US 7,501,418 B2
Fused heterocyclic isoxazoline derivatives and their use as anti-depressants
José Ignacio Andrés-Gil, Madrid (Spain); Manuel Jesús Alcázar-Vaca, Toledo (Spain); José Manuel Bartolomé -Nebreda, Toledo (Spain); Francisco Javier Fernández-Gadea, Toledo (Spain); Margaretha Henrica Maria Bakker, Alsbach-Haehnlein (Germany); and Antonius Adrianus Hendrikus Megens, Beerse (Belgium)
Assigned to Janssen Pharmaceutica, N.V., Beerse (Belgium)
Appl. No. 10/524,123
PCT Filed Aug. 13, 2003, PCT No. PCT/EP03/50377
§ 371(c)(1), (2), (4) Date Feb. 10, 2005,
PCT Pub. No. WO2004/018483, PCT Pub. Date Mar. 04, 2004.
Claims priority of application No. 02078373 (EP), filed on Aug. 15, 2002.
Prior Publication US 2006/0116378 A1, Jun. 01, 2006
Int. Cl. A01N 43/54 (2006.01); A01N 43/40 (2006.01); A61K 31/445 (2006.01); A61K 31/497 (2006.01); C07D 211/32 (2006.01); C07D 211/68 (2006.01); C07D 211/80 (2006.01); C07D 213/02 (2006.01); C07D 261/20 (2006.01); C07D 239/00 (2006.01); C07D 237/26 (2006.01); C07D 237/36 (2006.01); C07D 413/00 (2006.01); C07D 417/00 (2006.01); C07D 419/00 (2006.01); C07D 471/00 (2006.01); C07D 487/00 (2006.01); C07D 491/00 (2006.01); C07D 495/00 (2006.01); C07D 497/00 (2006.01)
U.S. Cl. 514—253.03  [514/254.02; 514/267; 514/318; 514/321; 514/322; 544/234; 544/250; 544/345; 544/368; 546/193; 546/198; 546/199] 7 Claims
 
1. A compound according to the general Formula (I)

OG Complex Work Unit Drawing
the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, or the N-oxide forms thereof, wherein:
X is CH2, N—R7, S or O;
R7 is selected from the group consisting of hydrogen, alkyl, Ar, Ar-alkyl, alkylcarbonyl, alkyloxycarbonyl and mono- and dialkylaminocarbonyl;
B is a radical, optionally substituted with r radicals R′, according to anyone of Formula (B-a) or (B-b) and fused to the isoxazolinyl moiety by either of the bond pairs (c,d), (d,e) or (e,f)

OG Complex Work Unit Drawing
wherein
Het is an optionally substituted 5- or 6-membered heterocyclic ring, selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl and triazolyl;
each R1 is, independently from each other, selected from the group consisting of hydrogen, hydroxy, amino, nitro, cyano, halo and alkyl and, only when R′ is attached to a N-atom, is further selected from the group of alkyloxyalkyl, alkyloxyalkyloxyalkyl, alkyloxycarbonylalkyl, fonnyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkylcarbonyl and mono- and dialkylaminocarbonyl;
r is an integer ranging from 0 to 6;
a and b are asymmetric centers;
(CH2)m is a straight hydrocarbon chain of m carbon atoms, m being an integer ranging from 1 to 4;
Pir is a radical according to any one of Formula (IIa), (IIb) or (IIc)

OG Complex Work Unit Drawing
optionally substituted with n radicals R8, wherein:
each R8 is independently from each other, selected from the group consisting of hydroxy, amino, nitro, cyano, halo and alkyl;
n is an integer ranging from 0 to 5;
R9 is selected from the group consisting of hydrogen, alkyl and formyl;
R3 represents an optionally substituted aromatic homocyclic or heterocyclic ring system together with an optionally substituted and partially or completely hydrogenated hydrocarbon chain of 1 to 6 atoms long with which said ring system is attached to the Pir radical and of which may contain one or more heteroatoms selected from the group of O, N and S;
Ar is phenyl or naphthyl, optionally substituted with one or more halo, cyano, oxo, hydroxy, alkyl, formyl, alkyloxy or amino radicals; and
alkyl represents a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, optionally substituted with one or more halo, cyano, oxo, hydroxy, formyl or amino radicals.