Title of Invention	INDOLE DERIVATIVES USEFUL FOR THE TREATMENT OF CNS DISORDERS
Abstract	The present invention relates to dopamine and serotonin receptor ligands having the general formula 1

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Field of the Invention The present invention relates to a novel class of indole derivatives having affinity for the dopamine D4 receptor. The compounds have antagonistic effect at the dopamine D4 receptor and are therefore useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses. Some of the compounds also have affinity for the dopamine D3 receptor, the 5-HT2A receptor and/or the 5-HT2C receptor and some of the compounds are serotonin reuptake inhibitors. Background of the Invention. Dopamine D4 ligands related to the compounds of the invention are known from WO 98/28293. The indane and dihydroindole derivatives disclosed herein have the general formula wherein A is an indole and Y is a group completing an indane, or a dihydroindole and the other substituents are as defined in the application. WO 00/23441 discloses compounds of the general formula wherein the substituents R1 R2, R3, m, n and p are as defined in the application. The compounds are said to show high affinity to dopamine D2 receptors and are also said to be serotonin reuptake inhibitors. The compounds are claimed to be useful for the treatment of schizophrenia and other psychotic disorders. Other compounds structurally related to the compounds of the invention are described in WO 99/58525. The compounds disclosed herein are said to be 5-HT2A ligands and serotonin reuptake inhibitors and have the general formula wherein the substituents are as defined in the application. The compounds are said to be useful for the treatment of schizophrenia. WO 00/31074 relates to compounds having the formula wherein X is CO or S02 and Y is N-R4 or CR4R5 and the substitutents are as described in the application. The compounds are said to be active at the 5-HT2A receptor, to have 5-HT reuptake inhibiting activity and to enhance 5-HT release. The applications, WO 94/18197, EP 329168, WO 93/16073, EP 732332, W098/37893 and WO 95/11680, disclose dopamine D4 ligands, which, like the compounds of the present invention, are substituted tetrahydroquinolinone and tetrahydroisoquinolinone derivatives. However, these compounds do not contain an indole as the compounds of the invention. The compounds are said to be dopamine D4 ligands useful as antipsychotics. The compounds of WO 93/16073 are also claimed to have antagonistic activity at 5-HT2 receptors. Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effect of neuroleptics. The side effects of 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 clozapines 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, 8383-393). 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 it has been reported that these compounds 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). Further, evidence for a genetic association between the "primarily inattentive" subtype of ADHD and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol Psychiat 2000, 5, 531-536). This clearly indicates a link between the dopamine D4 receptor and ADHD, and ligands affecting this receptor may be useful for the treatment of this particular disorder Dopamine D3 receptors also belong to the dopamine D2 subfamily of receptors, and they are preferentially located in the limbic brain regions (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 and 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, 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. Dopamine D3 agonists have also been considered relevant in the treatment of schizophrenia (Wustow et al. Current Pharmaceutical Design 1997, 3, 391-404). Various effects are known with respect to compounds, which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor, which was previously referred to as the 5-HT2 receptor, the following effects have been reported, e.g.: Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989,18,119), reduction of the negative symptoms of schizophrenia and of extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; "Migraine - Current trends in research and treatment"; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al. Psychopharmacology 1985, 86, 303-305 and Perregaard et al. Current Opinion in Therapeutic Patents 1993, 7,101-128). Some clinical studies implicate the 5-HT2 receptor subtype in aggressive behaviour. Further, atypical serotonin-dopamine antagonist neuroleptics have 5-HT2 receptor antagonistic effect in addition to their dopamine blocking properties and have been reported to possess anti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents.l999s 8(4), 350-351). Recently, evidence has also accumulated which support the rational for selective 5-HT2A antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000,2(1), 22-24). Compounds, which are 5-HT reuptake inhibitors, are well-known antidepressant drugs. 5-HT2C ligands have been found to augment the effect of 5-HT reuptake inhibitors in microdialysis experiments and animal models, and compounds having 5-HT reuptake inhibiting effect combined with affinity for the 5-HT2C receptor may therefore be particularly useful for the treatment of depression and other disorders responsive to serotonin reuptake inhibitors (PCT application No. PCT/DK00/00671). Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at the 5-HT transporter may have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients. Compounds with combined effect at the dopamine D4 receptor and the 5-HT2A receptor may have the benefit of improved effect on positive and negative symptoms of schizophrenia, and the benefit of effect on depressive and anxiety symptoms. Furthermore, 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. Summary of the Invention The object of the present invention is to provide compounds that are partial agonists or antagonists at the dopamine D4 receptor and such compounds with combined effects at the dopamine D4 receptor, the D3 receptor, the 5-HT2A receptor, the 5-HT2C receptor and/or the 5-HT transporter. A further object of the present invention is to provide compounds with such activities which have improved solubility compared to prior art compounds. Accordingly, the present invention relates to novel compounds of formula I (a) one of Yl and Y2 is N, which is bound to Y4, and the other of Y1 and Y2 is CO, CS, SO, orS02andY4isisCH2; (b) one of Y1 and Y2 is N, which is bound to Y4, and the other of Y1 and Y2 is CH2 and rts CO, CS, SO or S02; or (c) one of Y1 and Y2 is N, which is bound to Y4, and the other of Y1 and Y2 is CH2 and Y4 is CH2; Y3 is Z-CH2, CH2-Z or CH2CH2, and Z is 0 or S; provided that when Y1 is N, Y3 may not be Z-CH2; W is a bond or an O, S, CO, CS, SO or S02 group; n is 0-5, m is 0-5 and m + n is 1-10; provided that when W is O or S, then n > 2 and m > 1; when W is CO, CS, SO or S02, then n > 1 and m > 1; X is C, CH or N; provided that when X is C, the dotted line indicates a bond, and when X is N or CH, the dotted line is not a bond; In a second embodiment of the invention, one of Y1 and Y2 is N which is bound to Y4 and the other of Y1 and Y2 is CO, and Y4 is CH2. In a third embodiment of the invention, one of Y1 and Y2 is N, which is bound to Y4, and the other of Y1 and Y2 is CH2 and Y4 is CO. In a fourth embodiment of the invention, Y1 is a nitrogen bound to Y4 and one of Y4 and Y2 is CO and the other is CH2, In a fifth embodiment of the invention, Y1 is a nitrogen bound to Y4, Y2 is CO and Y4 is CH2. In a sixth embodiment of the invention, Y1 is a nitrogen bound to Y4, Y2 is CH2 and Y4 is CO. In a seventh embodiment of the invention, Y2 is a nitrogen bound to Y4 of and one of Y1 and Y4 is CO and the other is CH2. In an eighth embodiment of the invention, Y2 is a nitrogen atom bound to Y4, Y1 is CH2 and Y4 is CO. In a ninth embodiment of the invention, Y2 is a nitrogen atom bound to Y4, Y1 is CO and Y4 is CH2. In a tenth embodiment of the invention, one of Y1 and Y2 is N, which is bound to Y4, and the other of Y1 and Y2 is CH2 and Y4 is CH2. Such compounds are preferably in the form of pharmaceutically acceptable di-salts thereof. In a further embodiment of the invention, Y3 is CH2CH2 or CH2Z. In still further embodiments of the invention, X is C, X is N or X is CH The substituents R1 -R9 are in particular selected from hydrogen, halogen, cyano, nitro, amino, C1-C6-alkylamino, di-C1-C6alkylamino, C1-C6-alkyl, C3-8-cycloalkyl and trifluoromethyl, and R is hydrogen, C1-C6alkyl or acyl and /or W is a bond and n + m is 1 to 6, in particular 3 to 6. The compounds of the invention are partial agonists or antagonist at the dopamine D4 receptor. Many compounds have combined effect at the dopamine D4 receptor and dopamine D3 receptor affinity, 5-HT2A receptor affinity, 5-HT2c receptor affinity and /or 5-HT reuptake inhibiting effect. Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep. In anothpr aspect, the present invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutical^ acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents. In a further aspect, the present invention provides the use of a compound of Formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders. Detailed Description of the Invention The compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention. The term C1-C6-alkyl refers to a branched or unbranched 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, 2-methyl-l-propyl, pentyl andhexyl. Similarly, C2-6-alkenyl and C2-6~alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. The terms Cn5-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylamino, C1-C6 alkylcafbonyl, and the like, designate such groups in which the alkyl group is Cue alkyl as defined above. The termC1-C8-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C~atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc. The tenn aryl refers to a carbocyclic aromatic group, such as phenyl, naphthyl, in particular phenyl, including methyl substituted phenyl, or naphthyl. Halogen means fluoro, chloro, bromo or iodo. As used herein the term acyl refers to a formyl, C1-C6 -alkylcarbonyl, arylcarbonyl, aryl-C1-C6-alkylcarbonyl, C3-8-cycloalkylcarbonyl or a C3-8-cycloalkyl-C1-C6-alkyl-carbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group. The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, foT example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. 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 be used, and any pharmaceutically 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 about 0.1 to 50 mg of the active compound of the invention. The compounds of the invention may be prepared as follows: wherein R1 - R10, X, Y1, Y2, Y3, Y4, W, n, m and the dotted line are as previously defined and E is an aldehyde or an activated carboxylic acid group; wherein R1R2, Y3, W, n, m and the dotted line are as previously defined, one of Y5 and Y6 is NH or N * and the other of Y5 and Y6 is CO, CS, SO, S02 or CH2 and L is a leaving group such as e.g. halogen, mesylate or tosylate; or 4) Reducing the double bond in the tetrahydropyridinyl ring in derivatives of the following formula VH: wherein R110, Y1, Y2, Y3, Y4, W, m and n are as previously defined; 5) Reducing the amide carbonyl in a compound of formula VIII: wherein R1R10, X, Y3, W, n, m and the dotted line are as previously defined, one of Y7 and Y8 is NH and the other of Y7 and Y8 is CH2 and E is an aldehyde or an activated carboxylic acid; whereinR'-R10, X, Y3, W}n,m and the dotted line are as previously defined, one of Y7 and Y8 is NH and the other of Y7 and Y8 is CH2 and E is an aldehyde or an activated carboxylic acid; wherein R*-R9, Y1, Y2, Y3, X, W, m and n are as previously defined and R'OH is hydroxyethyl or hydroxymethyl polystyrene, Wang resin or analogous polyethylene glycol polystyrene resins; whereupon the compound of Formula I is" isolated as the free base or a pharmaceutically acceptable acid addition salt thereof. The alkylation according to method 1) and 3) is conveniently performed in an inert organic solvent 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 performed at a fixed temperature, which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or Af-methylpyrrolidin-2-one (NMP), preferably in the presence of a base. ■ The synthesis the amines of formula (II), 3-(piperidin-4-yl)-lif-indoles and 3-(3,6-dihydro-2Hpyridin-4-yl)-lH-indoles has been described in the literature (see e.g. EP-A1-465398). Alkylating reagents of formula (HI) are known from the literature (see Oshiro et al. J. Med. Chem. 2000, 43, 177-189 and EP-B1-512525), or they can be prepared by methods obvious to a chemist skilled in the art (see e.g. Kowalski et al. J.Heterocyclic Chem. 2000, 37, 187-189, Mokrosz et aL Pharmazie 1997, 52, 423-428 and Misztal et al. Med.Chem.Res. 1992, 2, 82-87). Alkylating reagents of formula (VI) can be prepared by methods obvious to a chemist skilled in the art, and amines of formula (V) are commercially available or described in the literature. The reductive alkylation according to methods 2) and 7) is performed by standard literature methods. The reaction can be performed in two steps, e.g. coupling of derivatives of formula II/Va and the reagent of formula IV/X by standard methods via the carboxyhc acid chloride or by use of 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. Carboxylic acids or aldehydes of formula IV/X can be prepared by methods obvious to a chemist skilled in the art. The alkylation according to method 3) is conveniently performed as described above or by reacting the nitrogen anion of V with VI. The nitrogen anion of V can be prepared in an inert organic solvent, e.g. dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or JV-methylpyirolidin-2-one (NMP), by the use of a strong base, e.g. NaH, before the alkylation. The reduction of the double bond according to method 4) is generally performed by catalytic hydrogenation at low pressure ( Reduction of amide groups according to methods 5) and 6) is most conveniently performed with lithium aluminium hydride or alane in an inert organic solvent such as e.g. tetrahydrofuran (THF) or diethylether from 0 °C to reflux temperature. Starting materials of formula (VIE) may be prepared by methods 2) and 3), whereas starting materials of formula (DC) may be prepared by methods 1), 7) and 8). The coupling according to method 8) is conveniently performed by the use of coupling reagents such as e.g. dicyclohexyl carbodiimide. The derivatives of structure (XI) is prepared by means of a solid phase synthesis sequence as outlined in Scheme 1 below. The first building block (XII), prepared by methods obvious to the chemist skilled in the art, is generally attached to the resin (polystyrene bound ethyl 4-nitrophenyl carbonate) using base e.g. NN-dimetiiylaminopyridine and N,N diisopropylethylamine at elevated temperature (e.g. 50-100 °C) in an aprotic solvent (e.g. DMF or DMSO) to yield (XHI) . After deprotection of the amino group by trifluoroacetic acid (resin XIV), the second diversifying building block was introduced by alkylation. The alkylation was performed at elevated temperature (50-100 °C) in an aprotic solvent such as DMF, acetone or acetonitrile leading to resin (XV). After deprotection of the carboxylic acid ester by trifluoroacetic acid (resin XVI), the third diversifying building block of formula (Va) was introduced by standard amide forming reaction sequence, e.g. converting the carboxylic acid to the corresponding acid chloride using thionyl chloride at low temperature in dichloromethane, acetonitrile or DMF followed by treatment with an amine. The final product was cleaved from the resin using diluted sodium methoxide in a methanol/tetrahydrofuran mixture at ambient temperature. Experimental Section Melting points were determined on a Buchi B-540 apparatus and are uncorrected. Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instruments. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (50 X 4.6 mm YMC ODS-A with 5μm particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times Rt are expressed in minutes. Preparative LC-MS-separation was performed on the same instrument. The LC conditions (50 X 20 mm YMC ODS-A with 5 nm particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection. ]H 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. TMS was used as internal reference standard. Chemical shifts are expressed as ppm values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qv=quintet, h=heptet, dd^double doublet, dt^double triplet, dq=double quartet, tt=triplet of triplets, m= multiplet, b=broad. NMR signals corresponding to acidic protons are to some extent omitted. Content of water in crystalline compounds was determined by Karl Fischer titration. For column chromatography, silica gel of type Kieselgel 60, 40-60 mesh ASTM was used. For ion-exchange chromatography, the following material was used: SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No. 220776. Prior to use, the SCX-columns were pre-conditioned with 10% solution of acetic acid in methanol (3 mL). Examples Preparation of intermediates A. Alkylating reagents l-(2-Chloroethyl)-334-dihydroquinolin-2(li?)-one A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethyl formamide (100 mL) was kept at 15-18 °C followed by the addition of a solution of 3,4-dihydroquinolin-2(li7)-one (10.0 g) in dimethyl formamide (150 mL). The resulting mixture was stirred at room temperature for 60 min followed by the addition of a solution of 2-chloroethyl acetate (10.0 g) in dimethyl formamide (50 mL) at a temperature of 20 °C. The resulting mixture was heated at 80 °C for 2 lA h, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSCU) and concentrated in vacuo. The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give crude l-(2-acetoxyethyl)-3,4-dihydroquinolin-2(li7)-one (10.2 g). A mixture of crude l-(2-acetoxyethyl)-3,4-dihydroquinolin-2(lH)-one, sodium methanolate (2.5 mL, 30% in methanol) and methanol (250 mL) was stirred at room temperature for 16 h and subsequently concentrated in vacuo. The residue was purified by flash chromatography on sihcagel (eluent: ethyl acetate/heptane 1:1) to give the corresponding alcohol as a red crystalline compound (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 mL) followed by the addition of trietylamine (8.2 mL). The resulting mixture was cooled to 5-6 °C followed by the addition of a solution of methane sulfonic acid chloride (2 mL) in tetrahydrofuran (25 mL). The mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in dimethyl formamide (50 mL) followed by addition of lithium chloride (4.9 g), and the resulting mixture was heated at 70 °C for 5 min. The mixture was poured onto brine, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSC1-C6), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a red oil (2.9 g). l-(3-Bromopropan-l-yl)-3,4-dihydroquinolin-2(lff)-one A suspension of sodium hydride (6.8 g, 60% in mineral oil) and dimethyl formamide (200 mL) was kept at 20-25 °C followed by the addition of a solution of 3,4-dihydroquinolin-2(lH)-one (25.0 g) in dimethyl formamide (180 mL). The resulting mixture was stirred at room temperature for 10 min followed by the addition of a solution of 1,3-dibromopropane (172 g) in dimethyl formamide (150 mL) at a temperature of 20-35 °C. The resulting mixture was stirred at 30 °C for 20 min and concentrated in vacuo. The residue was poured 3-Chloro-1 -(3 ,4-dihydro4ff4soquinolin-2-yl)propan-1 -one A solution of 3-chloropropanoyl chloride (10.5 g) in tetrahydrofuran (400 mL) was cooled down to 6 °C followed by the addition of a solution of 3,4-dihydro-liJ-isoquinoline (10.0 g). The resulting mixture was stirred at 10 °C for 30 min, filtered and concentrated in vacuo. The residue was subjected to a standard aqueous work up procedure followed by purification by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a colourless oil (10 g). Preparation of solid supported intermediates Preparation of 4-nitrophenyloxycarbonyloxyethyl polystyren A 2 L round bottom flask was charged with hydroxyethyl polystyren (62.9 g, 83 mmol, commercially available from Rapp Polymere, cat. no. HA 1 400 00), 7V-methyl-morpholine (20 mL, 183 mmol) and dry dichloromethane (900 mL). The suspension was cooled on an ice bath and 4-nitrophenyl chloroformiate dissolved in dry dichloromethane (400 mL) was added during 5 minutes. The mixture was stirred at room temperature for 16 h. The resin was filtered off and washed with dry dichloromethane (5 x 200 mL). The resin was dried in vacuo (20 °C5 72 h) to yield the title resin (79.6 g). isoquinolin-2-yl)propan-l-one (3.5 g) in butanone (60 mL). The mixture was boiled under reflux for 30 h followed by the addition of an additional amount of 3-chloro-l-(3,4-dihydro-lH-isoquinolin-2-yl)propan-l-one (2.0 g) and triefhylamine (1.6 mL) in tetrahydroftiran (50 mL). The resulting mixture was boiled under reflux for an additional 12 h. The mixture was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 100:4:4) to give the crude product. The title compound was isolated as the oxalate salt from acetone as a white crystalline compound (0.75 g). Mp 206-209 °C. !HNMR (DMSO-d6): 1.95 (q, 2H); 2.05-2.15 (m, 2H); 2.80 (t, 0.8H); 2.90 (t, 1.2H); 2.90-3.10 (m, 5H); 3.30 (t, 2H); 3.55 (d, 2H); 3.70 (t5 2H); 4.65 (s, 1.20H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H); 7.15-7.25 (m, 5H); 7.30-7.40 (m, 1H); 7.40 (d, 1H); 11.05 (s, 1H). MS m/z: 406 (MH+), 231. The following compound was prepared in a similar manner 6b, 7-Chloro-3-{l-[3-(3,4-dihydro-lH-isoquinolin-2-yl)-3-oxopropm^ lH-indole, hydrochloride from 7-chloro-3-(piperidin-4-yl)-lH-indole and 3-bromo-l-(3,4-dihydro-lH-isoquinolin-2- yl)propan-l-one. !H NMR (DMSO-de): 2.05-2.25 (m, 4H); 2.80 (t, 0.8H); 2.95 (t,1.2H); 3.00-3.20 (m, 5H); 3.30-3.45 (m, 2H); 3.55-3.65 (m, 2H); 3.65-3.75 (m, 2H); 4.65 (s51.2H); 4.75 (s, 0.8H); 7.00 (t, 1H); 7.15-7.25 (m, 6H); 7.70 (d, 1H); 10.70 (broad s, 1H);11.30 (s, 1H). MS m/z: 422 (MH+), 247. 6c, 5-Chlo7'o-3-{l-[4-(3J-dihydro-2H~quinolin-l-yl)-4-oxobutan-l-yl]piperi^ indole, hydrochloridefrom 5-chloro-3-(piperidin-4-yl)-lH-indole and 4-chloro-l-(3,4-diliydro-2H-quinolin-l-yl)butan-l-one. Mp 158-162 °C. 1NMR (DMSO-d6): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40 (d, 1H); 7.75 (s, 1H); 10.45 (broad s, 1H); 11.15 (s, 1H). MS m/z: 436 (MH+), 303. Example 7 7, 5-Fluoro-3~{l-[4-(3A-dihydro-lH4soquinolin-2-yl)-4-oxobutan-l-yllpip indole A mixture of 5-fluoro-3-(piperidin~4-yl)-li?-indole (3.0 g), butanone (200 mL), tetrahydrofuran (200 mL), methanol (30 mL), potassium iodide (11.4 g) and triethylamine (7.6 mL) was heated until reflux temperature followed by the addition of a solution of 4-chloro-l-(3J4-dihydro-l-Hr-isoquinolin-2-yl)butan-l-one (14.6 g) in butanone (50 mL). The mixture was boiled under reflux for 2 h, filtered hot and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 100:5:5) to give the crude product. The title compound was isolated as the free base from ethyl acetate as a white crystalline compound (0.9 g). Mp 146-148 °C. 1NMRDMSO-d6): 1.55-1.70 (m, 2H); 1.70-1.80 (m, 2H); 1.85-1.95 (m, 2H); 2.00 (q, 2H); 2.30 (q, 2H); 2.35-2.45 (m, 2H); 2.60-2.70 (m, IH); 2.75 (t, 0.8H); 2.80-3.00 (m, 3.2H); 3.65 (t, 2H); 4.60 (s, 1.2H); 4.70 (s, 0.8H); 6.85-6.95 (m, IH); 7.10-7.20 (m, 5H); . 7.25 (d, IH); 7.30-7.35 (m, IH); 10.85 (s, IH). MS m/z: 420 (MH+), 202. Example 8 8, 5-Chloro-3-{l-[4~(3A-dihydro-lH-isoquinolin-2-yl)-4-oxobutan-l indole A mixture of 5-fluoro-3-(piperidin-4-yl)-lH-indole (3.0 g)5 butanone (200 mL) and triethylamine (8.9 mL) was heated until reflux temperature followed by the addition of a solution of 4-chloro-l-(3s4-dihydro-177-isoquinolin-2-yl)butan-l-one (15.2 g) in butanone (80 mL). The mixture was boiled under reflux for 6 h. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 100:4:4) to give the crude product. The title compound was isolated as the free base from acetone as a white crystalline compound (0.6 g). Mp 172-175 °C. lHNMR (DMSO-d6): 1.55-1.65 (m, 2H); 1.65-1.75 (m, 2H); 1.90 (s, 2H); 2.00 (q, 2H); 2.30 (q, 2H); 2.40 (q, 2H); 2.65-2.80 (m, 1.8H); 2.80-3.00 (m, 3.2H); 3.70 (t, 2H); 4.60 (s, 1.2H); 4.70 (s, 0.8H); 7.05 (d, IH); 7.10-7.25 (m, 5H); 7.35 (d, IH); 7.55 (s, IH); 11.00 (s, IH). MS m/z: 436 (MH+)5 202. (d, 2H); 5.05 (broad s); 6.70-7.15 (m, 4H); 6.90 (t, IH); 7.20 (s, IH); 7.30-7.40 (m, IH); 7.50 (d, IH); 10.75 (broad s, IH); 11.05 (s, IH). MS m/z: 420 (MH+), 287. 9d, 5-Chloro-3-{l-[3-(3,4-dihydro-2H-quinolin-l-yl)propan-l-yl]piperidin-4-yl}-lH-indole, dihydrochloride from 5-cUoro-3-{l-[3-(2-oxo-3,4-dihydro-2i7-quinolin-l-yl)propan-l-yl]piperidin-4-yl}-lH-indole. Mp 201-204 °C. 'HNMR (DMSO-d6): 1.95 (t, 2H); 2.00-2.25 (m, 6H); 2.75 (t, 2H); 3.00-3.20 (m, 5H); 3.30 (t, 2H); 3.40 (t, 2H); 3.55 (d, 2H); 6.40 (broad s); 6.65 (s, IH); 6.85 (s, IH); 6.95 (d, IH); 7.00-7.10 (m, 2H); 7.20 (s, IH); 7.40 (d, IH); 7.75 (s, IH); 10.85 (broad s, IH); 11.20 (s, IH). MS m/z: 408 (MH+), 275. 9e, 5-Chloro-3-{l-f4-(3,4-dihydro-2H-quinolin-l-yl)butan-l-ylJpiperidin-4-yl}-lH-indole, dihydrochloride from5-cbJoro-3-{l-[4-(2-oxo-3,4-d^ydro-2ff-quinolm-l-yl)butan-l-yl]piperidin-4-yl}-lflr-indole. Mp 140-145 °C. JHNMR (DMSO-d6): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.00-2.25 (m, 4H); 2.75 (s, 2H); 2.95-3.25 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.75 (broad s, IH); 6.90 (broad s, IH); 7.00 (s, IH); 7.05-7.15 (m, 2H); 7.20 (s, IH); 7.40 (d, IH); 7.80 (s, IH); 10.70 (broad s, IH); 11.20 (s, IH). MS m/z: 422 (MH+), 289,188. 9f, 5-Chloro-3-{l-f5-(3,4-dihydro-2H-quinolin-l-yl)pentan-l-yl]piperidin-4-yl}-lH-indole, dihydrochloride from 5-cbJoro-3-{l-[5-(2-oxo-3,4-dmydro-2ff-quinoliri-l-yl)peritaii-l-yl]piperidin-4-yl}- lff-indole. Mp 101-106 °C. JHNMR (DMSO-d6): 1.30-1.45 (m, 2H); 1.65 (s, 2H); 1.70- 1.85 (m, 2H); 1.95 (s, 2H); 2.00-2.25 (m, 4H); 2.75 (s, 2H); 2.95-3.25 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.80 (broad s, IH); 6.90-7.15 (m, 4H); 7.20 (s, IH); 7.35 (d, IH); 7.75 (s, IH); 10.70 (broad s, IH); 11.20 (s, IH). MS m/z: 436 (MH+), 303. 9g, 7-Chloro-3-{l-[4-(3,4-dihydro-2H-quinolin-l-yl)butan-l-yl]piperidin-4-yl}-lH-i7idole, dihydrochloride from 7-chloro-3- {1 -[4-(2-oxo-3,4-dihydro-2H-quinoliti-1 -yl)butan-1 -yl]piperidin-4-yl} -\H- indole. Mp 214-219 °C. 'H NMR (DMSO-d6): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.00-2.15 (m, 2H); 2.15-2.30 (m, 2H); 2.70 (s, 2H); 2.95-3.15 (m, SB); 3.35 (s, 4H); 3.55 (d, 2H); 2.00-2.20 (m, 4H); 2.95-3.25 (m, 5H); 3.25-3.40 (m, 4H); 3.55 (d, 2H); 4.15-4.20 (m, 2H); 6.55 (t, IH); 6.65 (d, IH); 6.70-6.80 (m, 2H); 7.05 (d, IH); 7.20 (s, IH); 7.40 (d, IH); 7.75 (s, IH); 10.50 (broad s, IH); 11.15 (s, IH). MS m/z: 424 (MH+), 289,190. 9l,5-Fluoro-3-{l-f3-(3,4-dihydro-2H-quinolin-l-yl)propan-l-yl]-3,6-dihydro-2H-pyridin-4-yl}-lH-indole, dihydrochloride from5-fluoro-3-{l-[3-(2-oxo-3,4-dihydro-2F-qiunolin-l-yl)propaii-l-yl]-3,6-dih.ydro-2S'-pyridin-4-yl}-lH-indole. Mp 220-223 °C. !H NMR (DMSO-ds): 1.85-2.00 (m, 2H); 2.05-2.10 (m, 2H); 2.70-2.80 (m, 4H); 2.90-3.00 (m, IH); 3.15-3.30 (m, 2H); 3.30-3.35 (m, 2H); 3.40 (t, 2H); 3.55-3.65 (m, IH); 3.70-3.80 (m, IH); 4.00 (d, IH); 6.10 (s, IH); 6.70 (broad s, IH); 6.90 (broad s, IH); 6.95-7.05 (m, 2H); 7.05-7.10 (m, IH); 7.40-7.45 (m, IH); 7.55-7.65 (m, 2H); 11.10 (broad s, IH); 11.60 (s, IH). MS m/z: 390 (MH+), 203,146. 9m, 5-Fluoro-3-{l-[4-(3,4-dihydro-2H-quinolin-l-yl)butan-l-yll-3,6-dihydro-2H-pyridin-4-ylj-lH-indole, dihydrochloride from5-fluoro-3-{l-[4-(2-oxo-3)4-diliydro-2F-quinolin-l-yl)butaii-l-yl]-3,6-dihydro-2i7-pyridin-4-yl}-lH-indole. Mp 198-200 °C. !H NMR (DMSO-d6): 1.60-1.75 (m, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.70-2.80 (m, 4H); 2.85-3.00 (m, IH); 3.15-3.30 (m, 4H); 3.30-3.40 (m, 2H); 3.55-3.65 (m, IH); 3.70-3.80 (m, IH); 3.95 (d, IH); 6.10 (s, IH); 6.80 (broad s, IH); 6.90-7.20 (m, 3H); 7.00 (t, IH); 7.40-7.45 (m, IH); 7.55-7.65 (m, 2H); 10.95 (broad s, IH); 11.55 (s, IH). MS m/z: 404 (MH+), 271,217. 9n,5-Fluoro-3-{l-f5-(3,4-dihydro-2H-quinolin-l-yl)pentan-l-yl]-3,6-dihydro-2H-pyridin-4-yl}-lH-indole, dihydrochloride from5-fluoro-3-{l-[5-(2-oxo-3,4-dihydro-2iy-quinolin-l-yI)pentaii-l-yl]-3,6-dihydro-2iir- pyridin-4-yl}-lH-indole. Mp 167-169 °C. lE NMR (DMSO-d6): 1.30-1.45 (m, 2H); 1.70 (s, 2H); 1.75-1.90 (m, 2H); 2.00 (s, 2H); 2.70-2.85 (m, 3H); 2.85-3.00 (m, IH); 3.05-3.20 (m, 2H); 3.20-3.30 (m, IH); 3.35 (s, 2H); 3.55-3.65 (m, IH); 3.70-3.80 (m, IH); 3.95 (d, IH); 6.10 (s, IH); 6.80-7.25 (m, 4H); 7.00 (t, IH); 7.40-7.45 (m, IH); 7.55-7.65 (m, 2H); 11.00 (s, broad s, IH); 11.60 (s, IH). MS m/z: 418 (MH+), 231,188. Example 10 1 Oa, 4-Fluoro-3-{l-[3-(3} 4-dihydro-lH-isoquinoUn-2-yl)-3-oxopropan-l-yl]piperidin-4-yl}-lH-indole Polymer bound 3-[l-(4-fluoro-li?-indol-3-yypiperidin-l-yl)propionic acid (0.1 g, 0.08 mmol) and dry dichloromethane (1 mL) were mixed in a reactor tube. The mixture was cooled to 0 °C and treated for 2 h with a 2 M solution of thionyl chloride (0.4 mL, 0.8 mmol) in dichloromethane. The resin was filtered off and washed with dry dichloromethane (3x1 mL), resuspended hi dichloromethane (1 mL), and treated for 3 h at room temperature with 3,4-dihydro-lH-isoquinoline (0.05 g, 0.4 mmol). The resin was filtered off and washed with dichloromethane (3x1 mL), a 1:1 mixture of dichloromethane:triethyIamine (3x1 mL) and dry dichloromethane (3x1 mL). The resin was treated for 1 h with 1 mL of a mixture of sodium methoxide (2 mL, 5 N sodium methoxide in methanol), methanol (50 mL) and tetrahydrofuran (50 mL). After filtration, the resin was washed with methanol (1 mL). The combined filtrates were loaded on a pre-conditioned ion exchange column (500 mg SCX column, commercially available from Analytical Instruments, part no. 1210-2040), washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol. After evaporation of volatile solvents, the crude product was purified by preparative reversed phase HPLC chromatography. The resulting solution was subsequently loaded on a pre-conditioned ion exchange column washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol. Evaporation of volatile solvents afforded the title compound as an yellow oil (5 mg, 12 fxmol). LC/MS (m/z) 406 (MH+), RT = 3.61, purity: 66%. The following compounds were prepared in a similar manner (lOb-lOm) or by the use of 3,4-dihydro-2H-quinoline (lOn-IOz): 10b, 4-Fluoro-3-{l-[4-(3,4-dihydro-lH4soquinolin-2-yl)-4-oxobutan-l-ylfa IH-indole LC/MS (m/z) 420 (MH+), RT = 3.69, purity: 93% 10c, 4-Fluoro-3-{l-f6~(3A-dihydroAHAsoquinoli7i-2-yiy6-oxo IH-indole A mixture of 5-fluoro-3-(piperidin-4-yl)-lH-indole (5.0 g), triethylamine (6.35 mL) and tetrahydrofuran (500 mL) was cooled to 7 °C and subsequently added a mixture of succinic anhydride (2.5 g) in tetrahydrofuran (50 mL). The mixture was stirred at 8-10 °C for 2 h, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and the organic phase was washed with cold 2N aqueous hydrochloride solution and brine. The organic phase was dried (MgSCU), filtered and concentrated in vacuo (6.4 g). The residue (1.5 g) and 3,4-dihydro-lH-isoquinoline (0.63 g) was dissolved in a mixture of acetonitril (25 mL) and dimethyl formamide (10 mL), and the resulting mixture was cooled (5 °C) and subsequently added 1,3-dicyclohexylcarbodiimide (1.0 g). The mixture was stirred at room temperature for 16 h, filtered and poured into brine. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran, and the combined organic phase was washed with brine, dried (MgSCU) and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate) to give a white solid (1.0 g), which subsequently was added to a mixture of alane in tetrahydrofuran (100 mL) at 5-10 °C. The alane was prepared from lithium aluminium hydride (0.55 g) and concentrated sulphuric acid (0.72 g). The mixture was quenched by the addition of water (1 mL), 15 % aqueous sodium hydroxide solution (0.5 mL) and water (2.5 mL), and the resulting mixture was dried (MgSCU), filtered and concentrated in vacuo. The title compounds was crystallised from acetone as the dioxalate salt (0.8 g). Mp 105-111 °C. !H NMR (DMSO-de): 1.75 (s, 4H); 1.85-2.05 (m, 2H); 2.10 (d, 2H); 2.90-3.20 (m, 9H); 3.25 (t, 2H); 3.50 (d, 2H); 4.15 (s, 2H); 6.85-6.95 (m, 1H); 7.10-7.25 (m, 5H); 7.30-7.45 (m, 2H); 11.05 (s, 1H). MS m/z: 406 (MH+),273, 188. The following compound was prepared in a similar manner lib, 5-FluorO'3-{l-f4-(6J-dimethoxy-3J4'dihydro-lH4soquinolin'2-yl)butan-l-yl]piperidin-4~yl}-lH-indole, dioxalate from 5-fluoro-3-(piperidin-4-yl)-lH-indole and 6,7-dimethoxy-3,4-dihydro-lii/-isoquinoline. Mp 98-105 °C. *H NMR (DMSO-d6): 1.75 (s, 4H); 1.85-2.00 (m, 2H); 2.10 (d, 2H); 2.90-3.15 (m, 9H); 3.30 (s, 2H); 3.50 (d, 2H); 3.75 (d, 6H); 4.10 (s, 2H); 6.75 (s, 1H); 6.80 (s, 1H); 6.90-6.95 (m, 1H); 7.20 (s, 1H); 7.30-7.45 (m, 2H); 11.05 (s, 1H). MS m/z: 466 (MH+), 273, 248. Pharmacological Testing The compounds of the invention were tested in well-recognised and reliable tests. The tests were as follows: Inhibition of the binding of [3H]YM-09151-2 to human dopamine D4 receptors By this method, the inhibition by drugs of the binding of [^^-09151-2 (0-06 nM) to membranes of human cloned dopamine D4.2 receptors expressed in CHOcells is determined in vitro. Method modified from NEN Life Science Products, Inc., technical data certificate PC2533-10/96. The compounds of the invention have been found potently to inhibit the binding of tritiated YM-09151-2 to dopamine D4 receptors. The compounds have also been tested in a functional assay described by Gazi et al. in British Journal ofPhannacology 1999,128, 613-620. In this test, the compounds were shown to be partial agonists or antagonists at the dopamine D4 receptors. The compounds of the invention have also been tested in the following tests: Inhibition of the binding of [^Spiperone to D2 receptors The compounds of the invention were tested with respect to affinity for the dopamine D2 receptor by determining their ability to inhibit the binding of [ HJspiperone to D2 receptors by the method of Hyttel et aL J. Neurochem. 1985, 44,1615. Inhibition of the binding of [3H]Spiperone to human D3 receptors By this method, the inhibition by drugs of the binding [ H]Spiperone (0.3 nM) to membranes of human cloned dopamine D3 receptors expressed in CHO-cells is determined in vitro. Method modified from MacKenzie et al. Eur. J. Pharm.-Mol. Pharm. Sec. 1994,266, 79-85. Inhibition of the uptake of [3H] Serotonin into whole rat brain synaptosomes The compounds were tested with respect to their 5-HT reuptake inhibiting effect by measuring their ability to inhibit the uptake of [ H]serotonin into whole rat brain synaptosomes in vitro. The assay was performed as described by Hyttel Psychopharmacology 1978, 60,13. Inhibition of the binding of [3H]Ketanserin to 5-HT2A receptors The compounds were tested with respect to their affinity for 5-HT2A receptors by determining their ability to inhibit the binding of [3H]Ketanserin (0.50 nM) to membranes from rat brain (cortex) in vitro. Method described in Sanchez et al. DrugDev. Res. 1991,22, 239-250. 5-HT2c receptor efficacy as determined by fluorometry The compounds were tested with respect to their efficacy on 5-HT2C receptor-expressing CHO cells as determined by fluorometric imaging plate reader (FLIPR) analysis. This assay was carried out according to Molecular Devices Inc. instructions for their FLIPR Calcium Assay Kit and as modified from Porter et al. British Journal of Pharmacology 1999,128:13. The compounds were found to have no substantial or only weak affinity for the dopamine D2 receptor. Many of the compounds have been found to inhibit the binding of [ H]Spiperone to the dopamine D3 receptor, some of the compounds have been found to inhibit serotonin reuptake and some of the compounds have been found to be 5-HT2A receptor ligands and/or 5-HT2C receptor ligands. As mentioned above, the compounds of the invention have a good aqueous solubility as compared to related compounds disclosed in WO 98/28293. Accordingly, the compounds are expected to have improved bioavailability. Thus, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, side effects induced by conventional antipsychotic agents, migraine, ADHD and in the improvement of sleep. In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects. Formulation Examples The pharmaceutical formulations of Hie invention may be prepared by conventional methods 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, 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 apart of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it 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: one of Y1 and Y2 is N, which is bound to Y4, and the other of Y1 and Y2 is CO, CS, SO, or S02 and Y4 is CH2; Y3 is Z-CH2, CH2-Z or CH2CH2, and Z is O or S; provided that when Y1 is N, Y may not be Z-CII2, W is a bond or an O, S, CO, CS, SO or S02 group; N is 0-5, m is 0-5 and m + n is 3-6; provided that when W is O or S, then n > 2 and m > 1; when W is CO, CS, SO or S02, then n > 1 and m > 1; X is C, CH or N; provided that when X is C, the dotted line indicates a bond, and when X is N or CH, the dotted line is not a bond, R'-R9 are independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C1-C6-alkylamino, di-C1-C6-alkyl-amino, C1-C6-alkyl, C2-6alkenyl, C2-6- alkynyl, Ci-6-alkoxy, C1-C6-alkylthio, C1-C6-alky! substituted with hydroxy or thio, C3_8-cycloalkyl, C3_8-cycloalkyl-C1-C6-alkyl, acyl thioacyl, aryl, trifluoromethyl, trifluoromethylsulfonyl, and C1-C6alkylsulfonyl, R10 is hydrogen, C1-C6-alkyl, C2_6-alkenyl, C2.6-alkynyl, C1-C6-alkyl substituted with hydroxy or thiol, C3_8-cycloalkyl, C3_8-cycloalkyl-C1-C6-alkyl, aryl, aryl-Q. 6-alkyl, acyl, thioacyl, C1-C6-alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl, or a pharmaceuticallv accentable acid addition salt thereof The compound as claimed in claim 1, wherein the indole is bound to X via position 3 of the indole. The compound as claimed in claims 1 and 2, wherein one ofY1 and Yz is N, which is bound to Y4, and the other of Y1 and Y2 is CO, and Y4 is CH2. The compound as claimed in claim 3, wherein Y1 is a nitrogen bound to Y4, Y2 is CO and Y4 is CH2. The compound as claimed in claim 3, wherein Y is a nitrogen atom bound to Y4, Y1isCOandY4isCH2. The compound as claimed in claims 1 to 5, wherein Y is CH2CH2 or CH2Z. The compound as claimed in claims 1 to 6, wherein X is C. The compound as claimed in claims 1 to 6, wherein X is N. The compound as claimed in claims 1 to 6, wherein X is CH. The compound as claimed in claims 1 to 9, wherein R -R are independently selected from hydrogen, halogen, cyano, nitro, amino, Q.e-alkylamino, di-C1-C6-alkylamino, C1-C6-alkyl, C3_8-cycloalkyl and trifluoromethyl, and R10 is hydrogen, C1-C6-alkyl or acyl, or a pharmaceutically acceptable acid addition salt thereof. The compound as claimed in claim 1, which is selected from: 5-Fluoro-3-(l-[3-(l-oxo-3,4-dihydro-lH-quinolin-2-yl)propan-l-yl]piperidin-4-yl)-lH-indole; 5-Fluoro-1 -methyl-3-( 1 -[3-(2-oxo-3,4-dihydro-2H-quinolin-1 -yl)propan-1 - yl]piperidin-4-yl)-lH-indole; 5-Fluoro-1 -methyl-3 -(1 -[4-(2-oxo-3,4-dihydro-2H-quinolin-1 -yl)butan-1 - yl]piperidin-4-yl)-lH-indole; and l-(Butan-l-yl)-5-fluoro-3-(l-[4-(2-oxo-3,4-dihydro-2H-quinolin-l-yl)butan-^ yl]-336-dihydro-2H-pyridin-4-yl)-lH-indole; or pharmaceutically acceptable salts thereof. 12. A pharmaceutical composition characterized in that it comprises a compound as claimed in any one of claims 1 to 11, in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.

Documents:

024-chenp-2003-abstract.pdf

024-chenp-2003-claims duplicate.pdf

024-chenp-2003-claims original.pdf

024-chenp-2003-correspondnece-others.pdf

024-chenp-2003-correspondnece-po.pdf

024-chenp-2003-description(complete) duplicate.pdf

024-chenp-2003-description(complete) original.pdf

024-chenp-2003-form 1.pdf

024-chenp-2003-form 18.pdf

024-chenp-2003-form 26.pdf

024-chenp-2003-form 3.pdf

024-chenp-2003-form 5.pdf

024-chenp-2003-pct.pdf

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