NZ333519A

NZ333519A - Troponyl piperazines as selective dopamine d4 receptor ligands

Info

Publication number: NZ333519A
Application number: NZ333519A
Authority: NZ
Inventors: Jian-Min Fu; Xin Wang; Adi M Treasurywala
Original assignee: Hoechst Marion Roussel Inc
Priority date: 1996-08-22
Filing date: 1997-07-30
Publication date: 1999-10-28
Also published as: NO990796D0; HUP9903913A2; CA2259515A1; NO990796L; JP2000516629A; HUP9903913A3; IL128629A0; WO1998007711A1; ZA977445B; CN1227550A; AR009274A1; BR9711965A; EP0929537A1; AU3817197A; KR20000068255A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 333519 New Zealand No International No 333519 PCT/US97/13264 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 22 08 1996, Complete Specification Filed 30 07 1997 Classification (6) C07D295/10, A61K31/495, C07D295/12 Publication date 28 October 1999 Journal No 1445 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention Troponyl piperazines as selective dopamine D4 receptor ligands Name, address and nationality of applicant(s) as in international application form HOECHST MARION ROUSSEL, INC , 2110 East Galbraith Road, PO Box 156300, Cincinnati, Ohio 45215-6300, United States of America WO 98/07711 -1- PCT/US97/13264 troponyl piperazines as selective dopamine d4 receptor ligands 5 This invention relates to compounds that bind to the dopamine D4 receptor, to their preparation and their use for therapeutic and drug screening purposes Background to the Invention 10 Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and 15 homogeneous substrates with which chemical libranes can be screened to identify potential CNS-active drugs Recent evidence strongly implicates the dopamine receptor classified as D4 in the etiology of schizophrenia It has been suggested that compounds capable of 20 interfering with the function of this receptor, which is present in schizophrenics at levels that are six times normal, would be useful in the treatment of this disease (Seeman et al, Nature, 1993, 365 441) Some drugs currently on the market in fact exhibit the desired antagonism of D4 receptor activity, and bind with relative strong affinity to the receptor Yet because of their structure, these drugs interact also with related 25 dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia It would be desirable to provide compounds that exhibit not only a high degree of affinity for the D4 receptor, but also a relatively low degree of affinity for the D2 receptor In this specification, this desired combination of receptor binding properties is referred to as D4 selectivity 30 Products currently marketed to treat indications in which the D4 receptor function is implicated include the dibenzodiazepine, clozapine, and the dibenzoxazepine, Printed from Mimosa WO 98/07711 PCT/US97/13264 -2- isoloxapine Analysis of their dopamine receptor binding properties has shown that the preference for binding the D4 receptor relative to the D2 receptor is about 10 fold, for both products Similarly, both bind the D4 receptor with about the same affinity (Ki value approximately 20 nM) Other products, recently published in the scientific 5 literature, have shown similar D4 to D2 selectivity profile and D4 affinity values The use of certain troponyl piperazines as dopamine receptor agonists, for example to treat Parkinsonism and other related disorders, is described in EP 034,894 and in related scientific articles (see Bagli, J et al, J Med Chem 1984, 27 875 and Bagli, J 10 et al, J Med Chem 1986,29 186) It is an object of the present invention to provide a compound that binds to the D4 receptor 15 It is an object of the present invention to provide D4 receptor-binding compounds It is another object of the present invention to provide compounds which bind selectively to the D4 receptor, relative particularly to the D2 receptor 20 It is a further object of the present invention to provide a pharmaceutical composition comprising a compound of the present invention, as active ingredient It is another object of the present invention to provide a method effective to treat medical conditions for which administration of a D4 receptor antagonist is indicated, 25 such as to treat schizophrenia and anxiety Printed from Mimosa wo 98/07711 Summary of the Invention According to one aspect of the present invention, there is provided a compound of Formula I wherein R, is H, halo, aryl or aryl substituted with one or two groups independently selected from halo, Ci-^alkyl, C^alkoxy, nitro, tnfluoromethyl, trifluoromethoxy or cyano, wherein aryl is a five membered heteroaromatic ring which contains one heteroatom, R2 is C59 alkyl, phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, C^alkoxy, C14alkyl, tnfluoromethyl, trifluoromethoxy, nitro or phenyl, naphthyl, piperonyl, or the coumarinyl moiety s/n/v wherein R3 and R4 are selected independently from H, C-Malkyl and Ci^alkoxy, or 1,2-methylenedioxy phenyl, with the proviso that R2 is not phenyl or 3,4-dimethoxyphenyl when R1 is H i i 2' jul m pct/us97/13264 -3- ©*rf 2 t, • ^ WO 98/07711 -4- FCT/US97/13264 According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of Formula I and II in an amount effective to antagonize D4 receptor stimulation and a pharmaceutical^ acceptable earner, wherein is selected independently from H, halo, aryl and aryl substituted with one or two groups independently selected from H, halo, 10 ^alkyl, Ci^alkoxy, nitro, tnfluoromethyl, trifluoromethoxy and cyano R5 is selected independently from C49 alkyl, phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, CMalkoxy, Ci^alkyl, tnfluoromethyl, 15 tnfluoromethoxy, nitro or phenyl, naphthyl, phenyl fused to a 5 or 6-membered heterocycle, the coumann moiety wherein R3 and FU are selected independently from H, 20 C-Malkyl and C^alkoxy, or 1,2-methylenedioxy phenyl This is essentially Formula I without the provisio Formula II is to be used as a pharmaceutical composition Printed from Mimosa wo 98/07711 pct/us97/13264 -5- /^R2 \=/ a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R-, is H, halo, aryl or aryl substituted with one or two groups independently selected from halo, C14alkyl, C^alkoxy, nitro, tnfluoromethyl, trifluoromethoxy or cyano, R2 is C69 alkyl, phenyl or phenyl substituted with one or two groups wherein R3 and R4 are selected independently from H, Chalky! and C^alkoxy, or 1,2-methylenedioxy phenyl, with the proviso that R2 is not phenyl or 3,4-dimethoxyphenyl when Ri is H, comprising the step of coupling a reagent of Formula A selected independently from OH, cyano, halo, C^alkoxy, C^alkyl, tnfluoromethyl, trifluoromethoxy, nitro or phenyl, naphthyl, phenyl fused to a 5 or 6-membered heterocycle, the coumarin moiety O -5a- i with a reagent of Formula B H-N B in refluxing methanol, to provide the compound of Formula I In another of its aspects, the invention provides the use of compounds of Formulas I and II as D4 receptor antagonists for the treatment of medical conditions mediated by inhibition of D4 receptor antagonism, and use in treating schizophrenia and anxiety In a further aspect of the invention, there is provided an analytical method in which a compound of the invention is used to distinguish, in a receptor population, the D4 receptor from other receptor types, and particularly from the D2 receptor These and other aspects of the present invention are now described in greater detail hereinbelow f . ,i, WO 98/07711 -6- PCT/DS97/13264 Detailed Description and Preferred Embodiments Definitions 5 The term "C4 9alkyl" as used herein means straight alkyl radicals containing from lour to nine carbon atoms and branched chain alkyl radicals containing six to eight carbon atoms and includes pentyl, hexyl, 1-methylhexy! and the like The term "Ci^alkyl" as used herein means straight alkyl radicals containing from one to 10 four carbon atoms and branched chain alkyl radicals containing three or four carbon atoms and includes methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methyipropyl and the like 1-Methylethyl and 1-methylpropyl are also known as isopropyl and sec-butyl respectively 15 The term "C^alkoxy" as used herein means straight chain alkoxy radicals containing from one to four carbon atoms and branched chain alkoxy radicals containing three to four carbon atoms and includes methoxy, ethoxy, 1-methylethoxy, propyloxy, butoxy and the like 20 The term "halo" as used herein means halide and includes fluoro, chloro, bromo and lodo The term "heterocycle" as used herein means a five or six membered saturated or unsaturated nng wherein the heterocycle contains one to three heteroatoms 25 independently selected from nitrogen, oxygen and sulfur and includes 1,3-dioxole, thiophene, furan, pyrrole, imidazole, pyrazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, pyran, pyndine, pyrazine, pynmidine, pyndazine, piperidine, piperazine, morpholine, and the like Thus, some examples of "phenyl fused to a 5 or 6 membered heterocycle" are benzothiophene, isobenzofuran, chromene, indole, 30 isoindole, indazole, isoquinoline, quinolme, phtalazine, quinoxaline, quina7oline, cinnoline, isochroman, chroman, indolme, isomdoline, and the like Printed from Mimosa WO 98/07711 -7- PCT/US97/132M The term aryl as used herein means afive or six membered carbocylic unsaturated ring system which is either an aromatic (such as phenyl) or heteroaromatic ring which contains one or two nitrogen atoms, one or two oxygei atoms, one nitrogen and one oxygen atom, one nitrogen and one sulfur atom, or one sulfur atom, and includes, but 5 is not limited to, thiophene, furan, pyrrole, pyran, pyridine, pyrazine, pynmidine, pyndazine, isothiazole, isoxazole, pyrazoline, and pyrazine These aryis may be substituted as is appropriate to their chemical structure with one or two groups independently selected from halo, Cm alkyl, alkoxy, nitro, tnfluoromethyl, trifluoromethoxy and cyano Preferably aryl is phenyl substituted at the meta or para 10 position thereof with one substitutent The term "pharmaceutically acceptable salts" means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients for the intended use 15 "Pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobrom.j, sulfuric and phosphoric acid and acid metal salts such as 20 sodium monohydrogen orthophosphate and potassium hydrogen sulfate Illustrative organic acids which form suitable salts include the mono-, di- and tn-carboxylic acids Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumanc, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-25 toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2- hydroxyethanesulfonic acid Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base 30 forms, generally demonstrate higher melting points Printed from Mimosa WO 98/07711 -8- PCT/US97/13264 "Pharmaceutically acceptable basic addition salts" means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of >ts intermediates Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or banum hydroxides, ammonia, and 5 aliphatic, alicyclic, or aromatic organic amines such as methyl?mine, trimethylamine and picolme The selection of the appropriate salt may be imDortant so that the ester is not hydrolyzed The selection criteria for the appropriate salt wll be known to one skilled in the art 10 "Solvate" means a compound of Formula I or the pharmaceutically acceptable salt of Formula I wherein molecules of a suitable solvent are incorporated in a crystal lattice A suitable solvent is not substantially toxic at the dosage administered as the solvate to achieve the desired effect Examples of suitable solvents are ethanol and the like 15 The term "stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of corr ^unds with more than one chirat center that are not mirror images of one another (diastereoisomers) 20 The term "patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans The term "treat" or 'Ireating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the 25 appearance of symptoms of the named disorder or condition The term "therapeutically effective amount" means an amount of the compound which is effective in treating the named disorder or condition The term "pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order 30 to permit the formation of a pharmaceutical composition, i e , a dosage form capable Printed from Mimosa WO 98/07711 -9- PCT/US97/13264 of administration to the patient One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration The term "schizophrenia" means schizophrenia, schizophreniform disorder, schizoaffective disorder and psychotic disorder wherein the term "psychotic" refers to 5 delusions, prominent hallucinations, disorganized speech or disorganized or catatonic behavior See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington D C The invention relates to compounds that bind the dopamine D4 receptor in a selective 10 manner, relative to the dopamine D2 receptor In embodiments of the invention, compounds of Formula I and II include those in which Ri is H and R2 is C4 galkyl 15 In a specific embodiment of the invention, a compound of Formula I and II has Ri equal to H and R2 equal to n-pentyl In another embodiment of the invention, compounds of Formula I and II include those in which R1 is H and R2 is selected from naphthyl, phenyl, phenyl substituted with one 20 or two groups selected from methyl, methoxy, nitro, bromo, chloro, fluoro, tnfluoromethoxy, tnfluoromethyl, phenyl and cyano and phenyl fused to a 5 or 6-membered heterocycle In a specific embodiment of the invention, compounds of Formula I and II include those 25 in which R1 is H and R2 is the following 4-methylphenyl, 4-trifluoromethoxyphenyl, 4-tnfluoromethylphenyl, 4-nitrophenyl, 30 3-cyanophenyl, 3-tnfluoromethyphenyl, 4-bromophenyl, Printed from Mimosa WO 98/07711 -10- PCT7US97/13264 3,5 difluorophenyl, 2-cyanophenyl, 2-chlorophenyl, 2-nitrophenyl, 5 3-methylphenyl, 2-phenylphenyl, 3-bromophenyl, 3,5-bis(trifluoromethyl)phenyl, 3-nitrophenyl, 10 4-cyanophenyl, 3-methoxyphenyl„ 2-naphthyl, 1,2-methylenedioxyphenyl, (preferably, R2 together with the methylene to which it is 15 4-chlorophenyl, and 3-chlorophenyl In another embodiment of the invention, compounds of Formula I and II are those in which Ri is H and Ryis the coumarin moiety shown below, and R3 and FU are selected 20 from H and C^alkoxy A specific embodiment of the invention includes compounds of Formula I and II where Rt is H and R2 is 1-(6,7-dimethoxycoumann) and 1 -(7-methoxycoumarin) In another embodiment of the invention, compounds of Formula I and II include those in which Ri is selected from halo, aryl and aryl substituted with one or two groups independently selected from H. halo, Ci^alkyl, C^alkoxy, nitro, tnfluoromethyl, tnfluoromethoxy and cyano and R2 is selected from C4 galkyl, naphthyl, phenyl, phenyl attached form piperonyl) 25 Printed from Mimosa WO 98/07711 PCT7US97/I3264 -II- subslituted with one or two groups selected from methyl, methoxy, nitro, bromo, chloro, fluoro, trifluoromethoxy, tnfluoromethyl, cyano and phenyl, phenyl fused to a 5 or 6-membered heterocycle and the coumarin moiety shown below, wherein Ra and R4 are selected from H and CMalkoxy In more preferred embodiments of the invention, compounds Formula I and II include those in which R' is selected from halo and aryl attached at carbon 7 of the 7-membered nng and R2 is phenyl substituted with one or two groups selected from 10 methyl, methoxy, nitro, bromo, chloro, fluoro, trifluoromethoxy, tnfluoromethyl, cyano and phenyl, or R2 is naphthyl or a phenyl fused to a 5 or 6-membered heterocycle In specific embodiments of the invention, compounds Formula I and II include those in which R1 is selected from bromo and thienyl attached at carbon 7 of the 7-membered 15 ring and R2 is selected from 1,2-methylenedioxyphenyl and phenyl substituted with chloro In specific embodiments of the invention, the compounds of Formula I and II include 20 2-(4-benzyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, 2-(4-piperonyl-1-piperazmyl)-2,4,6-cycloheptatriene-1-one, 2-(4-hexyl-1 -piperazinyl)-2,4,6-cycloheptatnene-1 -one,, 2-[4-(3-methoxybenzyl)-1-piperazinyl]-2,4,6-cyc!oheptatnene-1-one, 2-[4-(4-cyanobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 25 2-[4-(4-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-trifluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(3-cyanobenzyl)-1 -piperazinyl]-2,4,6-cyc1oheptatriene-1-one, 5 Printed from Mimosa WO 98/07711 -12- rCTYUS97/13264 2-[4-(3 trifluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-(4-naphthyl-2-methyl)-1-pipBrazinyl)-2,4,6-cycloheptatriene-1-one, 2-[4-(3,5-difluorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(2-chlorobenzyl)-1 -piperazinyl]-2,4,6-cycloheptatnene-1 -one, 2-[4-(3-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4 (2-phenylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(3 bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-{4-[3,5-bis(tnfluoromethyl)benzyl]-1-piperazinyl}-2,4,6-cycloheptatriene-1-one, 2-[4-(3 nitrobenzyl)-1 -piperazinyl]-2,4,6-cyclohBptatriene-1 -one, 2-[4-(3 chlorobenzyO-l-piperazinylj^AG-cycloheptatriene-l-one, 2-[4-(4 chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 7-bromo-2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, 2-(4-piperonyl-1-piperazinyl)-7-thien-2-yl-2,4,6-cycloheptatnene-1-one, 2-{4-[1-(6,7-dimethoxycoumann)methyl]-1-piperazinyl}-2,4,6-cycloheptatnene-1-one, and 2 {4-[1-(7-methoxycoumann)methyl]-1-piperazinyl)-2,4,6-cycloheptatriene-1-one Preferred for their enhanced D4 potency are the following Formula I and Formula II compounds 2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, 2-(4-hexyl-1 -piperazinyl)-2,4,6-cycloheptatnene-1 -one, 2-[4-(3-methoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-cyanobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-trifluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-{3-trifluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, Printed from Mimosa WO 98/07711 PCT/US97/13264 -H- 2-(4-naphthyl-2-methyl)-1-piperazinyl]-2,4,6-cycloheptatriBne-1-on8, 2-[4-(3-bromobenzyl)-1-piperazlnyl]-2,4,6-cycloheplatnene-1-one, 2-(4-(3-chlorobBnzyl)-1-plperazinyl]-2,4,6-cyctohep1atnene-1-one, 2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 5 7-bromo-2-(4-piperonyl-1-piperazinyt)-2,4,6-cycloheptatrlene-1-one, and 2-(4-piperonyl-1-piperazinyl)-7-thlen-2-yl-2,4,6 cycloheptatriene-1-one, Particularly preferred compounds of Formula I and Formula II include 10 2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheplatriene-1-one, 2-[4-(3-methoxybenzyl)-1-piperazinyl]-2,4,6 cycloheplatriene-1-one, 2-[4-(4-cyanobenzyl)-1-piperazlnyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-\rt{|uoromethoxybenzyl)-1-piperazinyl]-2,4l6-cycloheptatnene-1-orel 15 2-[4-(4-tnfluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-nitrobenzyl)-1 -piperazinyl]-2,4,6-cycloheptatnene-1 -one, 2-[4-(3-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-methylbenzyi)-1-piperazinyl]-2,4,6-cycloheplatnene-1-one, 20 7-bromo-2-(4-piperonyl-1 -piperazinyl)-2,4,6-cycloheptatriane-1 -one, and 2-(4-naphthyl-2-methyl)-1 -piperazinyl]-2,4,6 cycloheptatriene-1 -one Most preferred compounds of Formula I and Formula II include 25 2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, 2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 2-[4-(4-tnfluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,416-cycloheptatriene-1-one, 30 2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, and 2-(4-naphthyl-2-methyl)-1-piperazinyl]-2,4,6 cycloheptatriene-1-one Printed frora Mimosa WO 98/07711 l'CT/L'S97/13264 -14- Acid addition salts of the compound of Formula I and II are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e g hydrochlonc, sulphuric or phosphoric acids and organic acids e g 5 succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable sails e g oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt Also included within the scope of the invention are solvates and hydrates of the invention The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a solution of base e g sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an appropnate solvent, such as ether The free 15 base is then separated from the aqueous portion, dned, and treated with the requisite acid to give the desired salt The compounds of the present invention can be prepared by processes analogous to those known in the art The present invention therefore provides, in a further aspect, a 20 process for the preparation of a compound of Formula I and II wherein R, is H or halo or a salt, solvate or hydrate thereof, which compnses one of two possible processes The first compnses coupling a reagent of Formula A 10 O A 25 with a reagent of Formula B B Printed from Mimosa WO 98/07711 -15- PCT/DS97/13264 in refluxmg methanol as described In EP 034,894- and can be used when the corresponding reagent of Formula B is available by synthesis or commercial means Reagent (A), wherein Ri is H or halo can be synthesized using established techniques 5 where the appropnate tropolone is treated with a methylating reagent (see Pietra, F Chem Rev 1973, 73 293 when R1 is H and Takeshita, H , Mori, A Synthesis, 1986, 57B when R* is halo) For example, treating tropolone with dimethyl sulfate and potassium carbonate in acetone 10 Compounds of Reagent B are either known, available commercially or can be prepared by conventional means For example, a useful method for preparing a compound of Reagent B is descnbed in EP 034,894 A compound of Formula I and II may also be prepared by coupling a reagent of 15 Formula C in the presence of base such as potassium carbonate in an enert organic solvent such as acetonitrile as described herein Reagent C compounds, wherein Ri is H or halo 25 are synthesized using established techniques, for example by treating reagent A with piperazine according to the procedure described by Bagli (J Med Chem 1984, C with a reagent of Formula D 20 X' R2(orR5) X= CI, Br Printed from Mimosa WO 98/07711 -16- PCI/US97/13264 27 875) Reagent D can be obtained commercially or can be synthesized by established techniques, for example by treating the corresponding alcohol with halogenating reagents such as CBr4 and triphenylphosphine (X = Br) or Ihionyl chloride (X = CI) 5 Compounds of Formula I and II wherein Ri is aryl or aryl substituted with one or two groups independently selected from H, halo, C^alkyl, Ci^alkoxy, nitro, tnfluoromethyl, trifluoromethoxy and cyano can be prepared from compounds of Formula I and II wherein Ri is halo using standard palladium catalysed cross coupling techniques in 10 reactions with a metallo-aryl compound RrM, wherein Ri is as defined above and M is an optionally substituted metal substituent, attached at any carbon node of the aryl group, suitable for cross-coupling reactions Examples of such M groups include (alkyl)3Sn-, (alkyl)2B , (HO)2B-, (alkoxy)2B-, Li, Cu, chloroZn or haloMg The most preferred M group is chloroZn The reaction takes place in an inert solvent, and 15 optionally in the presence of base, lithium chlonde and a suitable catalyst Suitable catalysts included palladium (II) and palladium (0) species such as palladium (II) acetate, palladium (II) chlonde and tetrakis(triphenylphosphine) palladium (0) The preferred catalyst is tetrakis(triphenylphosphine) palladium (0) Suitable inert solvents include acetonitrila N,N-dimethylformamide and tetrahydrofuran, with tetrahydrofuran 20 being preferred The reaction takes place at a temperature of from 25-100°C, preferably 50-100°C Compounds of formula RrM can be prepared from reagents of RrV, wherein Y is halo or tnflate, by standard metallation reactions either independently or in situ For example, the compound RrM wherein M is chloro-Zn can be prepared, in an in situ fashion prior to the cross coupling reaction, by treating RrBr 25 with n-bulyl lithium and zinc chloride In tetrahydrofuran at -78°C The clozapine-like binding profile of the present compounds indicates their utility as pharmaceuticals that may be useful as a neuroleptic for the treatment of various conditions in which D4 receptor stimulation is implicated, such as for the treatment of 10 anxiety and schizophrenia Accordingly, in another of its aspects, the present invention provides pharmaceutical compositions useful to treat D4-related medical conditions, in which a compound of Formula II is present in an amount effective to antagonize D4 Printed from Mimosa WO 98/07711 PCT/US97/132f>4 -17- receptor stimulation, together with a pharmaceutical^ acceptable carrier Compounds of Formula II are those compounds embraced by Formula I, but further include the compounds in which R2 is phenyl or 3,4-dimethoxyphenyl In another of its aspects, the invention provides a method for treating medical conditions for which a D4 5 antagonist is indicated, which compnsing the step of administering to the patient an amount of a compound of Formula II effective to antagonize D4 receptor stimulation, and a pharmaceutically acceptable carrier therefor For use in medicine, the compounds of the present invention can be administered in a 10 standard pharmaceutical composition The present invention therefore provides, m a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula II compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to antagonize D4 receptor stimulation 15 The compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions formulated accordingly Compounds of Formula I and II and their stereoisomers, solvates, hydrate, or pharmaceutically acceptable salts which are active when given orally can be formulated 20 as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid earner for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, 25 preservative, flavouring or colouring agent A composition in the form of a tablet can be prepared using any suitable pharmaceutical earner routinely used for preparing solid formulations Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose A composition in the form of a capsule can be prepared using routine encapsulation procedures For example, pellets containing the active 30 ingredient can be prepared using standard carriers and then filled into hard gelatin capsule, alternatively, a dispersion or suspension can be prepared using any suitable Printed from Mimosa WO 98/07711 -18- PCT/US97/13264 pharmaceutical earner, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule Typical parenteral compositions consist of a solution or suspension of the compound or 5 pharmaceutical^ acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolldone, lecithin, arachis oil or sesame oil Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just pnor to administration 10 Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders Aerosol formulations typically compnse a solution or fine suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartndge or refill for use with 15 an atomising device Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metenng valve which Is intended for disposal after use Where the dosage form compnses an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as flurochlorohydrocarbon 20 The aerosol dosage forms can also take the form of a pump-atomizer Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycenne Compositions for rectal administration are 25 conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter Preferably, the composition is in unit dose form such as a tablet, capsule or ampoule Suitable unit doses i e therapeutically effective amounts, can be determined dunng 30 clinical trials designed appropnately for each of the conditions for which administration of a chosen compound is indicated and will of course vary depending on the desired clinical endpoint It is anticipated that dosage sizes appropnate for administering the Printed from Mimosa WO 98/07711 -19- PCT/US97/13264 compounds of the examples will be roughly equivalent to, or slightly less than, those used currently for clozapine Accordingly, each dosage unit for oral administration may contain from 1 to about 500 mgs, and will be administered in a frequency appropriate for initial and maintenance treatments 5 For laboratory use as a ligand, the present compounds can be stored in packaged form for reconstitution and use The present compounds can be used to distinguish dopamine receptors from other receptor types, for example glutamate and opioid receptors, within a population of receptors and in particular to distinguish between the 10 D4 and D2 receptors The latter can be achieved by incubating preparations of the D4 receptor and of the D2 receptor with a D4 selective compound of the invention and then incubating the resulting preparation with a radiolabelled dopamine receptor ligand, such as 3H-spiperone The D2 and D4 receptors are then distinguished by determining the difference in membrane-bound radioactivity, with the D4 receptor exhibiting lesser 15 radioactivity, i e , lesser 3H-spiperone binding In another embodiment of the invention, the compound is provided in labelled form, such as radiolabelled form e g labelled by incorporation within its structure of 3H or 14C or by conjugation to 125l or 1Z3I Such radiolabelled forms can be used directly to 20 distinguish between dopamine D4 and dopamine D2 receptors Furthermore, radiolabelled forms of the present compounds can be exploited to screen for more potent dopamine D4 ligands, by determining the ability of the test ligand to displace the radiolabelled compound of the present invention 25 Example 1 (a) 2-(4-Piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one A mixture of 2-methoxytropone (1 36 g, 10 0 mmol) (Pietra, F Chem Review, 1973, 73 293) and 1-piperonylpiperazme (6 61 g, 30 0 mmol) in methanol (50 0 mL) was refluxed for 16 h After cooling to room temperature, the solvent was removed in vacuo 30 The residue was subjected to column chromatography using ethyl acetate as the eluent The title compound was obtained as a yellow oil (1 24 g, 38%) MS (FAB) 325 (M*+1) Printed from Mimosa WO 98/07711 -20- PCT/US97/13264 In a like manner, the following additional compound was prepared (b) 7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cyc!oheptatnene-1-one, from 7- bromo-2-methoxytropone (Takeshita, H , Mori, A Synthesis, 1986, 578) 5 Example 2(a) 2-(1-piperazmyl)-2,4,6-cycloheptatriene-1-one acetic acid salt This compound was prepared from 2-methoxytropone and piperazine according to the procedure of Bagli, J et al, J Med Chem 1984, 27 875 10 In a like manner, the following addition compound was prepared (b) 7-bromo-2-(1-piperazinyl)-2,4,6-cycloheptatnene-1-one acetic acid salt Example3 (a) 2-[4-(3-Methoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-15 one A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatnene-1-one acetic acid salt (0 171 g, 0 680 mmol, example 2a), 3-methoxybenzyl chloride (0 118 g, 0 750 mmol) and potassium carbonate (0 276 g, 2 00 mmol) in acetonitrile (2 00 mL) was stirred at room 20 temperature for 16 h The solvent was removed in vacuo The residue was tnturated with dichloromethane and filtered The filtrate was concentrated in vacuo to dryness and the residue was subjected to preparative thin layer chromatography using ethyl acetate methanol (9 1) as the eluent The title compound was obtained as a yellow oil (0 095g. 45%), MS (FAB) 311 (MVl) 25 In a like manner, the following additional compounds were prepared b) 2-(4-hexyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one from 1-bromohexane, yellow oil (51%), MS (ES) 275 (M+ +1) 30 c) 2-[4-(4-cyanobenzyl)-1-piperazinyl]-2,4,6-cycloheptatri9ne-1-one, from 4-cyanobenzyl bromide, yellow solid (44%), m p 136-138°C, MS (FAB) 306 (M+ +1) d) 2-[4-benzyl-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, from benzyl bromide Printed from Mimosa WO 98/07711 PCT/US97/13264 21- e) 2-[4-(4-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-orie, from a-bromo-p-xylene, MS (FAB) 295 (M* +1) f) 2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1 -one. from 4-(tnfluoromethoxy)benzyl bromide, MS (FAB) 365 (M* +1) g) 2-[4-(4-tnfluorornethylbenzyl)-1 -ptperazinyl]-2,4,6-cycloheptatnene-1 -one, from a'-bromo-a.a.a-trifluoroxylene, mp 111-113°C, HRMS (FAB) MH+ for CigH^FaNaO, Calc'd 349 1529, Found 349 1528 h) 2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, from 4-nitrobenzyl bromide, mp 108-110°C, HRMS (FAB) MH*" for C1BH19N3O3, Calc'd 326 1506, Found 326 1512 i) 2-[4-(3-cyanobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, from a-bromo-m-tolunitrile j) 2-[4-(3-tnfluoromethylbenzyl)-1-piperazinyl]-2,4.6-cycloheptatnene-1 -one, from a'-bromo-cc,a,a-tnfluoro-m-xylene, MS (FAB) 349 (M+ +1) k) 2-[4-(4-bromobenzyl)-1-piperazinyl]2,4,6-cycloheptatriene-1-one, from 4-bromobenzyl bromide, m p 122-124°C, MS (FAB) 359 (M+ +1) I) 2-(2-methyl-4-naphthyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, from 2-(bromomethyl)-naphthalene, MS (FAB) 331 (M* +1) m) 2-[4-(3,5-difluorobenzyl)-1-piperazinyl]-2l4,6-cycloheptatnene-1-one, from a-bromo-3,5-difluorotoluene n) 2-[4-(2-cyanobenzyl)-1-piperazinyl]-2,4,6 cycloheptatriene-1-one, from a-bromo-otolunitnle o) 2-[4-(2-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from 2-chlorobenzyl bromide p) 2-[4-(2-nitrobenzyl)-1-piperazinyl]-2,4l6-cycloheptatriene-1-onel from 2-nitrobenzyl bromide q) 2-[4-(3-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from a-bromo-m-xylerte r) 2-{4-[1 -(6,7-dimethoxycoumann)methyl]-1 -piperazinyl)-2,4,6-cycloheptatnene-1 -one, from 4-(bromomethyl)-6,7-dimethyoxycoumann s) 2-{4-[1-(7-methoxycoumann)methyl]-1-piperazinyl)-2,4,6-cycloheptatriene-1-one, from 4-(bromomethyl)-7-methyoxycoumann Printed from Mimosa WO 98/07711 PCT/US97/13264 -22- t) 2-[4-(2-phenylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, from 2-(bromornethyl)biphBnyl u) 2-[4-(3-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from 3-bromobenzyl bromide 5 v) 2-{4-[3,5-bis(tnfluoromethyl)benzyl]-1-piperazinyl}-2,4,6-cycloheptatriene-1-one, from 3,5-bis(tnfluoromethyl)benzyl bromide w) 2-[4-(3-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, from 3-mtroberizyl bromide x) 2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from 4-10 chlorobenzyl bromide, HRMS (FAB) MH+ for C1BH,9CIN20, Calc'd 315 1264, Found 3151270 y) 2-[4-(3-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from 3-chlorobenzyl bromide, HRMS (FAB) MH* for CiBHigCI^O, Calc'd 315 1264, Found 3151258 15 z) 7-bromo-2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, from 7-bromo-2-(1-piperazinyl)-2,4,6-cycloheptatnene-1-one of example 2b and 4-chlorobenzyl bromide Example 4(a) 2-(4-Piperonyl-1-piperazinyl)-2,4,6-cycloheptatriene-1-one, maleic acid 20 salt 2-(4-Piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one (0 949 g, 2 92 mmol, example 1a) was dissolved in diethyl ether (15 0 ml.) and a solution of maleic acid (0 373 g, 3 22 mmol) in methanol (0 50 mL) was added The resulting mixture was 25 stirred at room temperature for 16 h Filtration of the mixture gave the maleic acid salt as a yellow solid (1 09 g, 85%), m p 142-144°C, MS (ES) 325 (M+-C4H404) In a like manner, the maleic acid salts of the following additional compounds were prepared 30 Printed from Mimosa WO 98/07711 PCT/US97/13Z64 -23- b) 2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinylJ-2,4,6-cycloheptatnene-1-one (example 3f), m p 170-172°C, HRMS (FAB) MH* for C19Hi9F3N202 (free base), Calc'd 365 1523, Found 365 1477 (c) 2-(2-methyl-4-naphthyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one (example 31), 5 mp 170-172°C Example 5 2-(4-Piperonyl-1-piperazinyl)7-thien2-yl-2,4,6-cycloheptatnene-1-one To a solution of 2-brornothiophene (1 0 g, 6 1 mmol) in tetrahydrofuran (50 mL) at -10 78°C, was added n-butyl lithium (1 6 M in cyclohexane, 4 0 mL) and the resulting solution was stirred for 5 minutes At this time, ZnCfe (0 5 M in THF, 20 mL) was added and the solution was warmed to room temperature over 2 hours To the reaction mixture was then added palladium tetrakis(tnphenylphosphine) (200 mg) and a solution of the acetic acid salt of 7-bromo-2-(4-piperonyl-1-piperazmyl)-2,4,6-cycloheptatnene-1-15 one (300 mg, 0 74 mmol, example 1b) in tetrahydrofuran (5 mL) and the resulting mixture was refluxed for 18 hours The reaction was quenched with a saturated aqueous ammonium chlonde solution and the product, extracted into methylene chloride (3x 200 mL) The crude product was punfied by silica gel chromatography to provide the title compound as a dark yellow oil (50 mg, 50%) 20 Example 6 Receptor Binding Assay D2 and D4 receptor-binding affinities of the compounds of examples 1 and 2 were evaluated according to their ability to reduce binding of 3H-spiperone as compared to 25 the reference compound clozapine The potency of the test compound to reduce 3H-spiperone binding directly correlated to its binding affinity for the receptor D4 Receptor Preparation HEK 298 (human embryonic kidney) cells stably transfected with human D4 receptor 30 (D4 2 sub-type) were grown in NUNC cell factories for 5 days (75% confluency) without a media change and removed with versene (approximately 19 mg of cells per cell factory tray) The cells were then centnfuged in a Sorval centrifuge for 10 mm, 5000 Printed from Mimosa WO 98/07711 -24- PCT/IJS97/1326'4 rpm (GS3 rotor) and the pellets quickly frozen in liquid nitrogen and stored at -80°C until used in binding assay When used in the assay, cells were thawed on ice for 20 mm and then 10 ml of incubation buffer (50 mM Tns, 1 mM EDTA, 4 mM MgCI2l 5 mM KCI, 1 5 mM CaCI2, 120 mM NaCI, pH 7 4) was added The cells were then vortexed 5 to resuspend pellet and homogenized with a Kinematica CH-6010 Knens-LU homogenizer for 15 seconds at setting 7 Concentration of receptor protein was determined using the Pierce BCA assay D2 Receptor Preparation 10 GH4C1 (rat pituitary) cells stably transfected with the human D2 receptor (short isoform) were grown in HAM'S F10 media in NUNC cell factones for 5 days 100 p.M ZnS04 was added to the cells (the D2 promoter being zinc inducible) After 16 hours, fresh media was added to allow the cells to recover for 24 hours The cells were harvested using versine and then centnfuged in a Sorval centnfuge for 10 minutes, at 5000 rpm 15 (GS3 rotor) Pellets were quickly frozen in liquid nitrogen and stored at -80°C until used in the binding assays When used in the assay, cells were thawed on ice for 20 minutes Each cell factory produced approximately 72 mg of protein 10 ml of incubation buffer was added to the pellets which were then vortexed, resuspended and homogenized with a Kinematica CH-6010 Knens-LU homogenizer lor 15 -econds at 20 setting 7 The receptor protein concentration was determined using the Pierce BCA assay Total Spiperone Binding Assay The incubation was started by the addition of 100 [il (50 |ig protein) membrane 25 homogenate to a solution of 300 p.l incubation buffer and 100 (il (0 25 nM final conc) 3H-spiperone (90 Ci/mmol Amersham diluted in borosilicate glass vial) in 96-well polypropylene plates (1 mL per well) The plates were vortexed and incubated at room temperature for 90 minutes The binding reaction was stopped by filtenng using a Packard Harvester The samples were filtered under vacuum over glass fibre filter 30 plates (Whatman GF/B) presoaked for 2 hours in 0 3% polyethylemmine (PEI) in 50 mM Tns buffer (pH 7 4) The filters were then washed 6 times with 7 ml ice cold 50 mM Tns buffer (pH 7 4) The filter plates were dned overnight and 35 nl of Microscint- Printed from Mimosa WO 98/07711 PCT/US97/13264 -25- O (Packard) was added The plates were sealed and counted in the Packard Top Count (3 minutes per well) Non-Specific Binding Assay for D4 5 The incubation was started by the addition of 100 pi (50 pig protein) membrane homogenate to a solution of 200 pi incubation buffer, 100 pi 3H-spiperone (90 Ci/mmol Amersham diluted in borosilicate glass vial to 0 25 nM final conc) and 100 pi (30 pM final conc) of fresh dopamine (Research Biochemicals Inc , light protected and dissolved in incubation buffer) in 96-well polypropylene plates (1 mL per well) The 10 plates were vortexed and incubated at room temperature for 90 minutes at which time the binding reaction was stopped by filtering The filters were washed and counted using the same procedure as in the total binding assay described above to give the non-specific binding value (NSB) 15 Non-Specific Binding Assay for D2 This assay employed the same procedures as the non-specific binding assay for D4 with the exception that 2 pM (final conc ) of (-) sulpiride (Research Chemicals Inc) was used in place of dopamine 20 Displacement Binding Assay The incubation was started by the addition, in 96-well polypropylene plates (1 mL per well), of "lOO/il (50 pg protein) membrane homogenate to a solution of 200 pi incubation buffer, 100 p.1 (0 25 final conc) 3H-spiperone (90 Ci/mmol, Amersham, diluted in borosilicate glass vial) and 100 pi of test compound that was prepared from 1 25 mM stock dissolved in DMSO and stored at -20°C in polypropylene cryogenic storage vials until dilution in incubation buffer in 96-well polypropylene plates The plates were vortexed and incubated at room temperature for 90 minutes at which time the binding reaction was stopped by filtenng The filters were washed and counted using the same procedure as in the total binding assay descnbed above to give the displacement 30 binding value (BD) Calculations Printed from Mimosa 07/22/1999 09 21 20 page -1- WO 98/07711 -26- PCT/US97/13264 The test compounds were initially assayed at 1 and 0 1|aM and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 3H-spiperone binding Specific binding in the absence of test compound (B0) was the difference of total binding (Bt) minus non-specific binding (NSB) and similarly specific 5 binding (in the presence of test compound) (B) was the difference of displacement binding (Bd) minus non-specific binding (NSB) IC5o was determined from an inhibition response curve, logit-log plot of %B/B0 vs concentration of test compound Ki was calculated by the Cheng and Prustoff transformation 10 Ki= IC50/ (1 + [L]/Kd) where [L] is the concentration of 3H-spiperone used in the assay and Kp Is the dissociation constant of 3H-spiperone determined independently under the same binding conditions 15 Assay results are reported in the following Table, and show clearly the advantage in terms of D4 selectivity and or binding affinity of compounds of the invention over clozapine Printed from Mimosa WO 98/07711 PCT/US97/13264 -27- D4 AFflNITY AND SELECTIVITY COMPOUND STRUCTURE Ki (nm) D2/D4 clozapine XTp "o N ch3 23 10 2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1 -one 7 15 154 2-(4-hexyl-1-piperazinyl)-2,4,6-cycloheptatriene-1 -one c£o-\_v^^ 33 3 23 2-[4-(4-cyanobenzyl)-1 -piperazinyl]-2,4,6-cycloheptatriene-1 -one cn 29 5 169 2-[4-(3-methoxybenzyl)-1 -piperazinyl]-2,4,6-cycloheptatnene-1 -one 192 137 Printed from Mimosa WO 98/07711 -28- PCT/US97/13264 COMPOUND STRUCTURE Ki D2/D4 2-[4-(4-bromobenzyl)-1 • piperazinyl]-2.4,6- cycloheptatnene-1-one ^"c"h Br 0.82 935 2-[4-(4-tnfluoromethoxybenzyl)-1 -piperazlnyl]-2,4,6-cycloheptatriene-1 -one ocf3 2 18 367 2-[4-(4-trilluorometh//lbenzyl)-1- piperazinyl]-2,4,6- cycloheptatnene-1-one cf3 4 22 598 2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1 -one p.' 0 K> 6 67 1014 2-[4-(3-tnfluoromethylbenzyl)-1 - piperazinyl]-2,4,6- cycloheptatnene-1-one 21 5 28 2-(4-naphthyl-2-benzyl-1 -piperazinyl)-2,4,6-cycloheptatnene-1 -one 2 24 321 Printed from Mimosa WO 98/07711 -29- FCT/US97/13264 COMPOUND STRUCTURE Ki D2/D4 2-[4-(3-chlorobenzyl)-1 -piperazinyl]-2,4.6-cycloheptatnene-1 -one 164 47 2-[4-(3-bromobenzyl)-1 -piperazinyl]-2,4,6-cycloheptatriene-1 -one 9 58 53 2-[4-(4-methylbenzyl)-1 -piperazinyl]-2,4,6-cycloheptatriene-1 -one C£<>K ch3 1 46 443 2-[4-(3-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1 -one ci 1 41 805 7-bromo-2-(4-piperonyl-1 -p\peraz\nyl)-2,4.6-cycloheptatriene-1 -one 0 226 104 2-(4-piperonyl-1 -piperazinyl)-7- thien-2-yl-2,4,6-cycloheptatriene- 1-one <1? 11 9 34 SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/07711 -10 l'CT/US!>7/13264 Example 7 Functional Assay The D4 receptor responds to dopamine and other agonists by reducing adenyl cyclase mediated production of cyclic AMP Particular test compounds were 5 assayed for their ability to reverse dopamine inhibition of adenyl cyclase by the following procedure Forskolin was used to elevate the basal adenyl cyclase activity CHO Pro 5 cells stably expressing human D4 2 receptors were plated in 6 well 10 plates in DMEM (Dulbecco's Modified Eagle Medium)/F12(Nutrient Mixture F12 (Ham)) media with 10% FCS (fetal calf serum) and G418 (Geneticen Disulfate), and incubated at 37°C in a C02 incubator The cells were allowed to grow to about 70% confluence before use in the assay 1 *5 Antagonist Assay The culture media of each well was removed, and the wells were washed once with serum free media (SFM) (DMEM/F12) media Then 2 mL of fresh SFM+IBMX media (SFM with 0 5 mM IBMX, 3-isobutyM-methylxanthine, 0 1% ascorbic acid and 10 jiM pargyiine) was added to each well and then incubated at 37°C for 10 20 minutes in a CO2 incubator Following incubation, SFM+IBMX media was removed and fresh SFM+IBMX media was added to wells separately with one of a) forskolin (10 nM final conc), b) dopamine and forskolin (both 10 jiM final conc), and c) test compound (10"4 to 106 M), and dopamine and forskolin (both 10 ^iM final conc ) Basal adenyl cyclase activity was determined from wells wrth only SFM+IBMX 25 media added The cells were then incubated at 37°C for 30 minutes in a C02 incubator Following incubation the media was removed from each well and then washed once with 1 mL of PBS (phosphate buffered saline) Each well was then treated with 1 mL cold 30 95% ethanol 5 mM EDTA (2 1) at 4°C for 1 hr The cells from each well were then scraped and transferred into individual Eppendorf tubes The tubes were centnfuged for 5 mm at 4°C, and the supematants were transferred to new Printed from Mimosa WO 08/07711 -31- I'CT/US97/I3264 Eppendorf tubes, The pellets were discarded and the supernatants stored at 4°C until assayed for cAMP concentration cAMP content measured in fmoles/well for each extract was determined by EIA (enzyme-immunoassay) using Amersham Blotrak cAMP EIA kit (Amersham RPN 225) Total inhibition (l0) of forskolin-stimulated adenyl cyclase activity by dopamine was determined as the difference in concentration of cAMP in the forskolin-treated cells (Ci) and dopamino-forskolin treated cells (Cd) lo = Ci - Cd Net inhibition (I) of forskolin-stimulated adenyl cyclase activity by dopamine in the presence of an antagonist was determined as the difference in concentration of cAMP in the forskolin-treated cells (Ci) and test compound, dopamine and forskolin treated cells (C) I =C,-C The ability of the test compounds to reverse the dopamine inhibition (% reversal, %R) was determined by the formula1 %R = (1 - l/l0) X 100 COMPOUND % REVERSAL OF DOPAMINE EFFECT 1(XM 10|iM clozapine 6 58 2-(4-piperonyl-1 -piperazinyl]-2,4,6 cycloheptatriene-1 -one 32 65 2-(4-hexyl-1 -piperazinyl)-2,4,6-cycloheptatriene-l-one 45 50 Agonist Assay SUBSTITUTE SHEET (RULE 26) Printed from Mimosa </div>

Claims

<div class="application article clearfix printTableText" id="claims">



WO 98/07711 

-32- 

PCT/US97/13264 

To D4.2 stably expressing CHO cells prepared as previously described were added test compound and forskolin (10 faM final concentration) The cells were incubated, extracted and measured for cAMP concentration as above Agonist activity of a test compound would result in a decrease in cAMP concentration compared to cells treated with forskolin (Of) only No decrease was observed, therefore the test compounds exhibited no dopamine agonist activity It is predicted based on structural and biological functional similanties that the remaining compounds of the invention would also exhibit dopamine antagonist activity 

Printed from Mimosa 

/ 

-33- 

WE CLAIM- 

1 A compound of Formula I: 

r 'V- f* 

S '« h 

%J ' . V. ' 

a stereoisomer, or pharmaceutically acceptable salt thereof, 

wherein 

R, is H, halo, aryl or aryl substituted with one or two groups independently selected from halo, C^alkyl, C^alkoxy, nitro, tnfluoromethyl, trifluoromethoxy or cyano wherein aryl is a five membered heteroaromatic ring which contains one heteroatom, 

R2 is C69 alkyl, phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, C^alkoxy, C, 4alkyl, tnfluoromethyl, trifluoromethoxy, nitro or phenyl, naphthyl, piperonyl, or the coumarinyl moiety 

wherein R3 and R4 are selected independently from H, C^alkyl and C^alkoxy, 

or 1,2-methylenedioxy phenyl, 

with the proviso that R2 is not phenyl or 3,4-dimethoxyphenyl when R1 is H
2 A compound according to claim 1, wherein R2 is phenyl substituted ! 1 ~' 7 ~ , ,, — 

r 1 1 ' 1 ,u, t i r i 

2 0 JUL uro 

AMENDED SHEET Ljj-CFIVCQ 

WO 98/07711 

-34- 

PrT/US97/13264 

with one or two groups selected from methyl, methoxy, nitro, bromo, chloro, fluoro, trifluoromethoxy, tnfluoromethyl or cyano, 

phenyl, naphthyl, or phenyl fused to a 5 or 6-membered heterocycle
3 A compound according to claim 2, whenn R2 is 

4-methylphenyl, 4-tnfluoromethoxyphenyl, 4-tnfluoromethylphenyl, 4-nitrophenyl, 3-cyanophenyl, 3 tnfluoromethyphenyl, 4-bromophenyl, 3,5-difluorophenyl, 2-cyanophenyl, 2-chlorophenyl, 2-nitrophenyl, 3-methylphenyl, 2-phenylphenyl, 3-bromophenyl, 3,5-bis(tnfluoromethyl)phenyl, 3-nitrophenyl, 4-cyanophenyl, 3-methoxyphenyl, 2-naphthyl, 3-chlorophenyl, 4-chlorophenyl or 1,2-methyleriedioxy phenyl
4 A compound according to claim 3, wherein Ri is H, halo or aryl
5 A compound according to claim 4, wherein R-i is H, bromo or thiophene
6 A compound according to claim 5, wherein R, is attached at the 7-position of the 7-membered ring
7 A compound according to claim 6, wherein Ri is thiophene or R2 is 1,2-methylenedioxy phenyl
8 A compound according to claim 1, wherein R2 is the coumarin moiety, and R4 and R5are independently selected fromH or C^alkoxy
9 A compound according to claim 8, wherein R2 is 1-(6,7-dimethoxycoumarin) or 1-(7-methoxycoumarin)
10 A compound according to claim 9, wherein Ri is H
11 A compound according to claim 1 .wherein the compound is 2-(4-piperonyl-1 -piperazinyl)-2,4,6-cycloheptatnene-1 -one, 

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2-(4-hexyl-1 -piperazinyl)-2,4,6-cycloheptatnene-1 -one,, 

2-[4-(3-methoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-cyanobenzyl)-1 -piperazinyl]-2,4,6-cyclohepta1nene-1-one, 

2-[4-(4-methylbenzyl)-1 -pipe razinyl]-2,4,6-cycloheptatnene-1 -one, 

2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-tnfluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatn6ne-1-one, 

2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-cyanobenzyl)-1 -piperazinyl]-2,4,6-cycloheptatriene-1 -one, 

2-[4-(3-tnfluoromethylbenzyl)-1-piperazinyll-2,4,6-cycloheptalriene-1-one, 

2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheplatnene-1-one, 

2-(4-naphthyl-2-methyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(3,5-difluorobenzyl)-1-piperazinyl] 2,4,6-cycloheptatriene-1-one, 

2-[4-(2-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(3-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(2-phenylbenzyl)-1-pipBrazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-bromobenzyl)-1-pipe razinyl]-2,4,6-cycloheptatnene-1-one, 

2-{4-[3,5-bis(trifluoromethyl)benzyl]-1-piperazinyi}-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-chlorobenzyl)-1-piperazinyi]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,€-cycloheptatriene-1-one, 

7-bromo-2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

7-bromo-2-(4-piperoriyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, 

2-(4-piperonyl-1-piperazinyl)-7-thien-2-yl-2,4,6-cycloheptatnene-1-one, 

2-(4-[1-(6,7-dimethoxycoumann)methyl]-1-piperazinyl}-2,4,6-cycloheptatriene-1- 

one, or 

2-{4-[1-(7-methoxycoumann)methyl]-1-piperazinyl}-2,4,6-cyc!oheptatnene-1-one 

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12 A compound according to claim 11 wherein the compound is 

2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatriene-1-one, 

2-(4-hexyl-1-piperazinyl)-2,4,6-cycloheptatriene-1-one„ 

2-[4-(3-methoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-cyanobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-trifluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-1rifluororneth/lbenzy!)-1-ptperazinyl]-2,4,6-cyclohBptatnene-1 -one, 

2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-trifluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-bromobenzyl)-1-piperazinylJ-2,4t6-cycloheptatriene-1-one, 

2-(4-naphthyl-2-methyl)-1-piperazinyl]-2,4,6-cycloheptatnone-1-one, 

2-[4-(3-bromobenzyi)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, or 

2-(4-piperonyl-1-piperazinyl)-7-thien-2-yl-2,4,6-cycloheptatriene-1-one
13 A compound according to claim 12, wherein the compound is 

2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, 

2-[4-(3-methoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-cyanobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-trifluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-tnfluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4I6-cycloheptatriene-1-one, 

2-[4-(3-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cyctoheptatriene-1-one, 

2-[4-(4-methylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

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7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-one, or 2-(4-naphthy!-2-methyl)-1-piperazinyl]-2,4,6 cycloheptatriene-1-one
14 A compound according to claim 13, wherein the compound is 

2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatnene-1-onel 

2-[4-(4-bromobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-trifluoromethylbenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

2-[4-(4-tnfluoromethoxybenzyl)-1-piperazinyl]-2I4,6-cycloheptatriene-1-one, 

2-[4-(4-nitrobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, 

2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatnene-1-one, 

7-bromo-2-(4-piperonyl-1-piperazinyl)-2,4,6-cycloheptatriene-1-one, or 

2-(4-naphthyl-2-methyl)-1-piperazinyl]-2,4l6-cycloheptatnene-1-one
15 A compound of claim 1 wherein Ri is H and R2 is phenyl substituted with one substituent of halo, cyano, alkoxy, tnfluoromethoxy, tnfluoromethyl, or Cm alkyl, or 1,2-methylenedioxy phenyl 

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16 A pharmaceutical composition comprising a pharmaceutically acceptable earner and a therapeutically effective amount of a compound for Formula II 

Rt is selected independently from H, halo, aryl and aryl substituted with one or two groups independently selected from halo, CMalkyl, Ci-aalkoxy, nitro, tnfluoromethyl, tnfluoromethoxy and cyano 

R5 is selected independently from C4 g alkyl, phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, C,-4alkoxy, CMalkyl, tnfluoromethyl, tnfluoromethoxy, nitro or phenyl, naphthyl, phenyl fused to a 5 or 6-membered heterocycle, and the coumann moiety shown below wherein R3 and R4 are selected independently from H, Ci 4alkyl and C^alkoxy
17 The pharmaceutical composition of claim 16 provided that R2 is not phenyl or 3,4-dimethoxypheny when Ri is H 

II 

wherein 

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1 8 Use of a compound according to claim 1, optionally in combination with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for antagonizing the effects of dopamine at the D4 receptor in a patient.
1 9 Use of a compound according to claim 1, optionally in combination with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for A treating schizophrenia
20 Use of a compound according to claim 1, optionally in combination with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for treating anxiety
21 A compound according to claim 1 for use as a pharmaceutically active compound
22 A method of making a compound of Formula I 

a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, 

wherein 

R, is H, halo, aryl or aryl substituted with one or two groups independently selected from halo, C, 4alkyl, C14alkoxy, nitro, tnfluoromethyl, trifluoromethoxy or cyano, 

R2 is C69 alkyl, phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, C14alkoxy, C, 4alkyl, tnfluoromethyl, tnfluoromethoxy, nitro or phenyl, naphthyl, phenyl fused to a 5 or 6-membered heterocycle, the coumarin rnoiety 

AMENDED 3HEET 

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fct/us97/13264 

wherein Ra and R4 are selected independently from H, Ci-^alkyl and Ci^alkoxy, 

or 1,2-methylenedioxy phenyl, 

with the proviso that R2 is not phenyl or 3,4-dimethoxyphenyl when Ri is H, 

comprising the step of coupling a reagent of Formula A 

with a reagent of Formula B 

H—N N—^ B 

n f r2 

in refluxing methanol, to provide the compound of Formula I
23 A compound of Formula I as defined in claim 1 substantially as herein described with reference to any example thereof
24 A pharmaceutical composition as defined in claim 16 substantially as herein described with reference to any example thereof
25 Use of a compound of Formula I as claimed in any one of claims 18 to 21 substantially as herein described with reference to any example thereof
26 A method as claimed in claim 22 of making a compound of Formula I 

substantially as herein described with reference to any example thereof ~~~ - jh on '> v 

| ore 7 

Hoe 

By tt o authorisoa ageritsJ A J 3ARK & SON 

END OF CLAIMS Per 



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