利培酮中间体合成Word文档格式.docx

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利培酮中间体合成Word文档格式.docx

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

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