synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential...

Synthesis and Biological Evaluation of New Quinazoline and CinnolineDerivatives as Potential Atypical Antipsychotics1)

by Mario Alvarado, MarÌa Barcelo¬ , Laura Carro, Christian F. Masaguer, and Enrique Ravinƒ a*

Departamento de QuÌmica Orga¬nica, Laboratorio de QuÌmica Farmace¬utica, Facultad de Farmacia,Universidad de Santiago de Compostela, E-15782, Santiago de Compostela, Spain

(e-mail: [email protected])

Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained amino-butyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), andevaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and thedopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (� 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinitiestowards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypicalantipsychotics. The cinnoline derivative 23 (� 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2Ccompared to both the 5-HT2A and D2 receptors.

1. Introduction. ± Schizophrenia is a complex disorder affecting ca. 1% of thepopulation [2]. Classical (typical) neuroleptics such as haloperidol (1; Fig. 1) arecurrently used for the treatment of this disease, but their use is associated with severemechanism-related side effects, including induction of acute extrapyramidal symptoms(EPS) [3]. Also, these compounds are ineffective against negative symptoms ofschizophrenia. The clinical efficacy of classical antipsychotics in the treatment ofschizophrenia and other psychotic disorders is directly related to their ability to blockdopamine D2 receptors in the brain [4]. However, it has been reported that theblockage of the dopamine receptor in the striatum is closely associated withextrapyramidal side effects [5].

The introduction of clozapine (2) for treatment-resistant schizophrenia gave rise toa new group of atypical or nonclassical antipsychotics that have no EPS, and areeffective also against negative symptoms [6]. These drugs exhibit potent antagonism atmultiple receptor subtypes including serotonin and dopamine receptors, suggesting theimplication of the serotoninergic system in this pathology [7]. Meltzer et al. [8]suggested that in the efficacy of clozapine (2) and other atypical antipsychotics such asrisperidone (3) or olanzapine (4) the most-important factor is their relative affinitiesfor the D2 and 5-HT2A receptors [9]. They proposed that the ratio between the pKi for5-HT2A and that for D2 may be used to discriminate atypical antipsychotics (ratio�1.12) from classical antipsychotics (�1.09). Experimental and clinical studies seem to

CHEMISTRY & BIODIVERSITY ± Vol. 3 (2006)106

¹ 2006 Verlag Helvetica Chimica Acta AG, Z¸rich

1) This is the 33rd paper in the series −Synthesis and CNS Activity of Conformationally RestrictedButyrophenones×. For the preceding paper, see [1].

confirm the major role of the 5-HT2A receptor for the atypical profile of theantipsychotics [10]. Additionally, many of the atypical antipsychotic agents block notonly 5-HT2A, but also other serotonin receptors, particularly 5-HT2C [11]. It has alsobeen suggested that 5-HT2C receptor blockade is responsible for reducing EPS [12].These findings have made the 5-HT2C receptor a potential target in the treatment ofpsychotic illnesses [13].

Four decades after its introduction into the clinic, clozapine (2) remains theprototype of atypical antipsychotic drugs, and no currently available agents appear tohave the spectrum of efficacy of this drug. However, treatment with clozapine isassociated with an increased risk of agranulocytosis [14], which strongly limits itstherapeutic use. Hence, the discovery of a more-effective, side-effects-free therapy forthe treatment of schizophrenia remains a challenging research goal.

Over the last few years, we have been working on the modulation of thebutyrophenone system, with the aim of combining the antagonism at the 5-HT2 familyand the D2 receptors in a single molecule [15]. We have reported the synthesis,pharmacology, and molecular modeling of the −aminobutyrophenones× (substructure

CHEMISTRY & BIODIVERSITY ± Vol. 3 (2006) 107

Fig. 1. Structures of a typical (1) and of some atypical (2 ± 4) antipsychotics

marked bold) called QF 0104B (5) and QF0108B (6) [16], which show high affinity forthe 5-HT2A receptor subtype, withKi values of 1.6 and 2.7 n�, respectively, compound 5being most selective for the serotonin 5-HT2A receptor subtype, with a 5-HT2A/5-HT2CKi ratio as high as 150. These compounds are also potent D2 receptor antagonists,although they display Ki values higher than those at 5-HT2A receptors.

As part of our ongoing work on the development of strategies for the preparation ofnew atypical antipsychotics, we explored the possibility of synthesizing analogues of theaminobutyrophenones 5 and 6, in which the benzene ring of the tetralone core wasreplaced by an aromatic heterocyclic ring, such as pyrimidine or pyridazine, to form atetrahydro-quinazolinone or -cinnolinone system, respectively. The substitution of�CH� by �N� in aromatic rings has been one of the most-successful applications ofclassical isosterism [17]. Thus, as a continuation of our previous work in the synthesis ofaza analogues in the pyridine series [18], i.e., bio-isosteric replacement of the benzenering by a pyrimidine or pyridazine system, was raised. In this paper, we report thesynthesis of four novel diaza analogues of 5 and 6, and evaluate their activity againstseveral dopamine and serotonin receptors.

2. Results and Discussion. ± 2.1. Synthesis. The synthesis of the cyclohexanedionederivative 7, a key intermediate in our synthetic strategy, has been reported before from3,5-dimethoxybenzoic acid in a four-step procedure [18]. Our initial purpose was todevelop a more-convenient preparation of this intermediate. We, thus, envisaged aroute based on a tandem Michael addition/Claisen condensation process, which hasbeen reported for other cyclohexane-3,5-dione derivatives [19]. The synthesis of 7,depicted in Scheme 1, was carried out starting from methyl 4-methoxycrotonate (8),prepared from commercially available methyl 4-bromocrotonate in 85% yield, asdescribed in [20]. Compound 8 was reacted with methyl acetoacetate, and the resultingcyclic intermediate was subjected to hydrolysis and decarboxylation, which afforded 7in 50% yield (over two steps).

With the synthon 7 in our hands, we examined several procedures to fuse a diazinering to the cyclic diketone. For the synthesis of the quinazolinone nucleus, two differentapproaches were considered (Scheme 2). The first strategy (Route A) involved theconversion of 7 to the enaminone 9, followed by subsequent treatment with 1,3,5-triazine in an inverse-electron-demand Diels ±Alder reaction [21].

We first conducted some model experiments, with modifications of the solventsystems and the amino group of the enaminone. We found that the reaction of 3-amino-

Scheme 1

a) 1. Methyl acetoacetate, t-BuOK, t-BuOH, r.t., 12 h; 2. reflux, 24 h. b) 1. KOH, H2O, reflux, 2 h; 2. HCl,MeOH, reflux, 12 h; 50% (two steps).


5,5-dimethylcyclohex-2-en-1-one hydrochloride with 1,3,5-triazine in AcOH affordedthe corresponding quinazolinone in 87% yield [22]. Consequently, compound 9 wasprepared according to the method reported by Baraldi et al. [23]: the diketone 7 wastreated with ammonium acetate as nitrogen source and glacial AcOH to afford 9 in81% yield (Scheme 2). The latter was submitted (as the hydrochloride) to a [4� 2]cycloaddition with 1,3,5-triazine in AcOH, which afforded the quinazolinone derivative10 in 66% yield (53% overall yield from 7) [22].

The second approach (Route B in Scheme 2) was based on the followingconsideration. It is well-established that formamide acetals react with active methyleneketones in a Vilsmeier ±Haack-type reaction to produce enamino-ketones. The lattercan subsequently yield, with the appropriate bifunctional nucleophile, a number ofheterocycles such as pyrazoles, pyrimidines, or isoxazoles in a tandem Michaeladdition ± elimination/cyclodehydration process [24]. Accordingly, synthon 7 wastransformed by condensation with N,N-dimethylformamide dimethyl acetal

Scheme 2

a) AcO�NH4�, AcOH, benzene, 110�, 1 h; 81%. b) 1,3,5-Triazine, AcOH, 110�, 18 h; 66%. c)

(MeO)2CHNMe2, THF, reflux, 2 h; 95%. d) HN�CHNH2 ¥AcOH, AcOH, reflux, 12 h, 60%. e) BBr3,CH2Cl2, � 70�� r.t., 24 h; 45%. f) TsCl, pyridine, 0�, 48 h; 86%. g) (i-Pr)2NEt, 1,4-dioxane, reflux; 40%of 14, 51% of 15.


((MeO)2CHNMe2) into the enamino-ketone 11 in 95% yield. Then, cyclocondensationof 11with formamidine acetate in boiling AcOH afforded 10 in 60% yield. In summary,both Routes A and B afforded 10 from 7 in a similar number of steps and overall yield,but the latter route is potentially more versatile, because it allows the introduction of avariety of substituents in position 2 of the pyrimidine ring by using different amidines.

In the next step, the methyl ether of 10was cleaved with BBr3 in CH2Cl2 at 0�, whichafforded the corresponding hydroxy compound 12 in 45% yield. Forcing conditions ledto useless mixtures of compounds, and the use of other demethylating reagents did notimprove the yield. The subsequent tosylation of 12 with TsCl in pyridine furnished thesulfonate 13 in 86% yield, which was converted into the desired amines 14 and 15 bynucleophilic displacement of the TsO group by the corresponding substitutedpiperidines (21 or 22) in 1,4-dioxane using (i-Pr)2NEt as a base.

For the synthesis of the pyridazine-fused ring, the most-common method involves a1,4-dicarbonyl compound reacting with hydrazine, followed by an oxidative step to givean aromatic pyridazine. Accordingly, the cyclohexanedione 7 was alkylated with


Scheme 3

a) MeCOCH2Cl, EtONa, EtOH, reflux, 5 h; 60%. b) N2H4 ¥H2O, EtOH, r.t., 12 h; 75%. c) MnO2, THF,r.t., 12 h; 86%. d) 1. N2H4 ¥H2O, EtOH, r.t., 12 h; 2. MnO2, THF, r.t., 12 h; 40%. e) BBr3, CH2Cl2,� 50�� r.t., 12 h; 82%. f) TsCl, pyridine, DMAP, CH2Cl2, reflux, 12 h, 70%. g) THF, reflux, 72 h; 20% of23, 15% of 24, 55% of 25.

chloroacetone in the presence of EtONa to afford the triketone 16 in 60% yield(Scheme 3). In the next step, we built the pyridazine ring by treatment of 16 withhydrazine hydrate in EtOH, which afforded the hexahydrocinnolin-5-one 17 in 75%yield as a yellow solid. Subsequent aromatization with MnO2 in THF gave thetetrahydro congener 18 in 85% yield (64% over two steps). To shorten this part of thesynthesis, the hydrazine condensation and aromatization were performed in a one-potreaction. Treatment of 16 with hydrazine hydrate in EtOH at r.t. for 12 h, followed byaddition of MnO2 (3 equiv.) and stirring for 12 h at r.t., gave 18 in 40% overall yield.Consequently, the more-laborious procedure involving isolation of the intermediate 17affords a better overall yield.

Next, compound 18 was demethylated with BBr3 (as above) to afford the alcohol 19in 80% yield, which was subjected to tosylation by exposure to TsCl in the presence ofpyridine (1 equiv.) and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) inCH2Cl2. The resulting tosylate 20, obtained in 70% yield, was reacted either with theamine 21 or 22 (same conditions as those used for the preparation of 14 and 15), whichgave rise to the target amino ketones 23 (20%) and 24 (15%) in poor yields. This wasdue to cyclization of the starting material to 5a,6,6a,7-tetrahydro-3-methyl-5H-cyclo-propa[g]cinnolin-5-one (25 ; 55%), the result of base-promoted intramolecularalkylation.

2.2. Biological Studies. We performed different binding assays with the targetcompounds 14, 15, 23, and 24 at the serotonin 5-HT2A and 5-HT2C, and at the dopamineD2 human receptors. These experiments were performed as described before [16], andthe results are summarized in the Table. Among the new compounds, 15 exhibited thehighest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, with Ki

values of 32 and 160 n�, respectively, and it showed a 16-fold selectivity for 5-HT2Aover 5-HT2C. On the basis of the 5-HT2A/D2 antagonism hypothesis, compound 15, witha Meltzer×s ratio of 1.10, is in the borderline of potential atypical antipsychotics [8].

Those compounds bearing a cinnoline moiety, i.e., 23 and 24, lacked appreciableaffinity for the dopamine D2 receptors (Ki� 10 ��). Therefore, from the point of viewof the dopamine hypothesis of schizophrenia [4], these compounds are not suited as

Table. Binding Affinities of Target Compounds and Reference Antipsychotics towards Serotonin andDopamine Receptors

Compound Name Ki [n�] Ki ratioa) Meltzer×s ratiob)

5-HT2A 5-HT2C D2

14 QF3504B � 10000 500 630 � 0.05 ±23 QF3404B 9550 36 � 10000 0.004 ±5c) QF0104B 1.6 235 225 147 1.32

15 QF3508B 32 500 160 16 1.1024 QF3408B 600 15 � 10000 0.025 ±6c) QF0108B 2.7 130 57 48 1.181d) Haloperidol 165 7245 0.6 44 0.732d) Clozapine 9.1 10.5 225 1.15 1.21

a) Ki(5-HT2C)/Ki(5-HT2A). b) pKi(5-HT2A)/pKi(D2). c) Values taken from [16]. d) Positive control.


potential antipsychotics. However, they displayed the highest affinity for the 5-HT2Creceptor; and 23 could have an interesting profile as a selective 5-HT2C receptor ligand,with 265- and 280-fold lower affinities for the 5-HT2A and D2 sites, respectively. Similarto 23, compound 24 retained reasonable selectivity for the 5-HT2C receptor.

Note that in our new compounds, the diazine moiety may not be considered as abio-isostere for the benzene moiety in the 3-aminomethyltetralones 5 and 6, becausetheir pharmacological aspects are not identical.

3. Conclusions. ± We have accomplished the synthesis of two new quinazolinones(14, 15) and cinnolinones (23, 24) as diaza analogues of the known aminobutyrophe-nones 5 and 6. The binding affinities of the new compounds towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors were determined. Thereby, thequinazoline derivative 15 exhibited higher affinities at the serotonin 5-HT2A anddopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics.The cinnoline derivative 23 displayed a selective 5-HT2C receptor binding profile over5-HT2A and D2.

Experimental Part

General. All solvents were distilled prior to use: THF, benzene, and 1,4-dioxane from Na/benzophenone; MeOH, EtOH and t-BuOH from CaH2; CH2Cl2 from P2O5; pyridine from KOH. TLC:precoated silica-gel 60 F254 plates (Merck), detection by UV light (254 nm), exposure to I2 vapor, or byheating with Mostain (400 ml of 10% H2SO4, 20 g of (NH4)6Mo7O24 ¥ 6 H2O, 0.4 g Ce(SO4)2). Flash-column chromatography (FC): Kieselgel 60 (60 ± 200 mesh; Merck). Melting points (m.p.) weredetermined in open capillaries with a Gallenkamp capillary melting-point apparatus; uncorrected. IRSpectra: Perkin Elmer 1640 FTIR spectrophotometer; selected absorption bands in cm�1. 1H- (300 MHz)and 13C-NMR (75 MHz) spectra: Bruker WM-AMX ; chemical shifts � in ppm rel. to Me4Si, couplingconstants J in Hz. MS: Hewlett-Packard 5988A mass spectrometer (EI-MS; 70 eV); Finnigan Trace-MSmass spectrometer (CI-MS); Micromass Autospec (HR-MS); in m/z (rel.%). Elemental analyses werecarried out by the microanalytical service of the University of Santiago de Compostela, Spain.

Methyl 4-Methoxycrotonate (�Methyl (2E)-4-Methoxybut-2-enoate ; 8). A mixture of methyl 4-bromocrotonate (30 g, 167.6 mmol) and CaCO3 (16.77 g, 167.6 mmol) in anh. MeOH (250 ml) was heatedat reflux for 5 d. At this time, the mixture was filtered, and theMeOHwas removed in vacuo. The residuewas partitioned between Et2O (100 ml) and 1% aq. HCl (10 ml), and the aq. phase was extracted withEt2O (3� 20 ml). The combined org. layers were washed with H2O and brine, dried (Na2SO4), filtered,and concentrated under reduced pressure. The crude product was purified by bulb-to-bulb distillation toafford 8 (18.44 g, 84%). Colorless oil. B.p. 80�/15 Torr (lit. b.p. 120�/44 Torr [20]). IR (film): 1706 (C�O).1H-NMR (CDCl3): 3.39 (s, 4-MeO); 3.74 (s, MeOCO); 4.09 (dd, J� 4.3, 2.0, CH2O); 6.10 (dt, J� 15.8, 2.0,�CHCO); 6.92 (dt, J� 15.7, 4.3, CH2CH�). 13C-NMR (CDCl3): 51.6 (MeOCO); 58.7 (4-MeO); 71.2(OCH2); 120.9 (�CHCO); 144.7 (CH2CH�); 166.7 (C�O). CI-MS: 131 (17, [M�H]�).

5-(Methoxymethyl)cyclohexane-1,3-dione (7). Methyl acetoacetate (�methyl 3-oxobutanoate;2.94 ml, 27 mmol) was added dropwise to a soln. of t-BuOK (2.72 g, 23 mmol) in anh. t-BuOH(250 ml), and the mixture was stirred at r.t. for 30 min. Compound 8 (3.0 g, 23 mmol) was added, and themixture was stirred at r.t. for 12 h, and then refluxed for an additional 24 h. After cooling, a soln. of KOH(6.71 g) in H2O (5 ml) was added portionwise, and the resulting mixture was refluxed for 2 h, duringwhich 200 ml of solvent were distilled off. A 4 :1 mixture of EtOH and conc. HCl (90 ml) was then added,and heating to reflux was continued for 12 h. Finally, the mixture was concentrated under reducedpressure, and the crude product was purified by FC (SiO2; AcOEt) to afford 7 (1.79 g, 40%). Yellowishsolid. M.p. 100 ± 101�. IR (KBr): 1597 (C�O). 1H-NMR (CDCl3, keto form): 2.36 ± 2.43 (m, H�C(5));2.57 (dd, J� 15.5, 5.9, 1 H of CH2(4), 1 H of CH2(6)); 2.68 (dd, J� 15.7, 5.6, 1 H of CH2(4), 1 H of


CH2(6)); 3.23 (s, MeO); 3.26 (d, J� 17.9, 1 H of CH2(2)); 3.37 (d, J� 17.9, 1 H of CH2(2)); 3.42 (d, J� 3.6,OCH2). 13C-NMR (CDCl3, keto form): 32.2 (C(5)); 44.0 (C(4), C(6)); 57.7 (C(2)); 59.4 (MeO); 76.2(OCH2), 204.1 (C�O). 1H-NMR (CDCl3; enol form): 2.22 ± 2.47 (m, CH2(4), CH2(5), CH2(6)); 3.33 (s,MeOCH2); 5.44 (s, H�C(2)); 8.86 (br. s, OH). 1H-NMR ((D6)DMSO; enol form): 2.03 ± 2.26 (m,CH2(4), CH2(5), CH2(6)); 3.21 (s, MeO); 3.24 (d, J� 5.5, OCH2); 5.19 (s, H�C(2)). 13C-NMR (CDCl3,enol form): 34.4 (C(5)); 35.7 (C(4), C(6)); 59.3 (MeO); 75.8 (OCH2); 104.4 (C(2)); 191.9 (C�O).13C-NMR ((D6)DMSO; enol form): 33.7 (C(5)); 35.5 (C(4), C(6)); 58.5 (MeO); 75.3 (OCH2); 103.8(C(2)). CI-MS: 157 (58, [M�H]�).

3-Amino-5-(methoxymethyl)cyclohex-2-en-1-one (9). A mixture of 7 (0.5 g, 3.20 mmol), ammoniumacetate (0.49 g, 6.35 mmol), and glacial AcOH (0.5 ml) in benzene (10 ml) was heated at 90� for 1 h. Themixture was allowed to cool to r.t., and the solvent was removed under reduced pressure. The residue wasdissolved in CH2Cl2, neutralized with solid Na2CO3, filtered, dried (Na2SO4), filtered again, andconcentrated under reduced pressure. Purification by FC (SiO2; AcOEt/MeOH 4 :1) gave 9 (0.40 g,81%). Yellow solid. M.p. 108 ± 109� (m.p. hydrochloride: 189 ± 191�). IR (KBr): 3311 (NH), 1686(C�O). 1H-NMR (CDCl3): 2.10 ± 2.15 (m, H�C(5)); 2.30 ± 2.38 (m, CH2(4), CH2(6)); 3.27 ± 3.37 (m,MeOCH2); 4.60 (s, NH2); 5.24 (s, H�C(2)). 13C-NMR (CDCl3): 32.3 (C(4)); 34.9 (C(5)); 39.1 (C(6));59.3 (Me); 76.2 (OCH2); 100.4 (C(2)); 165.0 (C(3)); 197.3 (C�O). EI-MS: 155 (24, M�).

2-[(Dimethylamino)methylidene]-5-(methoxymethyl)cyclohexane-1,3-dione (11). Dimethylforma-mide dimethylacetal (85 mg, 0.71 mmol) was added dropwise to a stirred soln. of 7 (0.10 g, 0.64 mmol)in anh. THF (25 ml), and the soln. was refluxed for 1 h. The solvent was removed in vacuo, and theresidue was purified by FC (SiO2; AcOEt) to afford 11 (0.13 g, 95%). Yellow solid. M.p. 84 ± 85�. IR(KBr): 1660 (C�O). 1H-NMR (CDCl3): 2.25 ± 2.37 (m, 1 H of CH2(4), CH2(5), 1 H of CH2(6)); 2.57 (d,J� 12.5, 1 H of CH2(4), 1 H of CH2(6)); 3.17 (s, MeO); 3.33 (d, J� 5.3, OCH2); 3.34, 3.38 (2s, Me2N);8.02 (s, �CH). 13C-NMR (CDCl3): 32.6 (C(5)); 41.7 (C(4), C(6)); 45.0, 48.5 ((Me2N); 59.5 (MeO); 76.4(CH2O); 109.5 (C(2)); 162.5 (�CH�N); 195.0 (C�O). EI-MS: 211 (41, M�).

5,6,7,8-Tetrahydro-7-(methoxymethyl)quinazolin-5-one (10). Method A. To a soln. of the hydro-chloride of 9 (180 mg, 0.96 mmol) in glacial AcOH (15 ml) was added 1,3,5-triazine (114 mg, 1.40 mmol).The soln. was heated in a sealed tube at 110� for 18 h. The solvent was removed in vacuo, and the residuewas purified by FC (SiO2; hexane/AcOEt 1 :3) to afford 10 (140 mg, 66%).

Method B. A mixture of 7 (100 mg, 0.47 mmol) and formamidine acetate (49 mg, 0.47 mmol) inglacial AcOH (10 ml) was stirred at reflux for 12 h. The solvent was removed under reduced pressure, theresidue was dissolved in CH2Cl2 (25 ml), and washed with 5% aq. NaHCO3 soln. (3� 25 ml). The org.phase was dried (Na2SO4), filtered, and concentrated in vacuo. FC (SiO2; hexane/AcOEt 1 :1) gave 11(54 mg, 60%).

Data of 10. Yellow oil. IR (film): 1697 (C�O). 1H-NMR (CDCl3): 2.45 ± 2.60 (m, CH2(6)); 2.73 ±2.80 (m, H�C(7)); 2.99 (dd, J� 18.0, 10.0, 1 H of CH2(8)); 3.15 (dd, J� 17.7, 4.0, 1 H of CH2(8)); 3.31 (s,Me); 3.41 (d, J� 4.3, OCH2); 9.12 (s, H�C(4)); 9.17 (s, H�C(2)). 13C-NMR (CDCl3): 34.3 (C(7)); 35.3(C(8)); 41.9 (C(6)); 59.5 (Me); 75.8 (OCH2); 125.6 (C(4a)); 156.3 (C(4)); 161.6 (C(2)); 171.1 (C(8a));196.5 (C�O). EI-MS: 192 (3, M�).

5,6,7,8-Tetrahydro-7-(hydroxymethyl)quinazolin-5-one (12). To a soln. of 10 (100 mg, 0.52 mmol) inCH2Cl2 (20 ml) at � 70� was added a 1� soln. of BBr3 in CH2Cl2 (1.3 ml, 1.3 mmol), and the mixture wasstirred at r.t. under Ar gas for 24 h. The mixture was poured into ice-water (20 ml), made alkaline withsolid Na2CO3, and extracted with CH2Cl2 (3� 25 ml). The combined org. extracts were dried (Na2SO4),filtered, and concentrated under reduced pressure. The residue was purified by FC (SiO2; hexane/AcOEt1 :2) to give 12 (40 mg, 45%). Yellow solid. M.p. 87 ± 88�. IR (KBr): 3264 (OH), 1692 (C�O). 1H-NMR(CDCl3): 2.43 ± 2.65 (m, 1 H of CH2(6), H�C(7)); 2.81 (dd, J� 16.0, 1.5, 1 H of CH2(6)); 3.04 (dd, J�18.0, 9.8, 1 H of CH2(8)); 3.22 (dd, J� 18.0, 1.6, 1 H of CH2(8)); 3.75 (dd, J� 5.1, 1.4, OCH2); 9.15 (s,H�C(4)); 9.19 (s, H�C(2)). 13C-NMR (CDCl3): 34.9 (C(8)); 36.2 (C(7)); 41.6 (C(6)); 65.9 (OCH2);125.7 (C(4a)); 156.4 (C(4)); 161.6 (C(2)); 171.2 (C(8a)); 196.6 (C�O). EI-MS: 178 (60,M�). Anal. calc.for C9H10N2O2 (178.19): C 60.66, H 5.66, N 15.72; found: C 60.67, H 5.80, N 15.74.

5,6,7,8-Tetrahydro-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)quinazolin-5-one (13). To a stirredsoln. of 12 (0.15 g, 0.84 mmol) in pyridine (5 ml) at 0�was added tosyl chloride (TsCl; 0.80 g, 4.20 mmol),and the mixture was stirred at this temp. under Ar gas for 24 h. The mixture was poured into ice-water,


and extracted with CH2Cl2 (3� 25 ml). The combined org. extracts were washed with H2O (3� 25 ml),dried (Na2SO4), filtered, and concentrated in vacuo. FC (SiO2; hexane/AcOEt 2 :1) gave 13 (0.23 g,86%). Colorless solid. M.p. 89 ± 90�. IR (KBr): 1698 (C�O). 1H-NMR (CDCl3): 2.44 (s, Me); 2.60 ± 2.68(m, 1 H of CH2(6), H�C(7)); 2.75 (dd, J� 17.0, 3.4, 1 H of CH2(6)); 2.96 (dd, J� 17.8, 10.3, 1 H ofCH2(8)); 3.15 (dd, J� 17.8, 4.3, 1 H of CH2(8)); 4.07 (dd, J� 5.1, 3.7, OCH2); 7.35 (d, J� 8.0, H�C(3,5) ofC6H4); 7.76 (d, J� 8.2, H�C(2,6) of C6H4); 9.15 (s, H�C(4)); 9.20 (s, H�C(2)). 13C-NMR (CDCl3): 22.1(Me); 33.5 (C(7)); 34.5 (C(8)); 41.0 (C(6)); 71.9 (OCH2); 125.0 (C(4a)); 128.3 (C(3,5) of C6H4); 130.5(C(2,6) of C6H4); 132.8 (C(4) of C6H4); 145.8 (C(1) of C6H4); 156.6 (C(4)); 161.8 (C(2)); 169.8 (C(8a));194.9 (C�O). EI-MS: 332 (49,M�). Anal. calc. for C16H16N2O4S (332.38): C 57.82, H 4.85, N 8.43; found:C 57.90, H 5.02, N 8.43.

General Procedure for the Preparation of Compounds 14 and 15. A soln. of 13 (0.20 g, 0.60 mmol),the appropriate amine (21 or 22 ; 1.20 mmol), and (i-Pr)2NEt (0.10 ml, 0.60 mmol) in 1,4-dioxane (15 ml)was heated at reflux for 48 h. The solvent was removed under reduced pressure, the residue was dissolvedin CH2Cl2 (25 ml), and washed with H2O (3� 5 ml). The org. layer was dried (Na2SO4) andconcentrated, and the residue was purified by FC (SiO2; CH2Cl2/MeOH 19 :1).

Data of 7-{[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one (14). Yield: 40%. Orange solid. M.p. 139 ± 140� (i-PrOH). IR (KBr): 1691(C�O), 1611 (C�N).1H-NMR (CDCl3)2): 2.02 ± 2.27 (m, 3 H of N(CH2CH2)2CH); 2.42 ± 2.68 (m, 3 H ofCH2N(CH2CH2)2CH); 2.86 ± 3.12 (m, 1 H of CH2(6), H�C(7), CH2(8), N(CH2CH2)2CH); 3.31 (dd,J� 18.0, 2.7, 1 H of CH2(6)); 7.07 (dt, J� 8.8, 2.0, H�C(5) of bxz); 7.25 (dd, J� 8.5, 2.0, H�C(7) of bxz);7.65 (dd, J� 8.7, 5.1, H�C(4) of bxz); 9.19 (s, H�C(4)); 9.23 (s, H�C(2)). 13C-NMR (CDCl3)2): 30.9(N(CH2CH2)2C); 32.0 (C(7)) ; 34.7 (N(CH2CH2)2C) ; 36.9 (C(8)) ; 43.4 (C(6)) ; 54.3, 54.5(N(CH2CH2)2C); 63.4 (NCH2); 97.8 (d, J(C,F)� 27.1, C(7) of bxz); 112.9 (d, J(C,F)� 25.6, C(5) ofbxz); 117.6 (C(3a) of bxz); 123.0 (d, J(C,F)� 11.3, C(4) of bxz); 126.1 (C(4a)); 156.4 (C(4)); 161.0 (C(3)of bxz); 161.7 (C(2)); 164.2 (d, J(C,F)� 13.8, C(7a) of bxz); 166.5 (d, J(C,F)� 250.7, C(6) of bxz); 171.0(C(8a)); 197.5 (C�O). CI-MS: 381 (10, [M�H]�). Anal. calc. for C21H21FN4O2 (380.42): C 64.30, H5.56, N 14.73; found: C 64.21, H 5.56, N 14.44.

Data of 7-{[4-(4-Fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one (15) .Yield: 51%. Orange solid. M.p. 151 ± 153� (i-PrOH). IR (KBr): 1697 (C�O), 1677 (C�O). 1H-NMR(CDCl3): 1.80 ± 1.83 (m, N(CH2CH2)2CH); 2.10 ± 2.25 (m, 1 H of N(CH2CH2)2CH); 2.43 ± 2.50 (m, 3 H ofCH2N(CH2CH2)2CH); 2.80 ± 2.95 (m, 1 H of CH2(6), H�C(7), CH2(8)); 3.10 ± 3.30 (m, 1 H of CH2(6),N(CH2CH2)2CH); 7.14 (t, J� 8.5, H�C(3,5) of C6H4); 7.96 (dd, J� 8.6, 5.5, H�C(2,6) of C6H4); 9.19 (s,H�C(4)); 9.24 (s, H�C(2)). 13C-NMR (CDCl3): 29.1, 30.1 (N(CH2CH2)2C); 32.0 (C(7)); 36.9 (C(8));43.4 (C(6)); 43.9 (N(CH2CH2)2C); 54.1, 54.3 (N(CH2CH2)2C); 63.4 (NCH2); 116.3 (d, J(C,F)� 21.8,C(3,5) of C6H4); 127.0 (C(4a)); 131.3 (d, J(C,F)� 9.0, C(2,6) of C6H4); 132.8 (d, J(C,F)� 3.2, C(1) ofC6H4); 156.4 (C(4)); 161.7 (C(2)); 168.0 (d, J(C,F)� 254.5, C(4) of C6H4); 171.2 (C(8a)); 196.7 (C(5));201.3 (C�O). EI-MS: 367 (10, M�). Anal. calc. for C21H22FN3O2 (367.42): C 68.65, H 6.04, N 11.44;found: C 68.30, H 6.28, N 11.25.

5-(Methoxymethyl)-2-(2-oxopropyl)cyclohexane-1,3-dione (16). A mixture of 7 (5.40 g, 34.5 mmol),EtONa (2.30 g, 33.8 mmol), and chloroacetone (3 ml, 35.5 mmol) in EtOH (100 ml) was heated at refluxfor 5 h. After cooling, the precipitated NaCl was removed by filtration, and the filtrate was concentratedin vacuo. The residual syrup was dissolved in a mixture of CHCl3 (30 ml) and 10% aq. NaOH soln.(30 ml). The aq. phase was separated and re-extracted with CHCl3 (30 ml). The aq. phase was cooled inan ice bath, made acidic with concentrated HCl, and extracted with CHCl3 (3� 50 ml). The combinedorg. extracts were dried (Na2SO4), filtered, and the filtrate was evaporated in vacuo to dryness. FC (SiO2;hexane/AcOEt 1 :2) gave 16 (2.8 g, 60%). Yellowish oil. IR (film): 1712 (C�O), 1654 (C�O). 1H-NMR(CDCl3; enol form): 2.14 (s, Me); 2.16 ± 2.50 (m, CH2(4), H�C(5), CH2(6)); 3.29 (s, MeO); 3.30 ± 3.37(m, OCH2, CH2CO). 13C-NMR (CDCl3; enol form): 30.1 (Me); 33.7 (C(5)); 36.0 (CH2); 43.8 (C(6));62.0 (MeO); 76.1 (OCH2); 109.4 (C(2)); 187.4 (C(3)); 207.4 (C�O); 211.1 (C�O). EI-MS: 212 (42,M�).

1,4,5,6,7,8-Hexahydro-7-(methoxymethyl)-3-methylcinnolin-5-one (17). To a soln. of 16 (0.59 g,2.78 mmol) in EtOH (30 ml) was added hydrazine monohydrate (0.14 ml, 2.83 mmol), and the mixture


2) The benzisoxazole moiety is abbreviated as −bxz×.

was stirred at r.t. for 12 h. Removal of the solvent and purification of the residue by FC (SiO2; hexane/AcOEt 1 :2) gave 17 (0.43 g, 75%). Yellow solid. M.p. 106 ± 107� (cyclohexane). IR (KBr): 1586 (C�O).1H-NMR (CDCl3): 1.91 (s, Me); 2.12 ± 2.47 (m, CH2(6), H�C(7), CH2(8)); 2.83 (d, J� 19.9, 1 H ofCH2(4)); 3.06 (d, J� 19.9, 1 H of CH2(4)); 3.33 (s, MeO); 3.26 ± 3.39 (m, OCH2); 7.36 (br. s, NH,exchangeable with D2O). 13C-NMR (CDCl3): 23.8 (Me); 24.4 (C(4)); 29.0 (C(8)); 34.3 (C(7)); 39.7(C(6)); 59.3 (MeO); 76.0 (OCH2); 99.8 (C(4a)); 151.1 (C(3)); 152.1 (C(8a)); 194.8 (C�O). EI-MS: 208(100,M�). Anal. calc. for C11H16N2O2 (208.26): C 63.44, H 7.74, N 13.45; found: C 63.75, H 7.86, N 13.39.

7-(Methoxymethyl)-3-methyl-5,6,7,8-tetrahydrocinnolin-5-one (18). Method A. A mixture of 17(0.9 g, 4.3 mmol) and MnO2 (1.13 g, 12.9 mmol) in anh. THF (75 ml) was stirred at r.t. overnight. Themixture was filtered through Celite, and concentrated under reduced pressure. FC (SiO2; AcOEt)afforded 18 (0.76 g, 86%).

Method B. A soln. of 16 (0.59 g, 2.78 mmol) and hydrazine monohydrate (0.15 ml, 2.78 mmol) inEtOH (20 ml) was stirred at r.t. for 12 h. The solvent was removed in vacuo, the residue was dissolved inTHF (30 ml), and MnO2 (0.73 g, 8.34 mmol) was added. The mixture was stirred at r.t. for 12 h, filteredthrough Celite, and concentrated under reduced pressure. FC (SiO2; hexane/AcOEt 1 :2) afforded 18(0.23 , 40%).

Data of 18. Colorless solid. M.p. 76 ± 77� (cyclohexane). IR (KBr): 1704 (C�O). 1H-NMR (CDCl3):2.58 ± 2.67 (m, 1 H of CH2(6), H�C(7)); 2.78 (s, Me); 2.82 ± 2.89 (m, 1 H of CH2(6)); 3.17 (dd, J� 17.1,9.7, 1 H of CH2(8)); 3.37 (s, MeO); 3.45 (dd, J� 17.0, 2.9, 1 H of CH2(8)); 3.51 (d, J� 4.8, OCH2); 7.66 (s,H�C(4)). 13C-NMR (CDCl3): 22.3 (Me); 32.8 (C(8)); 34.4 (C(7)); 42.0 (C(6)); 59.3 (MeO); 75.9(OCH2); 122.0 (C(4)); 128.0 (C(4a)); 159.0 (C(3)); 160.4 (C(8a)); 197.5 (C�O). EI-MS: 206 (7, M�).Anal. calc. for C11H14N2O2 (206.25): C 64.06, H 6.84, N 13.58; found: C 64.25, H 7.02, N 13.47.

5,6,7,8-Tetrahydro-7-(hydroxymethyl)-3-methylcinnolin-5-one (19) . To a soln. of 18 (2.2 g,10.6 mmol) in CH2Cl2 (35 ml) at � 50� was added a 1� soln. of BBr3 in CH2Cl2 (11.7 ml, 11.7 mmol),and the mixture was stirred overnight at r.t. under Ar gas. Cold H2O (30 ml) was added, and the resultingmixture was basified with sat. aq. Na2CO3 soln. The aq. phase was extracted with CH2Cl2 (2� 15 ml), andthe combined org. extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. FC(SiO2; acetone) gave 19 (1.68 g, 82%). Colorless solid. M.p. 104 ± 105�. IR (KBr): 3322 (OH), 1703(C�O). 1H-NMR (CDCl3): 2.41 ± 2.45 (m, H�C(7)); 2.58 (dd, J� 16.7, 11.3, 1 H of CH2(6)); 2.70 (s,Me); 2.80 (dt, J� 16.8, 1.5, 1 H of CH2(6)); 3.11 (dd, J� 17.1, 10.0, 1 H of CH2(8)); 3.43 (dd, J� 17.0, 3.4,1 H of CH2(8)); 3.69 ± 3.79 (m, OCH2); 3.83 (br. s, OH); 7.70 (s, H�C(4)). 13C-NMR (CDCl3): 22.2 (Me);32.5 (C(8)); 36.5 (C(7)); 41.8 (C(6)); 65.5 (OCH2); 122.8 (C(4)); 128.5 (C(4a)); 159.6 (C(3)); 160.5(C(8a)); 197.8 (C�O). EI-MS: 192 (100, M�). Anal. calc. for C10H12N2O2 (192.22): C 62.49, H 6.29, N14.57; found: C 62.29, H 6.57, N 14.25.

5,6,7,8-Tetrahydro-3-methyl-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)cinnolin-5-one (20). To asoln. of 19 (0.10 g, 0.52 mmol) in CH2Cl2 (10 ml) was added TsCl (0.12 g, 0.62 mmol), pyridine (42 �l,0.52 mmol), and a cat. amount of DMAP, and the mixture was stirred at reflux under Ar gas overnight.Another portion of TsCl (60 mg, 0.31 mmol) and pyridine (20 �l, 0.26 mmol) was added, and the mixturewas refluxed for an additional 6 h. After cooling, the solvent was evaporated in vacuo, and the residuewas purified by FC (SiO2; AcOEt) to afford 20 (0.13 g, 70%). Colorless solid. M.p. 117 ± 118� (toluene).IR (KBr): 1702 (C�O). 1H-NMR (CDCl3): 2.45 (s, Me-C6H4); 2.52 (dd, J� 16.3, 11.9, 1 H of CH2(6));2.59 ± 2.69 (m, H�C(7)); 2.77 (s, Me); 2.83 (dd, J� 16.4, 2.7, 1 H of CH2(6)); 3.08 (dd, J� 17.0, 10.5, 1 Hof CH2(8)); 3.44 (dd, J� 16.6, 2.4, 1 H of CH2(8)); 4.11 (d, J� 5.2, OCH2); 7.36 (d, J� 8.1, H�C(3,5) ofC6H4); 7.65 (s, H�C(4)); 7.78 (d, J� 8.2, H�C(2,6) of C6H4). 13C-NMR (CDCl3): 22.1 (Me); 22.5 (Me);32.3 (C(8)); 33.9 (C(7)); 41.3 (C(6)); 72.2 (OCH2); 122.5 (C(4)); 127.9 (C(3a)); 128.3 (C(2,6) of C6H4);130.5 (C(3,5) of C6H4); 132.7 (C(1) of C6H4); 145.7 (C(4) of C6H4); 158.06 (C(3)); 161.0 (C(8a)); 196.1(C�O). EI-MS: 346 (100,M�). Anal. calc. for C17H18N2O4S (346.41): C 58.94, H 5.24, N 8.09; found: C59.09, H 5.30, N 7.85.

General Procedure for the Preparation of Compounds 23 and 24. A soln. of 20 (0.20 g, 0.60 mmol)and the appropriate amine (21 or 22 ; 1.20 mmol) in THF (15 ml) was heated at reflux for 48 h. Thesolvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (25 ml), which waswashed with H2O (3� 5 ml). The org. phase was dried (Na2SO4) and concentrated, and the residue waspurified by FC (SiO2; CH2Cl2/MeOH 19 :1) to afford the title compounds, together with 25 (see below).


Data of 7-{[4-(4-Fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one(23). Yield: 20%. Beige solid. M.p. 174 ± 176� (i-PrOH). IR (KBr): 1682 (C�O), 1676 (C�O).1H-NMR (CDCl3): 1.70 ± 1.83 (m, N(CH2CH2)2CH); 2.12 ± 2.25 (m, 1 H of N(CH2CH2)2CH); 2.42 ± 2.51(m, 3 H of CH2N(CH2CH2)2CH); 2.79 (s, Me); 2.81 ± 2.97 (m, H�C(7), CH2(8)); 3.03 (dd, J� 17.0, 8.4,1 H of CH2(6)); 3.12 ± 3.26 (m, N(CH2CH2)2CH); 3.55 ± 3.60 (m, 1 H of CH2(6)); 7.13 (t, J� 8.5,H�C(3,5) of C6H4); 7.70 (s, H�C(4)); 7.95 (dd, J� 8.6, 5.5, H�C(2,6) of C6H4). 13C-NMR (CDCl3): 22.5(Me); 28.9, 30.1 (N(CH2CH2)2C); 32.5 (C(7)); 34.6 (C(8)); 43.6 (C(6)); 43.8 (N(CH2CH2)2C); 54.0, 54.3(N(CH2CH2)2C); 63.4 (CH2N); 116.2 (d, J(C,F)� 21.7, C(3,5) of C6H4); 122.2 (C(4)); 128.6 (C(4a));131.2 (d, J(C,F)� 9.0, C(2,6) of C6H4); 132.8 (d, J(C,F)� 3.2, C(1) of C6H4); 159.2 (C(3)); 160.7 (C(8a));168.0 (d, J(C,F)� 254.5, C(4) of C6H4); 197.8 (C(5)); 201.3 (C�O). EI-MS: 381 (8,M�). Anal. calc. forC22H24FN3O2 ¥ 1/3 H2O (387.46): C 68.20, H 6.42, N 10.85; found: C 68.16, H 6.29, N 10.68.

7-{[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one (24). Yield: 15%. Beige solid. M.p. 128 ± 130� (i-PrOH). IR (KBr): 1708 (C�O), 1617 (C�N).1H-NMR (CDCl3)2): 1.95 ± 2.08 (m, N(CH2CH2)2CH); 2.11 ± 2.26 (m, 1 H of N(CH2CH2)2CH); 2.46 ±2.54 (m, 3 H of CH2N(CH2CH2)2CH); 2.80 (s, Me); 2.94 ± 3.10 (m, 1 H of CH2(6), H�C(7), CH2(8),N(CH2CH2)2CH); 3.58 ± 3.64 (m, 1 H of CH2(6)); 7.07 (dt, J� 8.8, 2.0, H�C(5) of bxz); 7.25 (dd, J� 8.5,2.0, H�C(7) of bxz); 7.69 (dd, J� 8.8, 5.2, H�C(4) of bxz); 7.71 (s, H�C(4)). 13C-NMR (CDCl3)3): 23.0(Me); 30.1 (N(CH2CH2)2C); 31.6 (C(7)); 32.3 (C(8)); 38.6 (N(CH2CH2)2C); 60.0 (CH2N); 97.7 (d,J(C,F)� 27.1, C(7) of bxz); 113.0 (d, J(C,F)� 25.6, C(5) of bxz); 117.6 (C(3a) of bxz); 121.9 (C(4)); 123.0(d, J(C,F)� 11.3, C(4) of bxz); 128.5 (C(4a)); 159.2 (C(3)); 160.7 (C(8a)); 161.1 (C(3) of bxz); 164.4 (d,J(C,F)� 13.8, C(7a) of bxz); 165.9 (d, J(C,F)� 250.7, C(6) of bxz); 197.1 (C(5)). EI-MS: 394 (15, M�).HR-EI- MS: 394.180695 (M�, C22H23FN4O2; calc.: 394.180504).

Data of 5a,6,6a,7-Tetrahydro-3-methyl-5H-cyclopropa[g]cinnolin-5-one (25). Yield: 55%. Yellowoil. IR (film): 1682 (C�O). 1H-NMR (CDCl3): 0.74 (dd, J� 10.5, 5.7, 1 H of cyclopropyl CH2); 1.41 (d,J� 8.5, 5.5, 1 H of cyclopropyl CH2); 2.03 ± 2.08 (m, H�C(7)); 2.10 ± 2.17 (m, H�C(6)); 2.65 (s, Me);3.39 (dd, J� 18.1, 4.9, 1 H of CH2(8)); 3.68 (d, J� 18.1, 1 H of CH2(8)); 7.51 (s, H�C(4)). 13C-NMR(CDCl3): 13.4 (cyclopropyl CH2); 14.5 (C(7)); 22.4 (Me); 25.9 (C(6)); 28.4 (C(8)); 123.0 (C(4)); 127.9(C(4a)); 156.1 (C(3)); 160.8 (C(8a)); 197.0 (C(5)). EI-MS: 174 (100, M�).

This work was supported by the Spanish Comisio¬n Interministerial de Ciencia y TecnologÌa (CICYT;Grant SAF2002-04195-C03-01).M. A. (on leave from the University of Narinƒo, Colombia) andM. B. aregrateful to the Agencia Espanƒola de Cooperacio¬n Internacional (AECI) and to the Ministerio deEducacio¬n y Ciencia, respectively, for predoctoral fellowships. We are also grateful to Dr.MarÌa I. Loza,Departamento de FarmacologÌa, Universidad de Santiago de Compostela, for performing biologicalassays.

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Received September 15, 2005


synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential...

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