利培酮中间体合成Word文档格式.docx
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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<
TD<
TD>
438079
Nov.,1982
<
CurrentU.S.Class:
514/269;
544/278;
544/282;
544/48
CurrentInternationalClass:
C07D211/32
(20060101);
C07D211/00
C07D211/70
C07D213/00
C07D213/50
C07D211/74
C07D513/04
C07D513/00
C07D471/04
C07D471/00
C07D401/12
();
A61K031/505
()
FieldofSearch:
544/282424/251
ReferencesCited[ReferencedBy]
U.S.PatentDocuments
3960863
June1976
Satoetal.
4342870
August1982
Kennisetal.
4443451
April1984
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:
Aisabivalentradicalhavingtheformula--CH.sub.2--CH.sub.2--,or##STR24##whereinR.sup.4andR.sup.5areeachindependentlyselectedfromthegroupconsistingofhydrogen,halo,aminoandloweralkyl;
4.Apharmaceuticalcompositionaccordingtoclaim3whereinAlkisan1,2-ethanediylradical.
5.Amethodoftreatingpatientssufferingfrompsychosomaticdisorderswhichcomprisesthesystemicadministrationtosaidpatientsofapharmaceuticallyacceptableamountofatleastonecompoundhavingtheformula##STR25##thepossiblestereochemicallyisomericformsandthepharmaceuticallyacceptableacid-additionsaltsthereof,wherein:
Aisabivalentradicalhavingtheformula--CH.sub.2--CH.sub.2--,or##STR26##whereinR.sup.4andR.sup.5areeachindependentlyselectedfromthegroupconsistingofhydrogen,halo,aminoandloweralkyl;
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:
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;
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