AU2006202521A1 - Substituted phenyl-piperazine derivatives - Google Patents

Description

13-Jun-2006 08:07 PM Watermark +61398196010 4/42 Pool Section 29 Reguaion 3,2(2)

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: Substituted phenyl-piperazine derivatives The following statement is a full description of this invention, including the best method of performing it known to us: COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:07 PM Watermark +61398196010 5/42 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PC]) (19) World Inteliectanl Property Organization rnuiiouuiinuuui ENNI Intemnaticml BaeE (43) International Publication Date 12 July 2001 (12.07.2001) (10) International Pnblication Number WO 01/49678 Al PCT (51) International Patent Classficatie.': CO7D 403/02.

403114,413114,405114, 471/04, A61K 311496, 31/5377.

A61P 25/0 (21) IntornationlAppliefion Numbr. PCT/DXO00721 (22) lamernaional Filing Date: Dcembcr 2000 (20.121M() Pilin Language: English Publication Laguage: English Priority Data: PA 1999 01225 30December 1999(30.121999) DK (71) Applicant (for all designted Sos except US); a LUNOSECIC A/S (DKtDK]; John MeidahW Petersen, Ottiuiavcel 9, DIC-2500 Wirby-Copenhagen (DK)- (72) Irnetor; and Isnors/Applicaats (for US only): RUHLANI) Thomas [IDD; 0stergaards Ail 16, DX-2500 Valby EROG-JENSEN, Christian ISBIDEI;Hom IDrsgade 23, DK-2100 Copenhagn ROTITLANDEB, Mario [DE/MK]; Harrestzupvang 3c, 21h, DK-2500 Valby NMUK ISEN, Gitte [DK/DK; Esk1cirggkd 34, 4ti MC-2760 Mhbv ANDERSEN, Kim DK/PKK]; Ringerbakken 22, DK-2830 Vnim MOLI'ZEN, Eimer, Kied [KID: 'lftekmsvej 29, DK-2820 Gen.

tafte (DX).

(74) Common Represtative: IL LUNDEECK AS: John Meidatl Potkrsun Ottilavcj 9, DK-250 Valby-Copenhagen (LK).

(81) Designated States (nadona9 Al, AG, AL, AM. AT AT (rtiity model), AU, AZ, BA, El, BG, B t, Wi. CA, CI, CN. CR. CU. CZ CZ (utility model), DAi BE (utilty wvodel) D, DK (atliy model), DM. D E, ER (utility model), 13S, FI, F! (utility model), GB, GD, GE, GGM, M, HU1, ID, 11 IN, IS, JR XE, KG, KP. KR, K, LC, LY, LR IS. LT. LU, Lv, MA, MD, MG, MX, MN, MW M, M474 NO, NZ, FL, rr, RO, RU, SD, SE, SG, S9, SIC SK (utility model), SL, TI, TM, Tt, fTT, 1, UA, My. US UZ VN, YU, ZA, ZW (8d) Designated States (regional): ARIPO patent (GH, GM, KB, IS. nW 4. SD. SL, 7, T7, UG, ZW, Eurasian patent (AM, AZ, BY. KG. Z, MD. RU, TJ TM). European patent (AT. B. C. CY. M DM P S, (RlGB. OR. B3 IT LU, MC, NL, PT SE, Ix). AF! patent (BP, 11, CF.

CG, C1 CM, GA. GN. OW, ML, MRt NE, SN, TD, TO).

Pnbusishe For two-kar coda and oer abbrevwiaonL Y4ki' to the "QuA?on ce Notes on Codes oaidAhr MvmIalion" appearing at she begining of each gular Isse oft#e PCY'6cean.

=I

=ar

SI

(54) ride. SUBSTIUTED P17171L3)YL-PERAZINE DERVATIVS, THEIR PREPARATON AND USE RR x R ~1

RI

R3 hl (57) Abstract: The present invention provides compounds of formula (I wherein X, Y Z. n and meare deined in the applicatiotThe compounds of tho invention have affinity for the 5-HTlA receptor COMS ID No: SBMI-03862394 Received by 1P Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:08 PM Watermark +61398196010 6/42 WO 02/49678 PCTDK00/00721

VO

0 0 Substituted phenyl-piperazine derivatives, their preparation and use

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The present invention relates to novel substituted phenyl-piparazine derivatives potantly binding to the 5-HTA receptor, pbmacetcal compositions containg these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and/or D3/D 4 ligands and are thus considered to be particularly useful for the treatment of depression and psychosis.

cO BackgroundArt Clinical and pharmacological studies have shown that S-HTA agonists and partial agonists are useful in the treatment of a range of affective disorders such as generalised anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression.

it has also been reported that 5-ITu ligands may be useful in the treatment of ischaemia.

An overview of 5-RTu antagonists and proposed potential thrapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schehter et aL, Serotonin, 1997, Vol.2, Issue 7. It is stated that 5-HTIA antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimers disease, and in combination with SSRI antidepressants also to be usefrl in the treatment of depression.

5-El reuptake inhibitors are well known antidepressant drugs and useful for the lreatment of panic disorders and social phobia.

The effect of combined administration of a compomund that inhibits santonin reuptake and a receptor antagonist has been evaluated in several studies (Innis, RB. et al., Eur. Phanracol, 1987, 143, p 195-204 and Gartaide, SE. B. J Phamacol. 1995, 115, p 1064- 1070, Blier, P. et al Trends PhamacoL Scid 1994, 15,220). In these studies, it was found that combined S-HTIA receptor antagonists and srotonin reuptake inhibitors would produce a more rapid onset of therapeutic action.

COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:08 PM Watermark +61398196010 7/42 WO01/49678 PCTIDKOO/00721 o 2 0 c Dopamine D 4 receptors belong to the dopamine D subfamily of receptors, which is considered to be responsible for the antipsychotic effects of nemuroleptics. The side effects of neuroleptic drugs, which primarily earert their effect via antagonism of D2 receptors, are known to be due to D 2 receptor antagnism in the strital regions of the braia Rowever, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyxamidal f side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity o for D4 than 12 receptors, and is lacking extrapyramidal side effects (Van Tol et al. Nature IN 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526 and Samer Exp.

0 Opin. Ther. Patents 1998,8,383-393).

A number of D 4 ligands, which were postulated to be selective D4 receptor antagonists (L 745,879 andU-101958) have been shown to posses antipsychotic potential (Mansbach et aL Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D 4 receptor agonists in vaious in vitro efficacy assays (Gazi et al. Br. J. Phamacol. 1998, 124, 889-896 and Gazi et al. Br. J Pharmnacol. 1999, 128, 613- 620). Furthnmore, it has been shown that clozapine, which is an efective antipsychoic, is a silent antagonists (Gazi et al. Br. J. Phaomacol. 1999, 128, 613-620).

Consequently, D4 ligands, which are partial D 4 receptor agonists or antagonists, may have beneficial effects against psychoses.

Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999,142, 78-84).

It has also been suggested that dopamine D 4 antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson's disease with L-dopa (Tahar et al Eur. J.

Pharmacol. 2000, 399, 183-186).

Dopamine D3 receptors also belong to the dopamine Da subfamily of receptors, and they are preferentially located in lIinbic regions of the brain (Sokoloff et al. Nature, 1990, 347, 146- 151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic activity (Wilner Int Clinicl Psychopharmacology 1997, 12, 297-308). Furthermore, an elevation of the level of D 3 receptors in the limbic part of COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:08 PM Watermark +61398196010 8/42 WO 01/49678 PCTIDK/00721 \O 3 N schizophrenic brains has been reported (Gurevich et al. Arch. Gen Psychiatry 1997, 54, 225-32). Thefore, D 3 receptor antagonists may offer the potential for an effective antipsychotic therapy, free of the extrapyramidal side effects of the classical antipsychotic drugs, which primarily exert their effect by blockade of D2 receptors (Shafer et al.

Psychopharmacology 1998, 135, 1-16; Schwartz et al. Brain Research Reviews 2000, 31, 277-287).

o Moreover, D3 receptor blockade results in a slight stimulation in the prefrontal cortex \IO (Merchant et al. Cerebral Cortex 1996, 6, 561-570), which could be beneficial against 0 S i10 negative symptoms and cognitive deficits associated with schizophrenia. In addition, dopamine D3 antagonists can reverse D2 antagonist-induced EPS (Milan et al. Eur.

Pharmacot. 1997, 321, R7-R9) and do not cause changes in prolactin (Reavill et at J.

Pharmacol. Exp. Ther. 2000, 294, 1154-1165). Consequently, D3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to BPS and hormonal changes.

Dopamine D3 agonists have also been considered relevant in the treatment of schizophrenia (Wustow et at Current Pharmnnaceutical Design 1997, 3, 391-404).

Accordingly, agents acting on the 5-TIAn receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired Purthennrmore, antagonists at the same time having potent serotonin reuptake inhibition activity and/or D4 and/or 1D activity may be particularly useful for the treatment ofvarious psychiatric and neurological diseases.

Structural similar compounds to the compounds of the present invention have been described earlier.

Thiophene derivatives are described in WO 9902516 as ligands for the 5-HTiA- receptor.

WO 9726252 describes piperazinyl derivatives as insecticides.

WO 9514004 describes substituted alkylamino-indole derivatives as 5-HTA,5-ITif and HTIrD- derivatives.

COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:09 PM Watermark +61398196010 9/42 WO 01/49678 PCT/DIC0010721

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It has now been found that compoumds of a certain class ofphenayl-piperazine derivatives bind to the 5-HTTIA receptor with high affinities. Furthermore, it has been found that many of these compounds have other highly beneficial properties as i.e. potent serotonin reuptake inhibition activity and/or affinity for the D4 and/or the D3 receptor.

Summary of the invention o Accordingly, the present invention relates to novel compounds of the general Faonnula I:

INOI

wherein Z represents NTH, NR' O or S; R' represents hydrogen, Cz-alyl R and Rg independently represent hydrogen halogen, Cle-alkyl, CsF-CYCloalkyl, CN, CPs or C- s-akoxy; or R7 and RB together form a 5- or Smebeed aryl or beteroaryl fused to thbenzen-rng; Y represents N, C or CHP; the dotted line represants an optional bond; R and R6e eprese~t H3 or Clalkyl; 2o X represents -0-or-8n is 2, 3, 4 or S; f(mx RRt m is 2 or 3;R2 Rwherin Z rep and R are independently selected fresents hyda grogenup consisting of-akhydrogn, halogen, C-a-alyl, Owakenyl, C-salknyl, C3e-cyloakyl, azyl, hydrxy, hydrox;y-C11alkyl C24-koxy, C34-yloalkox, Cz4-alkyslfnyl, acyl, NR9R'o whereinRg and R'o Sand R independent ly prssent hydrogn, Calky, Chalgen y Ca ky y Csc -cycloakyl orN, C aryl; -alkxy or t nd Rao togther with the nitroge o which they are yl or thetd form a -to the bienzenr Y represents N, C or CH-, the doftd Ernc reresents an optional bond, jR6 and e.

6 represent H or Cira4kyl; X represents or nis 2, 3,4or mis 2or%3

R

2

R

3 e' and =r independently selected from a group consisting of hydrogen, halogen, C1.

6 -alcyl, CI-4-alkenyl, Cj -alkyny1 C4-cycloakyl, ayl, hydrexy, hydroxy-CIakyt Ci 6-alkoxy, 0 3 j-cycloalkoxY, C 1 -ulkylsulfanyL, ary], NR'R" wherein R? and It 0 independently represent hydrogen, C1o-alcyL, C 2 -6-alkenyl, C24-allkyny4, Cg-cyoloulkyl or aryl; Or Rt 9 and It' 0 together with the nitrogen to which they are atahed form a 1- COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:09 PM Watermark +61398196010 10/42 WO 01/49678 PCT/DKOO/00721

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0 Smorpholinyl, 1-piperidinyl, -homopiperidinyl, 1-piperazinyl, 1-homopiperazinyl, 1- Simidazolyl, 1-pyrrolyl, or pyrazolyl, all of which may be further substituted with Ci.-alkyl; or two adjacent substituents of R

I

R together form a ring fsed to the phenyl ring selected ffrom the group consisting of cl N /Nr -N wherein W is 0 or S, and R' and R" are hydrogen or Ctz-alkyl:

O

SThe compounds of the invention have affinity for the 5-HTuAieceptor. Accordingly, the invention provides: A compound as above as a medicament A pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more phamnaceutically acceptable carriers or diluents.

The present invention provides the use of a compound of Formula I as defined above or an acid addition salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.

The invention provides a method for the treatment of diseases and disorders in humans caused by abnormalities in the serotonin system of the central nervous system comprising the administration of an effective amount of a compound of Formula I as above.

The compounds of the invention are considered usefil for the treatment of affective disorders, such as depression, generalised amxiety disorder, panic disorder, obsessive compulsive disorders, social phobia, and eating disorders, psychosis and neurological disorders such as ischaemia and senile dementia.

COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:10 PM Watermark +61398196010 11/42 WO 01149678 PCTKOO/00721

O

06 ~N Detailed Description of the Invention

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A preferred embodiment of the invention is the compound of formula I as above wherein Z is NH and the resulting indole is connected in position 3; Another preferred embodiment of the invention is the compound of formula I as above wherein R7 and R independently are selected from a hydrogen, halogen, Ciralkyl or R tn and R together form a fused pyridyl-ring; O Another preferred embodiment of the invention is the compound of fonmulal as above N wherein n is 2,3 or 4; o 10 Another preferred embodiment of the invention is the componmd of formula I as above wherein mis 2; Another preferred anembodiment of the invention is the compound of fonnula I as above wherein R and e 6 are both hydrogen; Another preferred embodiment of the invention is the compound of formula I as above wherein Y is N; Another preferred embodiment of the invention is the compound of formula I as above whaein R 2

I

3 4 and Rs are independently selected from hydrogen, alkoxy, NR 3

R

4 wherein R 3 and R' independently represent hydrogen, Cl-alkyl; or .R 3 and R' together form a 1-morpholino; or two of adjacent of Ra 3 and Rs together form a fused ring consisting of -O-CE2-O-, -O-COl-CH2-O-, or -CHz-CH 2 -CH 2 Another preferred embodiment of the invention is the compoumd of formula I as above wherein one or two of R 2 R, R are not hydrogen; The most prefered embodiment of the invention is the compound according to formnnula I as above, the compound being: 1- (l-[3-(dimethylamino)phenoxyphnyi4-[2-(1H-indol -3-yl)ylpiprazine; ,3-Benzcodioxolan-5-loy)phonyl]-4-[2-(H-indol-3-yl)etylpiperazine; 1- {l-[3-(dimethylamino)phenoxyhenyl}-&[3-(1H-indol-3-yl)prOpy]piper2ine, 1-[l-(1,3-Benzodioxolan-5-yoxy)phenyl]-4-[3-(lH-indol-3-yl)propyl]pipmazine COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:10 PM4 Watermark +61398196010122 12/42 WO 01/49678 PCTDKOO/00721 Sc 7 0 l4 2 3 -Benzo&Dixola-5-yox)pcny1J4P-<&choroindop3yi)piopy1ppj,,z l4[ 2 {l, 4 -lezodioxan--yoxy)phnyJ-43<5-fluooIrq..indol.YyI)popyJppmrozi, 0 1-[2-(1,4-Be doa-7~x~hnl--3(-hlr-Hidl3y~puybprzn l-[ 2 3 -Mathoxyphenoxy)phny1]-43-&coro-windo..3y)prpyipne 1c t 2 2 -Methoxyphenoxy)pbwyl4[3-(IH-jndo14.-yl)prpylpjpaziu 0 o 10 l-( 2 -Phenoxypheny1)-4-(1II-indol-3-y)btypperaie; ci 2 -(l 3 3 -Benzodioxolan-5 -yloxy)peny]4[4<(-lH I-indob o1)biiypjerhyj~ l4[ 2 3 -KDimoffiylamino)pkmaoxy)plienyA4-[2(6coroaindol.3y)etyljpprzne; l4[ 2 2 -Methoxyph~oxyphy444qnHidn-3yl)Ity1pip 0 i-f 2 -(4-Ma-thoxypheaosy)phanyl]-4-[3-(1-iudol-3-yl)propy]p ipoazhw; 1t{Z-henOxypheny)42-(6-cblaro-iH-ino1-3-y)ethyl]piperazinel-( 2 -Phenoxyphenyl}-4{3-(5-methy1-Im1ndo3y1)prjy]pp~zi 6 i-[ 2 2 -Meffoxphenoxy)phnyl]-4-[3-(5cboroIH-no3y)prpy]pjperagzje l-( 2 -PhMnoxypeny)4-[3-(H-indo1-3y1)yl~pipjzi l-( 2 -?heaoxypheny)4-3-(5-uronH-ndo3y)pro1yj,~rzj, 1i4 2 -Plienxyvhcay1)-43-(5-bromo-IHindolv3..y)popylpipr-ae l-[ 2 3 ethylao)pheno y)l]A.{ylhyplH...-mhy-idp 3yp py]pz 8 i; l-( 2 -Thenoxyphrny)-43-S-hioroH-ido3y]p*aypipThziie.

l-[ 2 -(2-MetJoayphnnay)phcayI}4{[3-(s-fHuoro.4IHndoI-3yJ)propyzlpipcrniuc; l-[ 2

-UJ,-

3 nzdioan-5-yloxy)pheny]-[3(5-iodoHndo1-3jr)pmpylpprazij COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:11 PM Watermark +61398196010134 13/42 NOWOO0 J49678 PC/DK00/0O721 Nl 1-(2-Pbeoxyphenyl)-4-[3-(7-obloro-lH-mlo- 3 ypropyllpipeazila; I-(2-Phennrypbny)4-3<5,7-imbto- -idol-3-yl)propylipPOT8zlO 1-[2,(2-Methoxyphenoxy)phcxny4--(7bromo-1H-ijolh3-yIpylpiP&8Zuf I-2-3-Diethylsmn)phenYphal-4-3-(5-fluoro--U-idol-3-y)PropylIpip nO, 1-[2-(2-Methoxyphenoxy)phenylA-[3-(5-iodo-IH-dOl-3-y)prOpylpip&8Zil0 1-[2-(1,3-flnzooxoa-5-yoy)pheny-4-13-(-hor?1HR-idO1-3-y)propy1pip8ziflQ 1-[2-(2,6-1Dmethoxypheoxy)pheniyI]-4-3-(5-ch(t-1-H-dol-3-YI)tOPYki)pe8iflCe o 1~2-(I,3-]Henzodioxolan-5-yloxy)phnyJ-4-L3-(1H-pyro3,2-J qinolin-3- INylApropyljpiperazine; 1-[2-(2-Meffioxyphanoxy)pm1J-4[3-(5,7-dfluoo-H-indo-31)popylpip&aziO ci I-(2-Phonoxypheny1)-3-(5-iodo-1H-ndo-3-y)propy1Jpiperazne 1-[2-(2-Mtoxyphenoxy)phenyl-4-3-(l-pyrrl[3,2-hquifoli-3-y)propyUpipm-iSnfe; 1-(2-(3-Metboxyphenory3phnyl-4-[3-(IH-pyrrolo[3,2-h] quinohl-3-yopropylhpiporzine; 1-[2-(1t4-Bc.odioxn--yky)phy11-3-(5-cthy1-m-indo-3-y)proVIpyuine; 1-[2-(2,6-Thmoffiuxyphwox)phonylJ-4-[3-(5-metyl-H-indol- 3 -y)popylhpipduhzlCe 1-[2-(3-Metaxyheoy)phnyl-4-[3-(H-indol-3-yl)propypGTaziC; 1-[2-(1,4-Banzodioxan-5-yloxy~phrnyl]4-3-(H-indol-3-yl)propylppcrazhie; 1-[2-(l,3-Benzodioxola-5-yloy)phcayl-4-[3-(5-bromo-I-idol-3-y)popyl~pipm-azine; 1- {2-[3-QMorphoin-4-yl)phonoxy]phonyl}-4-[3-(5-fluora-1H-indol-3-yl)propyl]piperzine; 1-(2-(3-Mothoxyphwoxy)phonylj-4-[3-(5-Whoro-IH-indol-3-ylbpropylpiprazin; 1-12-(3-Ethoxyphcnoxyophen14-[3-(5-methy-1H-indo-3-y1)propylpiperzino; 14[2-(2,6-Dimethoxyphenoy)phenyl-4-3-(5-odo-E-io-3-y1)popylpipcazii 1-(2yo)(Dtoxy= )y)hea$4 e3-5-lno-1H-(- No1 H--3-y)opy iprain; 1-(2-(2,6-Dimnethoxypbmoxy hsyl-4-3-(5-fluoo-H-inol-3-y)propylpiperazinc; 1- (24[3-Qdorphoin-4-yfrhoxy]pwayl}-4-3-(5bromo-lH-indol-3-yl*proy~piperazine; 1- {2-j3-(Morpholin-4-y1)phemoxylpheny1}-4-[3-(5-cWilro-1H-indo1-3-y1)propy1]pip=azino 1-(2-[3-4orpholinL4yphenoxypeny)-3-(5-iodo-H-inol-3-ylXproplpipmzin; 1-[2-(3-Methoxypbenoxy)phmiyl-4-[3-(7-fl oro-1E1-indol-3-yl)propyljpiporaine;, l-(2-Phozzoxyphonyl)-4-[3-(5,7-dimetbyl-1H-iudol-3-ylbproyllpiperzino; 1-[2-(1,3-Beuzdioxolan-5wyloxy~phanyl]-44[3-(74-brmo-1H-indol-3-yl)propyl~piperazine; 1-[2-(3,4,5-Trimethoxyphznoxy3phnylJ-4-[3-(5-bromo-IlH-indol-3-ylpropyllpipozinc COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:11 PM Watermark +61398196010 14/42 WO 01/49678 PCTIDKOO/00721 C- Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.

The term Cia alkyl refes to a branched or unlranced alkyl group having from one to six S carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, I-butyl, 2-butyl, 2methyl-2-propyl and 2-methyl-1-propyLo Similarly, C2 alkenyl and C2- alkynyl, respeclively, designate such groups having from NO two to six cabon atoms, inclusive and the groups are having at least one double bond or triple bond respectively; Halogen means fluoro, chioro, bromo, or iodo.

The term C, 4 -cycloalkyl designates a monocyclic or bicyclic caitocycle having three to 1s eight Catoms, such as cyclopropyl, cyoloptyt. cyclohexyl, cyclohepty, and cyclooctyL Prefwen-d embodiments are cyolopropyl, cyclopeatyl cyclohexyt The tern C16 alkoxy. C 14 alcylsulfanyl, C34yco0alkoxy, designate such groups in wbich the lkyl group is C 16 aikyl as defined above.

Acyl mews CHO and -CO-alkyl wherein the alkyl group is C14 alkyl as defined above.

or -mewbered rings which are aryl or heteroaxyl designates groups such as phenyl, pyfrolyl, pyridyl pyx dyl, nfurayl, thieyl Exemplary of rgani acid addition salts according to the inventin are those with malc, fumaric, benzoi, ascorbic, succinic, oxalic, bis-methylenesaliyic, methanesuifonic, etbanedisulonic, acetic, propinlic, tartarie, salicylic, citic, glucoi, lactic, malic, mmidelic, cirmamic, cifraconic, aspartic, steeow, palmitic, itaconic, glycolic. pwninobenzoic glutamic, bazeneeulfhnn, end theophylmine acetic acids, as well as the 8halotheophyllines, for example 8-bromot~Jeophylline Exemplary of inorganic acid addition salts accoiding to the invention are those with hydrochloric, hydrobromi, sulfuric, COMS ID No: SBMI-03662394 Received by P Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:11 PM Watermark +61398196010 15/42 WO 01/49678 PCT/DK0/00721

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0 sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably Spharmaceutically acceptable salts formed with non-toxic acids.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated fomns ar considered equivalent to the unsolvated forms for the V) purposes of this invention.

0 \0 Some of the compounds of the present invention contain chiral cantres and such compounds o 10 exist in the form of isomers enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.

Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeio 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 marix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, by fractional crystallisation of d- or 1- (tartrates, mandelates, or camphorsulphonate) salts for example. 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 discussed by Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sans, New York (1981).

Optically active componmds can also be prepared from optically active starting materials.

The compounds of the invention can be prepared by one of the following methods comprising: a) reacting a secondary amine of the formnla COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:12 PM Watermark +61398196010 16/42 WO 01149678 PCTDK00721

II

R_ 4

(R

2 Va

OM

o wherein Y and m are as defined above 0 ci 5 with an alkylating agent of the general formult

RR

RD

and R% Z and n are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate; b) reacting a compound of the fonnula

RD

0 Q, (CH2 0 x R RI

II

R3

IV

wherein X, Y, n and m are as defined above and Q(OHI)2 is a dio such as sabstituted ethylene glycol or propylene glycol or a polymer bound diol; with a hydrazine of the formula

HNHH,

V

COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:12 PM Watermark +61398196010 17/42 WO 0149678 PCTIDK0/09721 c) reducing an amide of fomula wherein Z, R-R, X, Y, n and m are as defined above.

d) reducing a compound of formula

VI

wherein Y, X and min are as defmined above The alkylations according to method a are generally performed by boiling the reactants under reflux or by heating them at a fixed temperature in a suitable solvent such as acetone, acetonitrile, methyl isobutyl ketone, tetrahydrofma, dioxane, ethanol, 2-propanol, ethyl acetate, NN-dimethylfbnamide, dimethyl sdfoxide or l-methyl-2-pyrrolidinone in the presence of a base sach as triethylamine or potassium carbonate and optionally a catalytic amount of potassium iodide.

1) COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:12 PM Watermark +61398196010 18/42 WO 01149678 PCTI/DK/00721 )Cn O±N-f vu4 x x 3 Secondary amines of formula IM are prepared by the reaction sequence outlined above. 2- FPluoro-nitrobenzeoe is reacted with a nucleophil of formula VII in an aprotic solvent such as N,N-dimethylfomamride using organic or inorganic basis at elevated temperatnre. After reduction of the intermediate nitro compound IX using standard conditions such as palladium catalysed hydrogenation or iron in acidic solvents, the aniline derivative X was transformed into the desired secondary amine of formula III. The piperazine formation was either performed by reaction with bis(2-chloroethyl)amine, hydrochloride at elevated 0to temperature or in a multistep synthesis according to published procedures (Kruse et al., Redl. Tray. Chim. Pays-Bas, 1988,107,303-309).

2)

XH

x xK xN Fe& R RzVA'

X

RI

xv Alteamatively, secondary amines of formula IM are prepared using the mono substituted cyclic diumines of formula XII as key intermediate. The substituent R is En appropriate COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:13 PM Watermark +61398196010 19/42 WO 01149678 PCTIDKO/00721 o 14 N protecting group such as a ethoxy-, methoxy- or 2-methyl-2-propyloxy-carbonyl group or a beuzyl group, or a suitable solid support such as a Merrifield resin or a solid supported carbamate group such as the wang resin based carbamat linker (Zaragoza, Tettahedron Lett., 1995, 36, 8677-8678). The mono substituted cyclic diamines of fbrmnula XII are prepared from commercially available starting materials or by methods obvious to the chemist skilled in the art. The mono substituted cyclic diamine of formula X3I are reacted with r -1,2-dichlorobezne-l-eyolopentadienylionl) hexathorophosphate at elevated 0 temperature in an aprotic solvernt such as dry tetrahydrofurm using an appropriate base such NO as potassiun carbonate. i-1,2-dichlorobzeno-ri c-yclopentadienyliron(I hexafluorophosphate are prepared in analogy to literature procedures (Pearson and Gelormai, J. Org. Chem. 1994, 59, 4561-4570). The tIus formed mono chloro derivative of formula XII are subsequently reacted with a nucleophile of formula VM IIIin an aprotic solvent such as dry tetrahydrofuran either by the use of an appropriate base such as potassium carbonate or by deprotonation of the nucleophile of fomula VIII using a base such as sodium hydride prior to the reaction. Decomplexation, performed according to literature procedures (Pearson et al., J. Org. Chem. 1996, 61, 1297-1305), followed by deprotection by methods obvious to the chemist skilled in the art or cleavage from the solid support according to literature procedures (Zaragoza, Tetrahedron Let., 1995,36, 8677- 8678 and Conti et al., Tetrahedron Lett, 1997, 38, 2915-2918) affiorded the desired secondary amines of formula IlL corresponding to secondary amines of formula XV, R =H.

Nucleophiles of formula VIII are commercially available, prepared by methods obvious to the chemist skilled in the art or according to literature procedures (Guillamet and Hretaui, J. Heterocyclic Chemn., 26, 193-196, 1989).

The alkylating agents of fonnrmula

(CA-G

R&

are prepared according literature procedures Med. Chem. 1983, 26, 1470-1477, Brodfihrer et al., J. Org. Chem. 1997, 62, 9192-9202, Anelli, et al., J. Org. Chan. 1987, 52, 2559-2562, Brodfuchrer, et al., 3. Org. Chem. 1997, 62, 9192-9202) or by methods obvious to the chemist skilled in the art.

The indole fornnation according to methodb is performed by the reaction of acetals of formula IV with aryl hydrazines of fonrmula V resulting in the corresponding hydrazones, COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:13 PM Watermark +61398196010 20/42 WO 01/49678 PCTIDKOO/00721 which subsequently are converted into indoles by means of the Fischaer indole synthesis. The synthesis sequence is preferably perfobrmed as a one-pot procedure using a Lewis acid catalysts, preferably zinc chloride or boron trifluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at an elevated temperature.

Acetals of formula IV are prepared by the reaction sequence 2) outlined above using mono tf substituted cyclic diamines of formula XII wherein IND 0, O R= (CHr PQ o 0 as key intennediates. The key intermediates of fbrmula XII are prepared by allkylation of cyclic diamines of fbrmula XI with acetals of formula 0 C1-(CH) 'Q

XVI

using the conditions described above for methods a.

Polymer bound acetals of formula XVI are prepared by reaction of aldehydes of formula G-

(CH

2 with commercially available 2,2-dimethyl-1,3-dioxolan4-yl-methoxymetyl polystyrene in a suitable solvent such as toluene, using p-toluenesulfonic acid as catalyst at elevated temperature. 4-Chlorobutanal, 5-chloropentanal, and 6-chloohexanal were prepared in analogy to the method described by Nomant et atl., Tetrahedron 1994, 50 11665.

The reductions according to Method c and d are generally performed by use of LiAH4,

AIR

3 or diborane in an inert solvent such as tetrahydrofrian, dioxane, or diethyl ether at room temnperature or at a slightly elevated teMrperature. The amides of formula VI are prepared from secondary amines of fbormula iM and a substituted indol-3-yalkylcarboxylic acids or carboxyic acid chlorides by methods obvious to the chemist skilled in the art The amides of formula VII are prepared from 3-unsubstituted indoles and secondary amines of formula III according to literature multistep procedures (Nichols aL, Synthesis 1999, 6, 935- 938 and Specter and Anthony, J. Am. Chem. Soc. 1954, 76,6208-6210) COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:14 PM Watermark +61398196010 21/42 WO 01149678 PCTIDKOOI/00721 \O 16 N Examples All reactions were carried out under a positive pressure of nitrogen. Melting points were detemrined on a Bilohi SMP-20 apparatus and are uncorrected.

Analytical LC-MS data were obtained on a PB Sciex API 150EX insnmienat equipped with IonSpray source and Shimadzu LC-8A/SLCO-1A LC system. The LC conditions (50 X 4.6 mm YMC ODS-A with 5 pim particle size) were linear gradient eltion with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to wateracetonitrile/tifluoroacetic acid o (1090:0.03) in 7 min at 2 mlmini. For compounds 3c, 3e, 3f and 31, the LC conditions \1 (Waters Symmetry, 30x46 mmm C18 3,5 my particle size) were linear gradient elution to with water/acetonitrile/trifluoroaceic acid (90:10:0.05) to water/acetonitrile/trifiuoroacetic acid (10:90:0.03) in 4 min at 2 mlhmin. Purity was determined by integration of the UV trace (254 am). The retention times Rt are expressed in minutes.

Preparative LC-MS-separation was performed on the same instrument The LC conditions X 20 mm YMC ODS-A with 5 pm particle size) were linear gradient elution with watudacetonitile/tifluoroacetic acid (80:20:0.05) to water/acetonitxile/tifluoroacetic acid (10:90:0.03) in 7 min at 22.7 mLmin. Fraction collection was performed by split-flow MS detection.

'H NMR spectra were recorded at 500.13 MHz an a Broker Avance DRXS00 instrument or at 250.13 MHz an a Broker AC 250 instrument Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.9%/oD) were used as solvents. TMS was used as intemal reference standardn. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: einglet, ddoublet, t=triplet, q=quartet, qutuintet, h=heptet, dd=ouble doublet dt-double triplet, dq=double quartet, tt-triplet of triplets, m=multiplet and b=broad singulet. NMR signals corresponding to acidic protons are generally omitted.

Content of water in crystalline compounds was deteimined by Karl Fischer titration.

Standard workup procedures refer to extraction with the indicated organic solvent from proper aqueous solutions, drying of combined organic extracts (anhydrous MgSO4 or NaSO4), filtering and evaporation of the solvent in vacuo. Par column chromatography, silica gel of type Kieselgel 60, 230-400 mesh ASTM was used. For ion-exchange chromatography, the following material was used: SCX-columns (1 g) from Varian Mega Band Elut®, Chrompack cat. No. 220776. Prior use the SCX-columns were prcanditioned with 10 solution of acetic acid in methanol (3 mL). For reversed phase chromatography, COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:14 PM Watermark +61398196010 22/42 WO 01/49678 PCT/DK00I00721 Va 17 the following material was used: C-18 columns (1 g) from Varian Mega Bond Elut®, Chrompack cat No. 220508). Prior use the C-S1-columns were pre-conditioned with methanol (3 mL) and water (3 mL). For decomplexation by irradiation, a ultaviolet light source (300 W) from Philipps was used.

Example 1 trn J-{2-[3-(dimethylamino) phnoxylphenyl4-[ 2-1H-indol-3-yl)eyllpiperazine, oxalate oa(ta).

O

o 1-Chloro-2-nitrobenzene (15.0 3-(dimethylauino)phenol (13.0 g) and potassium hydroxide (11.8 g) was dissolved in NN-dimethylfonnamide (350 mL) and boiled munder reflux for 18 hrs. The reaction was then cooled, and poured into water, and worked up by standard procedmue using ethyl acetate. The crude product was purified by silicagel chromatography (hptane:et yl acetate:triethylamine /80:10:10). The pure intermediate was dissolved in a mixture of ethanol (200 mL) and acetic acid (20 mL). After addition of Pd/C (5 4.5 the reaction mixture was shaken under hydrogen atmosphere (3 bar) for 3 bra. The reaction mixture was filtered and after neutralisation worked up by standard procedure using ethyl acetate affording pure aniline (11.2 The crude aniline, bis-(2chloroethyl)amine hydrochloride (8.6 g) and chlorobenzene (200 mL) was boiled under reflux for 48 bra. The reaction mixture was cooled to room terperature, and the volatile solvents evaporated in vacuo to give the erude (dimethylamino)phenoxyphenyl}piperazine (18.6 A solution of the crude piperazine, di-tert-butyl dicarbonate (32 g) and potassium carbonate (68 g) in tetrahydrofxranmwater 1:1, was heated at 50 *C for 18 Irs. The organic layer was searated and the water phase extracted with ethyl acetate. The collected organic phases were worked up by standard procedure followed by purification by silicagel chromatography (eptane:ethyl acetate I 8:2) affording pure 13BOC-protected 3 -dimethyl)phenoxyjphayl}pipmzine (9.4 A solution of the BOC-derivative in a mixture of dry THF (30 mL) and trinluoroacetic acid mL) was stirred at room teperature for 1 h. The volatile solvents were evaporated in vacu and ethyl acetate and 1 N aqueous sodium hydroxide were added. The organic phase was collected and worked up by standard procedure giving pure (dimethylamino)penoxyphenyllpiperaie A mixture of a part of the pure piperazine (1.37 3-(2-bromoethyl)-1E-indole (1.0 potassium carbonate (2.2 g), COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:15 PM Watermark +61398196010 23/42 WO 03149678 PCTIDKOO/00721 o 18 0 potassium iodide (cat) and methyl isobutyl ketone was boiled under reflux for 24 hrs. The mixture was cooled to room temperature, fitered, and the volatile solvents evaporated in vacuo to give an oil which was purifiedby silicagel chromatography (heptmie:ethyl acetate:triethylamine 26:70:4) to give the title compound as an oil. The title compound was s crystallised as its oxalate from acetone (1.27 Mp 210-203 0

C.

'H NMR/250MEHz (DIMSO-d): 2.85 6H); 3.00-3.35 12H); 6.15 111); 6.35 11); 6.45 1H); 6.85 1H); 6.95-7.15 6H); 720 111); 7.35 111); 7.55 IH); 10.90 o 1H). MS: m/z: 441 144. Anal. Calcd. for C2HlN40: C, 67.89; IH, 6.47; N, ID10.56. Found C, 67.34; 1, 6.59; N, 10.30.

The following compounds were prepared using the same general method: 1-[2-(1,3-Benzdioxa ol-5-yloxy)phenyl-4-[2-IH-indol-3-yl)thyl]pCerazi, oxalate (1ib). Mp 221-228 oc.H N-MR (2501EEz, DMSO-d 6 3.00-3.35 12E); 6.00 21); 6.40 (dd, 1K); 6.65 1H); 6.80-6.90 (nm, 2H); 6.95-7.15 5H); 7.20 1H); 7.35 (d, 1H); 7.55 10.90 1H). MS: m/z: 443 311, 131. Anal. Caled. For CH2aN30: C, 65.10; H, 5.54; N, 7.86. Found C, 64.86; H 5.55; N, 7.60.

Example 2 1-{z-[3-(dimethylamino)phenoy]phenyQ-4-[3-(H-indol-3-y)propylgpiperazine (2a).

To a suspension of litium aluminum hydride (8.0 g) in tetrahydrofurn (500 mL) was a solution of 3-indolepropionic acid (20 g) in tetrahydrofuran (100 added dropwise. The reaction mixture was stirred for I h at room temperature and subsequently cooled to 5 C.

After sequential addition of water (16 mL), 15% aqueous sodium hydroxide (8.0 mL) and water (40 mL), the reaction mixture was stirred at room temperature over night and filtred.

Evaporation of the volatile solvents gave pure 3-(lH-indol-3-y1)propano (19.1 g) as an oil 3-{1H-Indo-3-yt)propanol (18.6 g) and carbon tetrbomide (42.1 g) was dissolved in acetonitrile (1 L) and cooled to 0 0C and triphenylphospine (30.7 g) was added in small portions. The reaction was stirred for frthber 3 h at room temperature, tbe volatile solvents evaporated in vacuo and the remaining oil puifed by silicagel chromatography (heptane:ethyl acetate 2:1) to give 3-(3-bromopropyl)-1H-indole (25-6 g).

COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:15 PM Watermark +61398196010 24/42 WO 01/49678 PCT/DKOO/00721 Va 19 This intennediate was oupled to the piperatine moieties using the method dscribed in Example I to give the title compound isolated as an amorphous solid. iH NMM (250Mzf, DMSO-d): 1.80 211); 2.25-2.40 6H); 2.65 21); 2.85 6M1; 3.05 (Im, 6.10 (dcl, 111); 6.30 1H); 645 (dd, 1H); 6.80-7.10 (ra, 811); 7.30 111); 7.50 11); 10.70 MS: mhz: 455 (Miii), 295, 239,201, 130.

The following componuds were prepared analogously: IND 1-[2-(1,3-e~nzdioxlan-5-yloxcc~i--3-I-o--l)proylpzernn, xalate Mp 156-162 OC.'H NMR (250MHz, DSO-4): 1.80 2H); 2.25-240 6m); 2.70 (4 211); 3.05 (in, 6.00 2R1); 635 (dc, 1H); 6.55 6.85 6.90-7.15 (ra, 61); 7.30 112); 7,50 1H); 10.75 1M). MS: u/z: 456 297, 201, 130. Anal.

Calod. For C 23 14N30O 3 C, 73.81; H, 6.43; N, 9.23. Found C, 73.28; H, 6.45; N, 9.00.

3-Bezodaam tyoyr- ]4[-"olH-d-3Yp8yppazn drihydochioride Alp: 165 C (decomposition). 1f NMR (250Mlz DMO-4): 2.08 21); 2.73 (f2tM); 3.02 2H); 3.15 4H); 3.55 4H); 6.00 211); 6.40 I); 6.65 1H); 6.80 11), 6.85 111); 7.00 7,05 2R); 7,25 1H); 7,38 (s, 1H); 7.55 (dd, 10.45 111), 11.00 1H). MS 490 AnaL Cath& otf C2&HyC1 3 N303: C, 59.73; H, 5.38; N, 7.47. Found C, 59.13; 11,5.36; N, 7.26.

l-2- 2 -Mehoxjhenox)phenylj-4-3-(-fluoroHndol-3.yl)ppyJpips e, dihdrochlorid Mp: 183-189T0. 'HNMR (500MI, DMSO-d: 2.12 2.73 (t 3.05-3.25 611); 3.55 (4,211); 3.65 (4 211); 3.75 3H); 6.53 IM1; 6.88-720 9H); 7.27-7.40 311); 11.05 2H1). MS 460 Anal Cald for C28H 3 2C1.FNSO 2 C, 63.16; H, 6.06; N, 7.89. Found C, 63.04; 11,6.07; N, 7.88.

l-[ 2 4 -Berzodin-6-yVy)phey7J4-f3-(H-ndol3y)propypperazne

'H

NMR (250AMz, CODC): 1.90 (qul, 2H); 2.40-2.60 (in, 6H1); 2.79 3.15 41); 4.22 4H); 6.45 (in, 21); 6.77 11); 6.85-7.22 (mn 71); 735 1H); 7.60 (d 11); 7.92 (s, 111). MS 470 COMS ID No: SBMI-03862394 Received by IP Australia: rime 20:22 Date 2006-06-13 13-Jun-2006 08:15 PM Watermark +61398196010 2 4 25/42 IDWOtflV4967S PCTDKOOGO7Z1 02 (N .142-(1,4-Benzodioxan-S-ylory)phenylJ-44[345-fluoc-JH-indol-3-yl)propylJp#Mraine aff'H NM2R (25OMHz±. c)czs 1.90 (qul, 2H1); 2.38-2.53 6H1); 2.73 211L); 3.16 (t, 4H; 4.26 4M1; 6.38 (cid, 1lE); 6,60-6.75 (in, 211); 6.83-7. 10 (in, 6H1); 7M2-7.30 (ha, 311); 7.92 111). LC/MS 488 t 2.53, p'ority 99.8% 1-[24(1,4-Benzdioamn-S-yloxy)phenylJ-4-fl-(6-chloro -1H-indoI-3-ylpropyjperazine 'H11%MR (250M19z, CDCt3): 1.90 (qui, 2H1); 2-35-2.50 (mn, 611); 2.75 2IA) 3.18 (t, o ~~411) 4.28 4H1); 6.40 (dci, 111); 6.60-6.75 (in, 3H1); 6.W07.08 (mn, 61H); 7.32 (di, 1HI); 7.50 IND (di, 1H); 7.95 111). LC/M (ink): 504 ItA 2.60, purity 99.61/ J-p2-(1,4-Be7odioxnyb oy)phy]-4-p3-(6-chJoro-H-Mndol-3-yl)propyli~praine- 'HINME. (250M~iz, CDCI$:. 1.90 (qui, 211); 2.35-2,55 611); 2.75 (4 2H1); 3.15(1 4H1); 4.23 4H1); 6.45 (mn, 211); 6-78-6. 15 (in, 711); 1.32 111), 7.50 111); 7.92 111).

LCIMS Qu/z): 504 Pit 2.62, purity 99.7% 1'-[2-(2-Mflh)phaimyphIJ~j-6-c/6oro- H-indol-3-y~propyljlperabw (2i).

6-Chloro-3-(3-(4-[2-(2-metbory-phenoxy)-phenyl]-pipwin-1-yI}-propyrl-findole 11H NMR (250MEz, CDCh3): 1.90 (quf. 2H1); 2.3 5-2.5 0 (in, 6M1; 2.73 2E1); 3.19 411); 3.83 3H); 6.70-7.08 (in, 101H); 7-32 11-1), 7.49 111); 7.94 111). LCYMS 476 Pit purity 99.8% 1-[2-(3-Metwhox psyl-3-(6-oro-H-iol-3-yl)proypwrze UPj) 11H N1M4 (250M4Hz, CDC1,): 1.89 (qni, 211); 2.33-2.60 (in,611); 2,73 2H); 3.13 4H); 3.75 311); 6.49 (mn, 211); 6.58 (dci. 111); 6-95-7.20 (mn 7.32(d, 1H1, 7A49 (ci. 111); 7-92 111). LOWM Qu/z): 476 (hMli), Pit 2.64, purity 99.7% Example 3 J-[2-(2-Methoxyphenoxy)phenyj-4-[3-(1H-tndo-3-yl)propy~Iperazne (3a) 4-[4-Nifroplinoxy)carbonylorymethyl)phenoxymety polystyrene (267.0 g& 235 Mmc) was suspended in dry NN-diinethylfontnainide (2 N-Metylncpholine (238.0 g, 2.35 mol) and piperazine (102.0 g, 1.17 inol) were added and the mixture was tired at room temperature fir 16 bra. The resin was filtered off and washed with NN-diinetlylformanide COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:16 PM Watermark +61398196010 26/42 WO01/49678 PCTIDKOO/00721 o 21 0 N (2 X 1L), tetrahydrofuran (2 X 1 water (1 X 500 mL), methanol (2 X 1 L), tetrahydrofman (2 X 1 methanol (1 X 1 Finally, the resin wawasashed with dichloromethane (3 X 500 mL) and dried in vacuo (25 36 brs) to yield an almost colourless resin (240.0 g).

A part of the resin thus obtained (115.1 g, 92 mnol) was suspended in dry tetrahydrofuran IC (1.6 L) and q-1,2-dichlorobenzen- 5 -cyclopentadieuyliron(II) hexafluorophosphate (76.0 o g, 184 mmol) was added followed by potassium carbonate (50.9 g, 368 mmol). The reaction 0 mixture was stirred at 60 *C for 16 hrs. After cooling to room temperature, the resin was 0 o 10 filtered off and washed with tetrahydrofran (2 X 500 mL), water (2 X 250 mL), tetrahydrofutran (2 X 500 mL), water (2 X 250 mL), methanol (2 X 250 mnL), dichloromethan (2 X 500 mL), methanol (2 X 250 mt). Finally, the resin was washed with dichloromethane (3 X 500 mL) and dried in vacuo (25 OC, 36 hs) to yield a dark orange resin (142 g).

To a solution of 2-hydroxyanisole (22 g, 17.7 mmol) in tetrahydrofmuran (50 mL) was carefully added neat sodiun hydride (15.5 mmof) at room temperature (Caution: Generation of hydrogen). The mixture was stirred additional 30 min alter the generation of hydrogen ceased. Subsequently, a part of the above obtained resin (2.8 g, 1.72 mmol) was added and the mixture was stirred at 40 OC for 12 hrs. After cooling to room temperatur, the resin was filtered off and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran/water (2 X mL), NN-dimethylfbrmmide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetrahydrofran (3 X 50 mtL), and subsequently with methanol and tetrahydroftran (each mL, 5 cyoles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 12 brs).

The thus obtained resin (3.0 g, 1.84 mmol) and a 05 M solution of 1,10-phbeanthrolie in a 3:1 miture of pyridinewater (20 mL) was placed in a light-transparent reactor tube. For decomplexation, the suspension was vortexed and irradiated with visible light for 12 brs. A very characteristic feature of the decomplexation step is the appearance of the intensive red colour of the liquid phase during irradiation. The resin was filtered off and washed with methanol (2 X 25 mL), water (2 X 25 ml) and tetrahydrofaran (3 X 25 mL) until the washing solutions kept colourless (5 cycles) and the irradiation procedure was repeated until COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:16 PM Watermark +61398196010 27/42 WO 1/49678 PCT/rDKooon721 \O 22 Ci decomplexation was complete (5 cycles). After complete decomplexation, the resin was washed with dichloormethane (3 X 25 mL) and dried in vacuo (25 12 h).

;Z

The resin (approx. 2.5 g, 1.84 mmol) was suspended in a 1:1-mixture oftrifluoroacetic acid s and dichloromethane (25 mL) and stiired at room temperature for 2 bra. The resin was filtered off and washed with methanol (1 X 5 mL) and dichloromethane (1 X 5 mL). The tf liquid phases were combined and the volatile solvents were evaporated to yield a dark o brown oil (1.5 g)

O

S 10 The oil was dissolved in acetonitril (10 mL). To the thus obtained solution, potassium carbonate (46 mg, 0.33 nmnmol) and 3-(3-bromopropyl)-1H-indole (33 mg, 0.14 mmol) were added and the mixture was heated at 70 0 C for 12 hrs. Isocyanomethyl polystyrene (250 mg, 0.29 nmmmol) was added and the mixture was slowly cooled to room temperature.

The resin was filtered off and washed with methanol (1 X 2 mL) and dichloromethane (1 X 2 mL), The combined liquid phases were evaporated from volatile solvents to yield a dark brown oil. The crude product was purified by preparative reversed phase KPLC chromatography. The resulting solution was subsequently loaded on a pre-conditioned ion exchange column. The column was washed with methanol (4 mL) and acetonitrile (4 nimL), followed by elation of the product with 4 N solution of ammonia in methanol (4.5 mL).

Evaporation of the volatile solvents afforded the title compound 3a as yellow oil (66 mg).

LC/MS 442 Rt 4.15, purity. 93 The following compounds were prepared analogosfy 1-(2-Phaenyenyl)-4-[4-(H-indol-3-ylbutylJpipramine LC/MS 426 OMI), RT 4.36,purity. 79 1-[2-(1,3-Benzodiaoxlan-5-ylory)pheyJ-4-W[4-( -indol-3-ylbutyl]pperaine (3c): LC/MS 470 (Mlff), RT= 2.62, purity: 89 1-[2-(2-Mthoxyphany)phenyl-4-[2-(6-coro-I-indol-3-yl) ethylpperazine (3d): LC/MS 462 RT 4.35, purity: 76 COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun--2006 08:17 PM Watermark +61398196010282 28/42 IDWO 01/49678 PC'r(DKOO/00721 o 23 c-i1-[2YL13-Be~odioxolan-5-ylxy)phenylj-4-J2-(6-ddoro-II-indol-3-ylethy~iJerozine LCIMS (mlz) 476 (MfPT 2.64, purity: 89 1-(2-[3-(Tmethyambiw)phtoyphenyl4-[24(6-choro-H-indfo-3-yed$J~ppffade EC/M[S (rdz) 475 (MIX', 107- 2.32, purity: 91 l 1-[2-(2-Me-thoxphenory)phenyl]-4-[4-(10-indol-3-yiflnayllpxperazine LCIM o 456 (Mfl, R U= 4.3 1,purity.:90 o 10 I-[2-(4-Methpey)phenyl-4-p-H-io-3-ypropylpperazne LC/MS Qu/z) 442(MG-tj 1 RT =4-18, puritT. l7-(2-[3-(Dfrnfllylmno)phxyjphnyl-4-[4-H-dol-3-yl)buylJpperarte (31): LC/M 469 (MIfl, RT 2.27, purity: 98% l-(2-Phenoxjqhnyl-f2&dd4oro-H-indo-3-y)ethylppurwsne LC/MS 432 uvMOf, RT=4.40, purit Example 4 2-(4-ChdorobsgylXLS.-doxolan-4-ytmethorymehylpobyszyraze (44) A 2 L round bottom flask was charged with 2.2-dixnetyl-I,3-dioxolan-4-ylmcthoxymnetyl polystyren (90 g, 72 inmol], commerially available as (t)-l-(2,3-isopropyidene) glyceol polystyrene from Calboehemn-Novabioohem, cat no. 01-64-0291). Tolnee (900 rat) followed by p-toluenesulfonic acid miono hydrate (5.0 g, 26 inmoIl, sodium sulfate (25 g) and 5-abloropentanal (25.5 211 ammol) were added and the mixtur was boiled unmder reflux. for 12 brs. The reflux condenser was replaced by a Dean-Slarc apparains and the mixture was boiled -under reflux for an addidtioa 3 in. After cooling of the reacto mixture to 60 0C, th& resin was Dltexed off and washed with tonene (200 mL., tetrhydrofuran/pyridine 1, 200 tetrahydrothranwaterfpyridinae (10: 10: 1, 200 mL.), methanol (200 aL), water (200 mL), tetrahydroiba (200 rnL), dicblonomethane; (200 uL.), methanol (3 X 200 and diobloromerbae. (3 X 200 nit). The resin was dried in vacuo 12 is) to yield the title compound 4a, (974g) COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:17 PM Watermark +61398196010 29/42 IDWO 01149678 PCTDXoOIoo721 o 24 Thle following compounds were prepared avalogously: 2 -(3-ChloropropyQ-1,3-ioxolan-#ymehoymethylpoyayrmne (4b,) 2-(S-Chioropnyl)-LS-dioxolan-4-ymehoxymeekylpolyntyraw (4c) Example Co l-[ 2 -(lA4Bemdon--yloy)pheny4-f3S-fluoro-H-indol--ylpropylpperasne IND 01 2-(3-Chlorobutyl)-1,3-dioxolan-4-ylmetoxymethyl polystyree (70 g, 90.3 mmol) was suspended in dry NN-limethylformawide (700 ML)- Sodium iodide (68 gm 452 mmol) was added followed by diisPropylethylaznie (232 mL., 1.36 mol) and piperzine (117 1236 mol). The reaction mixturfe was heatd atS 8 0 C under sliting for 12 In. After cooling to room temperatur, the resi was ffitered off and washed with NN-dimetylrforznmide (3 X 500 niL), methaol. (3 X 500 niL), tetrahydrofurain (3 XC500 niL), and subseuently with emetaol and tetrahydrofuran (eah 250 niL, 5 cycles), Finally, the resin was washed 'with dichloromethae (3 XC 500 niL) and dried in vacua (25 0 C, 36 bra) to yield an almost.

colourless resn (76g) A part of the obtained resi (50 60.6 mmcl) was then supended in dry tetrahydrofln (600 niL). r( -1,2--Dic lobe-euecylopelienyioQ] hexafluorophosphate (48g 116-2 imol) was added folowed by Potassium carbonate (32 g& 233 nnl), The reaction iture was stirred at 60 0 C for 12 In. Aft=r cooling to room temperature, the resin was filtered off and washed with tetralydrotiira (2 X 500 niL), water (2 XC 250 maL), teralydrOflnn (2 X 500 MiL), methanol (2 X 250 tnt), dicliloromethane (2 XC 500 niL), melhanol. (2 X 250 mL). Finaly, the resin was washed 'with dichoomiae (3 X 500 mnL) and dried in vacua (25 0 C, 36 brs) to yield a dark orange resin (70 g).

To a solution. of 5-hydroxiy-1,4.bcnzodioxa .ne (2.8 9,18- =A=in) in tetrahydrofaran (50 =iL) was carefully added nea s6diiam hydride (15.5 rumol) at room temperatur (Caution: Generation of hydrogen), The mixtmr was stirried for an additional 30 milt alter the generation Of hydrogen ceRAst Subsequently, a part of the above obtained resin (2.8 g, 2.3 COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:18 PM Watermark +61398196010 30/42 SWO 01/49678 PCT/DK0/00721 o 0O Cl mmol) was added and the mixture was stirred at 40 "C for 12 hrs. After cooling to room teaperature, the resin was filtered off and washed with tetrahydrofuran (2 X 50 mL), tetrahydrofuran/water (2 X 50 mL), N,Nldimethylfomnamide (2 X 50 mL), water (2 X 50 mL), methanol (3 X 50 mL), tetrahydrofuran (3 X 50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3 X 50 mL) and dried in vacuo (25 12 hrs).

ci o A part of the obtained resin (200 mg, 0.15 mmol) and a 0.5 M solution of 1,10- \0 pheanthrole ine a (3:1)-mixture of pyridine/water (10 mL) was placed in a lightiransparent reactor tube. The suspension was vortexed and iradiated for 12 hrs. A very characteristic feature of the decompleation step is the appearance of the intensive red colour of the liquid phase during irradiation. The resin was filtered off and washed with methanol (2 X 10 mL), water (2 X 10 ml) and tetrahydrofan (3 X 10 mL) unil the washing solutions kept colourless (ca. 5 cycles) and the irradiation procedure was repeated until decomplexation was complete (ca. 4 cycles). After complete decomplexation, the resin was washed with dichloromethane (3 X 10 mL) and dried in vacuo (25 12 krs).

The obtained resin (160 mg, 0.15 mmol) and 4-fluorophenylhydrazine hydrochloride mg, 0.21 mmol) were mixed in a reactor tube. A 0.5 M solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added and the reaction tube was sealed. The reaction mixture was stirred for 12 brs at 70 After cooling to room temperature, the reaction mixture was filtered and the residual resin washed with dimethyl sulfxide (1,5 mL). Saturated aqueous sodium carbonate solution (1.5 mL) was added carefully to the combined filtrates(Caution: Generation of carbondioxide). The solution was loaded on a pro-conditioned reversed phase C-18 column. The column was washed with water (4 mL) and the product was eluted with methanol (4.5 mL). After evaporation of the volatile solvents, the crude product was purified by preparative reversed phase HPLC chromatography. The resulting solution was subsequently loaded on a preconditioned ion exchange column. The column was washed with methanol (4 mL) and acetonitrile (4 mL), followed by elation of the product with 4 N solution of ammonia in methanol (4.5 mL). Evaporation of the volatile solvents afforded the title compound 5a as yellow oil (2 mg). LC/MS 488 (M Rt 4.22, purity: 84 COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun--2006 08:18 PM Watermark +61398196010 314 31/42 NOW001/49678 IPCTIDKOOIOO7ZI o 26 The folowing compounds wer prepared analogously: 7-92-Ph wxyphenyQ-4-f3-(5-methyl-IH-frdo!-3-ylpropyljpipnrazine LCYMS (ink) 426 OM)f, RT 4.44, purity. 88 l-[2-(2-Methoxyphenory)phenmylj-4-[3-(S-chloro-II-indol-3-ylpropyljpperazne LCIMS (inlz) 476 RT =4-46, purity- 95 o 1-[2-(2-Methoryhenoxy)phenyUl-4-[3-(S-bromo-1H-ndol-3-yl~propy]pioerazne LCIMS 522 (Mat). itT purit: 91 1-(2-Phnoxypheny9)-4-(3-(1H-indl-3-yl)propyipz~erane tAMS Quiz) 412 (rfnt), itT 4.25, purity:. 98 1-(2-PhenoxgohenzyJ)S-[3-(S-fluoro-1H-tndoJ-3-yl)propyllpzperaztne L/M Quiz) is 430 (MMl 4 4.32, purity: 96 l-(2-PhenoxyphenyQ-4-fl45-bromoI-ido-3-yl)proy1Jpiperazine LCIMS (M/z) 492 (MUH), itT =4.60, purity- 84 6-Dimethorphenoxy)phenyll-4{3-(-bromo-1H-indo-3-yl~propylJpzperarine LC/MS (mhz) 552 itT 4.49, pmt 86 06.

1-f2-f3-(Dbmetthylwmm)phnorphenyl4-(5-mhyl-H-dol-3-y~propylpperzbz (Si1): LCME (rn/z) 469 (UK)l, itT =3.73, pnity: 86 1-(2-Phnwxyhenyl)-4[3-(-chdoroH-do-3-yl)proypiwsrazine L(YMS (Miz) 446 (UR4fl, RT3= 4.52, purity: 88 1-[-(1,3-Renzodioxola-S-ylorcy)phenyllj4-f3-(5-me*yl-H-idol-3-y~propyl~piperazine LC/MS ,(mlz) 470 (N{Fl,RiT 4.38,purity: 70% J-[2-(2-Mnhornyphenoy)phanylr4 43 Juoro-1 H-in do l-3-yI)propyljpip eraztn (51): LC/M 460 (MAH), KtT -4.24, purity: COMS ID No: SBMI-03862394 Received by II' Australia: Time (I-tm) 20:22 Date 2006-06-13 13-Jun-2006 08:19 PM4 Watermark +61398196010324 32/42 IDWO 01I49678 PCT13K00100721 o 27 l4 2 2 -MehohnPJ-oxy)heryU-4-[-(-7choro-IH-indo-3-yl~propyl7p'perazine LCJMS (inkz) 476 (MIHtX IT =4.42, purity: 96 S 2 3 -Renzodiroxoan--ylor)phnyQ4-p3-(5-ftuoroTH-indous3-ypropyppra LC'MS (nih) 474 RT -4.25, purity: 99 o 2 3 -Benodoxo1an5-yl)pheny]4-[3%S-id4H-indo3-yl)propypperazine IND LC/MS (mlz) 582 (MIH), 4.58, purity:. 85 I1-(2-Phenoxyphenyi)-4-fl-C/-chloro-1H-ndol-3-yl~ppylJpq~erozne LC/MS (inz) 430 (Mfl, RI? 4.3 8, purity: 87 1-(2-Phenoxyphenyl-4-[3-j5, 7-dfluoro-1H-bndoi-3-yl~propyljpziazine LCIMS (rlz) 448 (MAj, I? 4.44, purity: 84 -1-fl y2-MethoxyphenoxyphenylJ-44[3yz-bromo-rn-indol-3-yljpropyqlpiperfrine LC/MS (minz) 520 QM&fl, RI? 4.50, pury 77 l-(2-[3-(DIuneshlno)phnoyJphenyl-4-[3-(-fluoro-IH-do-3-yl)propylJpperaine LOME (nih) 473 RT 3.63, purity:, 96 l-[2-(2-Mahoxypkenoxy)phazyJ#[-3-(S-iodc-JJ1-idol-3-yppropyflpjpera~azn (Si): LC/MS (xn/z) 568 (MH4). RT 4.63, purity; 82 2S J-[2-(1,-Benmdioxolan-5-yloxy)phenyU-4-[3-(5-c-hloro-H-indoL-3-yl)propperosine LC/MS (inz) 49D RI? 4.45, purity: 90 1-[2-(Z6-Dbnethoxyphwzoxy)phenylp4-[3{S5-chloro~-frzidol-3-yl)propyljp,razine (Siv): LC/MS Qu/z) 506 RI? 4.46, purity 83 1-[2-(1,3-Besodioxcln--yloxy)phcny!J-44341Wpyrrolo3,2-hJ-quinolin.3yi)PropyJpiperazine LCMS (in) 507 (M11l. ItT =3.30, purity: 97 COMS ID Na:SBMi-03862394 Received by IP Australia: lime 20:22 Date 2006-06-3 13-Jun-2006 08:19 PM4 Watermark +613981960103/4 33/42 IDWO 01/49678 PCTJDKOOIOO72I o 28 1-[2-(2-Methorypknx~hn~4f-$ 7-iturH-inol-3-y1)propyljpprzn S) LCD/MS 478 Q(NEfl, R2>=4-.36, purity: 715 1-(2-Phaarjq~lhenY9-4-[3-(S-i od-1H bdd-3-yl~propyljffiperazfne LC/M 5.38 ci (MHfl, RT 4-69, purity. 92 o 1-[2-(2-Methoxyphenoxy)phenyQj-4-fl41(H-pyrrolo[3,2-hJquinolin-3-ylpropylJpr~eradtne LCDMS Qu/z) 493.2 (MRfl, PT =3.29, purity: 96 ci0 1-f2-(3-Methoxyphenoxy)phenyQj-4-fl-(IH-pyrrolo(3.2-hjquznolin-3-yl~popylJpipeazne LCD/MS 493 (Mfl), PT 3.3 8, puiity 96 lye J-[2(14Bnzodoroan--yloxy)phenyQ-4-3-(-melhy-1H-fndo-3-yI~propylJpzperazine LO'MS 484 (Mfl), XT? 4.35, paritr. 84 LCYMS (rofz) 486 (ITt), RI? 4.38, purity: 80 142-(3-Methojqpheaoxy)phny]-4-[3-(If-zdo1-3-yI)propylpprazine (Sad): LCD/MS 442 (MIft), RT =4.25, purit: 85 1-[2-(Ll4Beizdioxn-S-yoxy)pkml4-l-(H-indol-3-ylpropylffiperrne LCD/MS Qu/z) 471 (Mgt), RT=4.13, purity: 83 1-[2-(l,3-Benzodiolan-S-ylorcy)phanylj-4-f3-($-bromo-1H-indol-3-yipropylpp7erazine (Sal: LOMS Qu/z) 536 (MHlt, R? mm 4.49, purity: 88 112-[34MorpholinA-ypphenoaypheny-4-3-(5-luoro-H-indo-3-yl~propyljp4erazinw (Sag): LQI MS Qu/z) 515 (MIH), RT?-4.17,purity: 94%.

l-[2-(3-MnhorjqPhnoy)phenyJ-4-345-cloro-H-yzdoJ-3-ylpropypparazmne (Sail): LCD/MS 476 (MHfl, RT 4.53, purity 92 COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:19 PM4 Watermark +61398196010 3 4 34/42 IDWO 01I49678 PCI/DX00100O721 o 29 l-P--(-Ehoxyphenozy)phenyV-43-(-netJ-1H-indol-3-yopropyijpiperartne (54l): LVMS 470 RT =4.68, purity. 85 1-j2-(2, 6 -Dhmedwxyphenwy)phwwyIJ--3-(-od-1ff-indo--ypropygpieraztae (Saf3) LUDMS Qu/z) 598 (lvMi), ItT 4.61, purity: 70 o l-( 2 -P{Diethylamm)phnoxyphenyQ)43-(-fluwro4IH-ido-3-yppropyqpzperazine IND(Oak): LC/MS 501 (Mffl, RT 3.18, purity: 87 l-f 2 Y?,&-Dimethoxyphenory)phenyl]4j3-(-fluoro-1H-ndoU-3yI)propyglpjperajne (Sal): LCD/MS 490 (Mft), RT -4.26, purity: 88 l-( 2 3 -(Morphiolin-ftyl)pherwxy]phenygl-443-(S-bromoz-M-dol-3gyz)propyqgpperorne (5am): LCD/MS (ra/z) 415 (IvIf, ItT =4.42, purity: 78 l1- 2 3 fophoin-4-y)paoxypnyll4-[3-(-cMoro-W-ndolt3-yppropylpgpaljze (Sau): LCD/MS (uiz) 531 (MAlt, RT 4.34, purity: 81 l-( 2 1[ 3 -(Mopholin4-yOphnoxy]phy4fl-(S-iodII-inol-ylpropyg~pipraine LUDMS (na/z) 6.23 (MM 1 ItT -4.56, purit: 71 l-f 2 -(S-Methuphenoxy)$nhyl-4-l-(7-fuoro-H-ndol--yiprqyperaine (San): LCi'M Qu/z) 460 RT 4.38, purity: 70 1-(2-rhmaw)Ph,4~)-4-[33, 74dimethylIH-fndol-3-yI)pmpyljpi~peraztne(Sar): LCiMS Quiz) 440 (MRfl, ItT 4.64, purity: 78 l1-2-(,S-Benzodioxoian-S-yloxy)phenyy4-jsyz7-romoI4-indol3-ylpropylpperaine (Sns): LCNM(t4) 534 (Mn),RIT-4.46, purity: 75 %0.

l-[ 2 4 ,S-7iethoxyhey)pheny-4-[3(.bromoH-ndol-3ylpropygjpperadne LCD/MS (ru/z) 580 (MHlt. ItT 4.34, purity: 81 COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006406-13 13-Jun-2006 08:20 PM Watermark +61398196010 35/42 11WO 01/49678 PCTIDKOO/00721

;Z

n Pharmacological Testing The comnpormds of the invention were tested in well-recognised and reliable methods. The tests were as follows: Ci Inhibition of the binding of 3 H-YM-09151-2 to human dopamine D4 receptors By this method, the inbibition by drugs of the binding of 3 JYM-09151-2 (0.06 nM) to 0 membranes of human cloned dopamnine D4.2 receptors expressed in CHO-cells is determnnined in vitro. Method modified from NEN Life Science Products, Tnc., technical data certificate PC2533-10/96. The results are given in the following Table 1 as ICscrvalues.

Inhibition of the binding of 3 M-Spiperone to human D3 receptors By this method, the inhibition by drugs ofthe biing 3 HSpiperone (0.3 nM) to membranes of human cloned dopamine D3 receptors expressed in CEO-cells is determined in vitro. Method modified from LG. MacKenzi et al., Eur. J Pharm.-Mol. Pharm. Sec., 1994, 266, 79-85. The results are given in the following Table I as ICs-values.

The affinity of the compounds of the invention to 5-HTlAreceptrs was detamined by measuring the inhibition of binding of a radioactive ligand at 5-HTaxeceptors as described in the fbillowing test: Inhibition of 3 H-S-CrT Binding to Human -HTA Receptors.

By this method, the inhibition by drugs of the binding of the 5-1ET agonist 3 H-5-carboxamido tryptamine (31-5-CT) to cloned human 5-HTIA receptors stably expresed in transfected eLa cells (HA7) (Fargin, Ak et al, J Biol. Chem, 1989, 264, 14848) is determined in vitro. The assay was prfrmed as a modification of the method described by Harrington, MA. et at J Pharmacol. Rp. Ther, 1994, 268, 1098. Human COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:20 PM Watermark +61398196010 36/42 WO 01/49678 PCT/DK00/00721 31 HTIA receptors (40 jig of cell homogenate) were incubated for 15 minutes at 37 'C in mM Tris buffer at p1H 7.7 in the presence of 'H-5-CT. Non-specific binding was determined by including 10 pM ofmetergoline. The reaction was terminated by rapid filtration through Unifdter IF/B filters on a Tomtcc Cell Harvester. Filters were counted in a Packard Top Counter. The results obtained are presented in table 1 below.

Inhibition of 3 11-5-HT Uptake into Rat Brain Synaptosomes Using this method, the ability of drugs to inhibit the accumulation of H-5-IIT into whole rat brain synaptosomes is determined in vitro. The assay was performed as described by Hyttel, Psychophawmacology 1978, 60, 13. The results obtained are presented in table 1: Table 1: Compound No. Inhibition of Inbition of Binding 3 H_-5-HT Uptake (niM) ICso (al) lb 7.8 130 2b 16 2.8 3c 16 270/ inhiition af 100nM 3c 24 40% inhibition at 100 nM Sa 19 14 Se 10 13 f51 10 4.8 Sb 10 55% inhibition at Si 10 46 inhibition at 100nM 51 13 4.7 18 33 Sae 26 42% aInbbition at 100 M Sag 26 23 28 34% inhibition at 100 M COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:20 PM Watermark +61398196010372 37/42 IDWO01J49678 PCT11K00100721 o 32 (N Accordingy, as thie compounds of the invention show af finitis i the described tests, they arc considered useful in the treatment of affective disorders, such as depression, generalised anxiety disordr, panic disorder, obsessive compulsive disorders, social phobia, and eating disorders, psychosis and neurological disorders such as isebseania and smile dementia.

IN

COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13

Claims (2)

13-Jun-2006 08:21 PM Watermark +61398196010382 38/42 IDW001/49678 PCTI'DKGO/00721 o 33 ri Claims: 1. A compound represente by the general formula I IND, wherein Z represents NA, 0 or S; reprsent hydrogenCi. 6 -alkyl; R 7 and I& independenty rePreset hydrogen halogen, CjI-alkyl, C, 4 -CYcIlkyi CN, CF 3 or C, 4 -alikoxy; or fl7 and R 8 together form a 5- or &-mcnbercd aayl or heteroaryl fused to the benzene-ring. Y represents N, C or CRf; the dotted ine representa optional bond; e1 and R" represet H Or C 1 6-aWkyl X represnt-0- or uisZ2,3, nxis 2 or 3; WR, W1, 11' and r reindependently seeced from a group consisting of hydrogen, halogen, C 14 &-akyl, Ow4alkenl, C2.-akynyL Cj..sCyoloalkY yl .l hydroxy, hydroxy-Ct- alkyl, Ci 4 -alkoxy, C 34 U-cyclAlkxy, C 14 -ullcylulfanyl, sacy NR 9 R' 0 wheren le and K 10 independently rrset hydrogen C 14 5-alcyi, 9j4-alkenY], C-ALkYnyL C,..-cycloalkyl or aiyl orR 9 and 0 togethe with the nitrogen to wtdch the ae attached form a i- moipholinyl, 1-piperidinyL 1-homnopipeidinyL, 1-piperazinyL, I-homopiperazinyL, 1- imidazolyl, 1-pyrrolyL, or pyrazlyl, all of which may be furthier substituted wit Cj4-a~kyL or two adjacent substituents of K' j(5 together formn a ring fused to the phenyl ring selected from the group consisling of COMS ID No: SBMI-03862394 Received by IP Australia: lime 20:22 Date 2006-06-13 13-Jun-2006 08:21 PM Watermark +61398196010 39/42 O WO 149678 PCT/DKOOh/W721 34 EI 'WI R'( wherein W is O or S, and R' and R" are hydrogen or C4-alkyl: 2. The compound according to claim 1 wherein Z is NH and the aryl is connected in position 3; NO o 3. The compound according to any of the preceding claims wherein R and t8 N independently are selected from a hydrogen, halogen, C 1 alkyl or R 7 and R 8 together form. a fused pyridyl-ring; to 4. The compound according to any of the preceding claims wherein n is 2,3 or 4; The compound according to any of the preceding claims wherein mis 2; 6. The compound according to any of the preceding claims wherein R 6 and R 6 are both hydrogen; 7. Thecompound according to any of the preceding claims Y is N; 8. The compound according to any ofthe preceding claims wherein R 2 R 3 R 4 and R independently are selected from hydrogen, alkoxy, NRR 4 wherein R 3 and R independently represent hydrogen, C 1 alkyl; or R 3 and R 4 together fonnm a 1-morpholino; or two of adjacent of R 2 R 4 and R 5 together form a fused ring consisting of -O-COlz-O-, -O-CH 2 -CHz-O-, or -CH 2 -CMi 2 -C 2 9. The compound according to any of the preceding claims wherin one or two of R, R 2 R, R and R 5 are not hydrogen; The compoumd according to any of the preceding claims, said compound being l-(1-[3-(dimethylamino)phenoy]phenyl-4-[2-(H-indol-3-yl)thyl]piperazin; COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:21 PM Watermark +61398196010402 40/42 NOWO 01149678 PCTIDKOOIOO72I o (N 1-[141 ,3-BcnwDfioxoln-5-yloxy)phenyl4(2-(U-indol-3-yl)thyllpipmazine- 1-f l-[3-(dimtylamino)phenoxyJeayl.-4-[3-<1H--indol-3-yI)propyllpiparazine;

1411-(1,3-Bezodioxoan-5-yoxy)pieny]4-3-(H-indo-3-y)propylpipcrzino,; 1-[2-(1,3-Benzodioxolan-5-yloxy)pheay1}4-13-(6-chloxoJH-idol-3-y)pro-py1]piperazin, 1-(2-(2-MetboxYPbenoxy)phenylJ4-3-(-fluoro-H-indol-3-yl)PmOpylpipeateu, 1-(2-(1,4--IBerzodioxa-6-yloxy3phnyy1)A43-(lH-indol-3-y1)propy1]piperazine 1-[2-(1,4-Benzodioxan-5-yloxy)pheny1]--[3-(5-fluoro-1Hindol-3-y1)propy1]piprazin o 142-fl ,4-B~izodiaxan-5-yloxy)phenyl]-3-(6-chlom-IH-irdo3-yl)propyl~pipeateM INO1-1,4-Benzdioxan-6-yloxy)pbeay1>4 -[-(6-cfiora-lH-fiudo1-3-yI)propyllpipemzinv 0 o 10 l-(2-(2-Methoxyphenory)phnyl}'4-[3-(&-choo-LE-indol-3-ylpopyllpipcrzinc 1-[2-(3-Metbhoxyplnwxy)phenyl-4-3-(6-cbloro-1H-indol-3-yl~popyl~piperAziue 14[2-{2-Metoxypbaoxy)phnyl-4{3-(X*-indol-3-yl)propyl~piperzine; 1-(2-Phmioxyphenyl)-4-[4-(1H-kndol-3-yl)bnty]pipmazine, 1-[2-(t,3-3enzodioxolan-5-yloxy)phnyl]A-[4(I-indol-3-yI)butyl]piperazine; 14[2%(Mehoxyphochnyl]-4-[2-(6-loro-H-dl-3-yl)hylppwzine; 1-[2-(1,3-Benzodfioxolan-5-yloxy)pbcnyl]-4-[2-(6-rhlomo-1H-hiol-3-yl)cflxyl]pipcraine; 1-(2-(3mp~ethylamin)phnoyuphnylJ-4-2-(-cor-1H-indol-3-yl)cthylbpipcrazin; 1-[2-(2-Methoxyphwiox)pthenyl44-(lH-indo-3-y)bulpierazine; 1-[2-(4--Msloxphenoxy)phenyl]4-[3-(1H-indo1-3-yI)propyi]piperazmte; 1-[2-(3-(Dimefihymo~hnxy)phnyJA44-(l-ndo-3-y1)bvtyI]pipemtu-e4 Phenoxypheuyl)4-[2-(6-choro-lH-indol-3-yI)tyflpipaaznc; 1-[2-(1,4-Benzdioxmn-5-yloxy)phenylj-[3-(5-ftaoro-JM-indo1-3-y1~propyI~piperazie; 1-(2-PhennxPbenY1)-4-[3.<$=ethYl-lHindoI-3-y)pmopypipmzre l-[2-2-MetoxYphenoxY)phenY1A-[3-(5-bolom-H-indo-3-y)propy1]piperazine; 2s 1-r2-2-1ethovbMc xv)vhvl4435-bm w-Ti-n-3-v1Th5Mli nt- COMS ID No: SBMI-03862394 Received by IF Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:22 PM Waitermark +61398196010412 41/42 IDWO001149678 PCTIDKOO/00721 o 36 (N 14[2-(2-MethnxYPheoxy)phenY13-4-3-(7-horo-1-ido-3-y1)prcp'1pipra~ilC; 1-[2-(1.3-Bcnzodioxola-5-yoy)pany]-43-(5-UdrO-1H-inldO-3-yDPprpylJpipemzine; 1-([2P(1,3xBanzoioxo4a[35-y-oxyoph1ny1]-o-3--irod-1H-iO13Ym rpY]iPrfll 51-(2-Phenoxypheny)-4-3-7-dforo-1ll-indoI-3-YIpOy11propyl3pzifQ 1-[2-(3-IDhnethylamino)phmoxy)phy4-3-(5-fiiorQ-1f-ndol-3-yl)pOPYU~pipVY8zWO o1-[2-(2-Methoxypbenoxy)phny]-435odo- I-ido1-3-y1)poyUlpipraZifC IND1 14[2i(,3-flenzodioxolmn-5-yloxy)phny]-443-(5-blurO-fL-ildOL-3-y1)1ropylpiperazinC 1[2-(2,6-Dimethoxyphenoxy)phny]A(3-(5-choo-H-idl-3-yl)pIQpylPIPrtziU3, a dooa--lx~hnl--3(Hproo32h quinolin-3- y)propyljpiperazine; 1-[2-(2MeffioxphnoiqpayH-4-3-57-dfluwr-ndo3-y1*opy]pipezmo; 1-(2-PhenOXYPhnY1)-4-(3-(5-iodo-H-indo-3-y~pQo1ppl~rUZflB 1-[2-(2-Methoxyphwioy)phuy)43(-pyoo[3,2-h]q~ili-31)pTOPylp1Pi120,~ 14[2-(%Mtoyphenoy peay]-4-[3-(H-pyroo[32-h quinoin-3-y1)propy7lpiperazine; 1-[2-(1A4-Benzodioxn-5 -yloxy)phcnyl]4(3-(5-cthy-H-indo-3-Y1)popy1pip&8zilC 14[2-(2,6-Dimcthoxrhcnoxy)phwnyll-4-[3-(5mty-H-do1-3-yl)propyl]pipmmafe; 1-[2-(3-MethoxryphenoxyopzenylJ-4-[3-(1H-indol-3-yI)proylpipcr~ie; 1-[24(1,4-Benzdioxan-5-yloxy)phenyJ-4-p-(U-imo-3-y)poypYMemazu; 1-[2-(1,3-Benzodkoxolan-5-yloxy)plunyU-4-[3-(S-bromo-H-ido-3-y)propyJpiperaino; .1-{2-[3.(Morpholin4-y1)phcnoxyphy}-4-3-(-fluoro-H-do1-3-y)propyJpp&82il0 14[2-(3-Mcthoxyphenox)pheny]-4-[3-(5-cbo-1H-ino1-3-ylpropyJpipeazine; 1-[2-(3-Etoxyphenox~plrniyl]-4[3-(5-etl-1H-indol-3-y)propljpiporzinc; t-[2-(2,6-Ditoxypexy)phyIA-[3-(5odo-Iindo-3-y)propy]piprwiC: 1-[2-(3-(iym)phymM)eny]-[3-(5-uoro-l-do-3-y)pwpy)pipeazie; 1-[2-(2,6-DimetoxYPhnoxY)PhenYl-4-3-(5-fluoro-I{-dol-3-yl)roylpperzie; 1-{2-[p-(Morpholin-4-y)phonoxyphenyI}-4-[35-bomo-1lI-indo-3-yFlpopyIpipaaziue; I- (Z{3-(Mozpbolin-4-y)phwcry]pheay1}-44[3-(5-chloro-1H-indoI-3-ylpopyLlpiperaine; l-{2-[3-Q(forphobna-4-y)phenoxylphcnyI-443-(5-iodo-IIX-idol-3-yI)proyflpiperzine; t-(2-(3-MetlorYPhenoxy)Pbznyl]-(-3-(7-fltuoro-1H-indol-3-yI~pwpyl~pipcrazic, 1-(2-Phenaxypheayl)r4-[3-(5,1-dimoffiyl-lHi-ndlol-3-yl*proylpiperaine; 1-42-(1,3-Beazdioxolman-5-yloxy)phny)4-[3-(7-bromo-H-ino1-3-yropMyJpiprwzine COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13 13-Jun-2006 08:22 PM Watermark +61398196010 42/42 WO 01/49678 PCT/DK0/00721 037 N 1-[2-(3,4,S-Trimetoxyphenoxy)phenyl-4-[3-(5-bromo-1H-indol-3-yl)propylpiperazmie; ;Z 11. A pharmaceutical composition comprising at least one compound ofFormula I according to any of the claims 1-10 or apharmaceutically acceptable acid addition salt thereof or prodrmg thereof in a therapeutically effective amount and in combination with one 'fl or more pharmaceutically acceptable carriers or diluents. IN 12. The nusc of a compound ofFormula I according to anyofthe claims 1-10 or an acid 0 S 10 addition salt or prodrug thereof for the manufacture of a phatrmacetical preparation for the treatment of the above mentioned disorders. 13. A method for the treatment of affective or neurological diseases and disorders in humans caused by abnormalities in the serotonin system of the central nervous system comprising administrating an effective amounrmt of a compound of Formula I according to any of the claims 1-10; 14. A method according to claim 13 said disease being depression, psychosis, generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischaemia, senile dementia, and social phobia. COMS ID No: SBMI-03862394 Received by IP Australia: Time 20:22 Date 2006-06-13