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利培酮中间体合成
（1of1）
UnitedStatesPatent
4,485,107
Kennis, etal.
November27,1984
[[Bis（aryl）methylene]-1-piperidinyl]alkyl-pyrimidinones
二（芳基）亚甲基-1-哌啶基-嘧啶酮
Abstract
Novel[[bis（aryl）methylene]-1-piperidinyl]alkyl-pyrimidinones,whereinthepyrimidinone-ringisembracedwithinabicyclicsystem,beingusefulcompoundsinthetreatmentofpsychosomaticdisorders.
Inventors:
Kennis;LudoE.J.（Turnhout,BE）,Vandenberk;Jan（Beerse,BE）,Mertens;JosephusC.（Oud-Turnhout,BE）
Assignee:
JanssenPharmaceuticaN.V.（Beerse,BE）
Appl.No.:
06/517,612
Filed:
July27,1983
RelatedU.S.PatentDocuments
ApplicationNumber
FilingDate
PatentNumber
IssueDate
438079
Nov.,1982
CurrentU.S.Class:
514/269;544/278;544/282;544/48
CurrentInternationalClass:
C07D211/32 （20060101）;C07D211/00 （20060101）;C07D211/70 （20060101）;C07D213/00 （20060101）;C07D213/50 （20060101）;C07D211/74 （20060101）;C07D513/04 （20060101）;C07D513/00 （20060101）;C07D471/04 （20060101）;C07D471/00 （20060101）;C07D401/12 （）;A61K031/505 （）
FieldofSearch:
544/282424/251
ReferencesCited[ReferencedBy]
U.S.PatentDocuments
3960863
June1976
Satoetal.
4342870
August1982
Kennisetal.
4443451
April1984
Kennisetal.
PrimaryExaminer:
Rizzo;NicholasS.
AssistantExaminer:
Gibson;S.A.
Attorney,AgentorFirm:
Dellenbaugh;GeoffreyG.
ParentCaseText
CROSS-REFERENCETORELATEDAPPLICATIONS
Thisapplicationisacontinuation-in-partofourcopendingapplicationSer.No.438,079,filedNov.1,1982,nowabandoned.
Claims
Whatisclaimedis:
1.Achemicalcompoundhavingtheformula##STR21##thepossiblestereochemicallyisomericformsandthepharmaceuticallyacceptableacid-additionsaltsthereof,wherein:
Rishydrogen,hydroxyorloweralkyloxy;
R.sup.1isamemberselectedfromthegroupconsistingofhydrogenandloweralkyl;
Alkisaloweralkanediylradical;
Xisamemberselectedfromthegroupconsistingof--CH.sub.2--and--C（R.sup.2）.dbd.C（R.sup.3）--,saidR.sup.2andR.sup.3beingeachindependentlyhydrogenorloweralkyl;
Aisabivalentradicalhavingtheformula--CH.sub.2--CH.sub.2--,or##STR22##whereinR.sup.4andR.sup.5areeachindependentlyselectedfromthegroupconsistingofhydrogen,halo,aminoandloweralkyl;and
Ar.sup.1andAr.sup.2areeachindependentlyselectedfromthegroupconsistingofpyridinyl,thienylandphenyl,beingoptionallysubstitutedwithhalo,hydroxy,loweralkyloxy,loweralkylandtrifluoromethyl.
2.Achemicalcompoundaccordingtoclaim1whereinAlkisan1,2-ethanediylradical.
3.Apharmaceuticalcompositioninunitdosageformcomprisingperdosageunitapharmaceuticallyacceptablecarrierandanamounteffectivefortreatingpatientssufferingfrompsychosomaticdisordersofatleastonecompoundhavingtheformula##STR23##thepossiblestereochemicallyisomericformsandthepharmaceuticallyacceptableacid-additionsaltsthereof,wherein:
Rishydrogen,hydroxyorloweralkyloxy;
R.sup.1isamemberselectedfromthegroupconsistingofhydrogenandloweralkyl;
Alkisaloweralkanediylradical;
Xisamemberselectedfromthegroupconsistingof--CH.sub.2--and--C（R.sup.2）.dbd.C（R.sup.3）--,saidR.sup.2andR.sup.3beingeachindependentlyhydrogenorloweralkyl;
Aisabivalentradicalhavingtheformula--CH.sub.2--CH.sub.2--,or##STR24##whereinR.sup.4andR.sup.5areeachindependentlyselectedfromthegroupconsistingofhydrogen,halo,aminoandloweralkyl;and
Ar.sup.1andAr.sup.2areeachindependentlyselectedfromthegroupconsistingofpyridinyl,thienylandphenyl,beingoptionallysubstitutedwithhalo,hydroxy,loweralkyloxy,loweralkylandtrifluoromethyl.
4.Apharmaceuticalcompositionaccordingtoclaim3whereinAlkisan1,2-ethanediylradical.
5.Amethodoftreatingpatientssufferingfrompsychosomaticdisorderswhichcomprisesthesystemicadministrationtosaidpatientsofapharmaceuticallyacceptableamountofatleastonecompoundhavingtheformula##STR25##thepossiblestereochemicallyisomericformsandthepharmaceuticallyacceptableacid-additionsaltsthereof,wherein:
Rishydrogen,hydroxyorloweralkyloxy;
R.sup.1isamemberselectedfromthegroupconsistingofhydrogenandloweralkyl;
Alkisaloweralkanediylradical;
Xisamemberselectedfromthegroupconsistingof--CH.sub.2--and--C（R.sup.2）.dbd.C（R.sup.3）--,saidR.sup.2andR.sup.3beingeachindependentlyhydrogenorloweralkyl;
Aisabivalentradicalhavingtheformula--CH.sub.2--CH.sub.2--,or##STR26##whereinR.sup.4andR.sup.5areeachindependentlyselectedfromthegroupconsistingofhydrogen,halo,aminoandloweralkyl;and
Ar.sup.1andAr.sup.2areeachindependentlyselectedfromthegroupconsistingofpyridinyl,thienylandphenyl,beingoptionallysubstitutedwithhalo,hydroxy,loweralkyloxy,loweralkylandtrifluoromethyl.
6.Amethodaccordingtoclaim5whereinAlkisan1,2-ethanediylradical.
Description
BACKGROUNDOFTHEINVENTION
3-（1-Piperidinylalkyl）-4H-pyrido[1,2-a]pyrimidin-4-oneshavingthepiperidine-ringsubstitutedwithanarylcarbonylradicalorafunctionalderivativethereofaredescribedinU.S.Pat.No.4,342,870.
（1-Piperidinyl）alkyl-5H-thiazolo[3,2-a]pyrimidin-5-ones,-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-onesand-5H-thiazolo[3,2-a]-pyrimidin-5-oneshavingthepiperidine-ringsubstitutedwithanarylcarbonylradicalorafunctionalderivativethereofaredescribedinU.S.patentapplicationSer.No.370,653filedApr.21,1982,now4,443,451.
[[Bis（aryl）methylene]-1-piperidinyl]alkanonederivativesaredescribedinU.S.Pat.No.3,862,173.
Thecompoundsofthepresentinventiondifferfromthehereinabove-citedcompoundsbythesubstitutionofthepiperidine-ringorbythesubstitutionofthe[[bis（aryl）methylene]-1-piperidinyl]alkanemoietywithabicyclicpyrimidinoneradicalandbytheirusefulserotonine-antagonisticpropertiesmakingthosecompoundsattractiveinthetreatmentofdiseaseswhereinserotoninehasanon-neglectibleinfluencesuchas,forexample,inthetreatmentofpsychosomaticdisorders.
DESCRIPTIONOFTHEPREFERREDEMBODIMENTS
Thepresentinventionisconcernedwithanovelseriesof（1-piperidinylalkyl）pyrimidinonederivativeswhicharestructurallyrepresentedbytheformula##STR1##thepossiblestereochemicallyisomericformsandthepharmaceuticallyacceptableacid-additionsaltsthereof,wherein:
Rishydrogen,hydroxyorloweralkyloxy;
R.sup.1isamemberselectedfromthegroupconsistingofhydrogenandloweralkyl;
Alkisaloweralkanediylradical;
Xisamemberselectedfromthegroupconsistingof--S--,--CH.sub.2--and--C（R.sup.2）.dbd.C（R.sup.3）--,saidR.sup.2andR.sup.3beingeachindependentlyhydrogenorloweralkyl;
Aisabivalentradicalhavingtheformula--CH.sub.2--CH.sub.2--,--CH.sub.2--CH.sub.2--CH.sub.2--or##STR2##whereinR.sup.4andR.sup.5areeachindependentlyselectedfromthegroupconsistingofhydrogen,halo,aminoandloweralkyl;and
Ar.sup.1andAr.sup.2areeachindependentlyselectedfromthegroupconsistingofpyridinyl,thienylandphenyl,beingoptionallysubstitutedwithhalo,hydroxy,loweralkyloxy,loweralkylandtrifluoromethyl.
Intheforegoingdefinitionsthetermhaloisgenerictofluoro,chloro,bromoandiodo;"loweralkyl"ismeanttoincludestraightandbranchedsaturatedhydrocarbonradicals,havingfrom1to6carbonatoms,suchas,forexample,methyl,ethyl,1-methylethyl,1,1-dimethylethyl,propyl,butyl,pentyl,hexylandthelike;and"loweralkanediyl"ismeanttoincludebivalentstraightorbranchchainedalkanediylradicalshavingfrom1to6carbonatoms.
PreferredcompoundswithinthescopeofthepresentinventionarethosewhereinAlkisan1,2-ethanediylradical.
Themostpreferredcompoundswithinthescopeofthepresentinventionis6-[2-[4-[bis（4-fluorophenyl）methylene]-1-piperidinyl]-ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneorapharmaceuticallyacceptableacidadditionsaltthereof.
Thecompoundsofformula（I）cangenerallybepreparedbyreactinganappropriatereactiveesterofformula（II）withanappropriatelysubstitutedpiperidineofformula（III）.Inthereactiveester（II）A,X,R.sup.1andAlkareaspreviouslydescribedandWrepresentsareactiveleavinggroupsuchas,forexample,halo,particularly,chloro,bromoandiodo,orasulfonyloxygroup,e.g.,methylsulfonyloxy,4-methylphenylsulfonyloxyandthelike.
Inthepiperidine（III）R,Ar.sup.1andAr.sup.2areaspreviouslydescribed.##STR3##
TheforegoingreactionmaybecarriedoutfollowingstandardN-alkylatingprocedures.Saidreactionispreferablycarriedoutinanappropriatereaction-inertsolventsuchas,forexample,aloweralkanol,e.g.,methanol,ethanol,propanol,butanolandthelikealkanols;anaromatichydrocarbon,e.g.,benzene,methylbenzene,dimethylbenzene,andthelike;anether,e.g.,1,4-dioxane,1,1'-oxybispropaneandthelike;aketone,e.g.,4-methyl-2-pentanone;N,N-dimethylformamide;nitrobenzene;andthelike.Theadditionofanappropriatebasesuchas,forexample,analkaliorearthalkalinemetalcarbonateorhydrogencarbonate,maybeutilizedtopickuptheacidwhichisliberatedduringthecourseofthereaction.Asmallamountofanappropriatemetaliodide,e.g.,sodiumorpotassiumiodidemaybeaddedasareactionpromotor.Somewhatelevatedtemperaturesareappropriatetoenhancetherateofthereactionandpreferablythereactioniscarriedoutatthe
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