Fused heterocyclic isoxazoline derivatives and their use as anti-depressants

1. A compound according to the general Formula (I)

the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, or the N-oxide forms thereof, wherein:

X is CH 2 , N—R 7 , S or O;

R 7 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)

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 R 1 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;

(CH 2 ) 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)

optionally substituted with n radicals R 8 , wherein:

each R 8 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;

R 9 is selected from the group consisting of hydrogen, alkyl and formyl;

R 3 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.

2. The compound according to claim 1 , wherein R 3 is a radical according to any one of Formula (IIIa), (IIIb) or (IIIc)

wherein:

d is a single bond while Z is a bivalent radical selected from the group consisting of —CH 2 —, —C(═O)—, —CH(OH)—, —C(═N—OH)—, —CH(alkyl)—, —O—, —S—, —S(═O)—, —NH— and —SH—; or d is a double bond while Z is a trivalent radical of formula ═CH— or ═C(alkyl)—;

A is a 5- or 6-membered aromatic homocyclic or heterocyclic ring, selected from the group consisting of phenyl, pyranyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxadiazolyl and isoxazolyl;

P is an integer ranging from 0 to 6;

R 4 and R 5 are each, independently from each other, selected from the group consisting of hydrogen, alkyl, Ar, biphenyl, halo and cyano ; or

R 4 and R 5 may be taken together to form a bivalent radical —R 4 —R 5 — selected from the group consisting of —CH 2 —, ═CH—, —CH 2 —CH 2 —, —CH═CH—, —O—, —NH—, ═N—, —S—, —CH 2 N(-alkyl)—, —N(-alkyl)CH 2 —, —CH 2 NH—, —NHCH 2 —, —CH═N—, —N═CH—, —CH 2 O— and —OCH 2 —;

each R 6 is independently from each other, selected from the group consisting of hydroxy, amino, nitro, cyano, halo, carboxyl, alkyl, Ar, alkyloxy, Ar-oxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylthio, mono- and di(alkyl)amino, alkylcarbonylamino, mono- and di(alkyl)aminocarbonyl, mono- and di(alkyl)aminocarbonyloxy, mono- and di(alkyl)aminoalkyloxy; or

two vicinal radicals R 6 may be taken together to form a bivalent radical —R 6 —R 6 — selected from the group consisting of —CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —, —O—CH 2 —C(═O)—, —C(═O)—CH 2 —O—, —O—CH 2 —O—, —CH 2 —O—CH 2 —, —O—CH 2 —CH 2 —O—, —CH═CH—CH═CH—, —CH═CH—CH═N—, —CH═CH—N═CH—, —CH═N—CH═CH—, —N═CH—CH═CH—, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —C(═O)—, —C(═O)—CH 2 —CH 2 —, —CH 2 —C(═O)—CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 and

R 16 is selected from the group consisting of hydrogen, alkyl, Ar and Ar-alkyl.

3. A compound according to claim 2 , wherein X=O; m=1; B is a radical according to Formula (B-a) or (B-b), Pir is a radical according to Formula (IIa) wherein n=0 ; R 3 is a radical according to according to any one of Formula (IIIa), (IIIb) or (IIIc) wherein d is a double bond while Z is a trivalent radical of formula ═CH— or ═C(alkyl)—; A is a phenyl ring; R 4 is hydrogen or alkyl ; R 5 and R 16 are hydrogen; R 6 is hydrogen or halo and p=1.

4. A compound according to claim 1 , wherein Het is selected from the group consisting of pyridinyl, thienyl and pyrrolyl, each radical optionally substituted on a N atom with a radical selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkyloxyalkyloxyalkyl, alkyloxycarbonylalkyl, alkylcarbonyl, alkyloxycarbonyl and alkyloxyalkylcarbonyl.

5. A method of treating a warm-blooded animal suffering from depression, anxiety, movement disorders, psychosis, Parkinson's disease, or body weight disorders comprising administering a compound according to claim 1 to said animal.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to claim 1 .

7. A process for making a pharmaceutical composition comprising mixing a compound according to claim 1 and a pharmaceutically acceptable carrier.