Antibacterial quinoline derivatives

Patent metadata

Field	Value
Publication number	US-9617244-B2
Application number	US-201314391034-A
Country	US
Kind code	B2
Filing date	Apr 26, 2013
Priority date	Apr 27, 2012
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The present invention relates to novel substituted quinoline derivatives according to the general Formula (Ia) or Formula (Ib):

including any stereochemically isomeric form thereof, a pharmaceutically acceptable salt thereof, a N-oxide form thereof or a solvate thereof.

The claimed compounds are useful for the treatment of a bacterial infection. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of a bacterial infection and a process for preparing the claimed compounds.

First claim

The invention claimed is:

1. A compound of formula (Ia) or (Ib):

including any stereochemically isomeric form thereof, wherein
p is an integer equal to 1, 2, 3 or 4;
n is an integer equal to 1 or 2; provided that if n is 2 then both R 5 substituents are linked to the same carbon atom of the piperidine moiety;
R 1 is hydrogen, cyano, cyanoC 1-6 alkyl, formyl, carboxyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, polyhaloC 1-6 alkyl, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylthio, C 1-6 alkylthioC 1-6 alkyl, —C═N—OR 11 , amino, mono or di(C 1-6 alkyl)amino, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, R 9b R 10b N—C(═O)—, arylC 1-6 alkyl, arylcarbonyl, R 9a R 10a N—C 1-6 alkyl, di(aryl)C 1-6 alkyl, aryl, C 3-6 cycloalkyl, R 9a R 10a N—, R 9a R 10a N—C(O)—,
C 1-4 alkyl-S(═O) 2 —, or Het;

R 2 is hydrogen, C 1-6 alkyloxy, aryl, aryloxy, hydroxy, mercapto, C 1-6 alkyloxyC 1-6 alkyloxy, C 1-6 alkylthio, mono or di(C 1-6 alkyl)amino, amino, pyrrolidino or a radical of formula

wherein Y is CH 2 , O, S, NH or N—C 1-6 alkyl;
R 3 is hydrogen, halo, C 1-6 alkyl, aryl or Het;
is aryl 1 or Het;

R 5 is aryl, arylC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, Het, HetC 1-6 alkyl, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-6 alkyl, aryl-NH—C 1-6 alkyl, Het-NH—C 1-6 alkyl, C 2-6 alkenyl or halo;
R 6 is hydrogen, C 1-6 alkyl, arylC 1-6 alkyl, Het 1 , Het 1 C 1-6 alkyl or —C(═NH)—NH 2 ;
R 7 is hydrogen or C 1-6 alkyl;
R 8 is oxo; or
R 7 and R 8 together form the radical CH═CH—N═;
R 9a and R 10a together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 4-thiomorpholinyl, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical being optionally substituted with 1, 2, 3 or 4 substituents, each substituent being independently selected from C 1-6 alkyl, polyhaloC 1-6 alkyl, halo, arylC 1-6 alkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylthio, C 1-6 alkylthioC 1-6 alkyl, aryl, pyridyl or pyrimidinyl;
R 9b and R 10b each independently represent hydrogen, C 1-6 alkyl, aryl or Het;
R 11 is hydrogen or C 1-6 alkyl;
aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each being optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydroxy, hydroxyC 1-6 alkyl, halo, cyano, cyanoC 1-6 alkyl, nitro, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, C 2-6 alkenyl optionally substituted with phenyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyl, polyhaloC 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or di(C 1-6 alkyl)aminocarbonyl;
aryl 1 is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each being optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydroxy, hydroxyC 1-6 alkyl, halo, cyano, cyanoC 1-6 alkyl, nitro, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylthio, polyhaloC 1-6 alkyloxy, carboxyl,
C 1-6 alkyloxycarbonyl, aminocarbonyl, Het, mono- or
di(C 1-6 alkyl)aminocarbonyl, or C 1-4 alkyl-S(═O) 2 —;

Het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, piperidinyl, piperazinyl, morpholinyl, 4-thiomorpholinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each monocyclic and bicyclic heterocycle being optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halo, hydroxy, C 1-6 alkyl or C 1-6 alkyloxy;
Het 1 is a monocyclic saturated heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 4-thiomorpholinyl, imidazolidinyl, pyrazolidinyl; each monocyclic saturated heterocycle being optionally substituted with C 1-6 alkyl or arylC 1-6 alkyl;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

2. A compound according to claim 1 wherein R 1 is hydrogen, carboxyl, halo, C 1-6 alkylthio, aminoC 1-6 alkyl or Het.

3. A compound according to claim 1 wherein p is 1.

4. A compound according to claim 1 wherein R 2 is C 1-6 alkyloxy.

5. A compound according to claim 1 wherein R 3 is hydrogen.

6. A compound according to claim 1 wherein R 4 is phenyl optionally substituted with 1 substituent, said substituent being selected from halo, cyano, C 1-4 alkyl-S(═O) 2 — or C 1-6 alkylthio.

7. A compound according to claim 1 wherein R 4 is a monocyclic heterocycle selected from piperidinyl, pyrazolyl, furanyl or pyridinyl, especially pyrazolyl or pyridinyl; each monocyclic heterocycle being optionally substituted with 1 substituent selected from halo, hydroxy, C 1-6 alkyl or C 1-6 alkyloxy.

8. A compound according to claim 1 wherein
R 5 is phenyl; phenyl substituted with 1 or 2 substituents each being independently selected from halo or C 1-6 alkyl; benzyl; or benzyl wherein the phenyl moiety is substituted with 1 or 2 substituents each being independently selected from halo or C 1-6 alkyl.

9. A compound according to claim 1 wherein R 6 is hydrogen, C 1-6 alkyl or benzyl.

10. A compound according to claim 1 wherein
R 7 is hydrogen and R 8 is oxo.

11. A compound according to claim 1 wherein the compound is a compound of formula (Ia).

12. A compound according to claim 1 wherein
R 1 is placed in position 6 of the quinoline ring.

13. A compound according to claim 1 wherein
n is 1.

14. A compound according to claim 1 wherein aryl is phenyl, optionally substituted with one or two substituents each being independently selected from halo; cyano; alkyl; or alkyloxy.

15. A compound according to claim 1 wherein
Het is pyridinyl or pyrazolyl.

16. A compound according to claim 1 wherein
p is 1;
n is 1;
R 1 is halo; C 1-6 alkylthio; C 1-4 alkyl-S(═O) 2 ; or Het;
R 2 is C 1-6 alkyloxy;
R 3 is hydrogen;
R 4 is phenyl optionally substituted with halo;
R 5 is aryl; arylC 1-6 alkyl; C 3-6 cycloalkylC 1-6 alkyl; HetC 1-6 alkyl; or C 1-6 alkyl; and wherein
R 5 is placed in position 2 of the piperdine ring; and
R 6 is hydrogen.

17. A compound according to claim 1 wherein the compound is selected from the following compounds:

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Guillemont Jerome Emile Georges
• Motte Magali Madeleine Simone
• Lancois David Francis Alain
• Thomas Sebastein Robert Gaston
• Balemans Wendy Mia Albert

Classifications

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title