

First claim

The invention claimed is:

1. A compound of formula I

wherein
“- - - - -” is a bond or is absent;

R 0 represents H or, in the case “- - - - -” is a bond, may also represent (C 1 -C 3 )alkoxy;
R 1 represents H or halogen;
U represents CH or N when “- - - - -” is a bond, or, in case “- - - - -” is absent, U represents CH 2 , NH or NR 9 ;
V represents CH, CR 6 or N;

R 2 represents H, (C 1 -C 3 )alkylcarbonyl or a group of the formula CH 2 —R 3 ;
R 3 represents H, (C 1 -C 3 )alkyl or (C 1 -C 3 )hydroxyalkyl;
R 4 represents H or, in the cases wherein n is not 0 and R 5 is H, may also represent OH;
R 5 represents H, (C 1 -C 3 )alkyl, (C 1 -C 3 )hydroxyalkyl, (C 1 -C 3 )aminoalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, carboxy or (C 1 -C 3 )alkoxycarbonyl;
R 6 represents (C 1 -C 3 )hydroxyalkyl, carboxy, (C 1 -C 3 )alkoxycarbonyl or a group —(CH 2 ) q —NR 7 R 8 wherein q is 1, 2 or 3 and each of R 7 and R 8 independently represents H or (C 1 -C 3 )alkyl or R 7 and R 8 form together with the nitrogen atom bearing them a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring;
R 9 represents (C 1 -C 3 )alkyl, 2-hydroxy-ethyl, 2-hydroxy-propyl or 3-hydroxy-propyl;
A represents —(CH 2 ) p —, —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—;
G represents a phenyl group which is substituted once or twice in the meta and/or para position(s) by substituents selected independently from (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy and a halogen, or G is a group having one of the formulae G 1 and G 2 below

wherein
Q is O or S and X is CH or N; and
Y 1 , Y 2 and Y 3 each represent CH, or Y 1 and Y 3 each represent CH and Y 2 represents N, or Y 1 represents N, Y 2 represents CH or N and Y 3 represents CH, or Y 1 and Y 2 each represent CH and Y 3 represents N; and
n is 0 when A represents —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—, and n is 0, 1 or 2 when A represents (CH 2 ) p , p being 1, 2, 3 or 4, with the proviso that the sum of n and p is then 2, 3 or 4;
or a salt of such a compound.

2. The compound of formula I according to claim 1 , which is also a compound of formula I P3

wherein
“- - - - -” is a bond or is absent;

R 0 represents H or, in the case “- - - - -” is a bond, may also represent (C 1 -C 3 )alkoxy;
R 1 represents H or halogen;
U represents CH or N when “- - - - -” is a bond, or, in case “- - - - -” is absent, U represents CH 2 or NH;
V represents CH, CR 6 or N;

R 2 represents H, (C 1 -C 3 )alkylcarbonyl or a group of the formula —CH 2 —R 3 ;
R 3 represents H, (C 1 -C 3 )alkyl or (C 1 -C 3 )hydroxyalkyl;
R 4 represents H or, in the cases wherein n is not 0 and R 5 is H, may also represent OH;
R 5 represents H, (C 1 -C 3 )alkyl, (C 1 -C 3 )hydroxyalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxycarbonyl;
R 6 represents (C 1 -C 3 )hydroxyalkyl, carboxy, (C 1 -C 3 )alkoxycarbonyl or a group —(CH 2 ) q —NR 7 R 8 wherein q is 1, 2 or 3 and each of R 7 and R 8 independently represents H or (C 1 -C 3 )alkyl or R 7 and R 8 form together with the nitrogen atom bearing them a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring;
A represents —(CH 2 ) p —, —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—;
G represents a phenyl group which is substituted once or twice in the meta and/or para position(s) by substituents selected independently from (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy and a halogen, or G is a group having one of the formulae G 1 and G 2 below

wherein
Q is O or S and X is CH or N; and
Y 1 , Y 2 and Y 3 each represent CH, or Y 1 and Y 3 each represent CH and Y 2 represents N, or Y 1 represents N, Y 2 represents CH or N and Y 3 represents CH, or Y 1 and Y 2 each represent CH and Y 3 represents N; and
n is 0 when A represents —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—, and n is 0, 1 or 2 when A represents (CH 2 ) p , p being 1, 2, 3 or 4, with the proviso that the sum of n and p is then 2, 3 or 4;
or a salt of such a compound.

3. The compound of formula I according to claim 1 , which is also a compound of formula I P2

wherein
“- - - - -” is a bond or is absent;

R 0 represents H or, in the case “- - - - -” is a bond, may also represent (C 1 -C 3 )alkoxy;
R 1 represents H or halogen;
U represents CH or N, or, in case “- - - - -” is absent, U represents CH 2 or NH;
V represents CH or N;

R 2 represents H or a group of the formula —CH 2 —R 3 , R 3 being H, (C 1 -C 3 )alkyl or (C 1 -C 3 )hydroxyalkyl;
A represents —(CH 2 ) p —, —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—;
G represents a phenyl group which is substituted once or twice in the meta and/or para position(s) by substituents selected independently from (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy and a halogen, or G is a group having one of the formulae G 1 and G 2 below

wherein
Q is O or S and X is CH or N; and
Y 1 , Y 2 and Y 3 each represent CH, or Y 1 and Y 3 each represent CH and Y 2 represents N, or Y 1 represents N, Y 2 represents CH or N and Y 3 represents CH, or Y 1 and Y 2 each represent CH and Y 3 represents N; and
n is 0 when A represents —CH 2 CH 2 CH(OH)— or —COCH 2 CH(OH)—, and n is 0, 1 or 2 when A represents (CH 2 ) p , p being 1, 2, 3 or 4, with the proviso that the sum of n and p is then 2, 3 or 4;
or a salt of such a compound.

4. The compound of formula I according to claim 1 , which is also a compound of formula I P1

wherein
“- - - - -” is a bond or is absent;
R 1 represents H or halogen;
V represents CH or N;
U represents CH or N, or, in case “- - - - -” is absent, U represents CH 2 or NH;

G represents a phenyl group which is substituted once or twice in the meta and/or para position(s) by substituents selected independently from (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy and a halogen, or G is a group having one of the formulae G 1 and G 2 below

wherein
Q is O or S and X is CH or N; and
Y 1 , Y 2 and Y 3 each represent CH, or Y 1 and Y 3 each represent CH and Y 2 represents N, or Y 1 represents N, Y 2 represents CH or N and Y 3 represents CH, or Y 1 and Y 2 each represent CH and Y 3 represents N; and
n is 0, 1 or 2 and p is 1, 2 or 3, with the proviso that the sum of n and p is either 2 or 3;
or a salt of such a compound.

5. The compound of formula I according to claim 1 , which is also a compound of formula I CE

wherein
“- - - - -” is a bond, V represents CH and U represents CH or N, or “- - - - -” is a bond, V represents CR 6 and U represents CH, or also “- - - - -” is a bond, V represents N an

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Hubschwerlen Christian
• Ritz Daniel
• Rueedi Georg
• Surivet Jean-Philippe
• Zumbrunn-Acklin Cornelia

Classifications

• A61P31/00

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

• A61P31/04

  Antibacterial agents · CPC title

• C07D471/06 Primary

  Peri-condensed systems · CPC title

• C07D471/16 Primary

  Peri-condensed systems · 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