Indian Patents. 228179:4-(2-PHENYLSULFANYL-PHENYL)-1,2,3,6-TETRAHYDROPYRIDINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS

Title of Invention	4-(2-PHENYLSULFANYL-PHENYL)-1,2,3,6-TETRAHYDROPYRIDINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS
Abstract	The invention provides compounds represented by the general formula (I) wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.

Full Text	4-(2-Phenylsulfanyl-phenyI)-l,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors The present invention relates to novel compounds which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety. Background of the invention Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants. However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacotherapy. First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, sexual dysfunction is a side effect common to all SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely to happen. In order to cope with non-response, psychiatrists sometimes make use of augmentation strategies. Augmentation of antidepressant therapy may be accomplished through the co-administration of mood stabilizers such as lithium carbonate or triiodothyronin or by the use of electroshock. The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis et al. Eur. J. Pharmacol 1987, 143, 1095-204 and Gartside Br. J. Pharmacol. 1995, 115, 1064-1070, Blier et al. Trends in Pharmacol Science 1994, 15, 220). In these studies, it was found that 5-HT1A receptor antagonists would abolish the initial brake on 5-HT leurotxansmission induced by the serotonin reuptake inhibitors and thus produce an mmediate boost of 5-HT transmission and a rapid onset of therapeutic action. Several patent applications have been filed, which cover the use of a combination of a 5-HTIA antagonist and a serotonin reuptake inhibitor for the treatment of depression (see e.g. EP-A2-687472 and EP-A2-714663). Another approach to increase terminal 5-HT would be through blockade of the 5-HTIB autoreceptor. Microdialysis experiments in rats have indeed shown that increase of hippocampal 5-HT by citalopram is potentiated by GMC 2-29, an experimental 5-HTIB receptor antagonist. Several patent applications covering the combination of an SSRI and a 5-HTIB antagonist or partial agonist have also been filed (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877). It has previously been found that the combination of a serotonin reuptake inhibitor with a compound having 5-HT2C antagonistic or inverse agonistic effect (compounds having a negative efficacy at the 5-HT2C receptor) provides a considerable increase in the level of 5-HT in terminal areas, as measured in microdialysis experiments (WO 01/41701). This would imply a shorter onset of antidepressant effect in the clinic and an augmentation or potentiation of the therapeutic effect of the serotonin reuptake inhibitor (SRI). The combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition on depression is explored in clinical studies of compounds such as Duloxetine (Wong, Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate Expert Opinion on Investigational Drugs, 1993,7,10,1691-1699) and Venlafaxine (Khan-A et al, Venlafaxine in depressed outpatients Psychopharmacology Bulletin, 1991, 27,141-144). The present invention provides compounds which are serotonin reuptake inhibitors. Some of the compounds also have a combined effect of serotonin reuptake inhibition and 5-HT2c receptor modulation, which according to WO01/41701 would imply a faster onset of antidepressant activity. Moreover, some of the compounds posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition. Basically, the present compounds are suitable for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia. Summary of the invention The present invention provides compounds of the general formula I The invention provides a compound according to the above for use as a medicament. The invention provides a pharmaceutical composition comprising a compound according to the above or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. The invention provides the use of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia. The invention provides a method for the treatment of an affective disorder, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof. Definition of substituents Halogen means fluoro, chloro, bromo or iodo. The expression C1-6-alk(en/yn)yl means a C1-6-alkyl, C2-6-alkenyl or a C2-6-alkynyl group. The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-l-propyl. Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. The terms C1-6-alk(en/yn)yloxy, C1-6 alk(en/yn)ylsulfanyl, hydioxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, NRzRw-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl and halo-C1-6-alk(en/yn)yloxy designate such groups in which the C1-6-alk(en/yn)yl are as defined above. Halo means halogen. NR2Rw-C1-6-alk(en/yn)yl designate the group tetrahydropyridine derivatives which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety. Most of the tested compounds posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition as measured in the tests described in the examples section. Accordingly the present invention relates to a compound represented by the general formula I [ wherein R1 , R2, R3 R4 , R5 are independently selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C]-6-allc(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl5 halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, orNRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3.8-cycloalk(en)yl-C1-6-alk(en/yn)yl, orNRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, Ci-$-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; provided that at least one of R1, R2, R3, R4, R5, R6, R7, R8, and R9 is different from hydrogen; also provided that when R3 is methyl or methoxy, then at least one of R1, R2, R4, R5,R6, R7.. R8, R9 is different from hydrogen; or a salt thereof. more selected from a C1-6-alk(en/yn)yls hydroxy, hydroxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, e.g. one or two selected from hydroxy, bydioxy-C1-6 s-alkcyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R1 is selected from hydrogen; halogen; cyano; C1-6-alkyl; C1-6-alkyloxy; C1-6-alkylsulfanyl; halo-C1-6-alkyl; NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alkyl, cyanomethyl; NRxRy wherein Ry is selected from hydrogen, orC1-6alkyl, and Rx is NRzRw-C1-6-alk(en/yn)yl wherein R2 and Rw are independently selected from hydrogen, or C1-6-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, l-pyirolidinyl, 1-azetidinyl, 1-pyrrolyl orpyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R1 is hydrogen; another embodiment of R1 is C1-6-alkyl, such as methyl, ethyl, tert-butyl; a further embodiment of Rl is halogen, such as fluoro, bromo, or chloro; a further embodiment of R1 is C1-6-alkyloxy, such as methoxy; a further embodiment of R1 is halo-C1-6-alkyl, such as CF3. In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl. Typically, R is selected from hydrogen, halogen, cyano, C1-6-alkyl, C1-6-alkyloxy, C1-6-alkylsulfanyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R is hydrogen; another embodiment of R is C1-6-alkoxy, such as methoxy; another embodiment of R is halogen, such as fluoro, bromo, or chloro; another embodiment of R2 is C1-6-alkyl, such as methyl; another embodiment of R is halo-C1-6-alkyl, such as CF3. In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-allc(en/yn)ylsulfanyl, halo-C1-6-alkten/yntyl. Typically, R3 is selected from hydrogen, halogen, cyano, C1-6-allcyl, C1-6-allcyloxy, C1-6-alkylsulfanyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R is hydrogen; another embodiment of R is C1-6-alkyl, such as methyl, ethyl, tert-butyl; a further embodiment of R3 is C1-6-alkoxy, such as methoxy; a further embodiment of R3 is halogen, such as chloro, bromo, or fluoro; a further embodiment of R is C1-6-alkylsulfanyl, such as methylsulfanyl; a further embodiment of R3 is halo-C1-6-alkyl, such as CF3; a further embodiment of R3 is halo-C1-6-alkyloxy, such as trifluoromethyloxy. In a further embodiment of the compound of formula I, R2 and R3 together form a heterocycle fused to the phenyl ring selected from In a further embodiment, R5 is NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yls cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3.8-cycloalk(en)yl-C1-6-alk(en/yn)yl5 such as hydrogen, cyanomethyl, C1-6-alk(en/yn)yl. In a further embodiment R5 is NRxRy wherein Rx is NR2Rw-C1-6-alk(en/yn)yl, wherein R2 and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, or C3.8-cycloaUc(en)yl-C1-6-alk(en/)ai)yl, andRy is selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C]-6-alk(eo/yn)yl> C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. In a further embodiment R5 is NRxRy wherein Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl,1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C1-6-alk(en/yn)yl, hydroxy, hydroxy-C1-6-alk(en/yn)yl,C1-6 alk(en/yn)yloxy-C1-6-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl,C1-6alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R5 is selected from hydrogen; halogen; cyano; C1-6-alkyl; C1-6-alkyloxy; C1-6-alkylsulfanyl; halo-C1-6-alkyl; NRxRy wherein . Rx and Ry are independently selected from hydrogen, C1-6-alkyl, cyanomethyl; NRxRy wherein Ry is selected from hydrogen, or C1-6-alkyl, and Rx is NRZRW-C1-6-alk(en/yn)yl wherein Rz and Rw are independently selected from hydrogen, or C1-6-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl,1-imidazolyl, 1-pyrrolidinyl, l-azetidinyl51-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R5 is hydrogen; another embodiment of R5 is C1-6-allcyl, such as methyl, ethyl, tert-butyl; a further embodiment of R5 is halogen, such as fluoro, bromo, or chloro; a further embodiment of R5 is C1-6-alkyloxy, such as methoxy; a further embodiment of R5 is halo-Chalky 1, such as CF3. In a further embodiment of the compound of formula I, R6 is selected from hydrogen, halogen, C1-6-aUc(en/yn)yl, halo-C1-6-alk(en/yn)yl Typically, R6 is selected from hydrogen, halogen, C1-6-alkyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R6 is hydrogen; another embodiment of R6 is halogen, such as fluoro. In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl. Typically, R7 is selected from hydrogen, halogen, C1-6-alkyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R7 is hydrogen; another embodiment of R7 is halogen, such as fluoro. In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl3 C3. g-cycloalk(en)yl, C3-g-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR2Rw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3.8-cycloalk(en)yl"C1-6-alk(en/yn)yl, provided that if one of Rx and Ry is NRzRw-C1-6-alk(en/yn)yl then the other is selected from hydrogen, C1-6 alk(en/yn)yl5 cyano-C1-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C 1 usance en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula IR8 is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. In a further embodiment R8 is NRxRy wherein Rx and Ry are independently selected from hydrogen,C1-6 alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(eiVyn)yl, such as hydrogen, cyanomethyl, C1-6-alk(en/yn)yl. In a further embodiment R8 is NRxRy wherein Rx is MRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, --alk(en/yn)yl, C3-8-cycloalk(en)yl5 or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, andRy is selected from hydrogen, C1-6-allc(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. hi a further embodiment R8 is NRxRy wherein Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, l-azepinyl51- piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, l-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C1-6-alk(en/yn)yl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3.6-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R8 is selected from hydrogen; halogen; cyano; C1-6-alkyl; C1-6-alkyloxy; C1-6-alkylsulfanyl; halo-C1-6-alkyl; NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alkyl, cyanomethyl; NRxRy wherein Ry is selected from hydrogen, or C1-6-alkyl, and Rx is NRZRW-C1-6-alk(en/yn)yl wherein R2 and Rw are independently selected from hydrogen, or C1-6-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, l-pyrrolyl orpyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-allcyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R is hydrogen; another embodiment of R8 is halogen, such as fluoro, or bromo; a further embodiment of R is C1-6-alkyl, such as methyl; a further embodiment of R is halo-C1-6-alkyl, such as CF3; another embodiment of R8 is NRxRy wherein Rx is hydrogen and Ry is C1-6-alkyl, such as methyl. In a further embodiment of the compound of formula I, R9 is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl. Typically, R9 is selected from hydrogen, halogen, C1-6-alkyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R9 is hydrogen. Typically, the compound of formula I has at least one substituent in the phenyl ring(s), selected from any one of R1-R9, which is different from hydrogen, such as 1, 2, 3, or 4 substituents in the phenyl ring(s), selected from any one of R1R9, which is/are different from hydrogen, and the remaining substituents are hydrogen. Thus, in a further embodiment 1 substituent selected from any one of Rl-R9, which is different from hydrogen, is present in either of the two phenyl rings, such as 1 substituent selected from R;-R5, or the substituent is selected from R6-R9. In a further embodiment 2 substituents selected from Rl-R9, which are different from hydrogen, are present in either of the two phenyl rings, such as 1 substituent selected from R1-R55 and the other selected from R6-R9, or both substituents are selected from R1-R5; in this respect R2 and R3 may be taken together to form the heterocycle as defined above. In a further embodiment 3 substituents selected from R1-R9, which are different from hydrogen, are present in either of the two phenyl rings, such as 2 substituents selected from R1-R5 and the last substituent is selected from R6-R9. In each embodiment, as mentioned the remaining substituents are hydrogen. To illustrate this further without limiting the invention, some typical embodiments are outlined hereafter. Thus, in a further embodiment of the compound of formula I one substituent is present which is R2 as defined above, except hydrogen. In a further embodiment of the compound of formula I one substituent is present which is R3 as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R3 and Rs, wherein R3 and R8 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R3 and R6, wherein R3 and R6 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R and R7, wherein R3 and R7 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R1 and R3, wherein R1 and R3 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R2 and R3, wherein R2 and R3 are as defined above, except hydrogen, in this respect R2 and R3 may be taken together to form the heterocycle as defined above. In a further embodiment of the compound of formula I three substituents are present being R , R and R8, wherein R1, R3 and R8 are as defined above, except hydrogen. In each embodiment, as mentioned above the remaining substituents are hydrogen. did show serotonin reuptake inhibition, but did not show norepinephrine uptake inhibition in the test herein. The present invention also comprises salts of the present compounds, typically, pharmaceuticallyacceptable salts. Such salts include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. in general, tne solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention. The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or paitially purified optical isomers and any mixtures thereof including racemic mixtures are included within the scope of the invention. Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization of d- or 1- (tartrates, mandelates or camphorsulphonate) salts. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those disC1-6sed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis. Furthermore, when a double bond or a fully or partially saturated ring system is present in the moleC1-6le geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, moleC1-6les having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention. The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of the general fonnula (I), wliich are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The invention also encompasses active metabolites of the present compounds. As mentioned above, the compounds of formula I are serotonin reuptake inhibitors, and accordingly may be applicable for the treatment, including prevention, of affective disorders, such as depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder. Accordingly, in a further aspect the invention relates to a compound of formula I for use as a medicament. The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceuticallyacceptable carrier or diluent. The composition may comprise any one of the embodiments of formula I described above. In an embodiment of the pharmaceutical composition, the compound of formula I is present in an amount of from about 0.001 to about 100 mg/kg body weight per day. The present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of a disease or disorder, wherein a serotonin reuptake inhibitor is beneficial. The medicament may comprise any one of the embodiments of fonnula I described above. In partiC1-6lar, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of affective disorders. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of depression. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of anxiety disorders. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of general anxiety disorder. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of social anxiety disorder. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of post traumatic stress disorder. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of obsessive compulsive disorder. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of panic disorder. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of panic attacks. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of specific phobias. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of social phobia. In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of agoraphobia. A further aspect of the invention relates to a method for the treatment of a disease or disorder selected from the group consisting of an affective disorder, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia, in a living animal body, including a human, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I. In a further aspect, the present invention relates to a method of preparing a compound of formula I, comprising wherein Rl-R9 are as previously described, and R is a tert-butyl, methyl, ethyl, allyl or benzyl group or ROCO is a solid supported carbamate group, or b) chemical transformation of a compound with formula III Pharmaceutical compositions The compounds of the invention may be administered alone or in combination with pharmaceuticallyacceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable earners or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed.5 Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subC1-6taneous, intramusC1-6lar, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. Pharaiaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc. A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to about 1000 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg. For parenteral routes such as intravenous, intrathecal, intramusC1-6lar and similar administration, typically doses are in the order of about half the dose employed for oral administration. The compounds of this invention are generally utilized as the free substance or as a phannaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above. For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are partiC1-6larly suitable for intravenous, intramusC1-6lar, subC1-6taneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be a tablet, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. The compounds of the invention are prepared by the following general methods: a) Deprotection or cleavage from a polymer support of a compound with formula II wherein R1-R9 are as previously described, and R is a tert-butyl, methyl, ethyl, allyl or benzyl group or R OCO is a solid supported carbamate group, such as the Wang resin-based carbamate linker. b) Chemical transformation of a compound with formula HI to the corresponding diazonium compound and subsequently reacting with a thiophenol of formula IV wherein R1-R9 are as previously described, wherein R1-R9 are as previously described; and R" is either a hydrogen atom or R" can be a carbamate R OCO wherein R is a tot-butyl, methyl, ethyl, allyl or benzyl group or R OCO is a solid supported carbamate group, such as the Wang resin-based carbamate linker. The deprotection according to method a) was performed by standard techniques, known to the persons skilled in the art and detailed in the textbook Protective Groups in Organic Synthesis T.W.Greene and P.G.M. Wuts, Wiley Interscience, (1991) ISBN 0471623016. The cleav age from a polymer support, such as from the Wang resin based carbamate linker, according to method a) was performed according to literature known procedures (Zaxagoza Tetrahedron Lett. 1995, 36, 8677-8678 and Conti et al. Tetrahedron Lett. 1997, 38, 2915-2918). Stalling materials of formula II in method a) can be prepared by dehydrating a compound of formula V by treatment of V with an acid e.g. trifluoro acetic acid or concentrated HC1 in glacial acetic acid (1:5) as illustrated in the experimental procedure below. Starting materials of formula II can also be prepared by reacting a compound of formula VI with a thiophenol of formula IV in the presence of a palladium catalyst as illustrated in the experimental procedure below. Compounds of formula VI and IV wherein Rl-R9 are as previously described, and G is a bromine or iodine atom. The diazotation followed by reaction with a thiophenol IV according to the method b) can be performed by addition of the diazonium salt of the corresponding aniline to a solution of sodium salt of a thiophenol in an aqueous suspension of copper. The starting material of formula III and the corresponding diazonium salt can be prepared by methods analogues to those described in the literature (e.g. Berridge, M. S. et al. J. Med Chem. 1993, 36,1284-1290). Thiophenols of the formula IV are either commercially available or can be prepared according to methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions. The dehydration reaction and optional simultaneous deprotection of a compound of formula V in method c) was performed in a similar manner as described in Palmer et al J. Med. Chem. 1997,40,1982-1989 or by acid treatment as illustrated in the experimental procedure below. Starting materials of formula V in method c) can be prepared from the corresponding properly substituted 1-bromo-phenylsulfanylbenzenes of formula VII by metal-halogen exchange followed by addition of an appropriate electrophile of the formula VIII in a similar manner as described in Palmer et al. J. Med. Chem. 1997, 40,1982-19S9. Compounds of formula VIII and VII wherein R'-Ry and R' are as previously described, and G is a bromine or iodine atom. The properly substituted 1-bromo-phenylsulfanylbenzenes VII were prepared in a similar manner as described in the literature by reaction of properly substituted thiophenols with properly substituted aryliodides according to Schopfer and Schlapbach Tetrahedron 2001, 57, 3069-3073; Bates et al., Org. Lett 2002, 4, 2803-2806 and Kwong et al. Org. Lett. 2002, 4, 581-584. Starting materials of formula V in method c) were also prepared by reaction of thiophenols of formula IX with the corresponding properly substituted aryliodides or arylbromides X in the presence of a palladium catalyst as illustrated in the experimental procedure below. Compounds of formula IX and X wherein R1-R9 and R' are as previously described, and G is a bromine or iodine atom. Examples 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. Column: 30 X 4.6 mm Waters Symmmetry CI8 column with 3.5µM particle size; Solventsystem: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 mL/min. Purity was determined by integration of the UV (254 nm) and ELSD trace. The retention times (RT) are expressed in minutes. Preparative LC-MS-purification was performed on the same instrument. Column: 50 X 20 mm YMC ODS-A with 5µM particle size; Method: Linear gradient elution with 80% A to 100% B in 7 min and with a flow rate of 22.7 mL/min. Fraction collection was performed by split-flow MS detection. 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). For de-complexation by irradiation, a ultaviolet light source (300 W) from Philipps was used. As starting polymer supports for solid phase synthesis, Wang-resin (1.03 mmol/g? Rapp-Polymere5 Tuebingen, Germany) was used. Preparation of Intermediates 4-Hydroxy-4-[2-(4-chlorophenylsulfanyl)phenyl]-piperidm acid tert- butyl ester. A solution of BuLi (2.5 M in hexane, 12.0 ml, 30 mmol) was slowly added to a stirred solution of l-bromo-2-(4-chlorophenylsulfanyl)benzene (30 mmol) in dry THF (75 ml) under Argon at -78 °C. The solution was stirred for 10 min before 4-oxo-piperidine-1-carboxylic acid tert-bntyl ester (5.98 g5 30 mmol) was added in one portion. The solution was allowed to warm up to room temperature and then stirred for 3 h. Saturated aqueous NH4CI (150 ml) was added and the solution was extracted with ethylacetate (150 mL). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated in vaC1-6o. Crude product was purified by flash chromatography on silica gel (eluent: Ethylacetat/heptane 20:80) to produce the target 4-Hydroxy-4-(2-mercaptophenyl)-piperidine-l-carboxylic acid tert-butyl ester, 4 mL 1.6 M n-butyllithium in hexane (6.4 mmol) was added dropwise to 590 mg 2-bromo-thiophenol (3.1 mmol) in 5 mL dry THF at -78 °C. The solution was stirred 30 min. 640 mg jV-tert-butoxycarbonyl piperidone (3.2 mmol) in 5 mL dry THF was added dropwise and the reaction mixture was stirred 3 hours at -78 °C. The solution was poured into sat. NH4C1 (aq) and extracted with ethyl acetate (2x50mL). The combined organic phases were washed with brine, dried with MgSO4 and concentrated in vaC1-6o. Flash chromatography (ethyl acetate/heptane) yielded 650 mg product (2.1 mmol, 66%). Compounds of the invention: Example 1 Synthesis method A: Compound 2: 4-[2-(4-Chlorophenylsulfanyl)-phenylJ-l,2}3,6-tetrahydropyridine Concentrated aq hydrochloric acid (10 mL) was added to a stirred solution of \-tert-butoxycarbonyl-4-[2-(4-chlorophenylsu!fanyl)phenyl]piperidin-4-ol (0.84 g, 2 mmol) in acetic acid (30 mL). The solution was boiled under reflux overnight, cooled to room temperature and then stirred in an ice bath. An aqueous solution of NaOH (9.1 M, 40 mL) was slowly added and the unclear solution was extracted with ethyl acetate (2 x 40 ml). The combined organic phases were dried (MgS04) and the solvents evaporated in vaC1-6o. The crude material (0.48 g) was dissolved in ethyl acetate (3.2 mL) at 50 °C and a solution of oxalic acid (0.11 g) in EtOH (3.2 mL) was slowly added. The target compound was collected as a white oxalic salt. lH (DMSO-d6) 8 7.3-7.2 (m, 7H); 7.15 (m, 1H); 7.00 (m, 1H); 5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 2H); 2.6 (m, 2H); LC/MS (m/z) 302.1 (MH); RT = 2.29; purity (UV, ELSD): 100%, 100%; yield: 0.31 g (40%). Example 2 Synthesis method B: bis(dibenzylidene)palladium (23 mg; 0.04 mmol) were dissolved in 2.5 mL toluene and added to a solution of 4-hydroxy-4-(2-mercapto-phenyl)-piperidine-l-carboxylic acid rer/-butyl ester (200 mg; 0.64 mmol) and l-chloro-2-iodobenzene (200 mg; 0.84 mmol) in 4 mL toluene. Potassium tert-butoxide (80 mg; 0.68 mmol) was added and the reaction mixture was stirred under argon for 16 hours at 100°C. The reaction mixture was filtered through silica with ethyl acetate as eluent. The solvent was removed in vaC1-6o. The residue was dissolved in 4 mL glacial acetic acid and 1 mL concentrated HC1. The mixture was stirred for 16 hours at 100 °C. The solution was poured oa to ice and 8 mL 2S% aquous NaOH was added. The alkaline suspension was extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with brine, dried with MgSO4 and concentrated in vaC1-6o to give a brown oil. LC-MS: M+H: 302.1; retention time = 2.03 min; UV: 78%; ELSD 94%. Measurements of [3H]-5-HT uptake into rat cortical synaptosomes. Whole brains from male Wistar rats (125-225 g), excluding cerebellum, are homogenized in 0.32 M sucrose supplemented with ImM nialamid with a glass/teflon homogenizes The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (0.5 mg original tissue/well). Test compounds (or buffer) and 10 nM [3H]-5-HT are added to 96 well plates and shaken briefly. Composition of assay buffer: 123 mM' NaCl, 4.82 mMKCl, 0.973 mMCaCl2, 1.12 mM MgS04, 12.66 mM Na2HP04, 2.97 mM NaH2P04, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 02/5% C02 for 10 min at 37 °C and pH is adjusted 7.4. The inC1-6bation is started by adding tissue to a final assay volume of 0.2 mL. After 15 min inC1-6bation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1% polyethylenimine) under vaC1-6um and immediately washed with 3 x 0.2 ml assay buffer. Non-specific uptake is determined using citalopram (10 µM final concentration). Citalopram is included as reference in all experiments as dose-response C1-6rve. Preferred compounds of the present invention exhibit serotonin reuptake inhibition below 200 nM (IC50) in the assay above. More preferred are the compounds which exhibit inhibition below 100 nM and most preferably below 50 nM. [3H]Mesulergine binding to 5-HT2c receptors. Cell lines expressing 10-20µMol/mg protein human 5-HT2c-vsv receptors (Euroscreen) were harvested in ice-cold 50 mM Tris pH 7.7buffer containing 125 mM NaCl and stored at -80 ° C. On the day of the experiment cells were quickly thawed and homogenized in 50 mM Tris pH 7.7 using an Ultra-Thurax. Aliqouts consisting of 6-30µg protein, [3H]Mesulergine (1 nM) and testsubstance were inC1-6bated for 30 min at 37° C. Total binding was determined using assay buffer (50 mM Tris pH 7.7) and non-specific binding was defined in the presence of 100µM 5-HT. Bound and free [3H]Mesulergine was separated by vaC1-6um filtration on GF/B filters (pre-soaked in 0.1% PEI for Vi hour) and counted in a scintillation counter. 5-HT2C receptor efficacy as determined by fluorometry. This assay was carried out as described by Porter et al. British Journal of Pharmacology 1999, 128, 13 with the modifications described below. 2 days before the experiment CHO cells expressing 10-20µMol/mg protein human 5-HT2c-vsv receptors (Euroscreen) were plated at a density sufficient to yield a mono-confluent layer on the day of the experiment. The cells were dye loaded (Ca2+kit from MoleC1-6lar Devices, and according to their instructions) at 37 °C in a 5% CO2 inC1-6bator at 95% humidity. Lazer intensity was set to a suitable level to obtain basal values of approximately 8000 RFUs. The variation in basal fluorescence was less that 10%. EC50 values were assessed using increasing concentrations of test compound covering 3 decades. IC50 values were assessed challenging the ECss of 5-HT with concentrations covering 3 decades of test substances. Ki values were calC1-6lated using Cheng-Prusoff equation. Measurements of [3H]noradrenaline uptake into rat cortical synaptosomes. Fresh cortex from male Wistai' rats (125-225 g) are homogenized in 0.4M sucrose with a glass/teflon homogenizes The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (6 mg original tissue/mL = 4 mg/well). Test compounds (or buffer) and 10 nM [ H]-noradrenahne are added to deep 96 well plates and shaken briefly. Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl2, 1.12 mM MgS04, 12.66 mM Na2HP04, 2.97 mM NaH2P04, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 02/5% C02 for 10 min at 37 °C and pH is adjusted 7.4. The inC1-6bation is started by adding tissue to a final assay volume of 1 ml. After 15 min inC1-6bation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1% polyethylenimine) under vaC1-6um and immediately washed with 3x1 rnL assay buffer. Non-specific uptake is determined using talsupram (10µM final concentration). Duloxetine is included as reference in all experiments as dose-response C1-6rve. Claims: 1. A compound represented by the general formula I wherein R1 , R2 , R3 , R4 , R5 are independently selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alkten/yntylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, orNRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-8-cycloaIk(en)yl-C1-6-alk(en/yn)yl, or NRzRw-C1-6-alk(en/yn)yl> wherein Rz and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; provided that at least one of Rl, R2R3, R4, R5, R6, R7, R8, and R9 is different from hydrogen; also provided that when R3 is methyl or methoxy, then at least one of R1, R2, R\ R5, R6, R7, R8, R9 is different from hydrogen; or a salt thereof. 2. The compound of claim 1, wherein Rl is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, C].6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of Rx and Ry is NR2Rw-C1-6«alk(en/yn)yl then the other is selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; typically, R1 is selected from hydrogen, C1-6-alkyl, halogen, C1-6-alkyloxy, or halo-C1-6-alkyl; more typically, R1 is selected from hydrogen, C1-6-alkyl, or halogen. 3. The compound of any one of claims 1-2, wherein R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl; typically, R is selected from hydrogen, C1-6-alkoxy, halogen, C1-6-alkyl, or halo-C1-6-alkyl; more typically, R2 is selected from hydrogen, or C1-6-alkoxy. 4. The compound of any one of claims 1-3, wherein R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl; typically, R3 is selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, halogen, C1-6-alkylsulfanyl, halo-C1-6-alkyl, or halo-C1-6-alkyloxy; more typically, R' is selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, or halogen. 8. The compound of any one of claims 1 -7 wherein R6 is selected from hydrogen, halogen,C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl; typically, R6 is selected from hydrogen, or halogen. 9. The compound of any one of claims 1-8 wherein R is selected from hydrogen, halogen, C1-6alk(en/yn)yl, halo-C1-6-alk(en/yn)yl; typically, R7 is selected from hydrogen, or halogen. 10. The compound of any one of claims 1 -9 wherein R8 is selected from hydrogen, halogen, C1-6alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3- s-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3.8- cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of Rx and Ry is NR2Rw-C1-6-alk(en/yn)yl then the other is selected from hydrogen, C1-6 alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; typically, R is selected from hydrogen, C1-6-alkyl, halogen, halo-C1-6-alkyl, or NRxRy wherein RX is hydrogen and Ry is C1-6-alkyl; more typically, R8 is selected from hydrogen, C1-6-aikyl, halogen, orhalo-C1-6-alkyl. 11. The compound of any one of claims 1-10 wherein R9 is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl; typically, R9 is selected from hydrogen. 12. The compound of any one of claims 1-11 wherein the compound of formula I has 1-4 substituents in the phenyl ring(s), selected from any one of R-R9, which are different from hydrogen, and the remaining substituents are hydrogen. 13. The compound of claim 1, said compound being selected from 4-[2-(4-Fluorophenylsulfanyl)-phenyl]4,2,3,6-tetraliydropyridine, 4-[2-(4-Chlorophenylsulfanyl)-phenyl]-1,2,3,6-tetrahydropyridine, traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of any one of claims 1-13 or a pharmaceutically acceptable acid addition salt thereof.

Full Text

4-(2-Phenylsulfanyl-phenyI)-l,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors
The present invention relates to novel compounds which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety.
Background of the invention
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants.
However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue
pharmacotherapy.
First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, sexual dysfunction is a side effect common to all SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely to happen.
In order to cope with non-response, psychiatrists sometimes make use of augmentation strategies. Augmentation of antidepressant therapy may be accomplished through the co-administration of mood stabilizers such as lithium carbonate or triiodothyronin or by the use of electroshock.
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis et al. Eur. J. Pharmacol 1987, 143, 1095-204 and Gartside Br. J. Pharmacol. 1995, 115, 1064-1070, Blier et al. Trends in Pharmacol Science 1994, 15, 220). In these studies,

it was found that 5-HT1A receptor antagonists would abolish the initial brake on 5-HT leurotxansmission induced by the serotonin reuptake inhibitors and thus produce an mmediate boost of 5-HT transmission and a rapid onset of therapeutic action.
Several patent applications have been filed, which cover the use of a combination of a 5-HTIA antagonist and a serotonin reuptake inhibitor for the treatment of depression (see e.g. EP-A2-687472 and EP-A2-714663).
Another approach to increase terminal 5-HT would be through blockade of the 5-HTIB autoreceptor. Microdialysis experiments in rats have indeed shown that increase of hippocampal 5-HT by citalopram is potentiated by GMC 2-29, an experimental 5-HTIB receptor antagonist.
Several patent applications covering the combination of an SSRI and a 5-HTIB antagonist or partial agonist have also been filed (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).
It has previously been found that the combination of a serotonin reuptake inhibitor with a compound having 5-HT2C antagonistic or inverse agonistic effect (compounds having a negative efficacy at the 5-HT2C receptor) provides a considerable increase in the level of 5-HT in terminal areas, as measured in microdialysis experiments (WO 01/41701). This would imply a shorter onset of antidepressant effect in the clinic and an augmentation or potentiation of the therapeutic effect of the serotonin reuptake inhibitor (SRI).
The combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition on depression is explored in clinical studies of compounds such as Duloxetine (Wong, Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate Expert Opinion on Investigational Drugs, 1993,7,10,1691-1699) and Venlafaxine (Khan-A et al, Venlafaxine in depressed outpatients Psychopharmacology Bulletin, 1991, 27,141-144).

The present invention provides compounds which are serotonin reuptake inhibitors. Some of the compounds also have a combined effect of serotonin reuptake inhibition and 5-HT2c receptor modulation, which according to WO01/41701 would imply a faster onset of antidepressant activity. Moreover, some of the compounds posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition. Basically, the present compounds are suitable for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
Summary of the invention
The present invention provides compounds of the general formula I

The invention provides a compound according to the above for use as a medicament.
The invention provides a pharmaceutical composition comprising a compound according to the above or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
The invention provides the use of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a

medicament for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
The invention provides a method for the treatment of an affective disorder, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof.
Definition of substituents
Halogen means fluoro, chloro, bromo or iodo.
The expression C1-6-alk(en/yn)yl means a C1-6-alkyl, C2-6-alkenyl or a C2-6-alkynyl group.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-l-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl
and butynyl.
The terms C1-6-alk(en/yn)yloxy, C1-6 alk(en/yn)ylsulfanyl, hydioxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, NRzRw-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl and halo-C1-6-alk(en/yn)yloxy designate such groups in which the C1-6-alk(en/yn)yl are as defined above. Halo means halogen. NR2Rw-C1-6-alk(en/yn)yl designate the group

tetrahydropyridine derivatives which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety. Most of the tested compounds posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition as measured in the tests described in the examples section.
Accordingly the present invention relates to a compound represented by the general formula I

[
wherein
R1 , R2, R3 R4 , R5 are independently selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C]-6-allc(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl5 halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, orNRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3.8-cycloalk(en)yl-C1-6-alk(en/yn)yl, orNRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, Ci-$-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or

the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom;
provided that at least one of R1, R2, R3, R4, R5, R6, R7, R8, and R9 is different from hydrogen; also provided that when R3 is methyl or methoxy, then at least one of R1, R2, R4, R5,R6, R7.. R8, R9 is different from hydrogen; or a salt thereof.

more selected from a C1-6-alk(en/yn)yls hydroxy, hydroxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, e.g. one or two selected from hydroxy, bydioxy-C1-6 s-alkcyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R1 is selected from hydrogen; halogen; cyano; C1-6-alkyl; C1-6-alkyloxy; C1-6-alkylsulfanyl; halo-C1-6-alkyl; NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alkyl, cyanomethyl; NRxRy wherein Ry is selected from hydrogen, orC1-6alkyl, and Rx is NRzRw-C1-6-alk(en/yn)yl wherein R2 and Rw are independently selected from hydrogen, or C1-6-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, l-pyirolidinyl, 1-azetidinyl, 1-pyrrolyl orpyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R1 is hydrogen; another embodiment of R1 is C1-6-alkyl, such as methyl, ethyl, tert-butyl; a further embodiment of Rl is halogen, such as fluoro, bromo, or chloro; a further embodiment of R1 is C1-6-alkyloxy, such as methoxy; a further embodiment of R1 is halo-C1-6-alkyl, such as CF3.
In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl. Typically, R is selected from hydrogen, halogen, cyano, C1-6-alkyl, C1-6-alkyloxy, C1-6-alkylsulfanyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R is hydrogen; another embodiment of R is C1-6-alkoxy, such as methoxy; another embodiment of R is halogen, such as fluoro, bromo, or chloro; another embodiment of R2 is C1-6-alkyl, such as methyl; another embodiment of R is halo-C1-6-alkyl, such as CF3.
In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-allc(en/yn)ylsulfanyl, halo-C1-6-alkten/yntyl. Typically, R3 is selected from hydrogen, halogen, cyano, C1-6-allcyl, C1-6-allcyloxy, C1-6-alkylsulfanyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R is hydrogen; another embodiment of R is C1-6-alkyl, such as methyl, ethyl, tert-butyl; a further embodiment of R3 is C1-6-alkoxy,

such as methoxy; a further embodiment of R3 is halogen, such as chloro, bromo, or fluoro; a further embodiment of R is C1-6-alkylsulfanyl, such as methylsulfanyl; a further embodiment of R3 is halo-C1-6-alkyl, such as CF3; a further embodiment of R3 is halo-C1-6-alkyloxy, such as trifluoromethyloxy.
In a further embodiment of the compound of formula I, R2 and R3 together form a heterocycle fused to the phenyl ring selected from

In a further embodiment, R5 is NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yls cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3.8-cycloalk(en)yl-C1-6-alk(en/yn)yl5 such as hydrogen, cyanomethyl, C1-6-alk(en/yn)yl. In a further embodiment R5 is NRxRy wherein Rx is NR2Rw-C1-6-alk(en/yn)yl, wherein R2 and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, or C3.8-cycloaUc(en)yl-C1-6-alk(en/)ai)yl, andRy is selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C]-6-alk(eo/yn)yl> C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. In a further embodiment R5 is NRxRy wherein Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl,1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C1-6-alk(en/yn)yl, hydroxy, hydroxy-C1-6-alk(en/yn)yl,C1-6 alk(en/yn)yloxy-C1-6-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl,C1-6alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R5 is selected from hydrogen; halogen; cyano; C1-6-alkyl; C1-6-alkyloxy; C1-6-alkylsulfanyl; halo-C1-6-alkyl; NRxRy wherein . Rx and Ry are independently selected from hydrogen, C1-6-alkyl, cyanomethyl; NRxRy wherein Ry is selected from hydrogen, or C1-6-alkyl, and Rx is NRZRW-C1-6-alk(en/yn)yl wherein Rz and Rw are independently selected from hydrogen, or C1-6-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl,1-imidazolyl, 1-pyrrolidinyl, l-azetidinyl51-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R5 is hydrogen; another embodiment of R5 is C1-6-allcyl, such as methyl, ethyl, tert-butyl; a further embodiment of R5 is halogen, such as fluoro, bromo, or chloro; a further embodiment of R5 is C1-6-alkyloxy, such as methoxy; a further embodiment of R5 is halo-Chalky 1, such as CF3.
In a further embodiment of the compound of formula I, R6 is selected from hydrogen, halogen, C1-6-aUc(en/yn)yl, halo-C1-6-alk(en/yn)yl Typically, R6 is selected from hydrogen, halogen, C1-6-alkyl, halo-C1-6-alkyl. To further illustrate without limiting

the invention an embodiment of R6 is hydrogen; another embodiment of R6 is halogen, such as fluoro.
In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl. Typically, R7 is selected from hydrogen, halogen, C1-6-alkyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R7 is hydrogen; another embodiment of R7 is halogen, such as fluoro.
In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl3 C3. g-cycloalk(en)yl, C3-g-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR2Rw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3.8-cycloalk(en)yl"C1-6-alk(en/yn)yl, provided that if one of Rx and Ry is NRzRw-C1-6-alk(en/yn)yl then the other is selected from hydrogen, C1-6 alk(en/yn)yl5 cyano-C1-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C 1 usance en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula IR8 is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. In a further embodiment R8 is NRxRy wherein Rx and Ry are independently selected from hydrogen,C1-6 alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(eiVyn)yl, such as hydrogen, cyanomethyl, C1-6-alk(en/yn)yl. In a further embodiment R8 is NRxRy wherein Rx is MRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, --alk(en/yn)yl, C3-8-cycloalk(en)yl5 or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, andRy is selected from hydrogen, C1-6-allc(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. hi a further embodiment R8 is NRxRy wherein Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, l-azepinyl51-

piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, l-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C1-6-alk(en/yn)yl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3.6-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R8 is selected from hydrogen; halogen; cyano; C1-6-alkyl; C1-6-alkyloxy; C1-6-alkylsulfanyl; halo-C1-6-alkyl; NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alkyl, cyanomethyl; NRxRy wherein Ry is selected from hydrogen, or C1-6-alkyl, and Rx is NRZRW-C1-6-alk(en/yn)yl wherein R2 and Rw are independently selected from hydrogen, or C1-6-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, l-pyrrolyl orpyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-allcyl, in partiC1-6lar one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R is hydrogen; another embodiment of R8 is halogen, such as fluoro, or bromo; a further embodiment of R is C1-6-alkyl, such as methyl; a further embodiment of R is halo-C1-6-alkyl, such as CF3; another embodiment of R8 is NRxRy wherein Rx is hydrogen and Ry is C1-6-alkyl, such as methyl.
In a further embodiment of the compound of formula I, R9 is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl. Typically, R9 is selected from hydrogen, halogen, C1-6-alkyl, halo-C1-6-alkyl. To further illustrate without limiting the invention an embodiment of R9 is hydrogen.
Typically, the compound of formula I has at least one substituent in the phenyl ring(s), selected from any one of R1-R9, which is different from hydrogen, such as 1, 2, 3, or 4 substituents in the phenyl ring(s), selected from any one of R1R9, which is/are different from hydrogen, and the remaining substituents are hydrogen. Thus, in a further embodiment 1 substituent selected from any one of Rl-R9, which is different from hydrogen, is present in either of the two phenyl rings, such as 1 substituent selected from R;-R5, or the substituent is selected from R6-R9. In a further embodiment 2 substituents selected from Rl-R9, which are different from hydrogen,

are present in either of the two phenyl rings, such as 1 substituent selected from R1-R55 and the other selected from R6-R9, or both substituents are selected from R1-R5; in this respect R2 and R3 may be taken together to form the heterocycle as defined above. In a further embodiment 3 substituents selected from R1-R9, which are different from hydrogen, are present in either of the two phenyl rings, such as 2 substituents selected from R1-R5 and the last substituent is selected from R6-R9. In each embodiment, as mentioned the remaining substituents are hydrogen. To illustrate this further without limiting the invention, some typical embodiments are outlined hereafter.
Thus, in a further embodiment of the compound of formula I one substituent is present which is R2 as defined above, except hydrogen. In a further embodiment of the compound of formula I one substituent is present which is R3 as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R3 and Rs, wherein R3 and R8 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R3 and R6, wherein R3 and R6 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R and R7, wherein R3 and R7 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R1 and R3, wherein R1 and R3 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R2 and R3, wherein R2 and R3 are as defined above, except hydrogen, in this respect R2 and R3 may be taken together to form the heterocycle as defined above. In a further embodiment of the compound of formula I three substituents are present being R , R and R8, wherein R1, R3 and R8 are as defined above, except hydrogen. In each embodiment, as mentioned above the remaining substituents are hydrogen.

did show serotonin reuptake inhibition, but did not show norepinephrine uptake inhibition in the test herein.
The present invention also comprises salts of the present compounds, typically, pharmaceuticallyacceptable salts. Such salts include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.

in general, tne solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or paitially purified optical isomers and any mixtures thereof including racemic mixtures are included within the scope of the invention.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization of d- or 1- (tartrates, mandelates or camphorsulphonate) salts. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those disC1-6sed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New
York (1981).
Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis.
Furthermore, when a double bond or a fully or partially saturated ring system is present in the moleC1-6le geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, moleC1-6les having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of the general fonnula (I), wliich are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
As mentioned above, the compounds of formula I are serotonin reuptake inhibitors, and accordingly may be applicable for the treatment, including prevention, of affective disorders, such as depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
Accordingly, in a further aspect the invention relates to a compound of formula I for use as a medicament.
The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceuticallyacceptable carrier or diluent. The composition may comprise any one of the embodiments of formula I described above.
In an embodiment of the pharmaceutical composition, the compound of formula I is present in an amount of from about 0.001 to about 100 mg/kg body weight per day.
The present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of a disease or disorder, wherein a serotonin reuptake inhibitor is beneficial. The medicament may comprise any one of the embodiments of fonnula I described above.

In partiC1-6lar, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of affective disorders.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of depression.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of anxiety disorders.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of general anxiety disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of social anxiety disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of post traumatic stress disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of obsessive compulsive disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of panic disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of panic attacks.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of specific phobias.

In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of social phobia.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of agoraphobia.
A further aspect of the invention relates to a method for the treatment of a disease or disorder selected from the group consisting of an affective disorder, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia, in a living animal body, including a human, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.
In a further aspect, the present invention relates to a method of preparing a compound of formula I, comprising

wherein Rl-R9 are as previously described, and R is a tert-butyl, methyl, ethyl, allyl or benzyl group or ROCO is a solid supported carbamate group, or
b) chemical transformation of a compound with formula III

Pharmaceutical compositions
The compounds of the invention may be administered alone or in combination with pharmaceuticallyacceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable earners or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed.5 Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subC1-6taneous, intramusC1-6lar, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharaiaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of
the present invention.

Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to about 1000 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramusC1-6lar and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a phannaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or

glucose. The aqueous solutions are partiC1-6larly suitable for intravenous, intramusC1-6lar, subC1-6taneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be a tablet, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft

gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid
suspension or solution.
The compounds of the invention are prepared by the following general methods:
a) Deprotection or cleavage from a polymer support of a compound with formula II

wherein R1-R9 are as previously described, and R is a tert-butyl, methyl, ethyl, allyl or benzyl group or R OCO is a solid supported carbamate group, such as the Wang resin-based carbamate linker.
b) Chemical transformation of a compound with formula HI to the corresponding
diazonium compound and subsequently reacting with a thiophenol of formula IV

wherein R1-R9 are as previously described,

wherein R1-R9 are as previously described; and R" is either a hydrogen atom or R" can be a carbamate R OCO wherein R is a tot-butyl, methyl, ethyl, allyl or benzyl group or R OCO is a solid supported carbamate group, such as the Wang resin-based carbamate linker.
The deprotection according to method a) was performed by standard techniques, known to the persons skilled in the art and detailed in the textbook Protective Groups in Organic Synthesis T.W.Greene and P.G.M. Wuts, Wiley Interscience, (1991) ISBN 0471623016. The cleav age from a polymer support, such as from the Wang resin based carbamate linker, according to method a) was performed according to literature known procedures (Zaxagoza Tetrahedron Lett. 1995, 36, 8677-8678 and Conti et al. Tetrahedron Lett. 1997, 38, 2915-2918).
Stalling materials of formula II in method a) can be prepared by dehydrating a compound of formula V by treatment of V with an acid e.g. trifluoro acetic acid or concentrated HC1 in glacial acetic acid (1:5) as illustrated in the experimental procedure below. Starting materials of formula II can also be prepared by reacting a compound of formula VI with a thiophenol of formula IV in the presence of a palladium catalyst as illustrated in the experimental procedure below. Compounds of formula VI and IV

wherein Rl-R9 are as previously described, and G is a bromine or iodine atom.
The diazotation followed by reaction with a thiophenol IV according to the method b) can be performed by addition of the diazonium salt of the corresponding aniline to a solution of sodium salt of a thiophenol in an aqueous suspension of copper. The starting material of formula III and the corresponding diazonium salt can be prepared by methods analogues to those described in the literature (e.g. Berridge, M. S. et al. J. Med Chem. 1993, 36,1284-1290). Thiophenols of the formula IV are either commercially available or can be prepared according to methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions.
The dehydration reaction and optional simultaneous deprotection of a compound of formula V in method c) was performed in a similar manner as described in Palmer et al J. Med. Chem. 1997,40,1982-1989 or by acid treatment as illustrated in the experimental procedure below.
Starting materials of formula V in method c) can be prepared from the corresponding properly substituted 1-bromo-phenylsulfanylbenzenes of formula VII by metal-halogen exchange followed by addition of an appropriate electrophile of the formula VIII in a similar manner as described in Palmer et al. J. Med. Chem. 1997, 40,1982-19S9. Compounds of formula VIII and VII

wherein R'-Ry and R' are as previously described, and G is a bromine or iodine atom. The properly substituted 1-bromo-phenylsulfanylbenzenes VII were prepared in a similar manner as described in the literature by reaction of properly substituted thiophenols with properly substituted aryliodides according to Schopfer and Schlapbach Tetrahedron 2001, 57, 3069-3073; Bates et al., Org. Lett 2002, 4, 2803-2806 and Kwong et al. Org. Lett. 2002, 4, 581-584.
Starting materials of formula V in method c) were also prepared by reaction of thiophenols of formula IX with the corresponding properly substituted aryliodides or arylbromides X in the presence of a palladium catalyst as illustrated in the experimental procedure below. Compounds of formula IX and X

wherein R1-R9 and R' are as previously described, and G is a bromine or iodine atom.

Examples
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. Column: 30 X 4.6 mm Waters Symmmetry CI8 column with 3.5µM particle size; Solventsystem: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 mL/min. Purity was determined by integration of the UV (254 nm) and ELSD trace. The retention times (RT) are expressed in minutes. Preparative LC-MS-purification was performed on the same instrument. Column: 50 X 20 mm YMC ODS-A with 5µM particle size; Method: Linear gradient elution with 80% A to 100% B in 7 min and with a flow rate of 22.7 mL/min. Fraction collection was performed by split-flow MS detection.
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). For de-complexation by irradiation, a ultaviolet light source (300 W) from Philipps was used. As starting polymer supports for solid phase synthesis, Wang-resin (1.03 mmol/g? Rapp-Polymere5 Tuebingen, Germany) was used.
Preparation of Intermediates
4-Hydroxy-4-[2-(4-chlorophenylsulfanyl)phenyl]-piperidm acid tert-
butyl ester.
A solution of BuLi (2.5 M in hexane, 12.0 ml, 30 mmol) was slowly added to a stirred solution of l-bromo-2-(4-chlorophenylsulfanyl)benzene (30 mmol) in dry THF (75 ml) under Argon at -78 °C. The solution was stirred for 10 min before 4-oxo-piperidine-1-carboxylic acid tert-bntyl ester (5.98 g5 30 mmol) was added in one portion. The solution was allowed to warm up to room temperature and then stirred for 3 h. Saturated aqueous NH4CI (150 ml) was added and the solution was extracted with ethylacetate (150 mL). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated in vaC1-6o. Crude product was purified by flash chromatography on silica gel (eluent: Ethylacetat/heptane 20:80) to produce the target

4-Hydroxy-4-(2-mercaptophenyl)-piperidine-l-carboxylic acid tert-butyl ester,
4 mL 1.6 M n-butyllithium in hexane (6.4 mmol) was added dropwise to 590 mg 2-bromo-thiophenol (3.1 mmol) in 5 mL dry THF at -78 °C. The solution was stirred 30 min. 640 mg jV-tert-butoxycarbonyl piperidone (3.2 mmol) in 5 mL dry THF was added dropwise and the reaction mixture was stirred 3 hours at -78 °C. The solution was poured into sat. NH4C1 (aq) and extracted with ethyl acetate (2x50mL). The combined organic phases were washed with brine, dried with MgSO4 and concentrated in vaC1-6o. Flash chromatography (ethyl acetate/heptane) yielded 650 mg product (2.1 mmol, 66%).
Compounds of the invention:
Example 1 Synthesis method A:
Compound 2: 4-[2-(4-Chlorophenylsulfanyl)-phenylJ-l,2}3,6-tetrahydropyridine
Concentrated aq hydrochloric acid (10 mL) was added to a stirred solution of \-tert-butoxycarbonyl-4-[2-(4-chlorophenylsu!fanyl)phenyl]piperidin-4-ol (0.84 g, 2 mmol) in acetic acid (30 mL). The solution was boiled under reflux overnight, cooled to room temperature and then stirred in an ice bath. An aqueous solution of NaOH (9.1 M, 40 mL) was slowly added and the unclear solution was extracted with ethyl acetate (2 x 40 ml). The combined organic phases were dried (MgS04) and the solvents evaporated in vaC1-6o. The crude material (0.48 g) was dissolved in ethyl acetate (3.2 mL) at 50 °C and a solution of oxalic acid (0.11 g) in EtOH (3.2 mL) was slowly added. The target compound was collected as a white oxalic salt. lH (DMSO-d6) 8 7.3-7.2 (m, 7H); 7.15 (m, 1H); 7.00 (m, 1H); 5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 2H); 2.6 (m, 2H); LC/MS (m/z) 302.1 (MH*); RT = 2.29; purity (UV, ELSD): 100%, 100%; yield: 0.31 g (40%).

Example 2 Synthesis method B:

bis(dibenzylidene)palladium (23 mg; 0.04 mmol) were dissolved in 2.5 mL toluene and added to a solution of 4-hydroxy-4-(2-mercapto-phenyl)-piperidine-l-carboxylic acid rer/-butyl ester (200 mg; 0.64 mmol) and l-chloro-2-iodobenzene (200 mg; 0.84 mmol) in 4 mL toluene. Potassium tert-butoxide (80 mg; 0.68 mmol) was added and the reaction mixture was stirred under argon for 16 hours at 100°C. The reaction mixture was filtered through silica with ethyl acetate as eluent. The solvent was removed in vaC1-6o. The residue was dissolved in 4 mL glacial acetic acid and 1 mL concentrated HC1. The mixture was stirred for 16 hours at 100 °C. The solution was poured oa to ice and 8 mL 2S% aquous NaOH was added. The alkaline suspension was extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with brine, dried with MgSO4 and concentrated in vaC1-6o to give a brown oil. LC-MS: M+H: 302.1; retention time = 2.03 min; UV: 78%; ELSD 94%.

Measurements of [3H]-5-HT uptake into rat cortical synaptosomes.
Whole brains from male Wistar rats (125-225 g), excluding cerebellum, are homogenized in 0.32 M sucrose supplemented with ImM nialamid with a glass/teflon homogenizes The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (0.5 mg original tissue/well). Test compounds (or buffer) and 10 nM [3H]-5-HT are added to 96 well plates and shaken briefly. Composition of assay buffer: 123 mM' NaCl, 4.82 mMKCl, 0.973 mMCaCl2, 1.12 mM MgS04, 12.66 mM Na2HP04, 2.97 mM NaH2P04, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 02/5% C02 for 10 min at 37 °C and pH is adjusted 7.4. The inC1-6bation is started by adding tissue to a final assay volume of 0.2 mL. After 15 min inC1-6bation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1% polyethylenimine) under vaC1-6um and immediately washed with 3 x 0.2 ml assay buffer. Non-specific uptake is determined using citalopram (10 µM final concentration). Citalopram is included as reference in all experiments as dose-response C1-6rve.
Preferred compounds of the present invention exhibit serotonin reuptake inhibition below 200 nM (IC50) in the assay above. More preferred are the compounds which exhibit inhibition below 100 nM and most preferably below 50 nM.
[3H]Mesulergine binding to 5-HT2c receptors.
Cell lines expressing 10-20µMol/mg protein human 5-HT2c-vsv receptors (Euroscreen) were harvested in ice-cold 50 mM Tris pH 7.7buffer containing 125 mM NaCl and stored at -80 ° C. On the day of the experiment cells were quickly thawed and homogenized in 50 mM Tris pH 7.7 using an Ultra-Thurax. Aliqouts consisting of 6-30µg protein, [3H]Mesulergine (1 nM) and testsubstance were inC1-6bated for 30 min at 37° C. Total binding was determined using assay buffer (50 mM Tris pH 7.7) and non-specific binding was defined in the presence of 100µM 5-HT. Bound and free [3H]Mesulergine was separated by vaC1-6um filtration on GF/B filters (pre-soaked in 0.1% PEI for Vi hour) and counted in a scintillation counter.

5-HT2C receptor efficacy as determined by fluorometry.
This assay was carried out as described by Porter et al. British Journal of Pharmacology 1999, 128, 13 with the modifications described below. 2 days before the experiment CHO cells expressing 10-20µMol/mg protein human 5-HT2c-vsv receptors (Euroscreen) were plated at a density sufficient to yield a mono-confluent layer on the day of the experiment. The cells were dye loaded (Ca2+kit from MoleC1-6lar Devices, and according to their instructions) at 37 °C in a 5% CO2 inC1-6bator at 95% humidity. Lazer intensity was set to a suitable level to obtain basal values of approximately 8000 RFUs. The variation in basal fluorescence was less that 10%. EC50 values were assessed using increasing concentrations of test compound covering 3 decades. IC50 values were assessed challenging the ECss of 5-HT with concentrations covering 3 decades of test substances. Ki values were calC1-6lated using Cheng-Prusoff equation.
Measurements of [3H]noradrenaline uptake into rat cortical synaptosomes.
Fresh cortex from male Wistai' rats (125-225 g) are homogenized in 0.4M sucrose with a glass/teflon homogenizes The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (6 mg original tissue/mL = 4 mg/well). Test compounds (or buffer) and 10 nM [ H]-noradrenahne are added to deep 96 well plates and shaken briefly. Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl2, 1.12 mM MgS04, 12.66 mM Na2HP04, 2.97 mM NaH2P04, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 02/5% C02 for 10 min at 37 °C and pH is adjusted 7.4. The inC1-6bation is started by adding tissue to a final assay volume of 1 ml. After 15 min inC1-6bation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1% polyethylenimine) under vaC1-6um and immediately washed with 3x1 rnL assay buffer. Non-specific uptake is determined using talsupram (10µM final concentration). Duloxetine is included as reference in all experiments as dose-response C1-6rve.

Claims:
1. A compound represented by the general formula I

wherein
R1 , R2 , R3 , R4 , R5 are independently selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alkten/yntylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, orNRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-8-cycloaIk(en)yl-C1-6-alk(en/yn)yl, or NRzRw-C1-6-alk(en/yn)yl> wherein Rz and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or

independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom;
provided that at least one of Rl, R2R3, R4, R5, R6, R7, R8, and R9 is different from hydrogen; also provided that when R3 is methyl or methoxy, then at least one of R1, R2, R\ R5, R6, R7, R8, R9 is different from hydrogen; or a salt thereof.
2. The compound of claim 1, wherein Rl is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NRzRw-C1-6-alk(en/yn)yl, wherein Rz and Rw are independently selected from hydrogen, C].6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of Rx and Ry is NR2Rw-C1-6«alk(en/yn)yl then the other is selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; typically, R1 is selected from hydrogen, C1-6-alkyl, halogen, C1-6-alkyloxy, or halo-C1-6-alkyl; more typically, R1 is selected from hydrogen, C1-6-alkyl, or halogen.
3. The compound of any one of claims 1-2, wherein R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl; typically, R is selected from hydrogen, C1-6-alkoxy, halogen, C1-6-alkyl, or halo-C1-6-alkyl; more typically, R2 is selected from hydrogen, or C1-6-alkoxy.

4. The compound of any one of claims 1-3, wherein R is selected from hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl; typically, R3 is selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, halogen, C1-6-alkylsulfanyl, halo-C1-6-alkyl, or halo-C1-6-alkyloxy; more typically, R' is selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, or halogen.

8. The compound of any one of claims 1 -7 wherein R6 is selected from hydrogen, halogen,C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl; typically, R6 is selected from hydrogen, or halogen.
9. The compound of any one of claims 1-8 wherein R is selected from hydrogen, halogen, C1-6alk(en/yn)yl, halo-C1-6-alk(en/yn)yl; typically, R7 is selected from hydrogen, or halogen.
10. The compound of any one of claims 1 -9 wherein R8 is selected from hydrogen,
halogen, C1-6alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NRxRy wherein Rx and Ry are
independently selected from hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-
s-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NRzRw-C1-6-alk(en/yn)yl,
wherein Rz and Rw are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3.8-
cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of Rx and
Ry is NR2Rw-C1-6-alk(en/yn)yl then the other is selected from hydrogen, C1-6
alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-
alk(en/yn)yl; or Rx and Ry together with the nitrogen to which they are attached form
a 3-7-membered ring which optionally contains one further heteroatom; typically, R
is selected from hydrogen, C1-6-alkyl, halogen, halo-C1-6-alkyl, or NRxRy wherein RX is hydrogen and Ry is C1-6-alkyl; more typically, R8 is selected from hydrogen, C1-6-aikyl, halogen, orhalo-C1-6-alkyl.
11. The compound of any one of claims 1-10 wherein R9 is selected from hydrogen, halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl; typically, R9 is selected from hydrogen.
12. The compound of any one of claims 1-11 wherein the compound of formula I has 1-4 substituents in the phenyl ring(s), selected from any one of R*-R9, which are different from hydrogen, and the remaining substituents are hydrogen.
13. The compound of claim 1, said compound being selected from 4-[2-(4-Fluorophenylsulfanyl)-phenyl]4,2,3,6-tetraliydropyridine, 4-[2-(4-Chlorophenylsulfanyl)-phenyl]-1,2,3,6-tetrahydropyridine,

traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of any one of claims 1-13 or a pharmaceutically acceptable acid addition salt thereof.

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Patent Number

228179

Indian Patent Application Number

2524/CHENP/2005

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

28-Jan-2009

Date of Filing

04-Oct-2005

Name of Patentee

H. LUNDBECK A/S

Applicant Address

Ottiliavej 9, 2500 Valby-Copenhagen,

Inventors:

#	Inventor's Name	Inventor's Address
1	PUSCHL, Ask	Aksel Møllers Have 2, 4 th, DK-2000 Frederiksberg,
2	BANG-ANDERSEN, Benny	Lillegrund 33, Copenhagen S, DK-2300,
3	JORGENSEN, Morten	Godtgemt 24, 1, -3, Bagsværd, DK-2880,
4	JUHL, Karsten	Badensgade 13, st. tv, København S, DK-2300,
5	RUHLAND, Thomas	Møllehusene 15, DK-4000 Roskilde,
6	ANDERSEN, Kim	744 Fernwood Ct, Ridgewood, New Jersey 07450,
7	KEHLER, Jan	Nymøllevej 28, Kgs. Lyngby, DK-2800,

PCT International Classification Number

C07D 211/70

PCT International Application Number

PCT/DK04/00243

PCT International Filing date

2004-04-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/460,266	2003-04-04	Denmark
2	PA200300518	2003-04-04	Denmark