NZ537477A

NZ537477A - Use of N-[(4-phenyl-1-piperazinyl)alkyl]-substituted heteroarene carboxamide in the treatment of CNS diseases

Info

Publication number: NZ537477A
Application number: NZ537477A
Authority: NZ
Inventors: Peter Gmeiner; Harald Hubner; Karin Schlotter
Original assignee: Sanol Arznei Schwarz Gmbh
Priority date: 2002-07-04
Filing date: 2003-07-02
Publication date: 2007-12-21

Abstract

Disclosed are neuroreceptor active N-[(4-phenyl-1-piperazinyl)alkyl]-substituted heteroarene carboxamides of general formula (I) and the use thereof for the treatment of CNS diseases, for example, schizophrenia, different forms of depression, neurodegenerative disorders, sexual dysfunctions, ***e, alcohol, opiate and nicotine addiction, in addition to glaucoma, cognitive disorders, restless leg syndrome, hyperactivity syndrome (ADHS), hyperprolactinemia, hyperprolactinoma, locomotion disorders associated with Parkinson's disease, treatment of L-DOPA and neuroleptic-induced locomotion disorders, for example, akathisia, rigor, dystonia and dyskinesia, wherein the substituents shown in formula (I) are defined in the specification.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 537477 53 7 4 7 7 VERIFICATION OF TRANSLATION I, Anna Delia Henley-Btihrke of Hoffmann • Eitle Arabellastrasse 4 D-81925 Munich Federal Republic of Germany do hereby certify that I am conversant with the English and German language and am a competent translator thereof, and I further certify that to the best of my knowledge and belief the attached is a full, true, and accurate translation of the WO-Publication No. 2004/004729 (= PCT/EP2003/007060). Signed this 6th day of December 2004 ~5 JAN 2005 I —BAC E i y p p / WO/2004/004729 PCT/EP2003/007060 Utilization of Heteroarene Carboxamide as Dopamine-D3 Ligands for the Treatment of CNS Diseases Dopamine is considered an important neurotransmitter of the central nervous system. Dopamine acts by binding to five different dopamine receptors. Owing to their morphology and the manner of signal transmission, these may be classified as Dl-like (D1 and D5) and D2-like (D2, D3 and D4) receptors (Neve, K.A. The Dopamine Receptors. Humana Press, 1997). Especially the subtypes of the D2 family play an important role in regulatory processes of the central nervous system. While the D2 receptors are primarily expressed in the basal ganglia where they control neuromotoric circuits, D3 receptors are mainly found in the limbic system where emotional and cognitive processes are controlled. Disorders in the signal transduction of these receptors result in numerous neuropathological situations. Especially the D3 receptor is considered a promising target for the development of active ingredients to treat psychiatric diseases such as schizophrenia or unipolar depression, disturbances of consciousness as well as for the treatment of neurodegenerative diseases such as Parkinson's disease, but also for the treatment of drug addiction (Pulvirenti, L. et al. Trends Pharmacol. Sci. 2002,23, 151-153). Compounds having an aryl piperazine structure have already been described as dopamine receptor-active ligands (Robarge, M.J. J. Med. Chem. 2001, 44, 3175-3186). Benzamides and naphthamides having an aryl piperazine partial structure are also known as ligands of dopamine receptors (Perrone, R. J. Med. Chem. 1998, 41, 4903-4909; EP 0 779 284 Al). A phenyl piperazinyl naphthamide has recently been described as a selective D3-partial agonist showing promising activity in animal models which might be used for the treatment of ***e addiction (Pilla, M. et al. Nature 1999, 400, 371-375). For a few examples, aryl piperazinyl amides having oxygen-, sulfur- or nitrogen-containing heteroarenic acid components have been described (ES 2 027 898; EP 0 343 961; US 3,646,047; US 3,734,915). Cyano-substituted and tellurium-containing derivatives with a ferrocenyl partial structure, on the other hand, are not known in literature. In the course of our experiments concerning the effects of the structure of dopamine ligands we have discovered new compounds of the formulae (I) to (IV) which show hitherto unknown highly affine and highly selective binding characteristics to the D3 receptor in in vitro assays. These compounds could thus be valuable therapeutic agents for the treatment of diseases of the central nervous system such as schizophrenia, various forms of depression, neurodegenerative disorders, sexual dysfunction as well as ***e, opiate and nicotine addiction. Other specific areas of application are glaucoma, cognitive disorders, restless leg syndrome, hyperactivity syndrome (ADHS), hyperprolactinaemia, hyperprolactinoma, locomotion disorders associated with Parkinson's disease, treatment of L-DOPA- and neuroleptic-induced locomotion disorders, for example akathisia, rigor, dystonia and dyskinesias. The subject matter of the present invention are derivatives of 2-heteroarene carboxylic acid amides having an aryl piperazinyl partial structure in the form of the free base and salts thereof as represented by the following formulae (I) and (II): R (I) O (II) wherein in formula (I): - n = 1 - 4 and 3 intellectual property office of n.z. 11, NOV 2007 rfceived - R = hydrogen, alkyl or halogen and (a) X = S or 0: (i) when Rj is hydroxy, alkyloxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano, each of R2 and R3 are independently selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, (li) when Rj is hydrogen, alkyl, halogen or trifluoromethyl, R2 is selected from hydroxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl and cyano and R3 is selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, or (b) X = NH: R} is selected from hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, trifluoromethyl, acyl, alkoxycarbonyl, halogen and cyano and each of R2 and R3 are selected independently from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, with the proviso that the compound is not N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-2-indolylcarbamide, or (c) X = Te: Rl is selected from hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano and each of R2 and R3 are selected independently from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano. In one embodiment of the invention, the following applies in fomiula (I): - n= 1 - 4 and - X = Te, when R = hydrogen, alkyl or halogen and Rj is substituted by the radicals hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano and R2 and R3 are substituted individually or jointly by the radicals hydrogen, P:\WPDOCS\TXS\Specs\l 2510711 amendments.doc-11/13/2007 -4- hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, - X = S or O, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydroxy, alkyloxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano and R2 and R3 are substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, - X = S or O, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydrogen, alkyl, halogen or trifluoromethyl and R2 and R3 are substituted individually or jointly by the radicals hydroxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano, - X = NH, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, trifluoromethyl, acyl, alkoxycarbonyl or cyano, it being required that alkyl and alkyloxy contain at least two carbon atoms, and R2 and R3 are substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano and alkyloxy comprises at least two carbon atoms. There is also disclosed a compound of the general formula (I) or or or (I) 7 wherein: - n = 1 - 4 and - R = hydrogen, alkyl or halogen and intellectual property office of n.2. 14 NOV 2007 rfcfiv/ed P:\WPDOCS\TXS\Specs\125l071J amendments.doc-11/13/2007 -4a- (a) X = S or O: (i) when Ri is hydroxy, alkyloxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano, each of R2 and R3 is independently selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, 5 aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, (ii) when Ri is hydrogen, alkyl, halogen or trifluoromethyl, R2 is selected from hydroxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl and cyano and R3 is selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, 10 alkoxycarbonyl and cyano, or (b) X = NH: Ri is selected from hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, trifluoromethyl, acyl, alkoxycarbonyl, halogen and cyano and each of 15 R2 and R3 is independently selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, with the proviso that n = 3 and that the compound is not N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide, 20 or (c) X = Te: Ri is selected from hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano and each of R2 and R3 is independently selected from hydrogen, hydroxy, alkyloxy, 25 alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, wherein the groups alkyl, alkenyl, alkynyl and aryl are optionally substituted independently of each other, and pharmaceutically acceptable salts thereof. 30 intellectual property office of n.2 1 4 NOV 2007 r f r p i y f d P:\WPDOCS\TXS\Specs\12510711 amendments.doc-11/13/2007 -4b- In formula (II), n = 1 - 4 and Ri and R2 individually or jointly represent the radicals hydrogen, 5 hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano. In particular, the invention relates to physiologically acceptable salts of the compounds of the invention. • 10 A skilled practitioner will be aware that, depending on the choice of substituents, optically active compounds may result. In that case, both the racemates and each of the pure enantiomeric forms are subject matters of the present invention. intellectual property office of n.z 14 NOV 2007 rfr i=ivfd The substituents listed in the description and the accompanying claims especially comprise the groups discussed below. "Alkyl" may be a branched or unbranched alkyl group which preferably contains 1 to 10 carbon atoms, especially preferably 1 to 6 carbon atoms and most preferably 1, 2 or 3 carbon atoms, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, s-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, t-pentyl, 1 -methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl and n-hexyl. Alkyl groups may additionally be substituted with one or more substituents, for example with halogen or one or more phenyl groups. "Alkenyl" and "alkynyl" have at least one double or triple bond. They may be branched or unbranched and preferably comprise 2 to 6 carbon atoms. Alkenyls or alkynyls are preferably bound to the heteroarene or phenyl ring of the skeletal structure of the compound in such a manner that the double or triple bond is conjugated to the aromatic ring. Alkenyl and alkynyl may additionally be substituted with one or more substituents, preferably with phenyl; in that case the phenyl group is preferably located on the carbon atom 2 (if alkenyl or alkynyl is bound to the heteroarene or phenyl ring of the skeletal structure via the carbon atom 1). The alkenyls or alkynyls are preferably unsubstituted. "Alkyloxy" is the -O-alkyl group, wherein alkyl is preferably selected from the groups listed above for "alkyl". Preferably, alkyloxy is a Ci-C6-alkyloxy group, especially methoxy. In another embodiment, alkyloxy may also be a C2-C6-alkyloxy group. "Aryl" preferably is phenyl. Optionally, phenyl may also be substituted independently in one or more of the positions 2, 3 and 4, for example with alkoxy, trifluoromethyl or halogen, preferably with methoxy. "Acyl" especially comprises the groups -C(0)-alkyl and -C(0)-aryl, wherein alkyl and aryl are preferably selected from the groups given for "alkyl" and "aryl" above, especially -C(0)-Ci-C6-alkyl. For example, acyl is may be acetyl, propionyl, butyryl or -C(0)-phenyl. intellectual property office of n.z 14 NOV 2007 R F C E 1 v (r Q •v * ( "Alkoxycarbonyl" is the -C(0)-0-alkyl group, wherein alkyl is preferably selected from the groups listed for "alkyl" above. Preferably, alkoxycarbonyl is a (Ci-C6-alkyl)oxy carbonyl group "Halogen" is preferably fluorine, chlorine, bromine or iodine. "Physiologically acceptable salts" comprise non-toxic addition salts of a base, especially of a compound of the formula (I) in the form of the free base with organic or inorganic acids. Examples for inorganic acids include HC1, HBr, sulfuric acid and phosphoric acid. Organic acids include acetic acid, propionic acid, pyruvic acid, butyric acid, a-, p- or y-hydroxybutyric acid, valeric acid, hydroxyvaleric acid, capronic acid, hydroxycapronic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, glycolic acid, lactic acid, D-glucuronic acid, L-glucuronic acid, D-galacturonic acid, glycine, benzoic acid, hydroxybenzoic acid, gallic acid, salicylic acid, vanillic acid, cumaric acid, caffeic acid, hippuric acid, orotic acid, L-tartaric acid, D-tartaric acid, D,L-tartaric acid, meso-tartaric acid, fumaric acid, L-malic acid, D-malic acid, D,L-malic acid, oxalic acid, malonic acid, succinic acid, maleic acid, oxalacetic acid, glutaric acid, hydroxyglutaric acid, ketoglutaric acid, adipic acid, ketoadipic acid, pimelic acid, glutamic acid, aspartic acid, phthalic acid, propanetricarboxylic acid, citric acid, isocitric acid, methanesulfonic acid, toluenesulfonic acid and trifluoromethanesulfonic acid. Compounds of the formula (I) wherein X is represented by NH, S or O may be named as preferred structures. Preferred embodiments of the compounds of the formula (I) according to the invention are the following compounds of the general formulae (la) or (lb): (la) 7 (lb) wherein: - n=l-4, - R = hydrogen, C]-C6-alkyl or halogen, - when Rj is hydroxy, Cj-Cg-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, Cj-Cg-acyl, C)-C6-alkoxy carbonyl or cyano, each of R2 and R3 are independently selected from hydrogen, hydroxy, C1-C6-alkyloxy, Cj-Q-alky], C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Ci-C6-acyl, Cj-Cg-alkoxycarbonyl and cyano, - when R{ is hydrogen, Ci-Cg-alkyl, halogen or trifluoromethyl, R2 is selected from hydroxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, Cj-Cg-acyl, Q-Cg-alkoxycarbonyl and cyano, and R3 is selected from hydrogen, hydroxy, Cj-Q-alkyl, Q-Q-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Ci-Cg-acyl, Cj-Cg alkoxycarbonyl and cyano, and pharmaceutically acceptable salts thereof, fluorine, chlorine and bromine being preferred halogen substituents. Another preferred embodiment of the compounds of the formula (I) according to the invention are the following compounds of the general formula (Ic): (Ic) intellectual property office of n.z U NOV 2007 received 8 wherein: - ' n = 1 -4, - R = hydrogen, Cj -C6-alkyl or halogen, - R} is selected from hydrogen, hydroxy, Ci-Cg-alkyl, Cj-Cg-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, trifluoromethyl, Cj-Cg-acyl, Cj-Ce-alkoxycarbonyl, fluorine, chlorine, bromine and cyano, each of R2 and R3 are independently selected from hydrogen, hydroxy, C]-C6-alkyl, Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, C]-C6-acyl, Cj-Cg-alkoxycarbonyl and cyano, and pharmaceutical^ acceptable salts of these compounds, with the proviso that the compound is not N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide. In another preferred embodiment of the invention, the following applies for compounds of the general formula (Ic): (a) when R\ is hydroxy, C2-Cg-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, trifluoromethyl, Q-Cg-acyl, CpCe-alkoxycarbonyl or cyano, each of R2 and R3 are independently selected from hydrogen, hydroxy, C1-C6-alkyl, Ci-Cg-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Cj-C6-acyl, CpCe-alkoxycarbonyl and cyano, and (b) when Rj is hydrogen, Cj-C6-alkyl, Ci-C6-alkyloxy or halogen, R2 is selected from hydroxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, Cj-Cg-acyl, Ci-C6-alkoxycarbonyl and cyano, and R3 is selected from hydrogen, hydroxy, Ci-C6-alkyl, C]-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Ci-C6-acyl, Ci-C6-alkoxycarbonyl and cyano. intellectual property office of n.z 14 NOV 2007 receivejd In another preferred embodiment of the invention, the following applies for the compounds of the formulae (I), (la), (lb), and (Ic): the substituent Rj is in position 5 or 6 of the heterocycle, and the substituents R2 and R3 are in the positions 2 or 3, respectively, or in the positions 2 or 4, respectively, of the phenyl ring; the respective other substituent being in position 2 of the phenyl ring in the event that one of the two substituents R2 and R3 is a hydrogen atom. In a particularly preferred embodiment of the invention, n = 3 in the compounds of the formulae (I), (la), (lb), and (Ic). Preferred compounds of the general formula (II) as defined above are those wherein each of Rj and R2 is independently selected from hydrogen, hydroxy, Ci-C6-alkyloxy, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, fluorine, chlorine, bromine, trifluoromethyl, Cj-Ce-acyl, Ci-Cg-alkoxycarbonyl and cyano. Specific compounds of the general formula (II) are (B16): N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-ferrocenylcarbamide and (B17): N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2- ferrocenylcarbamide Another aspect of the present invention relates to compounds of the general formula (IV): (IV) 7 wherein: X = S, NH or O, intellectual property office of n.2. 1 h NOV 2007 received P:\WPDOCS\TXS\Specs\125i0711 amendments.doc-11/13/2007 - 10- - R is selected from hydrogen, Ci-C6-alkyl, fluorine, chlorine and bromine, - Ri is selected from hydrogen, Ci-C6-alkoxy, Ci-C6-alkyl, fluorine, chlorine, bromine, trifluoromethyl and cyano, Ri being in position 5 or 6 of the heterocycle, - R2 and R3 are independently selected from hydrogen, Ci-C6-alkyloxy, Ci-C6-alkyl, 5 fluorine, chlorine, bromine and trifluoromethyl, R2 and R3 being in the positions 2 or 3, respectively, or in the positions 2 or 4, respectively, of the phenyl ring, and the respective other substituent being in position 2 of the phenyl ring in the event that one of the two substituents R2 and R3 is a hydrogen atom 10 and pharmaceutically acceptable salts of this compound with the proviso that the compound is not N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide. A preferred aspect of the invention are compounds of the general formula (IV) as defined above, wherein 15 - when X = NH, then Ri is selected from hydrogen, C1-C3-alkyloxy, Ci-C3-alkyl, fluorine, chlorine, bromine and cyano, and - when X = S or O, then Ri is selected from hydrogen, Ci-C3-alkyl, fluorine, 20 chlorine, bromine, cyano and trifluoromethyl. The following compounds are specific embodiments of the compounds according to the invention: 25 (B18): N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-cyano-2-benzo [b]thiophenylcarbamide (B19): N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-5-cyano-2- benzo [b]thiophenylcarbamide (B20): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-6-cyano-2-30 benzo[b]thiophenylcarbamide (B21): N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-6-cyano-2-benzo [b]thiophenylcarbamide intellectual property office of n.z 1 4 NOV 2007 recffved P;\WPDOCS\TXS\Specs\12510711 amendments.doc-1 1/13/2007 -11 - (B1): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-2-benzo [bjthiophenylcarbamide (B2): N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-benzo[b]thiophenylcarbamide (B22): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-bromo-2-benzo[b]thiophenylcarbamide 5 (B23): N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-bromo-2-benzo [bjthiophenylcarbamide (BIO): N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-2-indolylcarbamide (Bll): N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-cyano-2-indolylcarbamide (B12): N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-bromo-2-indolylcarbamide 10 (B13): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-6-cyano-2-indolylcarbamide (B14): N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-bromo-2-indolylcarbamide (B15): N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-6-cyano-2-indolylcarbamide (B25): N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-cyano-2-indolylcarbamide (B7): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-cyano-2-15 benzo [b] furanylcarbamide (B3): N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]furanylcarbamide (B4): N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-2-benzo[b] furanylcarbamide (B5): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-bromo-benzo [b] furanylcarbamide 20 (B6): N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-5-bromo-2-benzo [b] furanylcarbamide (B8): N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]tellurophenylcarbamide (B9): N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-2-benzo [bjtellurophenylcarbamide 25 and pharmaceutically acceptable salts of these compounds. intellectual property office of n.z. 1 * NOV 2007 r f c f1v e_d Especially the compounds of the formulae (I), (la), (lb), (Ic), (II) and (IV) as defined above are suitable for therapeutic use as dopamine D3 ligands. Particular preference is given to compounds of the general formula (I) or pharmaceutically acceptable salts thereof, wherein X = NH, S or O, and to compounds of the formulae (la), (lb), (Ic) and (IV) or pharmaceutically acceptable salts thereof. The term "D3 ligands with high affinity" comprises compounds which show binding to human dopamine D3 receptors having a Ki value of preferably not more than 10 nM, especially preferably not more than 1 nM, in a radio ligand experiment (cf. Htibner, H. et al. J. Med. Chem. 2000, 43, 756-762, and the following section "Biological Activity"). One aspect of the present invention relates to selective D3 ligands. The term "selective D3 ligands" comprises compounds with a Ki value in the radio ligand experiment for the D3 receptor as described in the following section "Biological Activity" which is lower by a factor of at least 10 for at least five of the seven following receptors: dopamine receptors Dl, D21ong, D2 short and D4.4, serotonin receptors 5-HT1A and 5-HT2 and alpha-1-adrenoreceptor. Another aspect of the invention relates to dopamine D3 ligands with high selectivity. The term "D3 ligands with high selectivity" comprises compounds with a Ki value in the radio ligand experiment for the D3 receptor as described in the following section "Biological Activity" which is lower by a factor of at least 100 for at least three and preferably all of the of the dopamine receptors Dl, D21ong, D2short and D4.4. D3 ligands may show agonistic, antagonistic or partial-agonistic activity on the D3 receptor. The respective intrinsic activities of the compounds of the invention may be measured in mitogenesis assays as described in literature (Htibner, H. et al. J. Med. Chem. 2000, 43, 4563-4569, and Lober, S. Bioorg. Med. Chem. Lett. 2002, 12.17, 2377-2380). Depending on the pathophysiology of the underlying disease, a stronger agonistic, stronger antagonistic or partial-agonistic activity may be desirable. The present invention therefore permits an excellent fine-tuning of the desired activity. P:\WPD0CS\TXS\Specs\12510711 amendments.doc-11/13/2007 -13- Therefore, a therapeutic agent comprising one or more of the compounds of the general formulae (I), (la), (lb), (Ic), (II) and (IV) or one of the specific compounds as defined above, optionally in the form of a pharmaceutically acceptable salt, is a further subject matter of the invention. Preferably, this includes one or more of the 5 compounds of the general formulae (I), (la), (lb), (Ic) and (IV) or pharmaceutically acceptable salts thereof, wherein X = NH, S or O. There is also disclosed a medicament agent containing one or more of the compounds of the general formula (I), (la), (lb), (Ic) or (IV). The invention also relates to the use of one or more of the compounds of the general formulae (I), (la), (lb), (Ic), (II) and (IV) or one of the specific compounds listed, optionally in the form of a pharmaceutically acceptable salt, for the treatment, including therapy and prevention, of the indications given here and for preparing a 15 therapeutic agent for said indications. 20 It is preferred to choose those compounds of the invention which are selective D3 ligands for preparing therapeutic agents. D3 ligands with high selectivity are especially preferred. The compounds of the invention have potential use in the therapy or prevention of a number of disorders, especially those accompanied by a dysfunction of the dopamine metabolism or the dopaminergic signal cascade. 25 Examples for such disorders are ***e, alcohol, opiate and nicotine addiction; neurodegenerative disorders, especially Parkinson's disease; sexual dysfunction, especially male erectile dysfunction; depression, especially endogenous monophase depression ("major depression") and schizophrenia. 30 Other examples amenable to therapy or prevention with the compounds of the invention are hyperprolactinaemia; hyperprolactinoma; glaucoma; cognitive disorders; restless leg syndrome; hyperactivity syndrome (ADHS); locomotion disorders associated with intellectual property office of n.z 1 k NOV 2007 rfcfived P:\WPDOCS\TXS\Specs\12S107H ameiitimems.doc-11/13/2007 - 13a- Parkinson's disease, e.g. rigor, dystonia and dyskinesia; L-DOPA-induced disorders, such as anxiety, disturbed sleep, psychoses, dyskinesias and dystonias; idiopathic dystonias, especially Segawa syndrome; neuroleptic-induced (tardive) dyskinesia, dystonia and akathisia. intellectual property office of n.2 1A NOV 2007 rfhfived P:\WPDOCS\TXS\Specs\J25l07l! amendments.doc-11/13/2007 -14- The compounds of the invention are particularly well suited to prepare a therapeutic agent for treating DOPA-sensitive locomotion disorders. Such locomotion disorders may be dyskinesias, dystonias, rigor and tremor, for example. The term "DOPA-sensitive" is understood to mean that the locomotion disorder may be influenced 5 favourably by the administration of drugs which influence the dopaminergic signal transmission. A typical example is the Segawa syndrome, an idiopathic dystonia where the response to L-DOPA may be used as a diagnostic criterion. A preferred use is the preparation of a therapeutic agent for the treatment of 10 dyskinesias and dystonias which may occur spontaneously in connection with Parkinson's disease, but may also be induced by drugs. Among drug-induced dyskinesias and dystonias, especially those induced by neuroleptics and dopamine antagonists or dopamine agonists or L-DOPA may be mentioned. 15 In addition, the therapeutic agents may be used in medication-assisted ablactation after a pregnancy. Accordingly, there is disclosed a use of a compound of the general formula (I), (la), (lb), (Ic) or (IV) for preparing a medicament for the therapy or prophylaxis of ***e, 20 alcohol, opiate and nicotine addiction; neurodegenerative disorders; sexual dysfunction; depression or schizophrenia. Also disclosed herein is the use of a compound of the general formula (I), (la), (lb), (Ic) or (IV) for preparing a medicament for the therapy or prophylaxis of 25 hyperprolactinaemia; hyperprolactinoma; glaucoma; cognitive disorders; restless leg syndrome; hyperactivity syndrome (ADHS); locomotion disorders associated with Parkinson's disease; L-DOPA-induced disorders, Segawa syndrome; tardive locomotion disorders as well as for medication-assisted ablactation after pregnancies. 30 Also disclosed herein is the use of a compound of the general formula (III): intellectual property office of n.z 14 NOV 2007 rfofived P:\WPDOCS\TXS\Specs\125107U amendments.doc-11/13/2007 - 14a- rtf (III) 10 wherein: n = 1 - 4 and X = S, O or NH, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydrogen, alkyl, halogen, trifluoromethyl and each of R2 and R3 are substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkiynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, for preparing a pharmaceutical agent medicament for the therapy or prevention prophylaxis of ***e, alcohol, opiate and nicotine addiction; neurodegenerative disorders, especially Parkinson's disease; or sexual dysfunction. 15 Finally, the therapeutic agents of the invention may be used as a compound preparation for simultaneous or sequential administration, depending on the disease to be treated. For example, one unit offered for sale which contains L-DOPA medication for the treatment of Parkinson's disease may also comprise a pharmaceutical preparation which contains one of the compounds of the invention, for example with a high-selectivity, 20 partial-agonistic profile of action. L-DOPA and the compound of the invention may be present in the same pharmaceutical formulation, e.g. a compound tablet or in different units of application, e.g. in the form of two separate tablets. As needed, the two active ingredients may be administered simultaneously or at different times. 25 In a compound preparation, sequential administration may be achieved by providing a form of administration, for example an oral tablet, having two different layers with different release profiles for the various pharmaceutically active components. A skilled practitioner will appreciate that various forms of administration and application schemes are conceivable within the context of the invention all of which 30 are subject matters thereof. intellectual property office of n.z I 4 NOV 2087 rfofived 15 One embodiment of the invention therefore relates to a therapeutic agent which contains L-DOPA or a neuroleptic as well as a compound of the invention for the simultaneous or sequential administration to a patient. In general, the therapeutic agents of the invention consist of a pharmaceutical composition which, in addition to the D3 ligands as described above, contains at least one pharmaceutically acceptable carrier or excipient. A skilled practitioner will appreciate that, depending on the intended route of application, the pharmaceutical formulation may take different forms. For example, the pharmaceutical formulation may be adapted for intravenous, intramuscular, intracutaneous, subcutaneous, oral, buccal, sublingual, nasal, transdermal, inhalational, rectal or intraperitoneal administration. Suitable formulations and pharmaceutical carriers and excipients, respectively, amenable for this purpose such as fillers, disintegrants, binders, lubricants, stabilisers, flavouring agents, antioxidants, preservatives, dispersants or solvents, buffers or electrolytes are known to practitioners skilled in the field of pharmaceuticals and are described in standard works, for example those by Sucker, Fuchs and Speiser („Pharmazeutische Technologie", Deutscher Apotheker Verlag, 1991) and Remington ("The Science and Practice of Pharmacy", Lippincott, Williams & Wilkins, 2000). In a preferred embodiment of the invention, the pharmaceutical compositions containing the compounds according to the invention may be administered orally and may be present, for example, as a capsule, tablet, powder, granulate, coated tablet or in liquid form. The formulation may be prepared as a rapid-release form of administration if fast onset of action is desired. Suitable oral formulations are described in EP 0 548 356 or EP 1 126 821. If protracted release is desired, on the other hand, a formulation with delayed release of the active ingredient may be selected. Such oral formulations are also known from the prior art. 16 Alternative pharmaceutical preparations may, for example, be solutions for infusion or injection, oils, suppositories, aerosols, sprays, plasters, microcapsules or micro-particles. Another subject matter of the invention is the use of a compound of the general formula (III): wherein: n = 1 - 4 and X = S, O or NH, when R = hydrogen, alkyl or halogen and Rj are substituted by the radicals hydrogen, alkyl, halogen, trifluoromethyl and each of R2 and R3 is substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, for preparing a pharmaceutical agent for the treatment of one of the following diseases or disorders: ***e, alcohol, opiate and nicotine addiction; schizophrenia; various forms of depression, especially endogenous monophase depression ("major depression") or depressive phases of bipolar (manic-depressive) disorders; neurodegenerative disorders, especially Parkinson's disease; sexual dysfunction; hyperprolactinaemia; hyperprolactinoma; glaucoma; cognitive disorders; restless leg syndrome; hyperactivity syndrome (ADHS); locomotion disorders associated with Parkinson's disease, e.g. rigor, dystonia and dyskinesia; L-DOPA-induced disorders, such as anxiety, disturbed sleep, psychoses, dyskinesias and dystonias; idiopathic dystonias, especially Segawa syndrome; neuroleptic-induced (tardive) dyskinesia, dystonia and akathisia. In particular, a compound of the general formula (III) may be used to prepare a therapeutic agent for the treatment DOPA-sensitive locomotion disorders. These may occur spontaneously in connection with Parkinson's disease, but may also be induced by drugs. Among drug-induced locomotion disorders, intellectual property office of n.z 1 4 NOV 2007 rfofived 17 especially those induced by neuroleptics or dopamine antagonists or L-DOPA-induced dyskinesias and dystonias may be mentioned. It is preferred to use compounds of the general formula (III) for preparing the therapeutic agents of the invention, wherein - R is selected from hydrogen, Cj-Cg-alkyl, fluorine, chlorine and bromine, - Rj is selected from hydrogen, Ci-C6-alkoxy, Cj-Cg-alkyl, fluorine, chlorine, bromine and trifluoromethyl, and - each of R2 and R3 is independently selected from hydrogen, C]-C$-alkyloxy, Cj-Cg-alkyl, fluorine, chlorine, bromine and trifluoromethyl. It is also preferred to use compounds of the formula (III), wherein the substituent Ri is in position 5 or 6 of the heterocycle, and the substituents R2 and R3 are in the positions 2 or 3, respectively, or in the positions 2 or 4, respectively, of the phenyl ring; the respective other substituent being in position 2 of the phenyl ring in the event that one of the two substituents R2 and R3 is a hydrogen atom. A preferred compound of the general formula (III) for preparing the therapeutic agents of the invention, especially for the treatment of L-DOPA-induced dyskinesias, is the following compound: (B24): N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-2-indolylcarbamide The compounds of the formulae (I) bis (IV) were prepared according to methods described in literature (Glennon, R.A et al. J. Med. Chem. 1988, 31, 1968-1971). For this purpose, acid derivatives of the type (A) which were either available commercially or were synthesised as prescribed in literature were activated in the form of their carboxylic acid chlorides and reacted with the free base of the type (B) to obtain derivatives of the formula (I) (including (la), (lb) and (Ic), (III) or (IV): intellectual property office of n.z. 14 NOV 2007 rfcfived 18 H2N' / \ -N N n (b) =\/R2 A, (I), (III) or (IV) wherein n, R, Rj, R2 and r3 are as defined above for (I), (III) and (IV), respectively. As an alternative to the above-mentioned method of activating the acid derivatives, it is possible to use other reactions, for example activation of acids by hydroxyazabenzotriazole (Kienhofer, A. Synlett 2001, 1811-1812). For example, the compounds of the formula (II) may be prepared by activating ferrocene-2-carboxylic acid with HATU followed by a reaction with the bases of the type (B). Commercially available 2-methoxy- or 2,3-dichlorophenyl piperazines may be alkylated with bromobutyl phthalimide in xylene to prepare the aryl piperazinyl amines of the type (B). Subsequent hydrazinolysis of the phthalimide-substituted structures provides the primary amines of the type (B). This is illustrated by the following exemplary reaction scheme: P:\WPDOCS\TXS\Specs\l25107l 1 amcndments.doc-11/13/2007 -19- xylene N2H4 » ethanol f V { J o i> (B) (n = 3) -Br + Hi/ ^N \_y ') ,r2 r3 r2 Preferred embodiments will now be described by way of the following non-limiting examples. EXAMPLES 10 Synthesis of the amines of the type (B) 4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butylamine 2.3 g (10 mmol) of the free base of the 2,3-dichlorophenyl piperazine are dissolved in 10 ml of xylene and heated to 70°C. Then 1.4 g (5 mmol) of 4-bromobutyl phthalimide are dissolved in 20 ml of xylene and slowly dropped into the piperazine solution. The reaction mixture is heated at 125°C for 24 hours. After cooling to 0°C, 15 the mixture is filtered and the filtrate evaporated. The resulting N-4-(4-(2,3- dichlorophenyl)piperazin-l-yl)butylphthalimide is purified by flash chromatography on SiC>2 with ethyl acetate. Yield: 4.0 g (= 92 %) A solution of 80 % hydrazine hydrate (0.45 ml, 2.5 eq) in 5 ml of ethanol is dropped 20 into a suspension of N-4-(4-(2,3-dichlorophenyl)piperazin-lyl)butylphthalimide in 40 ml of ethanol. The mixture is heated at reflux for 3 hours, then cooled to room temperature, the precipitated solid filtered off, and the ethanolic solution evaporated in vacuo. intellectual property office of n.z t Purification by flash chromatography with CH2Cl2-MeOH-Me2EtN:90-8-2 provides the base 4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butylamine in a yield of 900 mg (= 60 %). MS: m/z 301(M+); IR: (NaCl): 3397; 2939; 2817; 1641; 1572; 1500; 1482; 1452; 1376; 1240; 1152; 1118; 1023; 917; 791; 749; 698; 661. 1H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.48-1.64 (m, 4H,CH2-CH2); 2.41-2.46 (t, J = 7.6, 2H, CH2N); 2.64 (m, 4H, pip); 2.72-2.76 (m, 2H, CH2NCO); 3.07 (m, 4H, pip); 6.93-6.99 (m, 1H, H5, phenyl); 7.11-7.17 (m, 2H, H4, H5, phenyl). Example 1 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2- benzo[b] thiophenylcarbamide 0,4 mmol of benzothiophene-2-carboxylic acid (0.071 g) are dissolved in 4 ml of dry toluene and 4 ml of dry chloroform. 0.02 ml of dry DMF and 0.11 ml (1.51 mmol) of SOCI2 are added, followed by heating in an oil bath to 90°C for 30 minutes. The solvent is then removed by rotation and dried in a fine vacuum. The acid chloride is dissolved in 40 ml of chloroform and added with stirring at 0°C to a solution of 0.4 mmol of 4-(4-(2-methoxyphenyl)piperazin-l-yl)butylamine (0.105 g) and 0.17 ml of Et3N in 5 ml of chloroform. After a reaction time of 14 hours, the reaction is washed with aqueous NaHC03 solution, the organic solvent dried with MgS04 and evaporated in vacuo. Purification by flash chromatography on silica gel CH2Cl2-MeOH:9-l provides 114 mg (68 % yield in 2 reaction steps) of N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]thiophenylcarbamide. Smp.: 147°C; MS: m/z 423 (M+); IR (NaCl): 3316; 2938; 2817; 1735; 1629; 1544; 1500; 1241; 1026; 731. ^H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.65-1.74 (m, 4H, CH2-CH2); 2.47 (t, 2H, CH2N, J=6.7 Hz); 2.65 (m, 4H, pip); 3.08 (m, 4H, pip); 3.48-3.53 (m, 2H, CH2NCO), 3.85 (s, 3H, OCH3); 6.72 (t, 1H, NH, J= 4.3 Hz); 6.84-7.01 (m, 4H, phenyl); 7.36-7.44 (m, 2H, H5, H6); 7.76 (s, 1H, H3); 7.79-7.85 (m, 2H, H7, H4). ^C-NMR (CDC13, 90 MHz) 8 (ppm): 162.4; 152.3; 141.2; 140.7; 139.1; 138.7; 126.2; 125.0; 124.9; 122.9; 122.7; 120.9; 118.2; 111.2; 57.9; 55.3; 53.4; 50.5; 40.0; 27.4; 24.3. C H N (%): C24H29N3O2S; "Intellectual property OFFICE OF N.Z. 1 4 NOV 2007 rftfived 21 Calc.: C 68.05; H 6.90; N 9.92; S 8.15; Found: C 68.11; H 6.95; N 9.93; S 8.09. Example 2 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-benzo [b] thiophenylcarbamide Synthesis analogous to example 1. Yield: 126 mg (68 % in 2 reaction steps) Smp.: 153°C. MS: m/z 462 (M+). IR (NaCl): 3298; 2967; 2934; 2809; 1640; 1599; 1576; 1530; 1442; 1420; 1301; 1167; 1131; 962; 882; 808; 781; 712. iH-NMR: (CDCI3, 360 MHz) 5 (ppm): 1.63-1.76 (m, 4H, CH2-CH2); 2.48 (t, J=6.9 Hz, 2H, CH2N); 2.66 (m, 4H, pip); 3.05 (m, 4H, pip); 3.49-3.54 (m, 2H, CH2NCO); 6.79 (br, t, J=5.3 Hz, 1H, NH); 6.84-6.86 (dd, J =1.6 Hz, J =7.5 Hz, 1H, phenyl); 7.08-7.16 (m, 2H, phenyl); 7.37-7.44 (m, 2H, H5, H6); 7.77-7.78 (s, 1H, H3); 7.80-7.90 (m; 2H, H4, H7). ^C-NMR (CDCI3, 90 MHz) 5 (ppm): 157.9; 156.1; 152.3; 151.1; 141.2; 129.9; 127.8; 123.0; 121.0; 118.2; 1.13,0; 112.3; 106.6; 109.7; 107.9; 57.9; 53.5; 50.5; 39.4; 27.4; 24.3. CHN(%):C23H25Cl2N3OS Calc.: C 60.25; H 6.11; N 8.78; Found: C 59.94; H 6.04; N 8.81. Example 3 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]furanylcarbamide Synthesis analogous to example 1. Yield: 75.2 mg (56 % yield % in 2 reaction steps) Smp.: 121°C. MS: m/z 431 (M+). IR (NaCl): 3311.2; 3060; 2937; 2815; 2216; 1654; 1592; 1500; 1321; 1240; 1178; 1145; 748. ^H-NMR (CDCI3, 360 MHz) 6 (ppm): 1.67-1.74 (m, 4H, CH2-CH2); 2.49 (t, 2H, CH2N, J=6.9 Hz); 2.69 (m, 4H, pip); 3.13 (m, 4H, pip); 3.56-3.50 (m, 2H, CH2NCO); 3.86 (s, 3H, OCH3); 6.85-6.87 (m, 1H, phenyl); 6.90-6.93 (m, 2H phenyl); 6.99-7.02 (m, 2H, phenyl andNH); 7.26-7.31 (m, 1H, H5); 7.37-7.42 (m, 1H, H6); 7.46-7.48 (m, 2H, H4, H3); 7.77-7.79 (m, 1H, H7). ^C-NMR (CDCI3, 90 MHz) 5 (ppm): 158.9; 154.7; 152.3; 148.9; 141.3; 127.7; 126.7; 123.6; 122.9; 122.7; 120.9; 118.2; 111.7; 111.2; 110.2; 58.0; 55.3; 53.5; 50.5; 39.2; 27.5; 24.3. j|y|TF'' PCTUAL PROPERTY' OFFICE OF N.Z H NOV 2007 RFOFLVE-Q 22 CHN (%): C24H29N3O3 O.3 H20; Calc.: C 69.81; H 7.23; N 10.18; Found: C 69.84; H 7.33; N 10.21. Example 4 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-benzo[b]furanylcarbamide Synthesis analogous to example 1. Yield: 105 mg (58 % yield in 2 reaction steps) Smp.: 150°C. MS: m/z 446 (M+). IR (NaCl): 3310; 2939; 2819; 1652; 1595; 1577; 1520; 1448; 1421; 1299; 1257; 1241; 1176; 1141; 1044; 960; 908; 780; 748; 713, 669, 645. *H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.67-1.75 (m, 4H, CH2-CH2); 2.52 (t, J=6.7 Hz, 2H, CH2N); 2.69 (m, 4 H, pip); 3.13 (m, 4H, pip); 3.51-3.56 (m, 2H, CH2NCO); 6.92-6.95 (dd, J=2.3 Hz, 7.3 Hz, 1H, phenyl); 7.00 (brt, J= 4.3 Hz, 1H, NHCO); 7.10-7.17 (m, 2H, phenyl); 7.26-7.31 (m, 1H, H4); 7.38-7.43 (m, 1H, H6); 7.46-7.48 (m, 2H, H3, H5); 7.66-7.68 (m; 1H, H7). 13c-NMR (CDCI3, 90 MHz) 5 (ppm): 158.9; 154.7; 151.2; 148.2; 134.0; 127.7; 127.5; 127.4; 126.8; 124.6; 123.7; 122.7; 118.6; 111.6; 110.2; 57.9; 53.3; 51.1; 39.2; 27.5; 24.2. CHN(%): C23H25CI2N3O2 Calc.: C 61.89; H 5.65; N 9.41; Found: C 61.74; H 5.86; N 9.05. Example 5 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-brom-2-benzo[b]furanylcarbamide Synthesis analogous to example 1. 5-Bromo-2-benzo[b]furanylcarboxylic acid was prepared according to literature (Dann, O. Liebigs Ann. Chem. 1986, 438-455). Yield: 107.8 mg (56 % yield in 2 reaction steps) Smp.: 124°C. MS m/z 485 (M+). IR (NaCl): 3450.0; 3289.9; 3068.2; 2927.4; 2765; 1650; 1567; 1535; 1500; 1438; 1238; 1178; 1022; 802; 748. iH-NMR (CDCI3, 360 MHz) 5 (ppm): 1.67-1.74 (m, 4H, CH2-CH2); 2.49 (t, J=6.9 Hz, 2H, CH2N); 2.69 (m, 4H, pip); 3.13 (m, 4H, pip); 3.56-3.60 (m, 2H, CH2NCO); 3.86 (s, 3H, OCH3); 6.85-6.87 (m, 1H, phenyl); 6.91-6.93 (m, 2H, phenyl); 6.97-7.00 (m, 1H, phenyl); 7.00 (brt, J=4.8 Hz, 1H, NH); 7.32-7.35 INTELLECTUAL PROPERTY OFFICE OF N.Z 1 4 NOV 2007 23 (d, J= 8.9 Hz, 1H, H4); 7.38-7.39 (m, 1H, H3); 7.48 (dd, J=8.7 Hz, J=2.0 Hz, 1H, Hg); 7.79-7.80 (m, 1H, Hy). 13C-NMR (CDC13, 90 MHz) 5 (ppm): 158.4; 153.3; 152.3; 150.1; 141.2; 129.7; 129.6; 125.2; 122.9; 120.9; 120.9; 118.2; 116.7; 113.1; 111.2; 109.4; 64.8; 57.9; 55.3; 53.5; 50.4; 39.3; 27.5; 24.3. CHN(%):C24H29BrN302; Calc.: C 59.26; H 5.80; N 8.64; Found: C 59.05; H 5.81; N 8.68. Example 6 N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-5-bromo-2- benzo[b]furanylcarbamide Synthesis analogous to example 5. Yield: 102 mg (47 % yield in 2 reaction steps) Smp.: 145°C. MS m/z 524 (M+); IR (NaCl): 3400; 2937; 2815; 2227; 1666; 1594; 1527; 1500; 1294; 1240; 1141; 1118; 1025; 842; 746. ^H-NMR (CDCI3, 360 MHz) § (ppm): 1.63-1.74 (m, 4H, CH2-CH2); 2.49-2.52 (t, J=6,7 Hz, 2H, CH2N); 2.68 (m, 4H, pip); 3.09 (m, 4H, pip); 3.49-3.56 (m, 2H, CH2NCO); 6.92-6.94 (dd, J=2.1 Hz, J=7.5 Hz, 1H, phenyl); 6.98-7.01 (brt, J=3,0 Hz, 1H, NH); 7.33-7.36 (d, J = 5.3 Hz, 1H, H4); 7.39 (m, 1H, H3); 7.48-7.51 (dd, J=8.7 Hz, J=2.0 Hz, 1H, H6); 7.80-7.81 (d, J=2.0 Hz; 1H, H7). ^C-NMR (CDC13, 90 MHz) 5 (ppm): 157.9; 156.1; 152.3; 151.1; 141.2; 129.9; 127.8; 123.0; 121.0; 118.2; 113.0; 112.3; 106.6; 109.7; 107.9; 57.9; 55.4; 53.5; 50.5; 39.4; 27.4; 24.3; 21.0. C H N(%): C23H24BrCl2N302 Calc.: C 52.57; H 4.67; N 8.03; Found: C 52.63; H 4.67; N 8.03. Example 7 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-cyano-2-benzo[b]furanylcarbamide 0.37 mmol (141 mg) of HATU and 0.37 mmol (69 mg) of the 5-cyano-2-benzo[b]furanylcarboxylic acid (Dann, O. Liebigs Ann. Chem. 1986, 438-455) are dissolved in 1 ml of DMF at 0°C and 0,74 mmol (0,13 ml) of DIEA are added. Then 0.33 mmol (87 mg) of 4-(4-(2-methoxyphenyl)piperazin-l-yl)butylamine is dissolved in DMF and dropped into the reaction solution at 0°C. After one hour, the reaction is taken up in CHC13 and washed with INTELLECTUAL PROPERTY OFFICE OF N.Z 1 <1 NOV 2007 r- nr- n / r n 24 NaHCC>3 solution and water. After drying with MgS04, the solvent is evaporated and purified by flash chromatography (SiC>2; petroleum ether-ethyl acetate: of 1-1 after ethyl acetate). Yield: 41 mg (28 %) Smp.: 96°C. MS m/z 432 (M+). IR (NaCl): 3400; 2937; 2815; 2227; 1666; 1594; 1527; 1500; 1294; 1240; 1141; 1118; 1025; 842; 746. iH-NMR (CDCI3, 360 Mhz) 5 (ppm): 1.67-1.74 (m, 4H, CH2-CH2); 2.49 (t, J=6.9 Hz, 2H, CH2N); 2.69 (m, 4H, pip); 3.13 (m, 4H, pip); 3.56-3.60 (m, 2H, CH2NCO); 3.86 (s, 3H, OCH3); 6.84-7.02 (m, 4H, phenyl); 7.12-7.15 (brt, }=5.1 Hz, 1H,NH); 7.50-7.51 (m, IH, H4); 7.55-7.57 (m, IH, H3); 7.65-7.68 (m, IH, H6); 8.03-8.04 (m, IH, H7). 13C-NMR (CDCI3, 90 MHz) 5 (ppm): 157.9; 156.1; 152.3; 151.1; 141.2; 129.9; 127.8; 123.0; 121.0; 118.2; 113.0; 112.3; 106.6; 109.7; 107.9; 57.9; 55.4; 53.5; 50.5; 39.4; 27.4; 24.3; 21.0. Example 8 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]tellurophenylcarbamide Synthesis analogous to example 7. Yield: 73 mg (58 %) Smp.: 85°C. MS m/z 521 (M+). IR (KBr): 3320; 3047; 2933; 2815; 1616; 1566; 1541; 1375; 1498; 1240; 1023; 748. ^-NMR (CDCI3, 360 MHz) 8 (ppm): 1.62-1.66 (m, 4H, CH2-CH2); 2.42-2.45 (t, J- 6.7 Hz, 2H, CH2N); 2.63 (m, 4H, pip); 3.04 (m, 4H, pip); 3.38-3.43 (m, 2H, CH2NCO); 3.78 (s, 3H, OCH3); 6.70-6.76 (brt, J= 4.3 Hz, IH, NH); 6.77-6.83 (m, 3H, phenyl); 6.94-6.96 (m, IH, phenyl); 7.09-7.14 (m, IH, H6); 7.28-7.32 (m, 1 H, H5); 7.74-7.76 (d, J=7,5 Hz, IH, H4); 7.84-7.86 (d, J =7.8 Hz, IH, H7); 8.13 (s, IH, H3). 13C-NMR(CDC13, 90 MHz) 8 (ppm): 166.1; 152,3; 147.9; 141.2; 140.2; 134.8; 132.3; 129.3; 125.8; 125.5; 122.9; 121.0; 118.2; 111.2; 57.9; 55.3; 53.3; 50.5; 40.4; 27.4; 24.4. Example 9 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2 benzo[b] tellurophenylcarbamide INTELLECTUAL PROPERTY OFFICE OF N.Z 14 NOV 2007 RFCFIVED 25 Synthesis analogous to example 7. Yield: 92 mg (45 %) Smp.: 92°C. MS m/z 560 (M+). IR (NaCl) : 3288; 2938; 2819; 1651; 1578; 1557; 1448; 1242; 1044; 734. iH-NMR (CDCI3, 360 MHz) 8 (ppm): 1.63-1.74 (m, 4H, CH2-CH2); 2.48-2.52 (t, J=7.1 Hz, 2H, CH2N); 2.66 (m, 4H, pip); 3.05 (m, 4 H, pip); 3.46-3.51 (m, 2H, CH2NCO); 6.70-6.72 (brt, J= 4.8 Hz, IH, NH); 6.83-6.86 (dd, J=1.8 Hz, J=7.8 Hz, IH, phenyl); 7.07-7.22 (m, 3H, phenyl, H6); 7.36-7.41 (m, IH, H5); 7.81-7.83 (d, J=7.6 Hz, IH, H4); 7.91-7.94 (d, J=7.6 Hz, IH, H7); 8.17 (m, IH, H3). 13C-NMR (CDCI3, 90 MHz) 8 (ppm): 166.1; 151.1; 147.9; 140.2; 135.0; 134.9; 134.0; 132.3; 129.2; 127.5; 127.4; 125.8; 125.5; 124.6; 118.6; 58.0; 53.3; 51.2; 40.4; 27.5; 24.4. Example 10 M-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-indolylcarbamide Synthesis analogous to example 1. Yield: 48 mg (58 % yield in two reaction steps) Smp.: 148°C. MS m/z 444 (M+). IR (NaCl): 3258; 3059; 2938; 2821; 1636; 1577; 1555; 1507; 1448; 1420; 1308; 1241; 1139; 1044; 961; 908; 779; 747; 733; 669; 647. *H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.67-1.74 (m, 4H, CH2-CH2); 2.47-2.51 (t, J=6.9 Hz, 2H, CH2N); 2.67 (m, 4H, pip); 3.13 (m, 4H, pip); 3.53-3.55 (m, 2H, CH2NCO); 6.59-6.66 (brt, J=4.3 Hz, IH, NH CO); 6.85 (s, IH, H3); 6.90-6.93 (m, IH, phenyl); 7.07-7.17 (m, 3H, phenyl, H5); 7.28-7.30 (m, IH, H6); 7.43-7.46 (m, IH, H7); 7.62-7.65 (m, IH, H4); 9.56 (s, IH, NH). 13C-NMR(CDC13, 90 MHz) 8 (ppm): 161.7; 160.4; 151.1; 136.2; 134.0; 130.9; 127.5; 127.4; 121.8; 120.8; 118.5; 111.9; 101.8; 68.2; 57.9; 53.3; 51.1; 39.5; 27.5; 24.3. Example 11 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-cyan-2-indolylcarbamide Synthesis analogous to example 7. Yield: 109 mg (42 %) INTELLECTUAL PROPERTY OFFICE OF IM.2 1 h NOV 200/ r f p. f iv e d 26 Smp.: 170°C. MS m/z 431 (M+). ^H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.74-1.78 (m, 4H, CH2-CH2); 2.54-2.65 (t, J =6.7 Hz, 2H; CH2N); 2.79 (m, 4H, pip); 3.17 (m, 4H, pip); 3.55-3.59 (m, 2H, CH2NCO); 3.85 (s, 3H, OCH3); 6.84-6.87 (d, J=8.5 Hz, IH, H5); 6.88-6.90 (m, 3H, phenyl); 6.99-7.05 (m, 2H, phenyl, H4); 7.07-7.12 (brt, J=3.9 Hz, IH, NHCO); 7.47-7.50 (dd, J=1.4 Hz, J=8.5 Hz, IH, H6); 7.52-7.54 (d, J= 8.5 Hz, IH, H7); 8.01 (s, IH, H3); 10.14 (s, IH, NH). 13C-NMR (CDC13, 90 MHz) 5 (ppm): 152.2; 140.7; 137.7; 133.3; 127.8; 127.3; 126.7; 123.4; 121.1; 120.2; 118.3; 111.3; 103.9; 102.9; 57.6; 55.4; 53.5; 50.0; 39.2; 27.0; 24.2. Example 12 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-bromo-2-indolylcarbamide Synthesis analogous to example 7. Yield: 112 mg (60%) Smp.: 188°C. iH-NMR (CDCI3, 360 MHz) 5 (ppm): 1.64-1.74 (m, 4H, CH2-CH2); 2.46-2.51 (t, J=7.1 Hz, 2H, CH2N); 2.68 (m, 4H, pip); 3.12 (m, 4H, pip); 3.49-3.64 (m, 2H, CH2NCO); 3.83 (s, 3H, OCH3); 6.68-6.71 (brt, J=5.3 Hz, IH, NHCO); 6.76-6.77 (d, J=1.8 Hz, IH, H4); 6.85-6.87 (d, J=7.8 Hz, IH, phenyl); 6.92-6.93 (d, J= 3.9 Hz, 2H, phenyl); 6.98-7.03 (m, IH, phenyl); 7.31-7.38 (m, 2H, H6, H7); 7.76-7.77 (m, IH, H3); 9.64 (s, IH, NH). Example 13 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-6-cyan-2-indolylcarbamide Synthesis analogous to example 1. Yield: 112 mg (58 % yield in 2 reaction steps) Smp.: 174°C. MS m/z 431 (M+). IR (NaCl): 2940; 2909; 2803; 2753; 2216; 1645; 1548; 1498; 1321; 1237; 1148; 820; 754; 742. *H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.67-1.82 (m, 4H, CH2-CH2); 2.47-2.51 (t, J=6.7 Hz, 2H, CH2N); 2.66 (m, 4H, pip); 3.68-3.70 (m, 2H, CH2NCO); 3.85 (s, 3H, OCH3); 3.09 (m, 4H. pip); 6.84-6.94 (m, 4H, phenyl, H3); 6.99-7.02 (m, IH, phenyl); 7.13-7.16 (brt, J= 5.5 Hz, IH, NHCO); 7.31-7.34 (m, IH, H5); 7.67-7.69 (d, J=8.5 Hz, H4); 7.84 (s, IH, H7); 11.22 (s, IH, NH). ^C-NMR (CDCI3, 90 MHz) 5 (ppm): 161.2; 152.2; 141.1; 135.2; 134.3; 130.5; 123.0; 122.9; 122.7; INTELLECTUAL PROPERTY OFFICE OF N.Z 1 4 NOV 2007 27 120.9; 120.2; 118.1; 117.4; 111.2; 106.6; 102.2; 57.8; 55.3; 53.8; 53.4; 50.4; 39.8; 30.1; 27.3; 24.3. CHN(%): C25H29N5O2 I.4H2O; Calc.: C 65.74; H 7.02; N 15.33, Found: C 65.98; H 7.30; N 14.87 Example 14 N-4-(4-(2,3-dichlorophenyl)piperazin-lyl)butyl-5-bromo-2-indolylcarbamide 0,24 mmol (58 mg) of HATU, 0,24 mmol of HOAt (33 mg) and 0,24 mmol (69 mg) of the 5-bromine-2-indolcarboxylic acid are dissolved in 5 ml of DMF at 0°C in 5 ml of DMF and 0,48 mmol (0,094 ml) DIEA are added. Then 0.26 mmol (78 mg) of 4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butylamine are dissolved in DMF and dropped into the reaction solution at 0°C. After three hours, the reaction is taken up in CHCI3 and washed with NaHC03 solution and water. After drying with MgS04, the solvent is evaporated and purified by flash chromatography (S1O2; CHCl3:MM, 98:2). Yield: 94 mg (74 %) MS m/z 524 (M+). IR (NaCl): 3234; 2932, 2821; 1637; 1577; 1545; 1282; 1046; 733. ]H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.57-1.73 (m, 4H, CH2-CH2); 2.51 (t, J=6.9 Hz, 2H, CH2N); 2.66 (m, 4H, pip); 3.07 (m, 4H, pip); 3.51-3.63 (m, 2H, CH2NCO); 6.64 (brt, J=5.3 Hz, IH, NHCO); 6.77 (d, J=1.8 Hz, IH, phenyl, H4); 6.90 (dd, J=2.1 Hz, J=7.5 Hz. IH, phenyl); 7.10-7.17 (m, 2H, phenyl); 7.31-7.38 (m, 2H. H6. H3); 7,76-7,77 (m, IH, H7); 9.68 (s, IH, NH). Example 15 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl~6-cyano-2-indolylcarbamide Synthesis analogous to example 7. Yield: 102 mg (59%) Smp.: 174°C. MS m/z 470(M+). IR (NaCl): 3215; 2926; 2821; 1634; 1570; 1506; 1239; 1034; 734. *H-NMR (CDCI3, 360 MHz) 5 (ppm): 1.69-1.82 (m, 4H, CH2-CH2); 2.51 (t, J=6.9 Hz, 2H, CH2N); 2.66 (m, 4H, pip); 3.06 (m, 4H, pip); 3.58-3.63 (m, 2H, CH2NCO); 6.85 (brt, J= 5.5 Hz, IH, NHCO); 6.88-6.91 (m, 2H, phenyl, H3); 7.09-7.17 (m, 2H, phenyl); 7.35 (dd, J=1.4 Hz, INTELLECTUAL PROPERTY OFFICE OF N.Z 1 4 NOV 2007 received 28 J=8.2 Hz, IH, H5); 7.70 (d, J=8.5 Hz, H4); 7.84 (s, IH, H7); 10,65 (s, 1 H, NH). Example 16 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-ferrocenylcarbamide Synthesis analogous to example 7. Yield: 155mg(71 %) MS m/z 475 (M+). IR (NaCl): 3318, 2939, 2816, 1630, 1543, 1500, 1241, 1027, 748. iH-NMR (CDC13, 360 MHz) 5 (ppm): 1.66-1.69 (m, 4H, CH2-CH2); 2.57 (t, J=6.7 Hz, 2H, CH2N); 2.77 (m, 4H, pip); 3.16 (m, 4H, pip); 3.39-3.44 (m, 2H, CH2NCO); 3.86 (s, 3H, OCH3); 4.17-4.21 (m, 3H, Ferr); 4.32-4.33 (m, 2H, Ferr); 4.68-4.69 (m, 2H, Ferr); 6.02 (brt, J=5.3 Hz, IH, NH); 6.85-6.94 (m, 3H, phenyl); 6.99-7.03 (m, IH, phenyl). 13C-NMR (CDCI3, 90 MHz) 5 (ppm): 170.3; 152.2; 140.9; 123.1; 120.9; 118.3; 111.2; 77.2; 76.3; 70.3; 69.7; 68.1; 57.9; 55.3; 53.4; 50.1; 39.2; 27.7; 23.8. Example 17 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-ferrocenylcarbamide Synthesis analogous to example 7. Yield: 85 mg (69 %) MS m/z 514 (M+). *H-NMR (CDCI3, 360 MHz) 6 (ppm): 1.63-1.66 (m, 4H, CH2-CH2); 2.48 (t, J=6.9 Hz, 2H, CH2N); 2.65 (m, 4H, pip); 3.08 (m, 4H, pip); 3.39-3.44 (m, 2H, CH2NCO); 4.17-4.21 (m, 3H, Ferr); 4.33-4.34 (m, 2H, Ferr); 4.64-4.65 (m, 2H, Ferr); 5.38 (brt, J=5.1 Hz, IH, NH); 6.92-6.98 (m, IH, phenyl); 7.11-7.17 (m, 2H, phenyl). Example 18 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-cyano-2-benzofb] thiophenylcarb amide 0.012 mmol (94 mg) of HATU and 0,012 mmol (25 mg) of the 5-cyano-2-benzo[b]thiophene carboxylic acid (Bridges, A. J. Tetr. Lett. 1992, 7499-7502) are dissolved in 1 ml of DMF and 4 ml of CH2C12 at 0°C and 0,024 mmol INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 <1 NOV 2007 RECEIVED 29 (0,06 ml) of DIEA added. Then 0.013 mmol (34 mg) of 4-(4-(2-methoxyphenyl)piperazin-l-yl)butylamine are dissolved in CH2C12 and dropped into the reaction solution at 0°C. After two hours, the reaction is taken up in CHCI3 and washed with NaHC03 solution and water. After drying with MgSC>4, the solvent is evaporated and purified by flash chromatography (SiC>2; methylene chloride-methanol: 98-2). Yield: 60 mg (91%) Smp.: 147°C. MS m/z 448 (M+). IR (KBr): 3336; 2929; 2816; 2225; 1635; 1500; 1240; 1028; 750. 'H-NMR (CDC13, 360 MHz) 5 (ppm): 1.73-1.77 (m, 4H, CH2-CH2); 2.59 (t, J=6.4 Hz, 2H, CH2N); 2.78 (m, 4H, pip); 3.14 (m, 4H, pip); 3.49-3.53 (m, 2H, CH2NCO) , 3.85 (s, 3H, OCH3); 6.84-6.92 (m, 5H, phenyl, NH); 6.99-7.04 (m, IH, phenyl); 7.60 (dd, J=1.4 Hz, J=8.5 Hz, IH, H6); 7.88 (s, IH, H3); 7.95 (d, J=8.5 Hz, IH, H7); 8.12 (d, J=l.l Hz. IH, H4). 13C-NMR(CDC13, 90 MHz) 5 (ppm): 170.3; 152.2; 140.9; 123.1; 120.9; 118.3; 111,2; 77.2; 76.3; 70.3; 69.7; 68.1; 57.9; 55.3; 53.4; 50.1; 39.2; 27.7; 23.8. C H N (%) C24H25C12N501H20; Calc.: C 64.35 H 6.48 N 12.01 S 6.87; Found: C 64.59 H 6.13 N 11.77 S 6.44. Example 19 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-cyan-2-benzo[b] thiophenylcarbamide Synthesis analogous to example 18. Yield: 57 mg (96 %) Smp.: 190°C. MS m/z 487 (M+). IR (KBr): 3319; 2929; 2819; 2227; 1633; 1560; 1448; 1242; 1045; 755. 'H-NMR (CDC13, 360 MHz) 6 (ppm): 1.65-1.76 (m, 4H, CH2-CH2); 2.49 (t, J=6.7 Hz, 2H, CH2N); 2.65 (m, 4H, pip); 3.04 (m, 4H, pip); 3.49-3.55 (m, 2H, CH2NCO); 6.78 (br, t, J=5.0 Hz, IH, NH); 6.85 (dd J=1.8 Hz, J=7.8Hz, IH, phenyl); 7.09-7.17 (m, 2H, phenyl); 7.62 (dd, J=1.4 Hz, J=8.5 Hz, IH, H6); 7.77 (s, IH, H3); 7.95 (d, J=8.2 Hz, H7); 8.13 (d, J=1.4 Hz, 1H,H4). 13C-NMR (CDCI3, 90 MHz) 5 (ppm): 161.4; 151.1; 144.5; 142.0; 138.8, 134.1; 129.4, 127.9; 127.5, 127.4; 124.7; 123.9; 123.8; 118.9; 118.4; 108.9; 57.9; 53.3; 51.2; 40.2; 27.4; 24.3. C H N (%) C20H26Cl2N4O S I.46 H20 INTELLECTUAL PROPERTY OFFICE OF N.Z M NOV 2007 RECEIVED 30 Calc.: C 56.11 H 5.28 N 10.90; Found: C 56.51 H5.06N 10.45. Example 20 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-6-cyano-2-benzo[b] thiophenylcarbamide Synthesis analogous to example 18. Yield: 30 mg (43%) Smp.: 124°C. MS m/z 448 (M1"). IR (KBr): 3290; 2937; 2816; 2225; 1619; 1543; 1500; 1242; 1026; 751. 'H-NMR (CDC13, 360 MHz) 6 (ppm): 1.72-1.90 (m, 4H, CH2-CH2); 2.90 (t, J=7.3 Hz, 2H, CH2N); 3.15 (m, 4H, pip); 3.31 (m, 4H, pip); 3.50-3.56 (m, 2H, CH2NCO), 3.82 (s, 3H, OCH3); 6.84- 6.92 (m, 3 H, phenyl); 7.01-7.07 (m, IH, phenyl); 7.13 (br, t, J=5.7, IH, NH); 7.53 (dd, J=1.4 Hz, J=8.2 Hz, IH, H5); 7.84 (d, J=7.8 Hz, IH, H4); 7.84 (s, IH, H3); 8.10-8.11 (m, IH, H7). ,3C-NMR (CDC13, 90 MHz) 8 (ppm): 161.5; 152.3; 141.9; 141.0; 140.4; 127.5; 127.4. 125.6; 124.2; 123.1. 120.9; 118.8; 118.1; 111.3; 109.5; 77.2; 76.3; 70.3; 69.7; 68.1; 57.9; 55.3; 53.4; 50.4; 40.1; 27.3; 24.2. Example 21 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-6-cyano-2-benzo [b] thiophenylcarbamide Synthesis analogous to example 18. Yield: 26 mg (43 %) Smp.: 137°C. MS m/z 486 (M4). IR (KBr): 3335; 2933; 2821; 2226; 1638; 1544; 1448; 1242; 1044; 735. 'H-NMR (CDC13, 360 MHz) 5 (ppm): 1.67-1.74 (m, 4H. CH2-CH2); 2.49 (t, J=6.4 Hz, 2H, CH2N); 2.65 (m, 4H, pip); 3.04 (m, 4H, pip); 3.49-3.54 (m, 2H, CH2NCO); 6.75 (br, t, J= 4.1 Hz, IH, NH); 6.84 (dd, J=1.8 Hz, 7.8 Hz, IH, phenyl); 7.08-7.17 (m, 2H, phenyl); 7,60-7,62 (m, IH, H5); 7.78 (s, IH, H3); 7.88-7.90 (m, 1H,H4); 8.19 (br, s, IH, H7). 13C-NMR(CDC13, 90 MHz) 5 (ppm): 161.4; 151.1; 143.6; 141.8; 140.3; 134.1; 127.5; 127.4; 125.2; 124.7. 124.2; 118.7; 118.4; 109.5; 109.5; 58.0; 53.3; 51.3; 51.2; 40.3; 27.4; 24.3. INTELLECTUAL PROPERTY OFFICE OF N.Z 1 h NOV 2007 RECEIVED 31 CHN (%): C24H25C12N5OH20; Calc.: C 59.02; H 5.57; N 14.34. Found: C 58.76; H 5,30; N 14.19. Example 22 N-4-(4-(2-methoxyphenyl)piperazin-lyl)butyl-5-bromo-2- benzo[b] thiophenylcarbamide Synthesis analogous to example 7. Yield: 73 mg (58%) Smp.: 156°C. MS m/z 502 (M+). IR (KBr): 3316; 2934; 2821; 1633; 1558; 1500; 1242; 1026; 750. !H-NMR (CDC13, 360 MHz) 5 (ppm): 1.69-1.72 (m, 4H,CH2-CH2); 2.57 (t, J=6.5 Hz, 2H, CH2N); 2.77 (m, 4H, pip); 3.12 (m, 4H, pip); 3.49-3.51 (m, 2H, CH2NCO); 3.85 (s, 3 H, OCH3); 6.83-6.91 (m, 4H, phenyl); 7.01-7.06 (m, IH, phenyl); 7.15 (brt, J=4.9 Hz, IH, NH); 7.42 (dd, J=8.5 Hz, J=1.8 Hz, IH, H6); 7.60 (d, J=8.5 Hz, IH, H7); 7.73 (s, IH, H3); 7.86 (d, :J=1.7 Hz, IH, H4). ,3C-NMR (CDC13, 90 MHz) 5 (ppm): 170.3; 152.2; 140.9; 123.1; 120.9; 118.3; 111.2; 77.2; 76.3; 70.3; 69.7; 68.1; 57.9; 55.3; 53.4; 50.1; 39.2; 27.7; 23.8. CHN: C24H28BrN302S (%): Calc.: C 57.37 H 5.62 N 8.36; Found: C 65.98 H 7.3 ON 14.87. Example 23 N-4-(4-(2,3-dichlorophenyl)piperazin-lyl)butyl-5-bromo-2-benzo[b] thiophenylcarbamide Synthesis analogous to example 7. Yield: 78 mg (60 %) Smp.: 178°C. MS m/z 541 (M+). IR (KBr; ): 3316; 2929; 2821; 1631; 1560; 1242; 1068; 756. 'H-NMR (CDC13, 360 MHz) 6 (ppm): 1.63-1.69 (m, 4H,CH2-CH2); 2.48 (t, J=6.7 Hz, 2H, CH2N); 2.64 (m, 4H, pip); 3.04 (m, 4H, pip); 3.48-3.53 (m, 2H, CH2NCO); 6.71 (br, t, J=5.1 Hz, IH, NH); 6.83-6.86 (m, IH, phenyl); 7.09-7.17 (m, 2H, phenyl); 7.51 (dd, J=1.8 Hz. J=8.5 Hz, IH, H6); 7.67 (s. IH, H3); 7.72 (d, 7=8.5 Hz, IH, H7); 7.95 (d, J=1.8 Hz, IH, H4). INTELLECTUAL PROPERTY OFFICE OF N.Z 1 h NOV 2007 RECEIVED 32 13C-NMR (CDCI3, 90 MHz) 5 (ppm): 161.9; 160.8; 140.7; 140.6. 139.2; 134.1; 129.3; 127.4; 127.3; 124.6; 124.1; 123.8. 118.9; 118.5; 57.9; 55.3; 51.2; 40.2; 27.5; 24.4. CHN (%): C23H24BrCl2N3OS0.25H20; Calc.: C 50.61 H 4.52 N 7.70 S 5.87; Found: C 50.61 H 4.49 N 7.64 S 5.87. Example 24 N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide Synthesis analogous to example 7. Yield: 89 mg (55 %) MS m/z 406 (M+). IR (NaCl): 3251; 3055; 2935; 2809; 1639; 1549; 1241; 1016; 746. 1 H-NMR (CDC13, 360 MHz) 5 (ppm): 1.67-1.74 (in, 4H,CH2-CH2); 2.48 (t, J-6.7 Hz, 2H, CH2N); 2.67 (m, 4H, pip); 3.11 (m, 4H, pip); 3.51-3.56 (m, 2H, CH2NCO); 3.85 (s, IH, OCH3); 6.59 (br, t, J= 4.9 Hz, IH, NHCO); 6.83-6.94 (m, 3H, phenyl); 6.97-7.02 (m, IH, phenyl); 7.11-7.15 (m, IH, H5); 7.25 (s, IH, H3); 7.29 (dd, J=l.l Hz, J=7.1 Hz, IH, H6); 7.43 (d, J=8.9 Hz, IH, H7); 7.63 (d, J=8.9 Hz, IH, H4); 9.50 (s, IH). Example 25 N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-cyano-2-indolylcarbamide Synthesis analogous to example 7. Yield: 102 mg (59 %) Smp.: 96°C. MS m/z 470 (IVT). IR (KBr): 3315; 2926; 2821; 2218, 1634; 1570; 1506; 1239; 1043; 734. 'H-NMR (CDC13, 360 MHz) 5 (ppm): 1.69-1.82 (m, 4H, CH2-CH2); 2.51 (t, J=6.9 Hz, 2H, CH2N); 2.66 (m, 4H, pip); 3.06 (m, 4H, pip); 3.58-3.63 (m, 2H, CH2NCO); 6.85 (br, t„ J=5.5 Hz, IH, NHCO); 6.88-6.91 (m, 2H, phenyl, H3); 7.09-7.17 (m, 2H, phenyl); 7.35 (dd, J=1.4 Hz, J=8.2 Hz, IH, H5); 7.70 (d, J=8.5 Hz, H4); 7.84 (s, IH, H7); 10.65 (s, IH, NH). 13C-NMR (CDC13j 90 MHz) 5 (ppm): 161.2; 151.1; 135.2; 134.3; 134.0; 130.5; 127.5; 127.4; 124.6; 123.1; 122.8; 120.1; 118.5; 117.2; 106.9; 102.0; 58.7; 53.3; 51.2; 41.1; 39.9; 24.4. CHN (%): C24H25C12N50H20; INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 4 NOV 2007 r F r c! v F d Calc.: C 59.02; H 5.57; N 14.34. Found: C 58.76; H 5.30; N 14.19. BIOLOGICAL ACTIVITY The biological activities of the compounds of the invention were determined in radio ligand binding assays. All radio ligand experiments were carried out in accordance with methods described by us (Htibner, H. et al. J. Med. Chem. 2000, 43, 756-762). For the measurement of the affinities to the receptors of the D2 family, membrane homogenates of ovarian cells of the Chinese hamsters (CHO cells) were used each of which stably expressed the human D21ong-, the human D2short- (Hayes, G. et al. Mol. Endocrinol. 1992, 6, 920-926), the human D3- (Sokoloff, P. et al. Eur. J. Pharmacol. 1992, 225, 331-337) or the human D4.4-receptor subtype (Asghari, V. J. Neurochem. 1995, 65, 1157-1165). In general, the binding assays were carried out by incubation of the receptor homogenates with the radio ligand [3H]Spiperon and the compound to be tested in different concentrations. The affinities to the Dl receptor were determined with native membrane homogenates obtained from the striatum of a pig and with the Dl-selective radio ligand [3H]SCH 23390. For the purpose of determining the binding strengths of the compounds to the serotonin receptor subtypes 5-HT1A and 5-HT2 cortex membrane preparations of a pig were incubated with the radio ligands [3H]8-OH-DPAT (for 5-HT1A) or [3H]Ketanserin (5-HT2) and the compounds. Indications of a simultaneous binding of the compounds to the serotonergic 5-HT2 receptor and to the adrenergic receptor subtype al upon labelling with the radio ligand [3H]Ketanserin were confirmed in a parallel experiment with selective blocking of the a 1 receptor by Prazosin. Therefore Ki values determined in the presence of 10 of Prazosin represent the sole bond to the 5-HT2 receptor. In addition, the affinity to al receptors of the pig were determined in a separate experiment with the a 1-selective radio ligand [3H]Prazosin. The results of the receptor binding assays on the dopamine receptor subtypes are summarised in table 1. All of the compounds tested in the binding assay showed good to very good affinities to the dopamine receptors with a clear binding preference to the subtypes of the D2 family. Independently of the partial structure, a clear 34 selectivity to the D3 receptor is always evident. The highest D3 affinity may be achieved if benzo [b]thiophene or indol is used as the heteroarene component. For example, compounds of the examples 1,2, 10 to 13 and 19 to 22 have excellent Ki values between 0.23 and 057 nM. The substitution pattern of the arylpiperazine component primarily influences the degree of selectivity of the D3 affinity vis-a-vis the other receptor subtypes. With selection coefficients of more than 1000, the 2,3-dichlorophenyl-substituted compounds (examples 2, 6, and 10) display a D3 selectivity hitherto not described with concomitant subnanomolar affinity. It is interesting that the ferrocenyl derivatives of the examples 16 and 17 are characterised by a high D4 affinity, example 17 with Ki values of 0.47 nM for the D3 receptor and 0.63 nM for the D4 receptor showing an extraordinary receptor binding profile. Tests to determine the intrinsic activity of the compounds of the examples were carried out in a mitogenesis assay as described in literature (Htibner, H. et al. J. Med. Chem. 2000, 43, 4563-4569; Lober, S. Bioorg. Med. Chem. Lett. 2002, 12.17, 2377-2380). A partial agonistic activity of 49 % of the maximum receptor stimulation is illustrative for the compound of example 1, which may be triggered by the full agonist Quinpirol as the reference compound. Curve calculations of this concentration-activity test resulted in an EC50 value of 0.38 nM. Table 1: Binding data and selectivity patterns of the compounds of the formulae (I) to (IV) for the dopamine receptors pDl, hD21ong, hD2short, hD3 and hD4.4 Ki-values in [nM]a D3 selectivity Compound D21ong/D3 D2short/D3 D4.4/D3 Dl D21ong D2short D3 D4.4 Example 1 670 87 52 0,23 15 380 230 Example 2 8800 3300 2600 0,5 340 6600 5200 Example 3 1100 110 84 1,1 30 100 76 Example 4 2900 320 80 1,2 93 270 67 Example 5 590 96 61 0,69 17 140 88 25 65 680 27 78 P:\WPD0CS\TXS\Spccs\12510711 amwdments.doc-11/13/2007 -35- Example 6 21000 10000 4800 3,4 3100 2900 1400 910 Example 7 1400 130 89 4,2 57 31 21 14 Example 8 380 63 39 0,72 35 88 54 49 Example 9 1400 91 48 0,55 150 170 87 270 5 Example 10 11000 3100 1600 0,56 1700 5500 2900 3000 Example 11 920 140 99 0,57 24 250 180 44 Example 12 390 110 44 0,24 16 460 180 67 Example 13 460 160 100 0,25 40 640 400 160 Example 14 4200 2300 770 0,73 600 3200 1100 820 10 Example 15 17000 340 110 0,35 630 970 310 1800 Example 16 1500 110 78 6,5 0,40 17 12 0,061 Example 17 630 31 19 0,47 0,63 66 40 1,3 Example 18 430 68 39 0,46 45 150 85 98 Example 19 1700 410 310 0,25 650 1600 1200 2600 15 Example 20 1100 210 130 0,33 37 640 390 110 Example 21 1700 180 60 0,26 72 690 230 280 Example 22 550 49 30 0,26 58 190 120 220 Example 23 4700 1700 970 3,2 1700 1500 300 530 Example 24 1200 200 160 0,70 40 290 230 57 20 Example 25 1700 140 27 0,91 210 150 30 230 a Average values from 2-9 individual experiments carried out as triplicates The investigation of the affinities to the serotonin receptor subtypes 5-HT1A and 5-HT2 and to the adrenergic receptor al is described in table 2. Irrespective of the partial structures of 25 the derivatives, a preferred binding to the 5-HT1A subtype when compared with 5-HT2 can be observed. With measured Ki values of 8 to 19 nM, the compounds of the examples 1, 3, 7, 8 and 16 are characterised by a high affinity to the al receptor. Considerations concerning structure/activity show a clear dependence on the substitution 30 pattern of the aryl piperazine partial structure for the binding to these receptors. As with the dopamine receptors, the binding to the 5-HT and to the al receptor is clearly diminished in the derivatives with a 2,3-dicholorphenyl radical which results in an extension of the selectivity spectrum vis-a-vis the D3 receptor affinity of these compounds. INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 h NOV 2007 dc rcix/cn 36 Table 2: Binding data of substances of the formulae (I) to (IV) for the serotonin receptors p5-HTl A, p5-HT2 and for the adrenergic receptor subtype pal Compounds Ki values in [nM]a 5-HT1A 5-HT2b alc ald Example 1 41 350 15 6,4 Example 2 360 2000 — 370 Example 3 17 660 14 3,3 Example 4 480 11000 — 160 Example 5 68 140 — 5,3 Example 6 2500 540 — 1300 Example 7 37 390 8,2 11 Example 8 69 420 15 3,5 Example 9 130 730 — 100 Example 10 610 1700 — 220 Example 11 83 440 24 5,9 Example 12 440 280 — 6,4 Example 13 47 220 — 4,3 Example 14 1600 690 — 500 Example 15 390 320 — 2000 Example 16 0,60 500 19 30 Example 17 27 250 — 73 Example 18 54 580 — 2,9 Example 19 190 280 — 230 Example 20 71 660 — 8,3 Example 21 110 290 — 45 Example 22 180 760 — 2,5 Example 23 430 14000 — 320 Example 24 32 420 11 7,3 Example 25 190 220 — 220 3 Average values from 2 to 6 individual experiments carried out with triplicates b Ki value in case of simultaneous incubation with 10 pM of Prazosin c Ki value derived from the highly affine binding site in case of labelling with [3H]Ketanserin d Ki value from the competitive experiment with the al selective radio ligand [3H]Prazosin </div>

Claims

<div class="application article clearfix printTableText" id="claims"> P:\WPDOCS\TXS\SpecsU2510711 amendments.doc-H/l 3/2007 -36a- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 5 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general 10 knowledge in the field of endeavour to which this specification relates. INTELLECTUAL PROPERTY OFFICE OF N.Z 1 h NOV 2007 p p n=! \/ e d P:\WPDOCS\TXS\Specs\12510711 amendments.doc-11/13/2007 -37- Claims A compound of the general formula (I) (I) 10 15 20 25 wherein: - n = 1 - 4 and - R = hydrogen, alkyl or halogen and (a) X = S or O: (i) when Ri is hydroxy, alkyloxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano, each of R2 and R3 is independently selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, (ii) when Ri is hydrogen, alkyl, halogen or trifluoromethyl, R2 is selected from hydroxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl and cyano and R3 is selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, or (b) or X = NH: Ri is selected from hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, trifluoromethyl, acyl, alkoxycarbonyl, halogen and cyano and each of R2 and R3 is independently selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, with the proviso that n = 3 and that the compound is notN-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide, INTELLECTUAL PROPERTY OFFICE OF N.Z. 14 NOV 2007 r f c f iv e d P:\WPDOCS\TXS\Specs\l2510711 ameadments.doc-11/13/2007 -38- (c) X = Te: Ri is selected from hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano and each of R2 and R3 is independently selected from hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl and cyano, wherein the groups alkyl, alkenyl, alkynyl and aryl are optionally substituted independently of each other, and a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein - n = 1 - 4 and - X = Te, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydrogen, hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano and R2 and R3 are substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, or - n = 1 - 4 and - X = S or O, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydroxy, alkyloxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano and R2 and R3 are substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, or - n = 1 - 4 and - X = S or O, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydrogen, alkyl, halogen or trifluoromethyl and R2 and R3 are substituted individually or jointly by the radicals hydroxy, alkenyl, alkynyl, aryl, acyl, alkoxycarbonyl or cyano, - n = 3 and INTELLECTUAL PROPERTY OFFICE OF N.Z 1 h NOV 2007 RECEIVED P:\WPDOCS\TXS\Specs\1251Q711 amendments.doc-11/13/2007 -39- - X = NH, when R = hydrogen, alkyl or halogen and Ri is substituted by the radicals hydroxy, alkyl, alkyloxy, alkenyl, alkynyl, aryl, trifluoromethyl, acyl, alkoxycarbonyl or cyano, where alkyl and alkyloxy contain at least two carbon atoms, and R2 and R3 are substituted individually or jointly by the radicals 5 hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano and alkyloxy comprises at least two carbon atoms. 10 The compound according to claim 1 having the general formula (la) or (lb): (la) (lb) 15 wherein: - n=l -4, - R = hydrogen, Ci-C6-alkyl or halogen, - when Ri is hydroxy, Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, Ci-C6-acyl, Ci- 20 C6-alkoxycarbonyl or cyano, each of R2 and R3 is independently selected from hydrogen, hydroxy, Ci-C6-alkyloxy, Ci-C6-alkyl, C2-C6 alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Ci-C6-acyl, Ci-C6-alkoxycarbonyl and cyano, - when Ri is hydrogen, Ci-C6-alkyl, halogen or trifluoromethyl, R2 is selected from 25 hydroxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, Ci-C6-acyl, Ci-C6-alkoxycarbonyl and cyano, IntbIectual^operty office of n.z 11, NOV 2007 rpOEIVED P:\WPDOCS\TXS\Specs\12510711 amendments.doc-11/13/2007 -40- and R.
3 is selected from hydrogen, hydroxy, Ci-C6-alkyl, Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Ci-C6-acyl, C1-C6 alkoxycarbonyl and cyano, wherein the groups Ci-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl are optionally substituted independently of each other, and a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 having the general formula (Ic): wherein: - n = 3, - R = hydrogen, Ci-C6-alkyl or halogen, - Ri is selected from hydrogen, hydroxy, Ci-C6-alkyl, Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, trifluoromethyl, Ci-C6-acyl, Ci-C6-alkoxycarbonyl, fluorine, chlorine, bromine and cyano, - each of R2 and R3 is independently selected from hydrogen, hydroxy, Ci-C6-alkyl, Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, C1-C6-acyl, Ci-C6-alkoxycarbonyl and cyano, wherein the groups Ci-C6-alkyl, C2-C6-alkenyl and C2-C6 alkynyl are optionally substituted independently of each other, and a pharmaceutically acceptable salt thereof, with the proviso that the compound is not N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide.
5. The compound according to claim 4, wherein INTELLECTUAL PROPERTY OFFICE OF N.Z 1 it NOV 2007 R F C F. IV EjD 1 P:\WPD0CS\TXS\Specs\12510711 aracndments.doc-11/13/2007 -41 - (a) when Ri is hydroxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, trifluoromethyl, Ci-C6-acyl, Ci-C6-alkoxycarbonyl or cyano, each of R2 and R3 are independently selected from hydrogen, hydroxy, Ci-C6-alkyl, 5 Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, trifluoromethyl, Ci-C6-acyl, Ci-C6-alkoxycarbonyl and cyano, and (b) when Ri is hydrogen, Ci-Cg-alkyl, Ci-C6-alkyloxy or halogen, R2 is 10 selected from hydroxy, C2-Cg-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, Ci-C6-acyl, Ci-C6-alkoxycarbonyl and cyano, and R3 is selected from hydrogen, hydroxy, Ci-C6-alkyl, Ci-C6-alkyloxy, C2-C6-alkenyl, C2-C6-alkynyl, phenyl that may optionally be substituted with a methoxy group or halogen, halogen, 15 trifluoromethyl, C1 -C6-acyl, C1 -Cg-alkoxycarbonyl and cyano, wherein the groups C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted independently of each other, and a pharmaceutically acceptable salt thereof. 20
6. The compound according to any one of claims 1 to 5, wherein - the substituent Ri is in position 5 or 6 of the heterocycle, and - the substituents R2 and R3 are in positions 2 and 3, respectively, or in positions 2 and 4, respectively, of the phenyl ring, the respective other substituent being in position 2 of the phenyl ring in the event that one of 25 the two substituents R2 and R3 is a hydrogen atom.
7. The compound according to any one of claims 1 to 3 and 6, wherein n = 3.
8. A compound of the general formula (IV): 30 INTELLECTUAL PROPERTY OFFICE OF N.Z. 11, NOV 2007 r f r j= iv e d P:\WPDOCS\TXS\Specs\l25107U amendments.doc-11/13/2007 -42- R 7 20 wherein: - X = S, NH or O, - R is selected from hydrogen, Ci-C6-alkyl, fluorine, chlorine and bromine, - Ri is selected from hydrogen, Ci-C6-alkyloxy, Ci-C6-alkyl, fluorine, chlorine, bromine, trifluoromethyl and cyano, Ri is in position 5 or 6 of the heterocycle, - R2 and R3 are independently selected from hydrogen, Cj-Cg-alkyloxy, Ci-C6-alkyl, fluorine, chlorine, bromine and trifluoromethyl, wherein R2 and R3 are in positions 2 and 3, respectively, or in positions 2 and 4, respectively, of the phenyl ring, the respective other substituent being in position 2 of the phenyl ring in the event that one of the two substituents R2 and R3 is a hydrogen atom, wherein the Ci-C6-alkyl groups are optionally substituted independently of each other, and a pharmaceutically acceptable salt thereof, with the proviso that the compound is not N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-indolylcarbamide.
9. The compound according to claim 8, wherein - when X = NH, then Ri is selected from hydrogen, C1-C3-alkyloxy, Ci-C3-alkyl, fluorine, chlorine, bromine and cyano, and - when X = S or O, then Ri is selected from hydrogen, Ci-C3-alkyl, fluorine, chlorine, bromine, cyano and trifluoromethyl.
10. The compound according to any one of claims 1 to 9 selected from N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-cyano-2-benzo[b]thiophenylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-5-cyano-2- P:\WPDOCS\TXS\Specs\125l0711 amendments.doc-11/13/2007 -43- N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-6-cyano-2-benzo[b]thiophenylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-6-cyano-2-benzo[b]thiophenylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]thiophenylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-benzo[b]thiophenylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-bromo-2-benzo [bjthiophenylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-5-bromo-2-benzo [b] thiophenylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-indolylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-cyano-2-indolylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-5-bromo-2-indolylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-6-cyano-2-indolylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-bromo-2-indolylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-6-cyano-2-indolylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-cyano-2-indolylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-cyano-2- benzo [b] furanylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-2-benzo[b] furanylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-2-benzo[b]furanylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-5-bromo-benzo [b] furanylcarbamide, N-4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butyl-5-bromo-2-benzo [b] furanylcarbamide, N-4-(4-(2-methoxyphenyl)piperazin-l-yl)butyl-2-benzo[b]tellurophenylcarbamide und N-4-(4-(2,3-dichlorophenyl)piperazin-1 -yl)butyl-2- benzo[b]tellurophenylcarbamide and a pharmaceutically acceptable salt thereof. intellectual PROPERTY OFFICE OF N.2 1 4 NOV 2007 rfofived P:\WPDOCS\TXS\Specs\125107!I amendments.doc-ll/13/2007 -44-
11. A medicament containing one or more of the compounds according to any one of claims 1 to 10.
12. The medicament according to claim 11 which additionally contains L-Dopa for simultaneous or sequential administration to the patient.
13. Use of a compound according to any one of claims 1 to 10 for preparing a medicament for the therapy or prophylaxis of ***e, alcohol, opiate and nicotine addiction; neurodegenerative disorders; sexual dysfunction; depression or schizophrenia.
14. The use according to claim 13, wherein the neurodegenerative disorder is Parkinson's disease.
15. Use of a compound according to any one of the claims 1 to 10 for preparing a medicament for the therapy or prophylaxis of hyperprolactinaemia; hyperprolactinoma; glaucoma; cognitive disorders; restless leg syndrome; hyperactivity syndrome (ADHS); locomotion disorders associated with Parkinson's disease; L-Dopa-induced disorders, Segawa syndrome; tardive locomotion disorders as well as for medication-assisted ablactation after pregnancies.
16. The use according to claim 15, wherein the medicament is provided for the therapy or prophylaxis of Segawa syndrome; spontaneous dyskinesia or dystonia associated with Parkinson's disease or tardive; or L-Dopa-induced dyskinesia or dystonia.
17. Use of a compound of the general formula (III): INTELLECTUAL PROPERTY OFFICE OF N.Z 11| NOV 2007 p F r, F i V E_D P:\WPDQCS\TXS\Specs\12510711 amendments, doc-11/13/2007 -45- (III) wherein: n = 1 - 4 and X = S, O or NH, when R = hydrogen, alkyl or halogen and Ri is 5 substituted by the radicals hydrogen, alkyl, halogen, trifluoromethyl and each of R2 and R3 are substituted individually or jointly by the radicals hydrogen, hydroxy, alkyloxy, alkyl, alkenyl, alkynyl, aryl, halogen, trifluoromethyl, acyl, alkoxycarbonyl or cyano, for preparing a medicament for the therapy or prophylaxis of ***e, alcohol, opiate and 10 nicotine addiction; neurodegenerative disorders; or sexual dysfunction.
18. The use according to claim 17, wherein the neurodegenerative disorder is Parkinson's disease. 15
19. Use of a compound as defined in claim 17 for preparing a medicament for the therapy or prophylaxis of hyperprolactinaemia; hyperprolactinoma; glaucoma; cognitive disorders; restless leg syndrome; hyperactivity syndrome (ADHS); locomotion disorders associated with Parkinson's disease; L-Dopa-induced disorders, Segawa syndrome; tardive locomotion disorders as well as for 20 medication-assisted ablactation after pregnancies. 25
20. The use according to claim 19, wherein the medicament is used for the therapy or prophylaxis of Segawa syndrome, spontaneous dyskinesia or dystonia associated with Parkinson's disease or tardive; or L-Dopa-induced dyskinesia or dystonia.
21. The use according to any one of claims 17 to 20, wherein - R is selected from hydrogen, C1-C6 alkyl, fluorine, chlorine and bromine, - Ri is selected from hydrogen, C1-C6 alkyloxy, C1-C6 alkyl, fluorine, chlorine, bromine and trifluoromethyl, and INTELLECTUAL PROPERTY OFFICE OF N.Z 14 NOV 2007 rfcfived P:\WPDOCS\TXS\Specs\1251G711 amendments.doc-11/13/2007 -46- - each of R2 and R3 is independently selected from hydrogen, C1-C6 alkyloxy, C1-C6 alkyl, fluorine, chlorine, bromine and trifluoromethyl, wherein the groups C1-C6 alkyl are optionally substituted independently of each other. 10
22. The use according to any one of the claims 17 to 21, wherein - the substituent Ri is in position 5 or 6 of the heterocycle, and - the substituents R2 and R3 are in positions 2 and 3, respectively, or in positions 2 and 4, respectively, of the phenyl ring; the respective other substituent being in position 2 of the phenyl ring in the event that one of the two substituents R2 and R3 is a hydrogen atom. 15
23. The use according to any one of the claims 17 to 22, wherein the compound is N-4-(4-(2-methoxyphenyl)piperazin-1 -yl)butyl-2-indolylcarbamide.
24. A process for preparing a compound of the general formulae (I) or (IV) as defined in any one of claims 1 to 10 comprising reacting a compound of the general formula (A) in activated form, 20 \_Y oh (a) with a compound of the general formula (B): 25 =\^.R2 ""tfuii,1,1 wherein n, R, Ri, R2, R3 and X are as defined for the general formulae (I) and (IV) in any one of claims 1 to 10. INTELLECTUAL PROPERTY OFFICE OF N.Z 14 NOV 2007 r f o p i V e d P:\WPDOCS\TXS\Specs\l2510711 amendments.doc-lt/13/2007 -47-
25. The process according to claim 24 wherein the activated form of the compound of the general formula (A) is the carboxylic acid halide.
26. Compounds of the general formula (I) according to claim 1 or compounds of the general formula (IV) according to claim 8; medicaments or uses thereof; and processes for preparing a compound of the general formula (I) or (IV); substantially as hereinbefore described with reference to the Examples, with the exception of Examples 16 and 17. END OF CLAIMS INTELLECTUAL PROPERTY OFFICE OF N.Z t 4 NOV 2007 rfcfived </div>