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Butyrophenone analogues: Synthesis of 2-methyl-3-ethyl-5-aminoethyl-4,5,6,7-tetrahydroindol-4-ones, and their affinities for d1, d2 and 5-ht2a receptors
Biwrgmic
& Medicinal
Chemhy
Letters, Vol. 5. No. 6. pp. 579-584, 1995 copyright 0 1995 Elsevia Sciula L&d Printed in Great Britain. All right8 reserved c960-894x/95 s9.5oto.00
O!XO-894X(95)00076-3
BUTYROPHENONE ANALOGUES: SYNTHESIS OF 2-METHYL-3-ETHYL-5 AMINOETHYL-4,5,6,7-TETRAHYDROINDOL-4-ONES, AND THEIR AFFINITIES FOR D1, D2 AND ~-HT~A RECEPTORS E. Ravifia*l, C. F. Masaguert, J. Cidt, I. Casariegot, J. A. Fontenla2, T. G” Fetreird, M. I. Cadavidz, M. I. Lad and M. L. de Ceballd ‘Dpt. of Organic Chemistry, L&oratory of iUea?cinal Chemistryand2Dpt.of Phamacology,Faculty of Pharmacy,uniwrsity of Santiagodecompostela,Imxmmtiago de ComJmelu. 3Dpt.of Neurophannacology, CajalInstitute,CSIC,28002~Madrid,Spain.
Starting from 2-methyl-3-ethyl-lH-4,5,6,7-tetrahydroindol4one3 we have prepared2-methyl-3ethyl-5-morpholinoethyl-1H-4,5,6,7-tetmhydroindol4one. (1) and2-methyl-3-ethyl-5-(4-o-methoxyphenyl-lpiperazinoethyl)-lH-4,5.6,7-tetrahydroindol-4-one (2) as butyrophenoneanaloguesof the neuroleptic molindone.The affinities of thesecompounds for Dt andD2 dopamineand5HT2A serotoninreceptorswere evaluatedin vitro. The affinity of 1 for 9 receptorsis lessthan that of molindone(pKi’s 6.23 and 7.48 respectively)andthat of 2 similar(pKt 7.55).Rothcompounds bindto 5HTw receptors,the affinity of 2 being significantlygreaterthanthat of molindone(p&Is of 7.04and5.85,andPAZ’Sof 7.50and6.18. respectively). Abstract.
Severalaminoketones possess potentantipsychotic(netuoleptic)activity: molindonet,first marketedin the USA in 1974,hasbeenusedin the treatmentof schizophrenia and psychosis,but its associatedincidenceof extrapyramidalsideeffects(EPS)is significant;the pyrtolo[2,3-glisoquinoline piquindone(Ro 22-1319)2 is an antipsychoticwith a low propensityto induceEPS;andhaloperidolis theprototypeof a groupof butyrophenone derivativeswith very potentantipsychoticactivity, amongthemthe mostpotentneuroleptics,spiperoneand fluanisone,which are 4-amino-pfluorobutyrophenone derivatives. The clinical efficacy of classical antipsychotics in the treatmentof schizophrenia andotherpsychoticdisorders is directly relatedto theirability to blockdopamine 9 receptorsin the brat@; however,it hasbeenreportedthatdopaminereceptorblockadein the striatumis closelyassociated with their extrapyramidalsideeffectsm. Furthermore,theclassicalantipsychotics areineffectiveagainstnegativesymptomsof schizophrenia suchasapathy,motorretardation.flat affectivity and povertyof speech.
Molindoac
Piquindone
579
_. Closaplne
580
E. bV6iA
H~lopcridol
et
al.
Spiperone
The discovery of clozapine in the 1960’sgave rise to a new group of “atypical” or “non-classical” antipsychotics whichhavereducedptqensity to produceEP!l andareeffective againstnegativesymptoms.The atypicalantipsychoticprofileof clozapinehasbeenattributedto its ability to block not only dopaminereceptors butalso5-l-R ttmptom Meltzere?aI9Jc havesuggested that theefficacy of atypicalantipsychotlcdrugsagainst negativesymptoms andtheir lackof EPSaredetermined by their relativeaffinitiesfor I& and5I-IT= receptors: clozapineand clozapine-like antipsychoticshave pKi (5HTw&) ratios > 1.12, whereasfor typical antipsychoticsthis ratio is < 1.09. A numberof mixed 5-I-lT2A/D2antagonistswhich may be consideredas belongingto the butyrophenone grouparenow available,e.g. cinuperone,setoperone and risperidone;clinical studieswith risperidonehave supportedthe theory that blockadeof IIITs receptorsmay amelioratethe EPS associated with b dopamine receptorblockadet1. In previouspape~9~-~~ we haverqorted theneurolepticactivity of 3-aminomethyla-tetralones(I) and2amincethylbenzocycl&kammes (II), both of whichareconformationallyrestrictedbutyrophenone analogues of halopetidol.Here we describethe preparationof 1 (a butyrophcnonehomologueof molindone)and the piperarinederivative2, andthe resultsof studiesof the affinities of both compoundsfor Dl, D2 and 5-I-lT2,4 rt?C+O#.
cc I
Ns4F 0
,N
Ciaaperoae
NRR
0 Ikemcyclic
-
NW
ti \
#-subslimtedpiperaziuea
I
NRIr G+ CM4 II
pFluorobenzoylpipeiidine
The synthesesof the compoundsstudiedare outlined in SchemesI and II16. In SchemeI, Knorr condensationof 2-hydroxyimino-3-pentanonewith 1,3-cyclohexadionein 70% acetic acid afforded the dihydroindolone2-methyl-3-ethyl-1H-4,5,6,7-tetrahydroindol-4-one (3)” (60% yield); protection of the nitrogenof 3 with benzenesulfonyl chloridein the presence of sodiumhydride(NaH) gavethe ketone4 (60%); andalkylationof 4 with ethyl bromoacetatc in thepresence of lithiumdiisopropylamide (LDA) gavetheketocstcr
Butyrophenone analogues
581
5 (45%)‘*. Alternatively, brominationof 4 with cupricbromideaffordedtheSbromoderivative6 (80%), which
reactedwith diethyl malonatein the presence of NaH in DMF to give the ketodiester7 (70%); hydrolyzed with ethanolicsodiumhydroxideto givediacid8 (85%);thendecarboxylated in thepresence of Cu20 to give the unprotected monoacid9 (95%). was
Theprotectedmorpholinoamides11 (SchemeI) and 16 (SchemeII) werepreparedin 6585% yield by reactionof protectedketoester5 with the appropriatedimethylaluminium amide(prepured in sihr). Alternatively, DCC-mediated couplingof the amine(1 equivalent)andthe unprotectedketoacid(9)19in the presenceof lhydroxybenzotriazole(HOBt) in methylenechlorideaffordedamides10 (SchemeI) and15 (SchemeII) in 55 80%yieldm. The nitrogenatomof the pyrrole ring wasprotectedby reactionwith benzenesulfonyl chlorideas previouslydesaibedt*.Reductionof thecarbonylgroupwith aluminiumhydride(AlH3) in THF yieldedamino alcohols12 (SchemeI) and 17 (SchemeII) in quantitativeyields.Theseaminoalcoholswereoxidized with pyridiniumdichromate(PDC) to give aminoketones 13 (Scheme1) and18 (SchemeII) in 5060% yields.The targetcompounds,1 and2, wereobtainedby removingthe benzenesulfonylprotectinggroupswith ethanolic sodiumhydroxide. SCHEME I
I Ii
1 (QF-04OOB)
E.
k%aA
SCBIZME
H
et al.
II
2 (QIW496B)
Table I lists the results of experiments to evaluate the affinities of compounds 1 and 2 for dopamine and serotonin receptors. Both compounds inhibited the binding of 3H-spiperone to & receptors (pI
583
Butyrophenone analogues
is replaced by an o-methoxyphenylpiperazine, the affinity for 5-HT2,4 of the resulting compound (2) iS significantly higher than that of molindone, while its affinity for D2 receptors is similar. These preliminary results, together with our previously reported conclusio&-t4 justify further study of indolones containing piperazine fragments or otber pharmacophores that are active at dopamine and serotonin receptors. Table I Compound
pKi ratios
pKl’sa ~-HT~A
5-HT&D2
DI
D2
Haloperidd
7.01
8.30
7.70
0.85
0.93
Mdindone
5.80
7.48
5.85
0.77
0.78
6.18k0.16
1 (QF-0400B)
5.67
6.23
6.04
0.91
0.97
6.98i0.23
(QF-0402B)
5.93
7.55
7.04
0.79
0.97
7.50zt0.2
2
a hhibitiat
conataats (pm
mrmbrsncs
(H-fl&)
for in vitro inhibition
and 3H-SCH
for these assays have becat pubhkd
by the compounds
23390 or3H-4Qerone dsewkre.
12-14ph
h/D2
PAz(~-HTzA)~
uuder study of 3H-ketansefine
binding to rat frontal
binding to striatal membranea (D1 or D2, respectively); valuea were cala~Iatcd using the Cheng-&off
cortex
detailed methods
equation2t;
and results
sbownartmansolthpeeinhibitionaw~coostnrtedNitheachdrug.Thcmcanstandardarorof~valucswas1o-1~~ bAarta hg
expaimatts:
1) for uwec aagollist
competitive -tratim;
autagonism
was quantikd
six re&ateexpe-riment9
as pA2. which was calculated from a Schild plot of log (dose ratic were performed.
Acknowledgementa This work was supported by the Spanish Interministerial Commission for Science and Technology (CICYT) under grant SAF 92-0957-CO2-01. We also thank the Xunta de Galicia for grants to C. F. Masaguer. References
and Notes
1. See for example (a) Lednicer. D.; Mitscher. L. A. The Organic Chemistry of Drug Synthesis; Wiley Interscience: New York, 1980; Vol 2, p. 455. (b) Horu, A. S. “Dopamine Receptors” in Comprehensive Medicinal Chemistry; Hansch. C.; Sammes, P. G.; Taylor, J. B., Ed.; Pergamon Press: Oxford, 1990; Vol 3. p. 133.
2. Olson, G. L.; Ho-Chuen, C.; Morgan, D. K.; Blount, J. F.; Todaro, L.; Berger, L.; Davidson, A. B.; Boff. E. J. Med. Chem. 1981. 24, 1026. 3. Seeman, P.; Chou-Wang, M.; Tadesco. J.; Wang. K. Synapse 197&l. 399. 4. Seeman. P.; Lee, T.; Chou-Wong, M.; Wang. K. Nature 1976,26X,717. 5. Perot&a, S. J.; Snyder, S. H. Am. J. Psychiatry 1980.173, 1518. 6. Sanberg. P. R Nature 1980, 284, 472. 7. Seeman, P.; Bzowej. N. H.; Guan, H. C.; Bergeron, C.; Becker, L. E.; Reynols, G. P.; Bird, E.D.; Riedeger, P.; Jelliger, K.; Watanabe, S.; Tourtellote, W. W. Synapse 1987.1.399.
584
E. RAmA
et
al.
8. Novak, K.; Welsch-Kunzie, S.; Kuschinsky. K. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1988.337, 440. 9. Meltzcr, H. Y .; Matsubara,S.; Lee,J. C. J. Phannacol.Exp. Z%er.1989,251,238. 10.Me&r. H. Y.: Mats&am, S.; Lee.J. C. Psychophurmacol. Bull. 1989.253.390.
1l.(a). Drugs Fut. 1988. 13, 10525.(b). Leysen.J. E.; Janssen.P. M. F.; Gcmmeren,W.; Wynants. J.; Pauwels,P. L.; Janssen. P. A. J. Molecuhr Pharmacology1992.41, 494. (c) A. A. H. P. Megens;F. H. L. Awouter~; A. Schotte;T. F. Meert;C. Dugovic; C. J. E. Niemegeem; J. E. LeysenPsychopharmkology, 1994,114, 9-23. 12.Cortizo, L.; Santana,L.; Raviila,E.; Orallo, F.; Fontenla,J. A.; Castro,E.; Calleja,J. M.; de Ceballos,M. L. J. Med. Chem.1991, 24. 2242. 13.Loza, M. I.; Verde, I.; Castro,E.; Orallo, F.; Fontenla.J. A.; Calleja,J. M.; Raviila, E.; Cortizo, L.; de Ceballos,M. L. Bio. Med. Gem. L&t. 1991,1, 1771. 14. Fontenla,J. A.; Osuna,J.; Rosa,E; Castro,E.; G-Ferreiro,T.; Loza. M. I.; Calleja, J. M.; Sanz, F.; Rodriguez,J.; Ravifla, E.; Fueyo,J.; Masaguer.C. F.; Vidal. A.; de Ceballos,M. L. J. Med. Che-m. 1994, 37,2564. 15.Recently,anarylpiperazinebindingsitewithin the & receptorhasbeenpostulated(Jaen.J. C.; Caprathe,B. W.; Wise, L. D.; Meltzer. L. T.; Pugsley,T. A.; Heffner, T. G. Bio. Med. Chem.L&t. 1993.3, 639. Likewise,it is known that the arylpiperazinestructureis a templatefor 5-I-H activity (Glennon, R. A.; Naiman,N. A.; Lyon, R. A.; Titeler, M. J. Med. Gem. 1988,31, 1968.Glennon,R. A. Drug. Dev. Res. 1992,26,251). Seealso&rone. R.; Berardi.F.; Colafubo,N. A.; Tortorella, V.; Fiorentino,F.; Olgiati, V.; Vanotti, E.; Govoni. S. J. Med. Chem.1994,37.99. 16. Completedetailsof the synthesesand spectraldatawill be publishedelsewhere.All compoundsgave satisfactory micro-analytical (C,H,N) and spectra1data (250 MHz lH NMR and IR). Yields given correspondto isolatedpurecompounds. 17. Hauptma. S.; Blume,A.; Hartmann,G.; Haendel,D.; Franke,P. 2. Chem.1966,3, 107. 18. Masaguer.C. F.; Raviffa, E.; Fueyo,J. Heterocycles1992,34, 1303. 19.Compound9 wasalsoobtainedby hydrolysisof 5 in ethanolicsodiumhydroxide.followedby acidification with cont. HCl(75% yield). 20. Replacingdicyclohexylcarbodiimide(DCC) by l-[(3-dimethylamino)propyl-3-ethyllcarbodiimide led to pooreryieldsof theamides. 21. Cheng,Y. C.; Prusoff, W. Biochem.Pharmocol.1973,22,309!3.
(Receivedin Belgium18 October 1994;accepted25 January 1995)
& Medicinal
Chemhy
Letters, Vol. 5. No. 6. pp. 579-584, 1995 copyright 0 1995 Elsevia Sciula L&d Printed in Great Britain. All right8 reserved c960-894x/95 s9.5oto.00
O!XO-894X(95)00076-3
BUTYROPHENONE ANALOGUES: SYNTHESIS OF 2-METHYL-3-ETHYL-5 AMINOETHYL-4,5,6,7-TETRAHYDROINDOL-4-ONES, AND THEIR AFFINITIES FOR D1, D2 AND ~-HT~A RECEPTORS E. Ravifia*l, C. F. Masaguert, J. Cidt, I. Casariegot, J. A. Fontenla2, T. G” Fetreird, M. I. Cadavidz, M. I. Lad and M. L. de Ceballd ‘Dpt. of Organic Chemistry, L&oratory of iUea?cinal Chemistryand2Dpt.of Phamacology,Faculty of Pharmacy,uniwrsity of Santiagodecompostela,Imxmmtiago de ComJmelu. 3Dpt.of Neurophannacology, CajalInstitute,CSIC,28002~Madrid,Spain.
Starting from 2-methyl-3-ethyl-lH-4,5,6,7-tetrahydroindol4one3 we have prepared2-methyl-3ethyl-5-morpholinoethyl-1H-4,5,6,7-tetmhydroindol4one. (1) and2-methyl-3-ethyl-5-(4-o-methoxyphenyl-lpiperazinoethyl)-lH-4,5.6,7-tetrahydroindol-4-one (2) as butyrophenoneanaloguesof the neuroleptic molindone.The affinities of thesecompounds for Dt andD2 dopamineand5HT2A serotoninreceptorswere evaluatedin vitro. The affinity of 1 for 9 receptorsis lessthan that of molindone(pKi’s 6.23 and 7.48 respectively)andthat of 2 similar(pKt 7.55).Rothcompounds bindto 5HTw receptors,the affinity of 2 being significantlygreaterthanthat of molindone(p&Is of 7.04and5.85,andPAZ’Sof 7.50and6.18. respectively). Abstract.
Severalaminoketones possess potentantipsychotic(netuoleptic)activity: molindonet,first marketedin the USA in 1974,hasbeenusedin the treatmentof schizophrenia and psychosis,but its associatedincidenceof extrapyramidalsideeffects(EPS)is significant;the pyrtolo[2,3-glisoquinoline piquindone(Ro 22-1319)2 is an antipsychoticwith a low propensityto induceEPS;andhaloperidolis theprototypeof a groupof butyrophenone derivativeswith very potentantipsychoticactivity, amongthemthe mostpotentneuroleptics,spiperoneand fluanisone,which are 4-amino-pfluorobutyrophenone derivatives. The clinical efficacy of classical antipsychotics in the treatmentof schizophrenia andotherpsychoticdisorders is directly relatedto theirability to blockdopamine 9 receptorsin the brat@; however,it hasbeenreportedthatdopaminereceptorblockadein the striatumis closelyassociated with their extrapyramidalsideeffectsm. Furthermore,theclassicalantipsychotics areineffectiveagainstnegativesymptomsof schizophrenia suchasapathy,motorretardation.flat affectivity and povertyof speech.
Molindoac
Piquindone
579
_. Closaplne
580
E. bV6iA
H~lopcridol
et
al.
Spiperone
The discovery of clozapine in the 1960’sgave rise to a new group of “atypical” or “non-classical” antipsychotics whichhavereducedptqensity to produceEP!l andareeffective againstnegativesymptoms.The atypicalantipsychoticprofileof clozapinehasbeenattributedto its ability to block not only dopaminereceptors butalso5-l-R ttmptom Meltzere?aI9Jc havesuggested that theefficacy of atypicalantipsychotlcdrugsagainst negativesymptoms andtheir lackof EPSaredetermined by their relativeaffinitiesfor I& and5I-IT= receptors: clozapineand clozapine-like antipsychoticshave pKi (5HTw&) ratios > 1.12, whereasfor typical antipsychoticsthis ratio is < 1.09. A numberof mixed 5-I-lT2A/D2antagonistswhich may be consideredas belongingto the butyrophenone grouparenow available,e.g. cinuperone,setoperone and risperidone;clinical studieswith risperidonehave supportedthe theory that blockadeof IIITs receptorsmay amelioratethe EPS associated with b dopamine receptorblockadet1. In previouspape~9~-~~ we haverqorted theneurolepticactivity of 3-aminomethyla-tetralones(I) and2amincethylbenzocycl&kammes (II), both of whichareconformationallyrestrictedbutyrophenone analogues of halopetidol.Here we describethe preparationof 1 (a butyrophcnonehomologueof molindone)and the piperarinederivative2, andthe resultsof studiesof the affinities of both compoundsfor Dl, D2 and 5-I-lT2,4 rt?C+O#.
cc I
Ns4F 0
,N
Ciaaperoae
NRR
0 Ikemcyclic
-
NW
ti \
#-subslimtedpiperaziuea
I
NRIr G+ CM4 II
pFluorobenzoylpipeiidine
The synthesesof the compoundsstudiedare outlined in SchemesI and II16. In SchemeI, Knorr condensationof 2-hydroxyimino-3-pentanonewith 1,3-cyclohexadionein 70% acetic acid afforded the dihydroindolone2-methyl-3-ethyl-1H-4,5,6,7-tetrahydroindol-4-one (3)” (60% yield); protection of the nitrogenof 3 with benzenesulfonyl chloridein the presence of sodiumhydride(NaH) gavethe ketone4 (60%); andalkylationof 4 with ethyl bromoacetatc in thepresence of lithiumdiisopropylamide (LDA) gavetheketocstcr
Butyrophenone analogues
581
5 (45%)‘*. Alternatively, brominationof 4 with cupricbromideaffordedtheSbromoderivative6 (80%), which
reactedwith diethyl malonatein the presence of NaH in DMF to give the ketodiester7 (70%); hydrolyzed with ethanolicsodiumhydroxideto givediacid8 (85%);thendecarboxylated in thepresence of Cu20 to give the unprotected monoacid9 (95%). was
Theprotectedmorpholinoamides11 (SchemeI) and 16 (SchemeII) werepreparedin 6585% yield by reactionof protectedketoester5 with the appropriatedimethylaluminium amide(prepured in sihr). Alternatively, DCC-mediated couplingof the amine(1 equivalent)andthe unprotectedketoacid(9)19in the presenceof lhydroxybenzotriazole(HOBt) in methylenechlorideaffordedamides10 (SchemeI) and15 (SchemeII) in 55 80%yieldm. The nitrogenatomof the pyrrole ring wasprotectedby reactionwith benzenesulfonyl chlorideas previouslydesaibedt*.Reductionof thecarbonylgroupwith aluminiumhydride(AlH3) in THF yieldedamino alcohols12 (SchemeI) and 17 (SchemeII) in quantitativeyields.Theseaminoalcoholswereoxidized with pyridiniumdichromate(PDC) to give aminoketones 13 (Scheme1) and18 (SchemeII) in 5060% yields.The targetcompounds,1 and2, wereobtainedby removingthe benzenesulfonylprotectinggroupswith ethanolic sodiumhydroxide. SCHEME I
I Ii
1 (QF-04OOB)
E.
k%aA
SCBIZME
H
et al.
II
2 (QIW496B)
Table I lists the results of experiments to evaluate the affinities of compounds 1 and 2 for dopamine and serotonin receptors. Both compounds inhibited the binding of 3H-spiperone to & receptors (pI
583
Butyrophenone analogues
is replaced by an o-methoxyphenylpiperazine, the affinity for 5-HT2,4 of the resulting compound (2) iS significantly higher than that of molindone, while its affinity for D2 receptors is similar. These preliminary results, together with our previously reported conclusio&-t4 justify further study of indolones containing piperazine fragments or otber pharmacophores that are active at dopamine and serotonin receptors. Table I Compound
pKi ratios
pKl’sa ~-HT~A
5-HT&D2
DI
D2
Haloperidd
7.01
8.30
7.70
0.85
0.93
Mdindone
5.80
7.48
5.85
0.77
0.78
6.18k0.16
1 (QF-0400B)
5.67
6.23
6.04
0.91
0.97
6.98i0.23
(QF-0402B)
5.93
7.55
7.04
0.79
0.97
7.50zt0.2
2
a hhibitiat
conataats (pm
mrmbrsncs
(H-fl&)
for in vitro inhibition
and 3H-SCH
for these assays have becat pubhkd
by the compounds
23390 or3H-4Qerone dsewkre.
12-14ph
h/D2
PAz(~-HTzA)~
uuder study of 3H-ketansefine
binding to rat frontal
binding to striatal membranea (D1 or D2, respectively); valuea were cala~Iatcd using the Cheng-&off
cortex
detailed methods
equation2t;
and results
sbownartmansolthpeeinhibitionaw~coostnrtedNitheachdrug.Thcmcanstandardarorof~valucswas1o-1~~ bAarta hg
expaimatts:
1) for uwec aagollist
competitive -tratim;
autagonism
was quantikd
six re&ateexpe-riment9
as pA2. which was calculated from a Schild plot of log (dose ratic were performed.
Acknowledgementa This work was supported by the Spanish Interministerial Commission for Science and Technology (CICYT) under grant SAF 92-0957-CO2-01. We also thank the Xunta de Galicia for grants to C. F. Masaguer. References
and Notes
1. See for example (a) Lednicer. D.; Mitscher. L. A. The Organic Chemistry of Drug Synthesis; Wiley Interscience: New York, 1980; Vol 2, p. 455. (b) Horu, A. S. “Dopamine Receptors” in Comprehensive Medicinal Chemistry; Hansch. C.; Sammes, P. G.; Taylor, J. B., Ed.; Pergamon Press: Oxford, 1990; Vol 3. p. 133.
2. Olson, G. L.; Ho-Chuen, C.; Morgan, D. K.; Blount, J. F.; Todaro, L.; Berger, L.; Davidson, A. B.; Boff. E. J. Med. Chem. 1981. 24, 1026. 3. Seeman, P.; Chou-Wang, M.; Tadesco. J.; Wang. K. Synapse 197&l. 399. 4. Seeman. P.; Lee, T.; Chou-Wong, M.; Wang. K. Nature 1976,26X,717. 5. Perot&a, S. J.; Snyder, S. H. Am. J. Psychiatry 1980.173, 1518. 6. Sanberg. P. R Nature 1980, 284, 472. 7. Seeman, P.; Bzowej. N. H.; Guan, H. C.; Bergeron, C.; Becker, L. E.; Reynols, G. P.; Bird, E.D.; Riedeger, P.; Jelliger, K.; Watanabe, S.; Tourtellote, W. W. Synapse 1987.1.399.
584
E. RAmA
et
al.
8. Novak, K.; Welsch-Kunzie, S.; Kuschinsky. K. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1988.337, 440. 9. Meltzcr, H. Y .; Matsubara,S.; Lee,J. C. J. Phannacol.Exp. Z%er.1989,251,238. 10.Me&r. H. Y.: Mats&am, S.; Lee.J. C. Psychophurmacol. Bull. 1989.253.390.
1l.(a). Drugs Fut. 1988. 13, 10525.(b). Leysen.J. E.; Janssen.P. M. F.; Gcmmeren,W.; Wynants. J.; Pauwels,P. L.; Janssen. P. A. J. Molecuhr Pharmacology1992.41, 494. (c) A. A. H. P. Megens;F. H. L. Awouter~; A. Schotte;T. F. Meert;C. Dugovic; C. J. E. Niemegeem; J. E. LeysenPsychopharmkology, 1994,114, 9-23. 12.Cortizo, L.; Santana,L.; Raviila,E.; Orallo, F.; Fontenla,J. A.; Castro,E.; Calleja,J. M.; de Ceballos,M. L. J. Med. Chem.1991, 24. 2242. 13.Loza, M. I.; Verde, I.; Castro,E.; Orallo, F.; Fontenla.J. A.; Calleja,J. M.; Raviila, E.; Cortizo, L.; de Ceballos,M. L. Bio. Med. Gem. L&t. 1991,1, 1771. 14. Fontenla,J. A.; Osuna,J.; Rosa,E; Castro,E.; G-Ferreiro,T.; Loza. M. I.; Calleja, J. M.; Sanz, F.; Rodriguez,J.; Ravifla, E.; Fueyo,J.; Masaguer.C. F.; Vidal. A.; de Ceballos,M. L. J. Med. Che-m. 1994, 37,2564. 15.Recently,anarylpiperazinebindingsitewithin the & receptorhasbeenpostulated(Jaen.J. C.; Caprathe,B. W.; Wise, L. D.; Meltzer. L. T.; Pugsley,T. A.; Heffner, T. G. Bio. Med. Chem.L&t. 1993.3, 639. Likewise,it is known that the arylpiperazinestructureis a templatefor 5-I-H activity (Glennon, R. A.; Naiman,N. A.; Lyon, R. A.; Titeler, M. J. Med. Gem. 1988,31, 1968.Glennon,R. A. Drug. Dev. Res. 1992,26,251). Seealso&rone. R.; Berardi.F.; Colafubo,N. A.; Tortorella, V.; Fiorentino,F.; Olgiati, V.; Vanotti, E.; Govoni. S. J. Med. Chem.1994,37.99. 16. Completedetailsof the synthesesand spectraldatawill be publishedelsewhere.All compoundsgave satisfactory micro-analytical (C,H,N) and spectra1data (250 MHz lH NMR and IR). Yields given correspondto isolatedpurecompounds. 17. Hauptma. S.; Blume,A.; Hartmann,G.; Haendel,D.; Franke,P. 2. Chem.1966,3, 107. 18. Masaguer.C. F.; Raviffa, E.; Fueyo,J. Heterocycles1992,34, 1303. 19.Compound9 wasalsoobtainedby hydrolysisof 5 in ethanolicsodiumhydroxide.followedby acidification with cont. HCl(75% yield). 20. Replacingdicyclohexylcarbodiimide(DCC) by l-[(3-dimethylamino)propyl-3-ethyllcarbodiimide led to pooreryieldsof theamides. 21. Cheng,Y. C.; Prusoff, W. Biochem.Pharmocol.1973,22,309!3.
(Receivedin Belgium18 October 1994;accepted25 January 1995)