Title of Invention

A HALOGEN SUBSTITUTED 4-PHENYL-1-PIPERANZINYL DERIVATIVE

Abstract

The present invention relates to substituted 4-phenyl-1-piperazinyl derivatives having formula (I), wherein W is C, CH or N, and the dotted line emanating from W indicates a bond when W is C and no bond when W is N or CH; R<sup>1</sup> and R<sup>2</sup> are independently selected from hydrogen and halogen, provided at least one of R<sup>1</sup> and R<sup>4</sup> is a halogen atom; X is CH<sub>2</sub>, O, S, CO, CS, SO or SO<sub>2</sub>; and Q is a group of formula (II) provided that X is not O or S when the group Q is attached via an N atom; and any of its enantiomers and acid addition salts thereof. These compounds have high affinity for D<sub>4</sub> receptors.

Full Text

4-Phenyl-l-piperazinyI, -piperidinyl and -tetrahydropyridyl derivatives Field of the Invention The present invention relates to a novel class of halogen substituted 4-phenyl-l-piperaziny!, 5 -piperidinyl and -tetrahydropyridyl derivatives having affinity for dopamine D4 receptors and D3 receptors. The compounds of the invention are considered useful in the treatment of certain psyciiiatric and neurologic disorders, including psychosis. Background of the Invention. 10 us patent No. 3.188.313 relates to certain 1-(1-, 2-, and 3-indolylalkyl)piperazines, which are said to have CNS depressant and tranqmllising effect. Other coEQpounds related to the compounds of the invention, which are said to interact with 15 the dopamine and/or the serotonin system, are known in the art. Thus, EP-B1-496 222, claims compounds having the formula 20 wherein Ar is a phenyl group, which may be substituted with halogen, alkyl, cyano, hydroxy etc. and Ind is 3-indolyl, which may be substituted with cyano, aminocaibonyl and aminocaxbonylamino. The compounds disclosed in EP-B 1-496 222 are said to be serotonine antagonists and agonists. It is also mentioned that the compounds have effect on dopamine accumulation in striatum and 5-HTP accumultation in N. Raphe. The compounds are said to 25 be useful as anxiolytica, antidepressiva, neuroleptica and antihypertonica. WO 99/09025 claims certain 2-(4-aiyl-pipera2rn-l-yl)methyl-lir-indole derivatives. The compounds are said to be dopamine D4 receptor agonists. Further, WO 94/24105 relates to 2-(2-(4-aryl-piperazin-l-yl)ethyl-LH"-indole derivatives, which are said to have selective 30 affinity for the dopamine D4 receptor subtype. EP-Bl-354 094 relates to certain oxindoles navmg me lormula wherein R1 is hydrogen, halogen or alkyl, R2 is hydrogen or alkyl, R2 is hydrogen, alkyl or -S-alkyl and Ar may be chlorophenyl and other substituted aryl groups. The compounds bind 5 to the 5-HT1A receptor and are said to be agonists, partial agonists or antagonists at this receptor. Certain of the compounds are said to possess activity at S-HT2 receptors. WO 98/08816 also describes oxindoles, which are said to be psychotropic drugs, and the application contains data showing the activity of certain of the compounds at the D4 receptor. Pharmazie, 1997, 52, 423-428 describes N-[3-(4-aryl-l-piperazinyl)alkyl] derivatives of 10 indolin-2(lH)-one, quinolin-2(lH)-one and isoquinolin-l(2fl)-one and their receptor aflSnities at the 5-HTIA and the S-HTIA receptor. The compound l-{3-(4-phenyl-l-piperazinyl)propyl)indolin-2(lif)-one is described as a S-HTZA antagonist with weak 5-HTIA agonistic properties. The compound is suggested as a potential antidepressant and/or anxiolytic agent 15 Subramanian et al.. Heterocyclic Commimications 1999, 5, 63-68 describes certain piperazinyl indolyl propanones claimed to show antagonism at dopamine D1/D2 receptors. Further, Bottcher et al., J. Med Chem. 1992, 35, 4020-4026. describes certain 3-(l,2,3,6-20 tetrahydro-1 -pyridylalkyl)indoles having dopaminergic activity. Fmally, Pol. J. Pharmacol Pharm. 1984, 36, 697-703 describes the confound l-(3-(4-(3-chlorophenyl)-l-piperazinyl)propyl)indane as having serotinolytic properties. 25 Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of wherein W is C, CH or N and the dotted one emanating from W indicate a bond when W is C and no bond when W is CH or N; 5 R1 and R2 are independently selected from hydrogen and halogen provided that at least one of R1 andR2 is a halogen atom; R3 is selected from hydrogen, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 10 trifluoromethyl, C1-6-alkoxy, aiyloxy, aralkoxy, hydroxy, amino, C1-6-alkylamino, di(C1-6-alkyl)amino, nitro and cyano n is 2, 3,4, or 5; 15 X is CH2,0, S, CO, CS, SO or SO2; and Q is a group of formiila wherein Z is a chain of 3 to 4 chain members, wherein the chain members are selected from C, CH, CH2, CO, N and NH, provided that only one of the chain members may be N or NH, said chain Z optionally containing one or two double bonds 20 R4R5R6R7R8andR9 are independently selected from hydrogen, halogen, trifluoromethyl, nitro, cyano, C1-6-alkyl, C2-6-alkenyl, C2-«-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, hydroxy, hydroxy-C1-6 alkyl, amino, C1-6-alkylamino, di(C1-6-alkyl)amino, acyl, aminocarbonyl,C1-6-alkylaminocarbonyl and neuroleptic drugs, which primarily exert their effect via antagonism of D2 receptors, are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors, and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991,350,610; Hadley Medicinal Research Reviews 1996,16, 507-526 and Sanner Exp. Opin. Ther. Patents 1998,8, 383-393). A number of D4 ligands, which were postulated to be selective D4 receptor antagonists (L-745,879 and U-101958) have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998,135,194-200). However, recently is has been reported that these compoimds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998,124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999,128, 613-620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent antagonists (Gazi et al. Br. J. Pharmacol. 1999,128, 613-620). Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses. Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999,142, 78-84. It has also been suggested that dopamine D4 antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson"s disease with L-dopa (Tahar et al. Etir. J. Pharmacol. 2000,399,183-186). Dopamine D3 receptors also belong to the dopamine D2 subfamily of receptors, and they are preferentially located in limbic regions of the brain (Sokoloff et al. Nature 1990, 347, 146- 151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic activity (Willner Int. Clinical Psychopharmacology 1997,12, 297-308). Furthermore, an elevation of the level of D3 receptors in the limbic part of schizophrenic brains has been reported (Gurevich et al. Arch. Gen. Psychiatry 1997,54,225-32). Therefore, D3 receptor antagonists may offer the potential for an effective antipsychotic therapy, free of the extrapyramidal side effects of the classical antipsychotic drugs, which primarily exert their effect by blockade of D2 receptors (Shafer et al. Psychopharmacology 1998,135,1-16; Schwartz et al. Brain Research Reviews 2000, 31,277-287). Moreover, D3 receptor blockade results in a slight stimulation in the prefrontal cortex (Merchant et al. Cerebral Cortex 1996, 6, 561-570), which could be beneficial against negative symptoms and cognitive deficits associated with schizophrenia. In addition, dopamine D3 antagonists can reverse D2 antagonist-induced EPS (Millan et al. Eur. J. Pharmacol. 1997, 321, R7-R9) and do not cause changes in prolactin (Reavill et al. J. Pharmacol Exp. Ther. 2000, 294, 1154-1165). Consequently, D3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes. 1 Dopamine D3 agonists have also been considered relevant in the treatment of schizophrenia (Wustow et al. Current Pharmaceutical Design 1997, 3, 391-404). According to the present invention, a novel class of dopamine D4 receptor ligands is provided. Most of the compoxmds of the invention also have high affinity for the dopamine D3 receptor and as mentioned above, dopamine D3 antagonistic properties of an antipsychotic drug may reduce the negative symptoms and cognitive deficits of schizophrenia and result in an improved side effect profile. Moreover, certain of the compounds of the invention have the further advantage of having only very weak effect at adrenergic alpha-1-receptors which imply a low propensity to cause orthostatic hypotension. Summary of the Invention Accordingly, the present invention relates to the novel compounds of formula I di(Ci.6-alkyl)animocarbonyl; provided that X is not 0 or S when the group Q is attached via an N atom; 5 and any of its enantiomers and acid addition salts thereof. According to a preferred embodiment of the invention, R^ and R^ are both halogen, in particular chloro. 10 In another embodiment of the invention, one of R1 and R2 is halogen and the other is hydrogen. In particular, the invention relates to such compounds -wherern R is halogen and R1 is hydrogen. If R2 is hydrogen and R1 is chloro, Q is preferably selected from indolinyl, 1,2,3,4-15 tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl or 1-indanyl. In one particular embodiment oftheinyention, when R is hydrogen and R is halogen, R is not chloro. 20 In a further embodiment of the invention, R1 and R2 are independently selected from hydrogen and chloro. In another particular embodiment of the invention W is N. 25 In a preferred embodiment of the invention X is CO or CH2. In a further embodiment of the invention, Z is a chain of 3 to 4 chain members, wherein the chain members are selected from C, CH, CH2, N and NH, provided that only one of the chain members may be N or NH. 30 Q may preferably be selected from optionally substituted 1-indolinyl, 3-indolyl, 1-indanyl, 2-oxo-l, 2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl. In particular, Q is unsubstituted or substituted with halogen. R3 is preferably hydrogen or halogen and if R3 is halogen it is preferably attached in the para position on the phenyl ring. 5 The compounds of the invention have been found to show high affinity for dopamine D4 receptors and dopamine D3 receptors, in certain cases combined with a very low effect at adrenergic alpha-1- receptors. The compounds of the invention are therefore considered useM for the treatment of 10 psychosis, including the positive and negative symptoms of schizophrenia. Moreover, certain of the compounds have the further advantage of having only very weak effect at adrenergic alpha-1-receptors which imply a low propensity to cause orthostatic hypotension. 15 Some of the compounds interact with central serotonergic receptors, e.g. the 5-HTIA or 5-HT2A receptors and/or they act as 5-HT reuptake inhibitors. These compounds of the invention may therefore also be useful for the treatment of 20 disorders caused by imbalances in the serotonergic system including affective disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression and aggression. In particular, compoimds with combined effects at dopamine D4 and 5-HT receptors and/or 25 the 5-HT transporter may have the benefit of improved effect on other psychiatric symptoms associated with schizophrenia, such as depressive and anxiety symptoms. Thus, in another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceuticaUy 30 acceptable acid addition salt thereof in combination with one or more pharmaceutically acceptable carriers or diluents. The invention also relates to the use of a compound of the invention for the manufacture of a medicament useful in the treatment of psychosis including the positive and negative symptoms of schizophrenia, affective disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, cognitive disorders and dyskinesia induced by treatment with L-dopa. 5 Detailed Description of the Invention Some of the compounds of general Formula I exist as optical isomers thereof and such optical isomers are also embraced by the invention. 10 The term C1-6-alkyl refers to a branched or imbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-l-propyl. The terms C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylamino, di(C1-6-aIkyl)amino etc. designate 15 such groups in which the alkyl group is C1-6-alkyl as defined above. The term aiyl refers to a carbocyclic aromatic group, such as phenyl, naphthyl, in particular phenyl, including methyl substituted naphthyl, or phenyl. 20 The term aralkyl means aryl-C1-6-alkyl, wherein aryl and C1-6-alkyl is as defined above. The terms aralkoxy and aryloxy means aiyl-C1-6alkyl-O- and aryl-O- where aryl and C1-6-alkyl are as defined above. 25 Halogen means fluoro, chloro, bromo or iodo.A group Q wherein Z is as defined above includes groups such as: wherein R4- R9 are as defined above and the dotted line indicates an optional bond. Preferred compounds of the invention are the compounds selected from 5 3-[4-(2,3-Dichlorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH"-nidol-l-yl)propan-l-one, 4-[4-(2,3-Dichlorophenyl)piperazin-l-yl]-l-(2,3-dihydro-IH-indol-l-yl)biitan-l-one, 5-[4-(2,3-Dichlorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)pentan-l-one, 4-[4-(2-Chlorophaiyl)piperazin-l-yl]-l-(2,3-dihydio-ljy-indol-l-yl)butan-l-one, The acid addition salts of the compounds of the invention may be phannaceutically acceptable salts fomed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaiic, benzoic, ascorbic, succinic, oxalic, bis-roethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandehc, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hy¬drochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The compoumds of the invention may be prepared as follows: a) Reducing the carbonyl group of a compound of formula III wherein R1 R2, R3, W, n, Q and the dotted line are as previously defined; 5 b) alkylating an amine offormulalV with a reagent of foimularV wherein R\ R^, R"", X, W, n, Q and the dotted line are as previously defined, and G is a suitable leaving group such as halogen, mesylate or tosylate; 10 c) reductive alkylation of an amine of the formula TV with a reagent of formula VII wherein R1 R2, R3, X, n, W, Q and the dotted line are as previously defined, and E is either 15 an aldehyde or an activated cafboxylic acid group; d) reducing the amide group of a compound of formula VHI wherein R1, R2 R3, X, n, W,Q and the dotted one are as previously defined; e) acylation or reductive alkylation of an amine of the formula II" 5 wherein T) is a chain of 3 to 4 chain members, wherein the chain members are selected fi:om C, CH, CH2, CO and NH, provided that one of the chain members is NH, and said chain optionally containing one or two double bonds, with a reagent of formula DC 10 wherein R1 R2 R3, n, W and the dotted line are as previously defined, and E is either an aldehyde or an activated carboxylic acid groxp) f) Lewis-acid catalyzed cleavage of a resin-bound ester of formula X by an amine of the 15 formula Q" g) reduction of the double bond in a compound of formula XI 5 wherein R , R , R , n, X and Q are as previously defined, whereupon the compoimd of formula I is isolated as the firee base or an acid addition salt thereof. The reduction according to method a) is preferably carried out in an inert organic solvent 10 such as diethyl ether or tetrahydrofuran in the presence of alane or lithimn aluminium hydride firom 0 °C to reflux temperature. Method b) may be used to prepare starting materials of formula III. The alkylation according to method b) is conveniently performed in an inert organic solvent 15 such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be perfonned at a fixed temperature, which is different firom the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or A""-methylpyirolidin-2-one (NMP), 20 preferably in the presence of a base. Amines of formula IV are either commercially available or known from the literature (e.g. Oshiro et al. /. Med. Chem. 1991,34,2014-2023, Oshiro et al. J. Med. Chem. 1998,41, 658-667, and Oshiro et al. J. Med. Chem. 2000,43,177-189). Alkylating reagents of formula V 25 are known firom the Hterature, or they can be prepared by methods obvious to a chemist skilled in the art by an analogues synthetic sequence. Thus, key intermediates such as halo-(2,3-dihydro-l/r-indol-l-yl)alkan-l-one are prepared by addition of a haloalkanoyl chloride to a 2,3-dihydro-lif-indole in the presence of base. Similarly, halo-(3,4-dihydro-liZ-isoquinolin-2-yl)alkan-l-one may be prepared firom a haloalkanoyl chloride and a 3,4- dihydro-lH-isoquinoline. The 2,3-(3ihydro-liy-mdoIes are either commercially available or prepared from the corresponding lif-indoles by reduction of the li7-indole with e.g. sodium cyanoborohydride in acetic acid or in trifluoroacetic acid whereas the 3,4-dihydro-liir-isoquinolines are commercially available or described in the Hterature. Alkylating haloalkyl-5 liif-indoles were prepared by literature methods (Benghiat et al. /. Med. Chem. 1983,26, 1470-1477) or analogues to methods described in the literature (Brodfiiehrer et al. J. Org. Chem. 1997, 62,9192 and WO 00/35872). Alkylating 3-haloaIkylindanes or other types of alkylating alky lindanes can be prepared from known indanylalkancarboxylic acids (Mukhopadhyay et al. J. Indian Chem. Soc. 1985, 62, 690-692 and Tanaka et al. /. Med. 10 Chem. 1994, S7,2071-2078) by well known procedures. Alkylating l-(haloalkyl)-3,4-dihydroquinolin-2(l/0-one can be prepared as described in EP-B1-512525. The reductive alkylation according to methods c) and e) can be performed in two steps, e.g. coupling of amines of formula VLTI" with reagent of formula VII/IX by standard methods 15 via the carboxylic acid chloride, activated esters or by use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide followed by reduction of the resulting amide with lithium aluminium hydride or alane. The reaction can also be performed by a standard one-pot procedure, e.g. by the use of reductive amination of amines of formula VI/II with aldehydes of formula VII/TX. Caiboxylic acids or aldehydes of 20 formula VII are either commercially available or described in the literature. Thus, key intermediates have been described in the hterature such as indanylalkancarboxylic acids (Mukhopadhyay et al. J. Indian Chem. Soc. 1985, 62, 690-692 and Tanaka et al. J. Med. Chem. 1994, 37, 2071-2078), substituted 3-(lH-indol-3-yl)propionic acids (Carbonnelle et al. Tetrahedron 1998, 39, 4471-4472) and (2,3-dihydro-li7-indol)aIkancarboxyhc acids 25 (WO 98/28293 and Ly et al. Tetrahedron Letts. 1999, 40, 2533-2536). Other substituted (li/"-indol-3-yl)alkancarboxylic acids can be prepared by chain elongation of readUy accessible 3-indoleglyoxylyl chlorides (Speeter et al. J. Am. Chem. Soc. 1954, 76, 6208-6210 and Nichols et al. Synthesis 1999, 6, 935-938). The 3-indoleglyoxylyl chlorides may be prepared from commercially available lH-indoles. Various substituted (lif-indol-3- 30 ylsulfanyl)alkancarboxylic acids can be prepared in an analogues manner as described for aminoalkylsulfanyl-m-indoles (Zelesko et al. J. Med. Chem. 1983, 26, 230-237 or WO 91/04973) by in situ alkylation of substituted sodium 3-indolylthiolate with alkyl haloalkanoates and subsequent hydrolysis of the ester group. Reduction of amide groups according to method d) is most conveniently performed with lithium aluminium hydride or alane in an inert organic solvent such as e.g. tetrahydrofuran or diethylether from 0 °C to reflux temperature. 5 Acylation according to method e) can be performed by standard hterature methods, e.g. coupling of amines of formula Q" with reagent of formula IX by standard methods via the carboxylic acid chloride, activated esters or by use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide. 10 The Lewis acid catalyzed conversion of an ester to an amide according to method f) can be performed by standard literature methods (Bam et al. Tet. Lett. 1996, 37, 3213-3216). The Resin bound ester X can likewise be synthesised according to the Hterature (see e.g. Bam et al. Tet. Lett. 1996,37,3213-3216). 15 The reduction of the double bond according to method g) is generally performed by catalytic hydrogenation at low pressure ( 20 Experimental Section Melting points were determined on a Buchi B-535 apparatus and are imcorrected. Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instnmients or on a Sciex API 150EX from Perldn Elmer. Spectra were obtained at two sets of operating conditions by the use of either electrospray ionisation or ACPI: one set to obtain moleciilar 25 weight information and the other set to induce fragmentation patterns. 1H NMR spectra were recorded at 250.13 MHz on a Bruker AC 250 or at 500.13 MHz on a Bruker DRX 500. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) were used as solvents. T^IS was used as internal reference standard. Chemical shifts are expressed as ppm values. The following abbreviations are used for multipHcity of NMR signals: s=singlet, d=doublet, 30 t=triplet, q=quartet, qv=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=tiiplet of triplets, m= multiplet, b=t»road. NMR signals corresponding to acidic protons are to some extent omitted. Content of water in crystalline compounds were determined by Karl Fischer titration. For column chromatography silica gel of type Kieselgel 60,40-60 mesh ASTM was used. Preparation of intermediates 5 A- Alkylating reagents 3-Chloro-l-(2,3-dihydro-liy-indol-l-yl)propan-l-one A mixture of 2,3-dihydro-li;f-indole (50 g), triethylamine (132 g) and tetrahydrofuran (1000 10 mL) was cooled down to 10 °C followed by the addition (over a period of 60 min) of a solution of 3-chloropropanoyl chloride (55 g) in tetrahydrofinan (400 mL). The mixture was filtered, and the remaining solution was evaporated in vacuo to dryness. The residue was purified by flash chromatography (eluent: ethyl acetate/heptane 1:3) giving the title compoimd as a crystalline white material (31 g). 15 The following compoimds were prepared in a similar maimer 4-Chloro-l-(2,3-dihydro-l.H"-indol-l-yl)butan-l-one fi-om 2,3-dihydro-lif-indole and 4-chIorobutanoyl chloride 20 5-Bromo-l-(2,3-dihydro-l.g-indol-l-yl)pentan-l-one firom 2,3-dihydro-li/"-indole and 5-bromopentanoyI chloride The following two compoimds were prepared as described in Benghiat et al. J. Med. Chem. 25 1983,26,1470-1477 3-(3-Bromopropyl)-lH-indole 3-(4-Bromobutyl)-lH-indole 30 3-(3-ChloTopropyl)-5-fluoro-lH-indole The compound 5-chloropentan-l-ol (16.2 mL) was dissolved in cold 5 mM 2,2,6,6-tetramethylpiperidine-1-yloxy (tonpo) in dichloromethane (240 mL) and cooled down to 0°C with an ice bath. Potassixnn bromide (0.5 M in water, 24 inL) was added, and this was 35 followed by the addition (in one portion at 5 °C xmder vigorous stirring) of a solution of sodium hydrogencarbonate (24 g) in aqueous sodium hypochlorite (0.3 M, 500 mL). The resulting mixture was stirred at 5 °C for 20 min, and the phases were separated. The water phase was extracted with dichloromethane (200 mL), and the combined organic phases were evaporated in vacuo giving 5-chloropentanal as a clear oil (16 g). Subsequently, 5-5 chloropentanal was suspended in water (100 mL) followed by addition of 4-fluorophenylhydrazine hydrochloride (19.5 g) and toluene (800 mL), and the mixture was stirred at room temperature for 15 min. Phosphoric acid (85%, 100 mL) was added and the mixture was boiled under reflux for 2 h. The mixture was cooled to room temperature and the phases were separated. The organic phase was washed with saturated aqueous sodium 10 hydrogencarbonate, dried (MgS04) and evaporated in vacuo to yield an orange oil. The crude product was purified by flash chromatography on silicagel (eluent: ethylacetate/heptane 1:4) to give the title compound as an orange oil (14 g). The following compound was prepared in a similar manner 15 3-(4-Chlorobutyl)-5-fluoro-lH-indole fi-om 6-chlorohexan-l-ol and 4-fluorophenylhydrazine hydrochloride 6-Chloro 3-(3-iodopropyl)-l-H-indole 20 The alcohol 2-(6-chloro-lH-indol-3-yl)ethanol (25 g, prepared analogues to compounds described in Demerson et al. J. Med. Chem. 1976,19, 391-395 from 6-chloro-li7-indole and oxalyl chloride) was dissolved in tetrahydrofuran (300 mL) foUowed by the addition of trietylamine (17.7 mL). The resulting mixture was cooled to 5-6 "C followed by the addition of a solution of methanesulfonic acid chloride (14.6 g) in tetrahydrofiiran (100 mL). The 25 mixture was stirred at room temperature for 2 h, filtered and evaporated to dryness in vacuo. The residue was dissolved in acetone followed by addition of sodium iodide (96.2 g), and the resulting mixture was boiled under reflux for 4 h. The mixture was poured onto brine and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgS04), filtered and concentrated m vacuo (38.2 g). The residue (30 g) was dissolved in 30 dimethylsulfoxide (DMSO, 200 mL) and added drop-wise to a suspension of NaCN (15 g) and DMSO (250 mL) at 80 °C. The resulting mixture was stirred at 100 "C for 1 h, cooled down to room temperature and poured onto brine. The aqueous phase was extracted with dietiiyl ether, and the combined organic phase was dried (MgS04), filtered and concentrated in vacuo to yield crude intermediate (22.5 g). The residue was dissolved in methanol (750 mL) and added a mixture of HCl/methanol resulting in a combined solution of about 1 M HCl in methanol. The mixture was stirred at room temperature for 24 h followed by heating at 40 °C for an additional 3 h. The solvent was removed in vacuo, and the residue was dissolved in a mixture of diethyl ether and water. The resulting mixture was stirred at room 5 temperature for 30 min. and the phases were separated. The aqueous phase was extracted an additional two times with diethyl ether and the combined organic phase was washed with brine, dried (MgS04), filtered and concentrated in vacuo (18.2 g). The residue was dissolved in tetrahydrofuran (300 mL) and added drop-wise to a suspension of LiAlH4 (11.6 g) in tetrahydrofuran (1000 mL). The resulting mixture was boiled under reflux for 3 h, cooled 10 down to 10 °C and worked up by the use of an equivalent amount of water. The organic phase was dried (MgS04), filtered and concentrated in vacuo (16.6 g). The residue (8 g) was dissolved in tetrahydrofuran (100 mL) and triethylamine (3.9 g) and cooled down to 10 °C followed by the addition of a solution of methanesulfonic acid chloride (4.4 g) in tetrahydrofuran (50 mL). The mixture was stirred at room temperature for 2 h and then 15 evaporated to dryness in vacuo. The residue was dissolved in acetone followed by the addition of Nal (28.6 g), and the resulting mixture was boiled under reflux for 3 h. The mixtiu-e was poured onto brine^ and the aqueous phase was extracted with tetrahydrofuran. The combined organic phase was dried (MgS04), filtered and concentrated in vacuo (17.4 g). 20 The following compound was prepared in a similar manner 4-(Indan-l-yl)butyl methanesulfonate from 4-(iQdan-l-yl)butanoic acid prepared as described by Mukhopadhyay et al. J. Indian 25 Chem. Soc. 1985, 62, 690-692. l-(4-Bromobutyl)-3,4-dihydroquinolia-2(lH)-one A suspension of sodium hydride (6.8 g, 60% dispersion in mineral oU) and dimethyl formamide (200 mL) was kept at 20-30 "C followed by the addition of a solution of 3,4-30 dihydroquiiiolin-2(liZ)-one (25 g) in dimethyl formamide (100 mL). The resulting mixture was stirred at room temperature for 30 min followed by the addition of a solution of 1,4-dibromobutane (184 g) in dimethyl formamide (200 mL) at a temperature of 20-40 °C. The reaction mixture was stirred at room temperature for 30 min and evaporated in vacuo. The remaining oil was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, treated with charcoal, dried (MgS04) and evaporated in vacuo. The remaining oil was purified by flash chromatography (eluent: ethyl acetate/heptane 1:1) giving the title compound as a red oil (36 g). 5 B. Acylating reagents (6-Chloro- l-y-rndol-3-ylsuIfanyl)acetic acid The compounds 6-chloro-lH-indole (15.1 g) and thiourea (7.6 g) were dissolved in methanol (150 mL) followed by the addition of a solution of iodine/potassium iodide (1 M, 100 mL) 10 imder stirring. The solution was stirred at room temperature for 2 h and then evaporated in vacuo to give an oil. Sodium hydroxide (1.5 M, 200 mL) was added, and the solution was heated at 90 °C for 90 min. This solution was cooled to room temperature and extracted with diethyl ether (discarded). The aqueous phase was added diethyl ether (100 roL) and ethyl chloroacetate (10 mL), and the resulting mixture was stirred at room temperature for 16 h. 15 The phases were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were collected and dried (MgS04). The suspension was filtered, and the organic phase was evsqwrated to dryness to give a brown oil (18.1 g). The oil was dissolved in ethanol (50 mL) followed by the addition of a solution of water (50 mL) and potassium hydroxide (4.0 g). The resulting mixture was boiled under reflux for 2 h and 20 cooled to room temperature. The pH of the mixture was adjusted to 3-4 by the addition of hydrochloride acid (1 M). Water was added (100 mL), and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgS04), filtered and evaporated m vacuo to give the title compound as an oil (12.3 g). 25 Preparation of the compounds of the mvention Example 1 la,3-f4"{2,3-Dichlorophenyl)piperazin-I-yl]-l-(2,3-dihydro-]H-indol-l-yl)propan-l-one A mixture of l-(2,3-dicblorophenyl)piperazine, hydrochloride (8.0 g) and potassium 30 carbonate (15 g) in a mixture of butanone (50 mL) and dunethyl formamide (5 mL) was heated to 50 °C followed by the addition of 3-chloro-l-(2,3-dihydro-l/^-indol-l-yl)propan-1-one (6.0 g). The resulting mixture was boiled imder reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (8.5 g). Mp 157-158 ""C. ^H NMR (DMSO-d^): 2.60 (s, 4H); 2.60-2.80 (m, 4H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, IH); 7.10-7-15 (m, 2H); 7.20 (d, IH); 7.25-7.35 (m, 2H); 8.10 (d, IH). MS m/z: 404"(MH+), 243. Ih, 4-f4-(2,3-Dichlorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)butan-l-one 5 A mixture of l-(2,3-diclilorophenyl)piperaziQe, hydrochloride (8.0 g) and diisopropylethylamine (10 mL) in dimethyl formamide (50 mL) was heated to 45 °C followed by the addition of 4-chloro-l-(2,3-dihydro-li?-indol-l-yl)butan-l-one (6.7 g). The resulting mixtm:e was heated at 100 °C for 6 h, cooled to room temperature and poured into water. The aqueous phase was extracted with diethyl ether, and the combined organic phases 10 were dried (MgS04), filtered and evaporated in vacuo to give a black oil (14.2 g). The oil was crystallised from acetone, and the formed crystals were reciystallised from ethanol to give a white crystalline material (3.8 g). Mp 134-136 "C. "H NMR (CDCI3): 1.90-2.05 (m, 2H); 2.45-2.60 (m, 4H); 2.65 (s, 4H); 3.00 (s, 4H); 3.20 (t, 2H); 4.10 (t, 2H); 6.90 (d, IH); 7.00 (t, IH); 7.05-7-25 (m, 4H); 8.25 (d, IH). MS m/z: 418 (MH^), 299,228,188. 15 Ic, 5-f4-(2,3-Dichlorophenyl)piperazin-l-yl]-l -(2,3-dihydro-lH-indoI-l -yl)pentan-l-one A mixture of l-(2,3-dichlorophenyl)piperazine hydrochloride (8.0 g) and diisopropylethylamine (15 mL) in butanone (50 mL) was heated to 45 °C followed by the addition of 5-bromo-l-(2,3-dihydro-l?r-indol-l-yI)pentan-l-one (5.4 g). The resulting 20 mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystaUine material was collected by filtration and washed with acetone (3.8 g). Mp 121-123 °C. "H NMR pMSOdg): 1-50-1.70 (m, 4H); 2.30-2.65 (m, 8H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, IH); 7.10-7-15 (m, 2H); 7.20 (d, IH); 7.25-7.35 (m, 2H); 8.10 (d, IH). MS m/z: 432 (MH+), 315,202. 25 The following compounds were prepared in a similar manner Id. 4-f4-(2-Chlorophenyl)piperazin-l-yl]-l-(2,3"dihydro-lH-indol-l-yl)butan-l-one fiiom l-(2-chlorophenyl)pipera2me, hydrochloride and 4-chloro-l-(2,3-dihydro-l^-indol-l-30 yl)butan-l-one. Mp 119-121 °C. "H NMR (DMSO-d«): 1.75-1.85 (m, 2H); 2.35-2.50 (m, 4H); 2.55 (s, 4H); 3.95 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, IH); 7.05 (t, IH); 7.10 (d, IH); 7.15 (t, IH); 7.20 (d, IH); 7.25 (t, IH); 7.40 (d, IH); 8.10 (d, IH). MS m/z: 384 (MH4-), 265,188. le, 4-[4-(3-Chlorophenyl)piperazi7i-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)butan-l-one from l-(3-chlorophenyl)piperazme, dihydrochloride and 4-chloro-l-(2,3-dihydro-liy-mdol-l-yl)butan-l-one. Mp 102-107 "C. "H NMR (DMSO-d^): 1.75-1.85 (m, 2H); 2.35 (t, 2H); 2.45-2.55 (m, 6H); 3.10-3.20 (m, 6H); 4.10 (t, 2H); 6.75 (d, IH); 6.85 (d, IH); 6.90 (s, IH); 5 6.95 (t, IH); 7.10 (t, IH); 7.15-7.25 (m, 2H); 8.10 (d, IH). MS m/z: 384 (MH+), 265,188. Example 2 2a, l-{3-f4-(2,3-Dichlorophe7iyl)piperazin-l-yl]propyl}-2,3-dihydro-lH-indole, 10 hydrochloride Lithium aluminium hydride (1.8 g) was suspended in tetrahydrofuran (30 mL) at 0 °C, and the suspension was added a solution of aluminium trichloride (1.8 g) in tetrahydrofuran (30 mL) at 0-5 "C over 15 min. To this mixture, a solution of la, 3-[4-(2,3-dichIorophenyl)-piperazia-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)propan-l-one (5 g) in tetrahydrofuran (50 mL) 15 was added at a temperature of 0-10 °C. The resulting mixture was stirred for 30 min at 5 °C and then for 2 h at room temperature. The reaction mixture was quenched with water and sodium hydroxide (28%) and filtered. The organic phase was evaporated to dryness in vacuo, and the title compound was precipitated as the hydrochloride salt and recrystallised from ethanol (3.8 g). Mp 214-226 °C. ^H NMR (DMSO-de): 2.05-2.20 (m, 2H); 2.95 (t, 2H); 20 3.10-3.35 (m, 8H); 3.35-3.50 (m, 4H); 3.60 (d, 2H); 6.70 (b s, 2H); 7.05 (t, IH); 7.10 (d, IH); 7.20 (d, IH); 7.30-7.40 (m, 2H); 11.45 (b s). MS m/z: 390 (MH+), 271,132. The following compounds were prepared in a similar manner 25 2b, l-{4-f4-(2,3-Dichlorophenyl)piperazin-l-yl]butyl}-2,3-dihydro-lH-indole, oxalate from lb, 4-[4-(2,3-dichlorophenyl)pipera2in-l-yl]-l-(2,3-dihydro-liir-indol-l-yl)butan-l-one. Mp 157-160 °C. 1H NMR (DMSO-d^): 1.55-1.65 (m, 2H); 1.65-1.75 (m, 2H); 2.90 (t, 2H); 2.95 (t, 2H); 3.05 (t 2H); 3.05-3.25 (m, 8H); 3.30 (t, 2H); 6.50 (d, IH); 6.55 (t, IH); 6.95 (t, IH); 7.00 (d, IH); 7.20 (d, IH); 7.30-7.40 (m, 2H). MS m/z: 404 (MH+), 285,174, 30 132. 2c, l-{5-f4-(2,3-Dichlorophenyl)piperazin-l-yl]peniyl}-2,3-dihydro-lH-indole, hydrochloride from Ic, 5-[4-(2,3-(iichlorophenyl)pipera2m-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)pentan-l-one. Mp 219-228 °C. "H NMR (DMSO-de): 1.35-1.45 (m, 2H); 1.60-1.70 (m, 2H); 1.80-1.90 (m, 2H); 2.95-3.05 (m, 2H); 3.10-3.30 {m, 8H); 3.40-3.65 (m, 6H); 6.85 (b s, 2H); 7.05-7.25 (m, 3H); 7.30-7.40 (m, 2H); 11.20 (b s). MS m/z: 418 (MH+), 299,188. 5 2d, l-(4-f4-(2-Chlorophenyl)piperazin-l-yl]butyl}-2,5-dihydro-lH-indole, oxalate from 1 d, 4-[4-(2-cliloroplienyl)piperaziQ-l-yl]-l-(2,3-dihydro-lH"-mdol-l-yl)butaii-l-one. Mp 146-148 °C. "H NMR (DMSO-dfi): 1.55-1.60 (m, 2H); 1.65-1.75 (m, 2H);.2.90 (t, 2H); 3.00 (t, 2H); 3.05 (t, 2H); 3.15 (b s, 8H); 3.30 (t, 2H); 6.50 (d, IH); 6.55 (t, IH); 7.00 (t, IH); 10 7.05 (d, IH); 7.10 (t, IH); 7.20 (d, IH); 7.35 (t, IH); 7.45 (d, IH). MS m/z: 370 (MH+), 251, 174. 2e, l-{4-f4-(3-Chlorophenyl)piperazin-l-yl]butyl}-2,3-dihydro-lH-indole, oxalate from le, 4-[4-(3-ciiloroplienyl)piperazin-l-yl]-l-(2,3-diliydro-lH-iBdol-l-yl)bTitan-l-one. 15 Mp 172-176 "C. "H NMR (DMSO-de): 1.55-1.60 (m, 2H); 1.65-1.75 (m, 2H); 2.85 (t, 2H); 2.95 (t, 2H); 3.00-3.20 (m, 6H); 3.30 (t, 2H); 3.40 (b s, 4H); 6.50 (d, IH); 6.55 (t, IH); 6.85 (d, IH); 6.90-7.05 (m, 4H); 7.25 (t, IH). MS m/z: 370 (MH+), 251,174. Example 3 20 3, l-(2,3-DichIorophenyI)-4-f4-(ijidan-]-yl)butyl]piperazine. oxalate A mixture of l-(23-dichloToplienyl)piperaziiie, hydrochloride (3.5 g) and diisopropylethylamine in a mixture of methyl isobutyl ketone (50 mL) and dimethyl formamide (5 mL) was heated to 60 °C followed by the addition of 4-(indan-l-yl)butyl 25 methanesulfonate (3.5 g) in methyl isobutyl ketone (10 mL). The resulting mixture was boiled xmder reflux for 5 h and reduced in vacuo. The product was purified by flash chromatography on silicagel (eluent ethylacetate) to give the crude product that subsequently was precipitated as the oxalate salt (0.7 g). Mp 171-176 °C. ^H NMR pMSO-d^): 1.35-1.45 (m, 3H); 1.55-1.75 (m, 3H); 1.80-1.90 (m, IH); 2.20-2.30 (m, 2H); 2.75-2.90 (m, 2H); 2.95 30 (t, IH); 3.10 (t, IH); 3.20 (b s, 8H); 7.10-7.15 (m, 2H); 7.15-7.25 (m, 3H); 7.30-7.40 (m, 2H). MS m/z: 403 (MH+). 4, 6-Chloro-3-{2-[4-(2,2-dichlorophenyl)piperazin-l-yl]et}rylsulfanyl}-lH-indole, oxalate A solution of (6-chloro-liiZ"-mdol-3-ylsulfanyl)acetic acid (1.75 g) in tetrahydrofuran (30 5 mL) was added carbonyldiimidazole (1.2 g), stirred at room temperature for 30 min and cooled to 5 °C. To this mixture was added l-(2,3-dichloroplienyl)piperazine (1.8 g) dissolved in tetrahydrofuran (20 roL), and the resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried (MgS04), jBltered and evaporated in vacuo to 10 give an oil (3.6 g). The oil was subjected to the same reaction conditions (reduction with alane) as described in example 2, and the product was purified by flash chromatography on silicagel (eluent: ethylacetate/heptane 5:1) to give an oil. The title compound was isolated as the oxalate salt (0.8 g). Mp 137-141 °C. 1H NMR (DMSO-d 15 s,lH). MS m/z: 442 (MH+), 291,182. Example 5 5a, 3-{3-f4-(2,2-Dichlorophenyl)piperazin-l -yl]propyl}-lH-indole, hydrochloride 20 A mixture of 3-(3-bromopropyl)-li/"-indoIe (1.19 g), potassium carbonate (1.4 g) and l-(2,3- dichlorophenyI)piperazine (1.27 g) in anhydrous acetonitrile (10 mL) was boiled under reJQux for 5 h and cooled to room temperature. The mixture was added silicagel (7 g), and the solvent wjis evaporated in vacuo. The compound was purified by flash chromatography on sihcagel (eluent: ethylacetate/heptane/triethylamine 49:49:2). Fractions containing the 25 compound were combined and evaporated in vacuo. Reciystallisation fix>m acetonitrile gave the title compound as a white crystalline material. The compoimd was precipitated as the hydrochloride salt (1 g). Mp 241-242°C. 1H NMR (DMSO-dg): 2.10-2.25 (m, 2H); 2.75 (t, 2H); 3.10-3.30 (m, 6H); 3.40 (t, 2H); 3.60 (d, 2H); 7.00 (t, IH); 7.05 (t, IH); 7.15 (d, IH); 7.25 (s, IH); 7.30-7.40 (m, 3H); 7.55 (d, IH); 10.90 (b s, IH); 11.40 (b s, IH). Ms m/z: 388 30 (MH+). The following compounds were prepared in a similar manner 5b, 3-{4-f4-(2,3-Dichlorophenyl)piperazin-l-yl]butyl}-lH-indole. hydrochloride nom i-(2,3-(liclilorophenyl)pipera2iiie and 3-(4-broniobutyl)-ljy-iiidole. Mp 121-122°C. "H NMR pMSO-ds): 1.45-1.55 (m, 2H); 1.65-1.75 (m, 2H); 2.35 (t, 2H); 2.50 (b s, 4H); 2.70 (t, 2H); 2.95 (b s, 4H); 6.95 (t, IH); 7.05 (t, IH); 7.10-7.15 (m, 2H); 7.25-7.30 (m, 2H); 7.35 (d, IH); 7.50 (d, IH); 10.75 (b s, IH). Ms m/z: 402 (MH+). 5 5c, 3-{3-f4-(2,2-Dichlorop}ienyl)piperazin-l-yl]propyl}-5-fluoro-lH-indole froml-(2,3-dicIiIoroplienyl)pipera2me and 3-(3-cIiloropropyl)-5-fluoro-l//-mdole. Mp 147-148°C.1HNMR (DMS0-d6): 1.75-1.85 (m, 2H); 2.30-2.45 (t, 2H); 2.45-2.60 (m, 2H); 2.70 (t, 2H); 3.00 (b s, 4H); 3.35 (b s, 2H); 6.85-6.95 (m, IH); 7.05-7.15 (m, IH); 7.20 (s, IH); 10 7.20-7.35 (m, 4H); 10.85 (b s, IH). Ms m/z: 406 (MH+). 5A,3-{4-[4-(2,2-Dichlorophenyl)piperazin-l-yl]butyl}-5-fluoro-lH-indole from l-(2,3-dicliloroplienyl)piperazme and 3-(4-chlorobutyl)-5-fluoro-l/r-mdole. Mp 147-148°C. ^HNMR (DMSO-d 5e, 6-Chloro-2-{3-f4-(2,3-dichlorophenyl)piperazin-l-yl]propyl}-lH-indole from l-(2^-diclilorophenyl)piperazine and 6-chloro 3-(3-iodopropyi)-iir-indoIe. ^HNMR 20 (CDCI3): 1.95 (t, 2H); 2.55 (t, 2H); 2.65 (b s, 4H); 2.80 (t, 2H); 3.10 (b s, 4H); 6.95-7.05 (m, 2H); 7.10 (d, IH); 7.10-7.20 (m, 2H); 7.35 (s, IH); 7.55 (d, IH); 7.95 (b s, IH). Ms m/z: 422 (MH+), 424. Example 6 25 6, l-{4-f4-(2,3-Dichlorophenyl)piperazin-l-yl]hutyl}-3,4-dihydroquinolin-2(lH)-one The free base of l-(2,3-dichloroplienyl)piperazme, hydrochloride (6.0 g) was liberated by the use ethyl acetate and aqueous ammonia. The remaining oil was dissolved in butanone (500 mL) followed by the addition of potassium carbonate (9.7 g), and the mixture was 30 heated to reflux temperature. To this mixture was added a solution of l-(4-bTomobutyl)-3,4-dihydroquinolin-2(lif)-one (7.9 g) in butanone (150 niL), and the resulting mixture was boiled under reflux for 10 h. The mixture was filtered hot and purified by flash chromatography (eluait: ethyl acetate/triethylamine 100:4) giving the title compound which was precipitated as the hydrochloride salt (2.5 g). Mp 234-235 °C. ^H NMR (DMSO-d 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.55 (t, 2H); 2.85-2.90 (m, 2H); 3.05-3.20 (m, 4H); 3.25 (t, 2H); 3.40 (d, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 7.00 (t, IH); 7.15 (d, IH); 7.20-7.30 (m, 3H); 7.30-7.40 (m, 2H); 11.35 (b s). MS m/z: 432 (MH+). 5 Example 7 lix,3"[4-(2,3-Dichlorophe7iyl)piperazin-l-yl]-l-(5-fluoro--2,3-dihydro-lH-indol-l- yl)propan-l-one 3-Broniopropanoyl chloride (1 g in 10 ml dry dichloromethane) was added with stiiring at 0° 10 C to a suspension of 1 g Wang resin (Rapp polymere, loading 0.95 mmol/g) in 10 ml dry dichloromethane containing 5 equivalents of diisopropylethyl amine. The mixture was stirred overnight at room temperature, filtered and washed with dry dichloromethane (6 x 100 ml). A solution of l-(2,3-dichlorophenyl)piperazine (2.5 equivalents) in dry acetonitrile containing diisopropylethyl amine (5 equivalents) was added to the dried resin and the 15 mixture heated to 70° C for 3 hours. The mixture was cooled to room temperature and the resin washed with dry acetonitrile and dichloromethane and dried. A solution of AICI3 (1.1 equivalent) in dry acetonitrile (5 ml) was added to the resin followed by a solution of 5-fluoro-2,3-dihydro-l//-iadole (3 equivalents) in dry acetonitrile (5 ml) and the mixture agitated for 3 hours. The reaction was quenched by addition of 2N NaOH (1.2 equivalent), 20 filtrated and the product purified by solid phase ion exchange chromatography (Varian SCX columns) using Gilson ASPEC 232 XL. Further purification was performed on a PE Sciex API 150EX instrument equipped with lonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (50 x 20 mm YMC ODS-A with 5 \xm particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to 25 water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by spht-flow MS detection. Purity was determined by integration of the UV trace (254 nm). The retention times RT are expressed in minutes. LC/MS (m/z) 422 (MH+), RT = 2.49, purity: 70.57% 30 The following compounds were prepared in a similar manner 7b,4-f4-(2J-Dichlorophenyl)piperazm-l-ylJ-l-(5-fluoro-2,3-dihydro-lH-indol-J-yl)butan-I-one: LC/MS (m/z) 436 (MH+), RT = 2.58, purity: 96.23% lc,5-f4-(2,3-Dichlorophmyl)piperazin-l-yl]-l-(5-fluoro-2,3-dihydro-lH-indol-l-yl)pentan-1-one: LC/MS (m/z) 450 (MH+), RT = 2.56, purity: 81.68% 7d, 3-[4-(2,3-Dichlorophenyl)piperazin-l-yl]-l-(3,4"dihydro-lH-isoquinolin-2-yl)-propan-5 1-one: LC/MS (m/z) 418 (MH+), RT = 2.43, purity: 72.99% 7e, 4-[4-{2,3-Dichlorophenyl)piperazin-l-yl]-l-(3,4-dihydro-lH-isoquinolin-2-yl)-butan-l-one: LC/MS (m/z) 432 (MH+), RT = 2.49, purity: 8L86% 10 7f, 5-[4-(2,3-Dichloro-phenyl)-piperazin-l-yl]-l-(3,4-dihydro-lH-isoquinolin-2-yl)-pentan-1-one: LC/MS (m/z) 446 (MH+), RT = 2.49, purity: 98.39% 8z,3-f4-{2-ChIorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH-indol"l-yl)propan-l-one: LC/MS (m/z) 370 (MH+), RT = 2.29, purity: 92.49% 15 8b, 5-f4-(2-Chlorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)pentan-l-one: LC/MS (m/z) 398 (MH+), RT = 2.37, purity: 70.1% 8c, 3-f4-(3-Chlorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)propan-l"One: 20 LC/MS (m/z) 370 (MH+), RT = 2.33, purity: 81.15% Sd,5-f4-(3-Chlorophe7iyl)piper(uin-l-ylJ-l-(2,3-dihydro-lH-indol-l-yl)pentcm-J-one: LC/MS (m/z) 398 (MH+), RT = 2.41, purity: 96.58% 25 Se,3-f4-(3-Chlorophertyl)piperazin-l-ylJ-l-(5-fluoro-2,3-dihydro-lH-indol-l-yl)propan-l-one: LC/MS (m/z) 388 (MH+), RT = 2.37, purity: 92.8% Sf,5-f4-(3-Chlorophenyl)piperazin-I-yl]-l-(5-fluoro-2,3"dihydro-lH-indol-l-yl)pentan-]-one: LC/MS (m/z) 416 (MH4-), RT = 2.45, purity: 96.43% 30 8g„3-f4-(2-Chlorophenyl)piperazin"l-yI]-l-(5-fluoro-2,3"dihydro-lH-indol-l-yl)propan-l-one: LC/MS (m/z) 388 (MH+), RT = 2.33, purity: 93.11% 8h, 4-[4-(2-Chlorophenyl)piperazin-l-yl]-l-(5-fluoro-2,3-dihydro-lH-indol-l-yl)hutan-l-one: LC/MS (m/z) 402 (MH+), RT = 2.43, purity: 89.76% 8i, 3-[4-(3-Chlorophenyl)piperazin-l-yl]-l-(3,4-dihydro-lH-isoquinolin-2-yl}-propan-l-one\ 5 LC/MS (m/z) 384 (MH+), RT = 2.31, purity: 92.21% Sj,5-f4-{3-Chlorophenyl)piperazin-l-yl]-]-{3,4-dihydro-lH-isoqumolin-2-yl)-pentan-l-one: LC/MS (m/z) 412 (MH+), RT = 2.37, purity: 95.37% 10 Z]L,3-f4-(2-Chlorophenyl)piperazin-l-ylJ-l-{3,4-dihydro-]H-isoqumolin-2-yl)~propan-]-one: LC/MS (m/z) 384 (MH+), RT = 2.27, purity: 91.51% 8\,4-f4-(2-Chlorophenyl)piperazin-I-ylJ-l-(3,4-dihydro-JH-isoquinolin-2-yl)-butan-l-one: LC/MS (m/z) 398 (MH+), RT = 2.35, purity: 97.56% 15 9a, l-(2,3-Dihydro-lH-indol-l-yl)-3-f4-(2-fluoro-phenyl)-piperazin-l-yl]-propan-l-one: LC/MS (m/z) 354 (MH+), RT = 2.14, purity: 91.64% 9b, l-(2,3-Dihydro-lH-indol-l-yl)-4-f4-(2-fluoro-phenyl)-piperazin-l-ylJ-butan-l-one: 20 LC/MS (m/z) 368 (MH+), RT = 2.24, purity: 76.25% 9c, I-(2,3-Dihydro-IH-indol"l-yl)-5-f4-(2-fluoro-phenyl)-piperazin-l-ylJ-pentan-l-one: LC/MS (m/z) 382 (MH4-), RT = 2.22, purity: 87.9% 25 9d, l-(5-Fluoro-2J-dihydro-2H-indol-l-yl)-3-[4-(2-fluoro-phenyl)-piperazin-l-yl]-propan-1-one: LC/MS (m/z) 372 (MH+), RT = 2.22, purity: 76.87% 9e,l-{5"Fluoro-2,3-dihydro-lH-iTidol-l-yl)-4-f4-P-fluoro-phenyl)-piperazin-l-yl]-butan"l-one: LC/MS (m/z) 386 (MH+), RT = 2.31, purity: 86.01% 30 9f, l-(5-nuoro-2J-dihydro-lH4ndol-l-yl)-5-f4-(2-fluoro-phenyl)-piperazin-l-yl]-pentan-l-one: LC/MS (m/z) 400 (MH+), RT = 2.31, purity: 97.52% 9g,3-f4-(2,4-DifIuoro-phenyI)-piperazm-l-yl]-J-{2,3-dihydro-lH-indol-]-yl)propan-]-one: LCMS (m/z) 372 (MH+), RT = 2.2, purity: 94.79% 9h, 4-[4-(2,4~Difluoro-phenyl)-piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)butan-l-one: 5 LC/MS (m/z) 386 (MH+), RT = 2.29, purity: 79.75% 9i, 5-f4-(2,4-Difluoro-phenyl)-piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)pentan-l-one: LC/MS (m/z) 400 (MH+), RT = 2.29, purity: 99.06% 10 9],3-[4-(2,4-Difluoro-phenyl)-piperazin-l-yl]-l-(5-fluoro-2,3-dihydro-lH-indol-l-yl)propan-l-one: LC/MS (m/z) 390 (MH+), RT = 2.27, purity: 87.99% 9k, l-(3,4-Dihydro-]H-isoquinolin-2-yl)-4-f4-(2-fluoro-phenyl)-piperazin-l-ylJ-butan-l-one: LC/MS (m/z) 382 (MH+), RT = 2.22, purity: 87.75% 15 91, l-(3,4-Dihydro-lH-isoquinolin-2-yl)-5-f4-(2-fluoro-phenyl)-pipera2in-l-yl]-pentan-l-one: LC/MS (m/z) 396 (MH+), RT = 2.22, purity: 85.52% 9Ta,3-f4-(2,4-Difluoro-phenyl)-piperazin-l-yl]-l-(3,4-dihydro~lH-isoquinoIm-2-yl)-20 propan-1-one: LC/MS (m/z) 385 (MH+), RT = 2.22, purity: 87.01% 9n,5-f4-(2,4-DifluoTo-phenyl)-piperazin-l-yl]-l-(3,4-dihydro-JH-isoquinoJin-2-yl)-pentan-1-one: LC/MS (m/z) 414 (MH+), RT = 2.31, purity: 87.84% 25 10^,3-f4-{3,4-Dichlorophenyl)piperazin-l-ylJ-l-(2,3-di}iydro-lH-indol-l-yl)propan-l-one: LC/MS (m/z) 404 (MH+), RT = 2.47, purity: 76.03% lQib,4-f4-(3,4-DichIorophenyl)piperazin-l-yl]-l-(2,3-dihydro-lH-indol-l-yl)butan-l-one: LC/MS (m/z) 418 (MH+), RT = 2.58, purity: 99.32% 30 10c, 3-f4-(3,4-Dichlorophenyl)piperazin-l-ylJ-l-{5-fluoro-2,3-dihydro-lH-indol-l-vl)propan-l-one: LC/MS (m/z) 422 (MH+), RT = 2.52, purity: 80.99% 10d,3-[4-(3.4-Dichlorophenyl)piperazin-l-yl]"l-(3,4-dihydro-lH-isoquinolin-2-yl)-propan-1-one: LC/MS (m/z) 418 (MH+), RT = 2.45, purity: 83.31% l0e, 5-[4-(3,4-Dichlorophenyl)piperazin-l-yl]-l-(3,4-dihydro-lH-isoquinolin-2-yl)-pentan-5 1-one: LC/MS (m/z) 446.1 (MH+), RT = 2.52, purity: 98.79% Pharmacological Testing 10 The compounds of the invention were tested by the use of well-recognised and reliable methods. The tests were as follows: Inhibition of the binding of [3H]YM-OPISI-Z to human dopamine D4 receptors 15 By this method the inhibition by drugs of the binding of [^H]YM-09151 -2 (0.06 nM) to membranes of human cloned dopamine D42 receptors expressed in CHO-cells is determined in vitro. Method modified from NEN Life Science Products, Inc., technical data certificate PC2533-10/96. The results are given in the following Table 1 as ICso-values. 20 Inhibition of the binding of [3H]Spiperone to human D3 receptors By this method the inhibition by drugs of the binding [^Spiperone (0.3 rM) to membranes of hmnan cloned dopamine D3 receptors expressed in CHO-cells is determined in vitro. 25 Method modified fi:om MacKenzie et al. Eur. J. Phamu-Mol. Pharm. Sec. 1994,266,79-85. The results are given in the following Table 1. Inhibition of binding of [3H]Prazosine to rat alpha-1 receptors 30 By this method the inhibition by drugs of the binding of [3H]Prazosine (0.25 nM) to alpha-1 receptors in membranes from rat brain is determined in vitro. Method modified from Hyttel et al. J. Neurochem. 1985,44,1615-1622. The results are given in the following Table 1. 35 Inhibition of the binding of [3H]Spiroperidol to D2 receptors The compounds were tested with respect to affinity for the dopamine D2 receptor by determining their ability to inhibit the binding of [3H]-spiroperidol to D2 receptors by the 5 method of Hyttel et al. J. Neuroche. 1985,44,1615. In general, the compounds of the invention have been foimd to have high affinity for dopamine D4 receptors and dopamine D3 receptors. The compounds have only weak or no affinity for the dopamine D2 receptor. 10 One important effects of adrenergic alpha-1-receptor blockade is postural hypotension resulting from a fall in central venous pressure due to dilation of small capacitance vessels. This effect may further be accompanied by a decrease in cardiac output. Certain compounds of the invention have the further advantage of having only very weak effect at adrenergic 15 alpha-1-receptors which imply a low propensity to cause orthostatic hypotension. Certain of the compounds interact with central serotonergic receptors, such as the 5-HTIA and/or the 5-HT2A receptors and/or they act as 5-HT reuptake inhibitors. 20 Accordingly, the compounds of the invention are considered useful in the treatment of psychosis including the positive and negative symptoms of schizophrenia, affective disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression cognitive disorders and dyskinesia induced by treatment with L-dopa comprising. 25 The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may 30 be used, and any phamaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used. Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg. The total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably 5 about 0.1 to 50 mg of the active compound of the invention. Formulation Examples The pharmaceutical formulations of the invention may be prepared by conventional methods 10 in the art. For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: com starch, potato starch, 15 talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients. Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution 20 to desired volume, sterilisation of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. Typical examples of recipes for the formulation of the invention are as follows: Tablets containing 5.0 mg of active compound calculated as the free base: Patent Claims 1. A halogen substituted 4-pheuyl-l -piperazinyl derivative of formula I 5 whereiii W is C, CH or N, and the dotted line emanating from W indicates a bond when W is C and no bond when W is N or CH; R1 and R2 are independently selected from hydrogen and halogen, provided at least one ofR1 and R2 is a halogen atom; 10 R3 is selected from hydrogen, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, trifluoromethyl, C1-6-alkoxy, aryloxy, aralkoxy, hydroxy, amino, C1-6-alkylamino, di(C1-6-aIkyl)an3ino, nitro and cyano 15 nis2,3,4or5; X is CH2, 0, S, CO, CS, SO or SO2; and Q is a group of formula wherein Z is a chain of 3 to 4 chain members, wherein the chain members are selected from C, CH, CH2, CO, N and NH, provided that only one of the chain members may be N or NH, and said chain Z optionally containing one or two double bonds; 5 R4", R5 R6 R7R8 and R9 are independently selected from R4 R5 R6 R7 R8 and R9 are independently selected from hydrogen, halogen, trifluoromethyl, nitro, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsnlfonyl, hydroxy, hydroxy-C1-6 alkyl, amino, C1-6-alkylamino, 10 di(Ci.6-alkyl)aniino, acyl,aminocarbonyl, C1-6-alkylaminocarbonyl and diC1-6-alkyl)aminocarbonyl; provided that X is not O or S when the group Q is attached via an N atom; and any of its enantiomers and acid addition salts thereof. 15 2. A compoimd according to claim 1 wherein R1 and R2 are both halogen. 3. A compound according to claim 2 wherein R1 and R2 are both chloro. 20 4. A compound according to claim 1 wherein one of R1 and R2 is halogen and the other is hydrogen. 5. A compound according to claim 4 wherein R2 is halogen. 25 6. A compound according to claim 4 wherein R1 is halogen. 7. A compound according to claim 1 whereia R1 and R2 are independently selected from hydrogen or chloro. 30 8. A compound according to claims 1-7 wherein W is N. 9. A compound according to claims 1 to 8 wherein X is CO or CH2. 10. A compound according to claims 1-9 wherein Z is a chain of 3 to 4 chain members, wherein the chain members are selected from C, CH, CH2, N and NH, provided that only 5 one of the chain members may be N or NH. 11. A compound according to claim 10 wherein Q is optionally substituted 1- indolinyl. 10 12. A compound according to claim 10 wherein Q is optionally substituted 3-indolyl. 13. A compound according to claim 10 wherein Q is optionally substituted 1-indanyl. 15 14. Acompound according to claiml O wherein Q is optionally substituted 2-0X0-1,2,3, 4-tetrahydroquinolinyl. 15. A compound according to claim 10 wherein Q is optionally substituted 1,2,3,4- tetrahy droisoquinolinyl. 20 16. A compoimd acccording to claims 9 to 15 wherein Q is unsubstituted or substituted with halogen. 17. A compound according to claim 1 wherein R3 is hydrogen or R3" is attached in the 25 para position on the phenyl ring. 18. A componnd according to claim 17 wherein R3 is halogen. 19. A pharmaceutical composition characterised in that it comprises a compound of any of 30 claims 1 to 18 in a therapeutically effective amount together with one or more phaimaceutically acceptable earners or diluents. 20. Use of a compound of any of Claims 1 to 18 for the manufacture of a medicament useful in the treatment of psychosis including the positive and negative symptoms of schizophrenia, affective disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, cognitive disorders and dyskinesia induced by treatment with L-dopa. 5 21. A method of treating psychosis including the positive and negative symptoms of schizophrenia, affective disorders such as generahsed anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, cognitive disorders and dyskinesia induced by treatment with L-dopa comprising administration of a therapeutically acceptable amount of a compound according to any of claims 1 to 18. 22. A halogen substituted 4-phenyl-l -piperazinyl derivative substantially as herein described and exemplified. 23. A phannaceutical composition substantially as herein described and exemplified.

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