Potential antidepressants displayed combined α2-adrenoceptor antagonist and monoamine uptake inhibitor properties

J . Med. Chem. 2001, 44, 787-805

787

P oten tia l An tid ep r essa n ts Disp la yed Com bin ed r₂-Ad r en ocep tor An ta gon ist a n d

Mon oa m in e Up ta k e In h ibitor P r op er ties

Alex A. Cordi,* Isabelle Berque-Bestel,^†Thierry Persigand, J ean-Michel Lacoste, Adrian Newman-Tancredi,

Valerie Audinot, and Mark J . Millan

Institut de Recherches Servier, 11, rue des Moulineaux, F-92150 Suresnes, France

Received J uly 21, 2000

Classical antidepressants are thought to act by raising monoamine (serotonin and noradrena-

line) levels in the brain. This action is generally accomplished either by inhibition of monoamine

metabolism (MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants

and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer

from a time lag (3-6 weeks) before robust clinical efficacy can be demonstrated. This delay

may reflect inhibitory actions of noradrenaline at presynaptic R_2A-adrenergic auto- or

heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presyn-

aptic R_2A-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties

could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature,

only two molecules have been described with such a pharmacological profile. Of these,

napamezole (2) was chosen as a point of departure for the design of 4(5)-[(3,4-dihydro-2-

naphthalenyl)methyl]-4,5-dihydroimidazole (4a ), which displayed the desired profile: R_2A-

adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this

original molecule, a series of derivatives was designed and synthesized, encompassing

substituted as well as rigid analogues. Structure-activity relationships permitted the selection

of 14c (4(5)-[(5-fluoroindan-2-yl)methyl]-4,5-dihydroimidazole) as a development candidate.

In tr od u ction

The monoaminergic hypothesis of depression assumes

that the principle symptoms of depression reflect an

insufficient concentration of noradrenaline (NA) and

serotonin (SER) in corticolimbic synaptic clefts. Classical

antidepressants are thought to act by raising mono-

amine levels in the brain. This is accomplished either

by inhibition of monoamine metabolism (MAO inhibi-

tors) or by blockade of monoamine uptake (tricyclic

antidepressants: TCAs; selective SER reuptake inhibi-

tors: SSRIs; and selective NA reuptake inhibitors:

SNRIs). Historically, the monoaminergic hypothesis

F igu r e 1. Reference compound structures.

initially emphasized the role of NA,¹but over the past

decade, following the demonstration of the efficacy and

release, could be a status quo or even an overall decrease

safety of SSRIs,²as exemplified by the success of

in the neurotransmission. The same consideration may

fluoxetine (1; Figure 1), the importance of serotoninergic

be applied to the action of SSRIs which activate presyn-

mechanism has been underlined.

aptic 5-HT_1Aand 5-HT_1Bserotoninergic autoreceptors.

Currently, the major handicap of used antidepressant

These presynaptic receptors also slowly desensitize

agents, irrespective of their mechanism of action, is the

leading to a gradual increase of therapeutically effective

4-6 week delay required to establish therapeutic ef-

monoamine concentration in the presence of antidepres-

ficacy.³This time lag may reflect monoaminergic mech-

sant agents. This hypothesis may be tested either by

anisms. Thus inhibition of NA uptake by antidepres-

coadministration of a TCA, a SSRI, or a SNRI with an

sants increases levels of NA in the synaptic cleft, which

antagonist of these auto- or heteroreceptors or by

reinforces postsynaptically transmission, and also ac-

administration of a drug endowed with both proper-

tivates presynaptic R_2A-adrenergic autoreceptors,⁴which

ties.^5-10

decreases the release of NA as well as the release of

A second strategy implying the discovery of molecules

SER through R_2A-adrenergic heteroreceptors located on

serotoninergic terminals. The immediate consequence

of these two opposite processes, inhibition of uptake and

acting both as NA^11,12and/or SER¹³uptake inhibitors

and as antagonists at presynaptic auto- or heterorecep-

tors has been little exploited. Our research effort aimed

to identify a molecule endowed with NA and/or SER

uptake inhibitor properties and antagonist activity at

presynaptic R₂-adrenergic autoreceptors. We considered

napamezole from Sterling Laboratories (2; Figure 1)¹⁴

* To whom correspondence should be addressed. Tel: 33-1-5572-

2235. Fax: 33-1-5572-2430. E-mail: alex.cordi@fr.netgrs.com.

^†Present address: Faculte´ de Pharmacie, Universite´ de Paris-Sud,

F-92296 Chaˆtenay Malabry, France.

Published on Web 02/03/2001

788 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Sch em e 1. Method A^a

Cordi et al.

a

Reagents: (a) (EtO)₂P(O)CH₂CO₂Et, NaH, THF; (b) DIBAL-H, CH₂Cl₂or (1) LiAlH₄, THF, (2) IBX, THF; (c) TMSCN, ZnI₂; (d) NH₃,

MeOH; (e) NaCN, NH₄Cl, MeOH, H₂O; (f) Raney Ni, NH₃, MeOH or LiAlH₄, THF or AlH₃, ether; (g) HC(dNH)NH₂‚AcOH, EtOH or

BrCN, CH₂Cl₂; (h) (1) HCO₂H, HCl, (2) HCl, H₂O; (i) (1) LiAlH₄, THF, (2) BrCN, CH₃CN, K₂CO₃; (j) H₂/Pd/C, EtOH.

to be a prototype for this novel class of compounds and

a source of inspiration for our design. Although claimed

as a SER uptake blocker displaying R₂-adrenoceptor

antagonist properties, this compound manifests far

higher affinity for the latter site than for the former site

(see Table 1). Atipamezole (3; Figure 1),¹⁵a potent R₂-

adrenoceptor antagonist, displays an imidazole moiety

substituted in the 4(5)-position, encouraging exploration

of various substitutions of the imidazoline in the na-

pamezole skeleton (4). This change permitted a dif-

ferentiation of the two nitrogen atoms and revealed

their potential ability to afford contrasting pharmaco-

logical profiles. In addition, we have evaluated the

importance of the imidazole nucleus by replacing it with

different heterocycles (5-8), examined the importance

of the dihydronaphthalene skeleton by undertaking

diverse modifications (9-15), and, finally, rigidified the

molecule (16-24) in order to define the active conforma-

tion required for pharmacological efficacy.

which cyclized to imidazolines by reaction with forma-

midine acetate in EtOH. The imidazolines were usually

isolated as fumarate salts affording highly crystalline

salts from mixtures of i-PrOH and acetone.

Various ethylenediamines were obtained by reduction

of aminonitriles produced by Strecker reaction or one

of its variations, as observed in our previous work on

spiroimidazolines.¹⁶Another method that allowed access

to some aminonitriles was the substitution of a halide

or any other leaving group by the anion of the synthon

N-(diphenylmethylene)aminoacetonitrile developed by

O’Donnell (method B, Scheme 2).¹⁷

Substrates of the Strecker reaction were aldehydes

26a -j, 69 and ketone 67 obtained mainly through

Wadsworth-Emmons reaction of triethyl phosphono-

acetate on various 2-indanones and 2- tetralones. Esters

were either reduced directly in aldehydes using DIBAL-H

or reduced first to alcohol by LiAlH₄and further

oxidized using pyridinium chromate or iodoxybenzoic

acid (IBX)¹⁸to aldehydes.

Ch em istr y

Synthesis of aminoimidazolines and oxazolines was

accomplished via reaction of cyanogen bromide with the

corresponding ethylenediamines or 2-aminoethanols

(Scheme 1). These last intermediates were prepared

Most of the compounds were obtained following

general synthetic routes described in Scheme 1 (method

A). The key intermediates were ethylenediamines 28a -j

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 789

Sch em e 2. Method B^a

a

Reagents: (a) MeMgCl, TiCl₄; (b) CF₃CO₂H, trityl-OH; (c) NBS, AlBN; (d) (i) (C₆H₅)₂CdNCH₂CN, KOH, TBAB, (ii) 1 N HCl, ether;

(e) LiAlH₄, THF; (f) HC(dNH)NH₂‚AcOH, EtOH.

Sch em e 3^a

a

Reagents: (a) KO-t-Bu, toluene; (b) NaBH₄, MeOH; (c) CF₃CO₂H, CH₂Cl₂.

either by hydrolysis followed by reduction of the ami-

nonitrile 27a or by reduction of the cyanohydrin 29a ,

respectively.

step procedure, where the aldehyde was first condensed

with di(p-methoxyphenyl)methylamine²³in the presence

of 4 Å molecular sieves and then reacted with TMSCN.

High-yield reduction of the aminonitrile with LiAlH₄

afforded two diastereoisomeric ethylenediamines which

were easily separated by column chromatography on

silica gel eluting with a gradient (0-5%) of MeOH/NH₄-

OH (9/1) in CH₂Cl₂. The ethylenediamines were depro-

tected in a mixture of AcOH/H₂O (9/1), and the resulting

diamines were cyclized classically by reaction with

formamidine acetate. The use of di(p-methoxyphenyl)-

methylamine in the Strecker reaction brought two

advantages to the synthetic practice: (1) there was no

hydride substitution during the LiAlH₄reduction of the

aminonitrile and (2) the chromatographic separation of

the diastereoisomers was made easier, the introduction

of bulky groups close to the stereogenic position ampli-

fying the difference between the two isomers.

On the basis of the work of Ghatak,²⁴the ketone

intermediate 59 in the synthesis of 21a ,b was obtained

by 6-endo-aryl cyclization leading to the desired trans

ring junction (Scheme 6). The precursor of this cycliza-

tion was prepared by successive condensation of (2-

bromophenyl)methyl bromide with the monoacetal of

1,4-cyclohexanedione and tranformation of the keto

group in an exo-methylene group by Wittig reaction.²⁵

In the synthesis of the imidazole derivative 5, another

method (Scheme 3) was used. Alkylation of the 1-te-

tralone with 1-trityl-4-chloromethylimidazole¹¹led to 39

which was submitted to the reduction of the keto group

affording the alcohol which was deprotected and dehy-

drated at the same time, by trifluoroacetic acid.

In the case of rigid molecules, synthesis of corre-

sponding aldehydes 41, 43, 45a ,b, 53a ,b and ketone 59

required additional steps. For instance, the different

tetrahydrocyclopropanaphthalenyl aldehydes 41, 43,

and 45a ,b were prepared by carbene addition to the

corresponding olefins (Scheme 4) and transformation of

the esters into the aldehydes by reduction followed by

oxidation. As described (Scheme 5

) for molecules 20a ,b, analogues of 19a ,b,^19,20the spiro

cyclopropylic ester was formed from interaction of

1-indanone 47 with ethyl 2-methylenephosphonoacetate

in alkaline conditions.²¹The ketone functionality of the

indanone was reduced using NaBH₃CN in the presence

of ZnI₂,²²and the ester group was reduced by LiAlH₄

into the corresponding alcohol, which was further

oxidized to the aldehyde 53b using pyridinium chro-

mate. The Strecker reaction was accomplished via a two-

790 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

Sch em e 4^a

a

Reagents: (a) ZnEt₂, ICH₂Cl, C₂H₄Cl₂; (b) Rh₂(Acac)₄, N₂CHCO₂Et, ether; (c) (i) LiAlH₄, THF, (ii) CrO₃‚pyridine; (d) NaCN, NH₄Cl,

MeOH, H₂O; (e) LiAlH₄, THF; (f) HC(dNH)NH₂‚AcOH, EtOH, SiO₂chromatography: CH₂Cl₂/MeOH/NH₄OH.

Ta ble 1. Binding Affinities (pK_i) at Native Rat Receptors and

The dioxolane moiety was mildly cleaved using pyri-

Uptake Sites for Compounds with Substitution of the Aromatic

Moiety

dinium tosylate.²⁶

The synthesis of 22 (Scheme 7) took advantage of the

symmetry of the molecule which exists as a single

stereoisomer. Starting from 1,2-di(bromomethyl)ben-

zene, a double alkylation of dimethyl malonate led to

the five-membered ring 63. Transformation of the ester

groups into dibromide derivative 64 through reduction

and formation of the ditosylate derivative²⁷allowed the

formation of the four-membered ring 65 through dialky-

lation of the synthon N-(diphenylmethylene)amino-

acetonitrile. Straightforward reduction and cyclization

afforded the desired product 22.

The synthesis of compound 23 (Scheme 8) started

with preparation of the corresponding ketone 67 through

a modified Wittig-Horner reaction.²⁸Application of

classical conditions for the Strecker reaction, followed

by reduction and cyclization, led to 23 in moderate

yields.

Finally, the diastereoisomers 24a ,b (Scheme 9) are

further examples of successful use of the di(p-methoxy-

phenyl)methylamine as an ammonia substitute in the

Strecker reaction leading to easier separation of the

a

Mean of at least two independent determinations made in

diastereoisomers at the diamine level and more efficient

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

nt: not tested.

reduction of the nitrile group, avoiding nucleophilic

hydride substitution. The key aldehyde 69 was obtained

by alkylation of 2-methyl-1-tetralone by ethyl 2-bromo-

acetate, followed by reduction and oxidation.

bioavailability (ip and po) and antidepressant proper-

ties. Detailed reports of the pharmacological profiles of

selected compounds will appear elsewhere.

The primary evaluation consisted in determination

of affinity at rat R₁- and R₂-adrenoceptors by competition

with [³H]prazosin and [³H]RX 821,002, respectively, on

membranes prepared from rat cerebral cortex. In addi-

tion, affinities at SER and NA reuptake sites were

determined by competition experiments employing [³H]-

paroxetine and [³H]nisoxetine, respectively, and mem-

branes prepared from rat frontal cortex (Tables 1-6).

Biology

Molecules were evaluated in in vitro assays to define

their affinity at R₁- and R₂-adrenoceptors and SER and

NA reuptake sites. The results of this primary evalua-

tion allowed elaboration of structure-activity relation-

ships (SARs) discussed in this paper. In addition, certain

compounds were further evaluated in vivo to define their

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 791

Sch em e 5^a

a

Reagents: (a) LDA, ClP(O)(OEt)₂, THF; (b) DHP, PPTS, CH₂Cl₂; (c) NaH, toluene; (d) NaBH₃CN, ZnI₂, DCE; (e) KOtBu,

CH₂dC(OPO₃Et₂)CO₂Et, DMSO; (f) LiAlH₄, THF; (g) CrO₃, pyridine, CH₂Cl₂; (h) KCN, NH₄Cl, MeOH/H₂O and MeOH/NH₃, or

(p-CH₃OC₆H₄)₂CHNH₂, CH₂Cl₂and TMSCN; (i) AcOH/H₂O; (j) HC(dNH)NH₂‚AcOH, EtOH.

Antagonist actions at R₂-adrenoceptors were demon-

strated for selected compounds by modulation of [³⁵S]-

GTPγS binding at hR_2A-adrenoceptors expressed in CHO

cells, as previously reported²⁹(Table 7).

aromatic moiety, the most striking effect lies with the

chloro substitution at position 8, which increases affinity

at R₂-adrenoceptors (0.5 log unit), whereas affinities at

SER and NA uptake sites are only marginally affected

(0.3 and 0 log unit, respectively). The other substituents

at position 8 show less favorable profiles with the

fluorine being less potent, the methoxy group being

selective for the R₂-adrenoceptor and SER uptake sites

but losing efficacy at NA uptake sites, and the methyl

substitution leading to a specific SER uptake effect.

Among substituents at position 7, only fluorine mani-

fests an interesting profile with a substantial increase

in affinity at SER uptake sites (1.4 log units), ac-

companied, however, with a loss of affinity at R₂-

adrenoceptors (0.4 log unit). All other substituents in

Discu ssion

Compound 4a demonstrates how a small displace-

ment of one atom (nitrogen) can profoundly affect the

pharmacological profile of a molecule. Comparing na-

pamezole (2) with its isomer 4a (Table 1), affinity at

R₂-adrenoceptors is lowered by 1.4 log units, while

affinities at SER and NA uptake sites are increased by

0.7 and >1.3 log units, respectively, leading to a

molecule with an equilibrated receptorial profile. In this

new series of molecules, regarding substitution of the

792 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

Sch em e 6^a

a

Reagents: (a) LDA, THF; (b) Ph₃P⁺MeI^-, t-C₅H₁₁O^-Na⁺, toluene; (c) Bu₃SnH, AlBN, toluene; (d) PPTS, CH₂Cl₂; (e) KCN, NH₄Cl,

MeOH/H₂O, MeOH/NH₃; (f) LiAlH₄, THF; (g) HC(dNH)NH₂‚AcOH, MeOH.

Sch em e 7^a

Sch em e 8^a

a

Reagents: (a) (EtO)₂P(O)CH₂COCH₃, K₂CO₃, H₂O; (b) KCN,

NH₄Cl, MeOH, H₂O; (c) LiAlH₄, THF; (d) HC(dNH)NH₂‚AcOH,

EtOH.

Replacement of 4(5)-imidazoline by 4(5)-imidazole, as

in 5 (Table 2), significantly abolishes affinities at uptake

sites (-1.2 log units for both SER and NA uptake) but

enhances affinity at R₂-adrenoceptors by 1.9 log units.

This result supports the selectivity of the imidazole

moiety for R₂-adrenoceptors as exemplified by the

structures of atipamezole (3)¹⁵and MPV 1743³⁰which

are potent and selective R₂-adrenoceptors antagonists.

It implies that affinity at R₂-adrenoceptors is more

tolerant than affinities at bioamine uptake sites to the

pK_aof the critical nitrogen. Addition of an amino group

at position 2 of the 4(5)-imidazoline, as in 6, induces a

loss of affinity at R₂-adrenoceptors (-0.5 log unit)

accompanied by an increase of affinity at R₁-adrenocep-

tors (0.8 log unit) leading to a R₁-adrenergic selective

molecule, whereas affinities at SER and NA uptake sites

are not modified. Replacement of one nitrogen by

a

Reagents: (a) K₂CO₃, butanone; (b) LiAlH₄, THF/Et₂O; (c)

TsCl, pyridine; (d) LiBr, DMF; (e) NaH, (C₆H₅)₂CdNCH₂CN, THF,

HCl/Et₂O; (f) H₂, Ni, MeOH/NH₃; (g) HC(dNH)NH₂‚AcOH, MeOH.

this position induce a modest selectivity for SER uptake

sites compared to affinity at NA uptake sites and R₂-

adrenoceptors, with a lower overall level of activity. The

same trend can be found in the only example of

substitution at position 6.

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 793

Sch em e 9^a

a

Reagents: (a) ICH₂CO₂Et, KO-t-Bu, THF; (b) (i) NaBH₃CN, ZnI₂, C₂H₄Cl₂, (ii) LiAlH₄, THF, (iii) IBX, THF; (c) (i) (4-MeOC₆H₄)₂CHNH₂,

molecular sieves, CH₂Cl₂, (ii) TMSCN; (d) LiAlH₄, THF; (e) SiO₂chromatography: CH₂Cl₂/EtOH/NH₄OH; (f) AcOH, H₂O; (g)

HC(dNH)NH₂‚AcOH, EtOH.

Ta ble 2. Binding Affinities (pK_i) at Native Rat Receptors and

Uptake Sites for Compounds with Replacement of the

4(5)-Imidazoline Residue by Other Heterocycles

F igu r e 2. Imidazoline and imidazole tautomerism.

This mode of analysis is complicated, however, by the

tautomerism exhibited by imidazoline and imidazole

residues (Figure 2), each nitrogen in both heterocycles

being alternatively a basic sp²nitrogen with its lone pair

of electrons lying in the plane of the five-membered ring

(N³) or a less basic more sp³nitrogen with its lone pair

of electrons either conjugated with a π-system or

involved in an aromatic ring current (N¹). In addition,

at physiological pH, imidazoline residues are protonated

inducing a degeneracy of the electronic properties of the

two nitrogens but not of their spatial attributes.

Modification of the 3,4-dihydronaphthalene skeleton,

initially by oxidation, leading to the aromatic naphtha-

lenyl derivative 9 (Table 3), results in an increase of

the affinity at NA uptake sites only, with no sensible

change of affinity at either R₂-adrenoceptors or SER

a

Mean of at least two independent determinations made in

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

nt: not tested.

oxygen, in this specific heterocycle, leads either to the

5-(2-aminooxazoline) or to the 4-(2-aminooxazoline)

derivative, 7 and 8 respectively. In the former case,

affinity at R₂-adrenoceptors is preserved, and in the

latter case, affinity at SER uptake sites is maintained,

indicating that the two intracyclic nitrogen atoms might

contribute differently to affinities at R₂-adrenoceptors

and SER uptake sites, respectively. An additional

element supporting this analysis lies in the observation

that, in 2, both nitrogens are equivalent and lie in the

optimal position for high affinity at R₂-adrenoceptors,

while there is no nitrogen in the position responsible

for affinity at SER uptake sites, resulting in a pharma-

cological profile favoring affinity at R₂-adrenoceptors.

uptake sites. Reduction of the 3,4-dihydronaphthalenyl

group affords 10a as a mixture of diastereoisomers (≈50/

50) which exhibits enhanced affinities at R₂-adrenocep-

tors and SER uptake sites without any influence on

affinity at NA uptake sites. As previously demonstrated

for the parent molecule 4a , addition of a 8-chloro

substitution to this structure (10b) further increases

this effect. In contrast, replacement of the CH₂group

in position 4 by an oxygen atom (11a ) or a gem-dimethyl

moiety (12) reduces affinities at R₂-adrenoceptors and

SER uptake sites while keeping affinity at NA uptake

sites constant. Replacement of 3,4-dihydronaphthalenyl

skeleton by an indene ring (13) increases affinity at R₂-

adrenoceptors. In this structure, reduction of the double

794 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

Ta ble 3. Binding Affinities (pK_i) at Native Rat Receptors and

Uptake Sites for Compounds with Modification of the

3,4-Dihydronaphthalene Moiety

Ta ble 4. Binding Affinities (pK_i) at Native Rat Receptors and

Uptake Sites for Derivatives of Dihydroindans

a

Mean of at least two independent determinations made in

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

Ta ble 5. Binding Affinities (pK_i) at Native Rat Receptors and

Uptake Sites for Compounds with Partial Rigidification of the

Skeleton

a

Mean of at least two independent determinations made in

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

nt: not tested.

bond (14a ) leads to a selective R₂-adrenergic ligand by

increasing affinity at R₂-adrenoceptors (1.7 log units

compared to 4a ) without changing the other interac-

tions. Replacement of the 3-methylene group by oxygen

(15a ) decreases affinity at SER uptake sites by 1.1 log

units compared to 13.

a

Mean of at least two independent determinations made in

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

nt: not tested.

Aromatic substitution of the indan derivatives 14a -e

(Table 4) reinforces the SARs discovered in the dihy-

dronaphthalene skeleton (4a -j). Substitution by a

fluorine at position 4 (14b equivalent to position 8 in

4c) increases slightly affinity at R₂-adrenoceptors while

depressing slightly affinity at uptake sites and confers

overall a selective R₂-adrenoceptor antagonist profile to

the molecule. The same substitution at position 5 (14c

equivalent to position 7 in 4f) increases slightly affinity

at SER uptake sites while depressing slightly affinity

at R₂-adrenoceptors and significantly at NA uptake

sites, conferring an equilibrated R₂-adrenoceptor an-

tagonist and SER uptake inhibitor profile to the mol-

ecule. In an attempt to avoid the new chiral center in

position 2 of the indan moiety created by these substitu-

tion patterns, symmetrical disubstitution in position 5,6

was investigated. Molecule 14d demonstrates a pro-

found decreased affinity at R₂-adrenoceptors and a slight

decreased affinity at NA uptake sites, with a significant

increased affinity for the SER uptake sites.

In an attempt to clarify the active conformation of

these compounds at their different sites of action, the

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 795

Ta ble 6. Binding Affinities (pK_i) at Native Rat Receptors and

Uptake Sites for Compounds with Complete Rigidification and

Methyl Substitution of the Skeleton

F igu r e 3. Cyclopropyl rigidifications of molecule 4a .

can be added to structure 10, thereby reducing the

number of freely rotating bonds to one. These transfor-

mations also confine the imidazoline ring to a specific

part of the configurational space available to the parent

molecule. The 1,2-methano compounds 16a ,b demon-

strate a decreased affinity at NA uptake sites while

affinities at R₂adrenergic and SER uptake sites are

modulated by specific configuration of the diastereo-

isomer (Table 5). The cyclopropyl derivative obtained

when bonds 1 and 3 were reduced to a unique bond (17)

loses affinity at all three sites. In contrast, one of the

diastereoisomers of the 4-cyclopropyl derivative (18b)

retains affinity at NA uptake sites. The most interesting

pair of diastereoisomers is obtained when 2 and 3

become the bonds of a cyclopropyl ring leading to 19a ,b.

Potentiation occurs at R₂-adrenergic sites (1.1 log units)

and SER uptake sites (1.3 log units) without affecting

NA uptake sites in one diastereoisomer (19a ), while

decreased affinity for R₂-adrenergic sites and NA uptake

sites accompanied with a slight increase in affinity at

SER uptake sites is obtained in the other diastereoiso-

mer (19b). This trend is not observed when the identical

cyclopropyl rigidification is carried out on the indan

skeleton. The more potent diastereoisomer (20b) is a

selective R₂-adrenoceptor antagonist.

a

Mean of at least two independent determinations made in

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

Ta ble 7. Binding Affinities (pK_i) and Antagonist Potency (pK_B)

at hR_2A-Receptors Expressed in CHO Cells

Total rigidification of the parent molecule (4a ) was

accomplished in compounds 21a ,b where the two dia-

stereoisomers differ only by the spatial position of one

of the nitrogen atoms (N³in the tautomer drawn, Table

6). In 21a , this nitrogen is equatorial with its lone pair

of electrons projecting perpendicularly to the main plane

of the molecule, and in 21b, this nitrogen is axial with

its lone pair of electrons oriented toward the aromatic

ring. The other nitrogen atom (N¹in the tautomer

drawn) occupies more or less the same position in the

two diastereoisomers. This difference has a profound

effect on affinity at R₂-adrenoceptors (Table 6), 21a

being more potent than 21b by nearly 2 orders of

magnitude. On the other hand, it has a minimal effect

regarding affinity at SER uptake sites, 21a being more

potent than 21b by only 0.2 log unit. This result

confirms our previous analysis that N³is the critical

nitrogen atom for R₂-adrenergic affinity while N¹con-

trols affinity at SER uptake sites. Recent work by

Kozikowski’s group on tropane analogues³¹also empha-

sizes the importance of geometry between aromatic

moieties and the basic nitrogen, as Z and E isomers of

the phenylmethylene-7-azatricyclo[4.3.1.0^3,7]decane de-

rivative displayed contrasting activities at NA, SER, and

DA uptake sites.

Since neither of our totally rigid compounds is par-

ticularly potent at ΝΑ uptake sites, we synthesized 21

as an alternative strategy to rigidify the parent molecule

4a with, in this case, the lone pair of the nitrogen lying

in the plane of the aromatic ring. Results from the

a

Mean of at least two independent determinations made in

triplicate; the dispersion on pK_ivalues is only about 0.2 log unit.

skeleton was rigidified by means of cyclopropyl rings

(Figure 3). New bonds (1-4) bridging unbonded carbons

796 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

Finally, affinity at ΝΑ uptake sites is more difficult

to improve. The only change achieving a significant

increase was aromatization of the dihydronaphthalene.

This can be understood as a shortening of the distance

between a protonated nitrogen atom and an aromatic

ring (2 or 3 atoms apart versus 4 or 5 atoms). The most

striking effect emerged from the analysis of different

means for rigidification of the molecule. Indeed, each

rigidification which improved affinities at R₂-adreno-

ceptors and SER uptake sites decreased affinity at NA

uptake sites and vice versa. This observation reinforces

the conviction that a fundamental difference, such as

the distance between a critical nitrogen atom and an

aromatic ring, exists between these two sets of proper-

ties: on the one hand, affinities at R₂-adrenoceptors and

SER uptake sites and, on the other hand, affinity at NA

uptake sites. As long as enough flexibility is preserved

in the molecule the two conditions are compatible, but

as rigidity increases to improve affinities at R₂-adreno-

ceptors and SER uptake sites, a conformation necessary

to accommodate the NA uptake site becomes inacces-

sible and, in parallel, potency at this site diminishes.

In addition, affinity at NA uptake sites is very sensitive

to steric crowding as potency decreases when substitu-

tion is implemented at position 4(5) of the imidazoline

or position 1 of the tetrahydronaphthalenyl skeleton.

In addition to the results discussed above, we also

determined the affinities of specific compounds at R₁-

adrenoceptors. In most of cases, these affinities were

lower than for R₂-adrenoceptors with a difference close

to 2 log units for the most interesting compounds.

Finally, according to the hypothesis stated in the

Introduction, these SARs are based on the principle that

the interaction at R₂-adrenoceptors is antagonistic in

nature. We verified this by [³⁵S]GTPγS binding (Table

7). In the absence of the NA, no compound manifested

intrinsic activity, whereas the increase of [³⁵S]GTPγS

binding elicited by NA was dose-dependently inhibited

by all compounds tested. The pK_bs were, generally, in

good agreement with the pK_is determined in the same

cell line (Table 7) as the regression curve appears as a

straight line with a correlation coefficient and slope close

to unity: 0.916 and 0.986, respectively.

F igu r e 4. Critical structural and conformational features for

interaction with the R₂adrenoceptor site and the SER and NA

uptake sites.

biological evaluation (Table 6) demonstrate that this

orientation is inappropriate as the molecule loses all

activity.

The last change envisaged was the introduction of a

methyl substituent on the parent molecule (4a ) either

at position 4(5) of the imidazoline (23) or at position 2

of the naphthalene moiety (24a ,b). In the former case,

this modification has a deleterious effect on affinities

at R₂-adrenoceptors and NA uptake sites whereas af-

finity at SER uptake sites remained unchanged. In the

latter case, one diastereoisomer (24a ) displays enhance-

ment affinity at SER uptake sites while the other (24b)

exhibits decreased affinity at R₂-adrenoceptors.

To sum up, analysis of this series of napamezole (2)

analogues reveals several critical features modulating

affinities at R₂-adrenoceptors and SER and NA uptake

sites. Notably, R₂-adrenergic affinity is favored by the

presence of a sp²nitrogen atom, at a distance from an

aromatic ring which is best accommodated by a four-

atom chain in extended conformation. This nitrogen

must be able to attain a conformation in which its lone

pair of electrons points perpendicularly to the plane of

the aromatic ring and it is intolerant to steric crowding

in its close vicinity. Further, a broad range of pK_as

encompassing imidazole (pK_a≈ 7) and 2-aminoimida-

zoline (pK_a> 10) is acceptable for this nitrogen atom.

In addition, substituents in position 8 of the dihy-

dronaphthalene, in particular chlorine, selectively en-

hance this property (structure I, Figure 4).

In contrast, affinity at SER uptake sites is dependent

on the presence of a protonated nitrogen atom located

at a slightly higher distance from an aromatic ring with

a much broader tolerance in terms of the precise

orientation of the lone pair of electrons. Potentiation

occurs selectively when the aromatic ring is substituted

by a fluorine at position 7. On the other hand, system-

atic replacement of a CH₂group by an oxygen atom at

position 4 of dihydronaphthalene or at position 3 of

indene leads to a decreased potency. Both affinities at

R₂-adrenoceptors and SER uptake sites are incompatible

with the presence of additional bulky substituents at

position 4 of the dihydronaphthalene (structure II,

Figure 4).

On the basis of this analysis, compound 14c (S 34324)

was chosen for further pharmacological characterization

of the functionnal properties of R₂-adrenoceptor antago-

nist and SER uptake inhibitor endowed with NE uptake

inhibition potency. The separation and stereospecific

synthesis of the four isomers of 14c will be reported

later. Today, in vivo experiments indicate that com-

pound 14c is active in behavioral and neurochemical

models predictive of antidepressant activity (data not

shown).

Exp er im en ta l Section

Biology. 1. Deter m in a tion of Affin ity for r R₁-Ad r en o-

cep tor s. Binding affinity was determined as described³²by

competition with [³H]prazosin (Amersham, Les Ulis, France).

Rat cerebral cortex was homogenized using a polytron in 20

volumes (w/v) of buffer (50 mM Tris-HCl pH 7.4, 4 mM CaCl₂,

0.1% w/v ascorbic acid and 10 µM). The homogenate was

centrifuged (35000g, 20 min, 4 °C) and the pellet was resus-

pended in the same volume of buffer for a second centrifuga-

tion. The final pellet was resuspended in 80 volumes of buffer

and used for binding (final concentration 1/100 w/v). Mem-

branes were incubated in triplicate with 0.2 nM [³H]prazosin

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 797

Ta ble 8. Preparation Methods for the Imidazolines 4a -j, 9a , 11a -c, 12, 13, 14a -e, and 15a -c

compd

method

last step yield (%)

formula

elemental analysis

C, H, N, Cl

mp (°C)

4b

4c

4d

4e

4f

4g

4h

4i

4j

A

B

A

B

A

B

83

55

88

90

62

75

57

45

48

77

52

73

60

58

28

64

71

59

78

73

66

61

57

C

₁₄H₁₅ClN₂‚C₄H₄O₄

₁₄H₁₅FN₂‚C₄H₄O₄

₁₅H₁₆N₂O‚C₄H₄O₄

₁₅H₁₆N₂‚C₄H₄O₄

₁₄H₁₅FN₂‚C₄H₄O₄

₁₅H₁₅F₃N₂‚C₄H₄O₄

₁₅H₁₈N₂O‚C₄H₄O₄

₁₅H₁₈N₂‚C₄H₄O₄

₁₄H₁₄N₂‚C₄H₄O₄

₁₃H₁₄N₂O‚C₄H₄O₄

₁₂H₁₄N₂O₂‚C₄H₄O₄

₁₃H₁₆N₂O‚C₄H₄O₄

₁₆H₂₀N₂‚0.5C₄H₄O₄

₁₃H₁₄N₂‚C₄H₄O₄

₁₃H₁₆N₂‚0.5C₄H₄O₄

₁₃H₁₅FN₂‚0.5C₄H₄O₄

₁₃H₁₄F₂N₂‚0.5C₄H₄O₄

₁₅H₂₀N₂‚C₄H₄O₄

₁₂H₁₂N₂O‚C₄H₄O₄

₁₂H₁₁FN₂O‚C₄H₄O₄

₁₈H₁₆N₂O‚C₄H₄O₄

191-195

183-185

206-208

182-184

155-157

169-171

136-138

137-139

177-178

149-150

148-150

145-146

137-139

178-179

161-162

208-210

212-215

187-190

201-202

198-200

154-156

148-151

152-153

C, H, N

H, N; C: calcd, 63.68; found, 63.00

H, N; C: calcd, 66.65; found, 66.08

C, N; H: calcd, 4.83; found, 5.25

C, H, N

9a

11a

11b

11c

12

13

14a

14b

14c

14d

14e

15a

15b

15c

H, N; C: calcd, 65.20; found, 64.34

C, H, N

and competing ligand in a final volume of 0.5 mL, for 1 h at

22 °C. Nonspecific binding was defined with 10 µM phentola-

mine.

experiments, freshly prepared membranes (final concentration

1/80 w/v) were incubated in triplicate with 2nM [³H]paroxetine

and competing ligand in a final volume of 0.4 mL for 2 h at 25

°C. The high concentration of [³H]paroxetine was necessary

due to its low specific activity (<20 Ci/mmol). The incubation

buffer contained 50 nM Tris-HCl (pH 7.4), 120 nM NaCl and

5 mM KCl. Nonspecific binding was defined with 10 µM

citalopram.

2. Deter m in a tion of Affin ity for r R₂-Ad r en ocep tor s.

Binding affinity was determined as described³³by competition

with [³H]RX 821002 (Amersham, Les Ulis, France). Rat

cerebral cortex was homogenized using a polytron in 20

volumes (w/v) of buffer (Tris-HCl 50 mM, pH 7.5 at 25 °C,

EDTA 1 mM and guanylyl imidodiphosphate, GppNHp, 100

µM). The homogenate was centrifuged (35000g, 20 min, 4 °C)

and the pellet was resuspended in the same volume of buffer

for a second centrifugation. The final pellet was resuspended

in 300 volumes of buffer and used for binding (final concentra-

tion 1/400 w/v). For binding experiments membranes were

incubated with [³H]RX 821002 (0.4 nM final) and competing

ligand for 1 h at 22 °C. Nonspecific binding was defined with

phentolamine (10 µM).

3. Deter m in a tion of Affin ity for CHO-h R_2A-Ad r en ocep -

tor s. Binding affinity was determined as described³²by

competition with [³H]RX 821002 (Amersham, Les Ulis, France).

Membranes were prepared from CHO-hR_2Acells stably ex-

pressing the human adrenergic R_2A-receptor (provided by Prof.

A. D. Strosberg, Inst. Cochin, Paris, France). Cells grown in

adherent culture were harvested by centrifugation and ho-

mogenized using a polytron. The homogenate was centrifuged

(43000g, 30 min, 4 °C) and the membrane pellet resuspended

in buffer (Tris-HCl 33 mM, pH 7.5, EDTA 1 mM) with 10

strokes in a Potter homogenizer sonicated for 15 s and stored

at -80 °C until use. For binding experiments, ∼10 µg

membranes were incubated with [³H]RX 821002 (0.8 nM final)

and competing ligand, for 1 h at 22 °C. Nonspecific binding

was defined with phentolamine (10 µM).

6. Liga n d Bin d in g a t Na tive Ra t NA Reu p ta k e Sites.

Binding affinity was determined as described³⁵by competition

with [³H]nisoxetine (Amersham, Les Ulis, France). Membranes

were prepared from rat frontal cortex by homogenization with

a polytron followed by two centrifugations at 20000g. The

pellet was resuspended each time in 60 volumes of incubation

buffer. For binding experiments, freshly prepared membranes

(final concentration 1/100 w/v) were incubated in triplicate

with 2 nM [³H]nisoxetine and competing ligand in a final

volume of 0.5 mL for 4 h at 4 °C. The incubation buffer

contained 50 mM Tris-HCl (pH 7.4), 120 mM NaCl and 5 mM

KCl. Nonspecific binding was defined with 10 µM desipramine.

In all the experiments, at the end of the incubation period,

membranes were filtered through Whatman GF/B filters

pretreated with 0.1% de polyethylenimine followed by three

successive washes with ice-cold buffer. Radioactivity retained

on the filters was determined by scintillation counting.

7. Da ta An a lysis. Binding isotherms were analyzed by

nonlinear regression using the program Prism (GraphPad

Software Inc., San Diego, CA) to determine IC₅₀values. These

were converted to inhibition constants (K_i) via the Cheng-

Prusoff equation:³⁶K_i) IC₅₀/{(L/K_D) - 1}, where L is the

concentration of [³H]ligand and K_Dis its disscociation constant.

In practice, the amount of free [³H]ligand varies minimally

(<10%) from the total [³H]ligand added, so L was routinely

taken as equal to total [³H]ligand. The K_Dvalues were: 0.4

4. [³⁵S]GTP γS Bin d in g Assa y. Efficacy at CHO-hR_2A

receptors was determined by the binding of [³⁵S]GTPγS

(Amersham, Les Ulis, France) as described.²⁹Membranes (40

µg/mL) were preincubated 30 min at room temperature in the

presence of drugs or GTPγS diluted in binding buffer (20 mM

HEPES, pH 7.4, 100 mM NaCl, 3 µM GDP and 3mM MgCl₂).

Incubation was started by the addition of 0.2 nM [³⁵S]GTPγS

and further followed 60 min at room temperature. Nonspecific

binding was defined using nonradiolabeled GTPγS (10 µM).

5. Liga n d Bin d in g a t Na tive Ra t SER Reu p ta k e Sites.

Binding affinity was determined as described³⁴by competition

with [³H]paroxetine (NEN, Les Ulis, France). Membranes were

prepared from rat frontal cortex by homogenization with a

polytron followed by two centrifugations at 20000g. The pellet

was resuspended each time in incubation buffer. The final

resuspension was made in 40 volumes of buffer. For binding

nM for [³H]RX 821002 at rat R₂-receptors and 0.4 nM at hR_2A

-

receptors, 0.1 nM for [³H]prazosin, 1.2 nM for [³H]nisoxetine,

and 0.13 nM for [³H]paroxetine.

In the GTPγS binding experiment, antagonist potencies are

expressed as pK_B) -log K_B, with K_B) IC₅₀/1 + ([ago]/EC₅₀

-

ago), where IC₅₀is the inhibitory concentration of antagonist

that gives 50% inhibition of [³⁵S]GTPγS binding in the pres-

ence of a fixed concentration of agonist ([ago], NA 10 µM) and

EC₅₀ago is the EC₅₀of the agonist when tested alone.

Ch em istr y. Reagents were commercially available and of

synthetic grade. ¹H NMR spectra relative to TMS were

recorded on Bruker 200 or 400 MHz spectrometers. Infrared

spectra were obtained as Nujol emulsion, on a Bruker Fourier

transform spectrometer. All new substances were homo-

798 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

geneous in TLC and exhibited spectroscopic data consistent

with the assigned structures. Elemental analyses (C, H, N)

were performed on a Carlo Erba 1108 instrument and are in

agreement with the calculated values within the (0.4% range

unless otherwise stated. Melting points were obtained on a

Reichert hot stage microscope and are uncorrected. Silica gel

60, Merck 230-400 mesh, was used for both flash and

medium-pressure chromatography. TLC were performed on

precoated 5- × 10-cm, Merck silica gel 60 F254 plates (layer

thickness 0.25 mm).

4a was obtained as a white powder (0.53 g, 65%), mp 165-

166 °C. ¹H NMR (DMSO-d₆): δ 8.20 (m, 1H), 7.05 (m, 4H),

6.45 (s, 2H), 6.30 (s, 1H), 4.40 (m, 1H), 3.85 (t, 1H), 3.45 (dd,

1H), 2.75 (t, 2H). Anal. (C₁₄H₁₆N₂‚C₄H₄O₄) C, H, N.

Following the typical procedure described above, part of the

imidazolines listed in Table 8 were prepared, starting from

the appropriate tetralones.

2-Am in o-4(5)-[(3,4-d ih yd r on a p h t h a len -2-yl)m et h yl]-

4,5-d ih yd r oim id a zole, Br om h yd r a te (6). A solution of

BrCN (0.12 g, 1.1 mmol) in CH₂Cl₂(5 mL) was added dropwise

to a solution of 28a (0.21 g, 1 mmol) in CH₂Cl₂(5 mL), cooled

at 0 °C. After 2 h stirring, the solid was collected by filtration

and dried to afford 6 as a white powder (0.23 g, 75%), mp 143

°C. ¹H NMR (DMSO-d₆): δ 7.10 (m, 3H), 7.05 (d, 1H), 6.30 (d,

1H), 4.20 (m, 1H), 3.70 (t, 1H), 3.30 (dd, 1H), 2.75 (t, 2H), 2.40

(m, 2H), 2.20 (t, 2H). Anal. (C₁₄H₁₇N₃‚HBr) C, H, N, Br.

2-Am in o-4-[(3,4-d ih yd r on a p h t h a len -2-yl)m et h yl]-4,5-

d ih yd r ooxa zole, Hyd r och lor id e (7). 2-Am in o-3-(3,4-d i-

h yd r on a p h t h a len -2-yl)p r op ion ic Acid , H yd r och lor id e

(30). A solution of 27a (4.14 g, 21 mmol) in formic acid (20

mL) was saturated at 0 °C with anhydrous HCl. When the

gas evolution subsided, the acid was evaporated under reduced

pressure and the waxy residue was dissolved in HCl (6 N, 30

mL) and brought to reflux overnight. The solvent was evapo-

rated under reduced pressure and the residue crystallized from

EtOH to afford 30‚HCl as a white powder (4.88 g, 92%). ¹H

NMR (DMSO-d₆): δ 9.50-8.20 (bd, 4H), 7.20-7.00 (m, 4H),

6.35 (s, 1H), 4.05 (m, 2H), 3.00-2.70 (m, 4H), 2.40-2.00 (m,

2H).

2-Am in o-4-[(3,4-d ih yd r on a p h t h a len -2-yl)m et h yl]-4,5-

d ih yd r ooxa zole, Hyd r och lor id e (7). A suspension of 30‚

HCl (5.32 g, 21 mmol) in anhydrous THF (125 mL) was added

dropwise to a suspension of LiAlH₄(3.3 g, 87 mmol) in

anhydrous THF (500 mL) cooled at -10 °C. After 1 h stirring

at room temperature, the reaction mixture was hydrolyzed by

the successive careful addition of water (3.3 mL), NaOH (3.3

mL) and water (6.6 mL). Ether (300 mL) was added and the

suspension was stirred for 45 min, filtered and the filtrate

concentrated. The residue was purified by column chromatog-

raphy (SiO₂, CH₂Cl₂/EtOH/NH₄OH ) 90/9/1) to afford 2-amino-

3-(3,4-dihydronaphthalen-2-yl)propanol as a colorless oil (1.49

g, 35%). A solution of BrCN (0.90 g, 8.6 mmol) in THF (20

mL) was added dropwise at 0 °C, to a solution of the amino

alcohol in THF (12 mL) in the presence of K₂CO₃(1.20 g, 8.6

mmol). After 1 h stirring at room temperature, the solid was

filtered and the THF was evaporated under reduced pressure.

The residue was taken up in EtOH (25 mL) and treated with

ethereal HCl. The precipitate was then filtered and recrystal-

lized from a i-PrOH (10 mL)/diethyl ether (30 mL) mixture to

give 7 as a white powder (0.45 g, 16%), mp 168-170 °C. ¹H

NMR (DMSO-d₆): δ 9.50-8.50 (bd, 3H), 7.20-6.95 (m, 4H),

6.35 (s, 1H), 4.85 (m, 1H), 4.60-4.35 (m, 2H), 2.90-2.65 (m,

3H), 2.60 (m, 1H), 2.25 (m, 2H). Anal. (C₁₄H₁₆N₂O‚HCl) C, H,

N.

2-Am in o-5-[(3,4-d ih yd r on a p h t h a len -2-yl)m et h yl]-4,5-

d ih yd r ooxa zole, F u m a r a te (8a ). 2-Hyd r oxy-3-(3,4-d ih y-

d r on a p h th a len -2-yl)p r op ion itr ile (29a ). A solution of 26a

(3.44 g, 20 mmol) and ZnI₂(0.25 g, 0.8 mmol) in CH₂Cl₂(100

mL) was treated dropwise with TMSCN (2.18 g, 22 mmol).

After 20 h stirring, the solution was evaporated under reduced

pressure and the residue was used without further purifica-

tion.

2-Am in o-5-[(3,4-d ih yd r on a p h t h a len -2-yl)m et h yl]-4,5-

d ih yd r ooxa zole, F u m a r a te (8a ). A solution of 29a (15.6 g,

79 mmol) in anhydrous THF (125 mL) was added dropwise to

a suspension of LiAlH₄(3.3 g, 87 mmol) in anhydrous THF

(500 mL) cooled at -10 °C. After 1 h stirring at room

temperature, the reaction mixture was hydrolyzed by the

successive careful addition of water (3.3 mL), NaOH (3.3 mL)

and water (6.6 mL). Ether (300 mL) was added and the

suspension was stirred for 45 min, filtered and the filtrate

concentrated. The residue was purified by column chromatog-

raphy (SiO₂, CH₂Cl₂/EtOH/NH₄OH ) 90/9/1) to afford 2-amino-

3-(3,4-dihydronaphthalen-2-yl)propanol as a colorless oil (5.90

Meth od A: 4(5)-[(3,4-Dih yd r on a p h th a len -2-yl)m eth yl]-

4,5-d ih yd r oim id a zole, F u m a r a te (4a ). Eth yl (3,4-Dih y-

d r on a p h th a len -2-yl)a ceta te (25a ). A solution of triethyl

phosphonoacetate (56 g, 0.25 mol) in anhydrous THF (70 mL)

was added dropwise to a suspension of NaH (6 g, 0.25 mol) in

anhydrous THF maintained at 0 °C under an N₂atmosphere.

The reaction mixture was stirred at 10 °C for 30 min, cooled

at 0 °C and a solution of â-tetralone 24a (36.5 g, 0.25 mol) in

anhydrous THF (50 mL) was added dropwise. The solution was

stirred for 3 h at 20 °C, hydrolyzed at 0 °C by the addition of

water (200 mL). The organic solvents were evaporated under

reduced pressure and the residue extracted with CH₂Cl₂(3 ×

200 mL). The combined organic phase was washed with brine,

dried (MgSO₄) and concentrated to afford 25a as a brown oil

which was purified through vacuum distillation as a colorless

1

oil (46.5 g, 86%), bp 88-91 °C/0.03 mmHg. H NMR (CDCl₃):

δ 7.20-6.95 (m, 4H), 6.35 (s, 1H), 4.20 (q, 2H), 3.20 (s, 2H),

2.85 (t, 2H), 2.35 (t, 2H), 1.25 (t, 3H).

(3,4-Dih yd r on a p h th a len -2-yl)a ceta ld eh yd e (26a ). A so-

lution of DIBAL-H in CH₂Cl₂(1 M, 170 mL) was added

dropwise to a solution, cooled at -60 °C, of 25a (18.6 g, 0.086

mol) in CH₂Cl₂(360 mL). After 2 h stirring at -60 °C, the

reaction mixture was hydrolyzed by successive additions of

NH₄Cl (10%, 35 mL) and HCl (1 N, 42 mL). The temperature

was brought to 20 °C in 1 h and the solid was filtered and

washed with CH₂Cl₂(2 × 50 mL). The pooled filtrates were

washed with water (100 mL) and brine, dried (MgSO₄) and

concentrated. The crude product was purified by column

chromatography (SiO₂, cyclohexane/AcOEt ) 95/5) to yield 26a

as a colorless oil (9.2 g, 62%). ¹H NMR (CDCl₃): δ 9.75 (t, 1H),

7.15-6.95 (m, 4H), 6.40 (s, 1H), 3.30 (s, 2H), 2.85 (t, 2H), 2.30

(t, 2H).

2-Am in o -3-(3,4-d ih y d r o n a p h t h a le n -2-y l)p r o p io n i-

tr ile (27a ). A solution of 26a (3.44 g, 20 mmol) and ZnI₂(0.25

g, 0.8 mmol) in CH₂Cl₂(100 mL) was treated dropwise with

TMSCN (2.18 g, 22 mmol). After 20 h stirring, the solution

was evaporated under reduced pressure and the residue

poured into a solution of NH₃in MeOH (7 N, 200 mL). The

reaction mixture was kept in a sealed vessel for 4 h and

concentrated. The residue was taken up in HCl (1 N, 100 mL),

washed with ether (50 mL), the aqueous phase was basified

by addition of NaOH (6 N) and extracted with CH₂Cl₂(3 × 50

mL). The pooled organic phases were washed with brine, dried

(MgSO₄) and concentrated to afford 27a as an oil (2.8 g, 71%)

used without purification.

3-(3,4-Dih yd r on a p h t h a len -2-yl)p r op a n e-1,2-d ia m in e

(28a ). A mixture of 27a (2.57 g, 13 mmol), Raney Ni (2 g) in

MeOH (120 mL) and a solution of NH₃in MeOH (7 N, 50 mL)

was hydrogenated under 1 atm for 16 h. The reaction mixture

was filtered over Celite, concentrated and purified by column

chromatography (SiO₂, CH₂Cl₂/MeOH/NH₄OH ) 90/9/1) to

yield 28a as a colorless oil (1.45 g, 55%). ¹H NMR (DMSO-d₆):

δ 7.10 (m, 3H), 6.95 (d, 1H), 6.25 (s, 1H), 3.20 (m, 1H), 2.85

(dd, 1H), 2.70 (m, 3H), 2.25 (d, 2H), 2.10 (t, 2H).

4(5)-[(3,4-Dih yd r on a p h t h a len -2-yl)m et h yl]-4,5-d ih y-

d r oim id a zole, F u m a r a te (4a ). A mixture of 28a (0.50 g, 2.5

mmol) and formamidine acetate (0.29 g, 2.75 mmol) in EtOH

(20 mL) was stirred for 20 h. The solvent was evaporated under

reduced pressure and the residue was taken up in CH₂Cl₂(10

mL). After treatment with NaOH (2 N, 5 mL), the aqueous

phase was extracted with CH₂Cl₂(3 × 20 mL). The pooled

organic phases were dried (MgSO₄) and concentrated. The

remaining oil was dissolved in EtOH (10 mL) and treated with

a solution of fumaric acid (290 mg, 2.5 mmol) in EtOH (5 mL);

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 799

g, 37%). To a solution of the amino alcohol (1 g, 5 mmol) in

THF (30 mL) in the presence of K₂CO₃(0.75 g, 5.4 mmol), a

solution of BrCN (0.57 g, 5.4 mmol) in CH₂Cl₂(5 mL) was

added dropwise at 0 °C. After 1 h stirring at room temperature,

the solid was filtered and the THF was evaporated under

reduced pressure. The oily residue was dissolved in EtOH (25

mL) and treated with fumaric acid (0.25 g, 2.15 mmol). The

mixture was refluxed for 30 min and stirred at 20 °C for 3 h.

The solid 8a was collected by filtration and dried under

vacuum as a white powder (0.43 g, 30%), mp 213 °C. ¹H NMR

(DMSO-d₆): δ 7.20-7.00 (m, 4H), 7.75 (d, 1H), 6.45 (s, 1H),

6.35 (s, 1H), 5.00 (m, 1H), 3.80 (dd, 1H), 3.40 (dd, 1H), 2.80 (t,

2H), 2.60 (m, 2H), 2.25 (t, 2H). Anal. (C₁₄H₁₆N₂O‚C₄H₄O₄) C,

H, N.

2-Am in o-5-[(8-ch lor o-3,4-d ih yd r on a p h th a len -2-yl)m e-

th yl]-4,5-d ih yd r ooxa zole, F u m a r a te (8b). The compound

was obtained as described for 8a , as a white powder (32%),

mp 186-188 °C. ¹H NMR (DMSO-d₆): δ 7.25 (m, 1H), 7.15

(m, 2H), 6.70 (s, 1H), 6.45 (s, 2H), 5.25 (m, 1H), 3.90 (t, 1H),

3.50 (dd, 1H), 2.80 (t, 2H), 2.75 (m, 2H), 2.30 (t, 2H). Anal.

(C₁₄H₁₅ClN₂O‚C₄H₄O₄) C, H, N.

g, 5.1 mmol) in CCl₄(175 mL) was heated under reflux for 1

h. The suspension was then cooled to 10 °C, filtered and the

filtrate concentrated to afford 34 (10.5 g, 76%) as a white solid,

mp 123-124 °C. ¹H NMR (CDCl₃): δ 8.15 (d, 1H), 7.95 (d, 1H),

7.70 (d + dd, 2H), 7.85 (d, 1H), 7.75 (d, 1H), 7.35 (t, 1H), 4.70

(s, 2H).

2-Am in o-3-(8-ch lor o-2-n a p h t h yl)p r op ion it r ile (35). A

solution of 34 (5 g, 19 mmol) in CH₂Cl₂(75 mL) was added

dropwise under an N₂atmosphere, to a cooled (0 °C) suspen-

sion of N-(diphenylmethylene)aminoacetonitrile (4.5 g, 20.4

mmol), tetrabutylamonium bromide (0.6 g, 1.86 mmol) and

powdered KOH (85%, 1.3 g, 19.7 mmol) in CH₂Cl₂(75 mL).

After stirring for 1 night at room temperature, the suspension

was filtered and the filtrate concentrated. The resulting oily

residue was taken up in ether (200 mL) and HCl (1 N, 200

mL) and stirred vigorously overnight. The aqueous phase was

separated, basified with NaOH (6 N), extracted with CH₂Cl₂

(3 × 80 mL), dried (MgSO₄) and concentrated to afford

compound 35 as a brown oil (3.3 g, 73%) which was used

without further purification.

4(5)-(8-Ch lor o-2-n a p h t h ylm et h yl)-4,5-d ih yd r oim id a -

zole, F u m a r a te (9b). Starting from 35, the compound 9b was

obtained as described for 4a , as a white powder (86%), mp

172-175 °C. ¹H NMR (DMSO-d₆): δ 8.05 (s, 1H), 8.00 (d, 1H),

7.95 (d, 1H), 7.90 (dd, 1H), 7.65 (dd, 1H), 7.45 (t, 1H), 6.45 (s,

2H), 4.50 (m, 1H), 3.75 (m, 1H), 3.50 (m, 1H), 3.10 (m, 2H).

Anal. (C₁₄H₁₃ClN₂‚C₄H₄O₄) C, H, N, Cl.

Following the typical procedures described above, some of

the imidazolines listed in Table 8 were prepared, starting from

the appropriate bromides.

4(5)-[(3,4-Dih yd r on a p h t h a len -2-yl)m et h yl]im id a zole,

F u m a r a te (5). 4-[(1,2,3,4-Tetr a h yd r on a p h th a len -1-on -2-

yl)m eth yl]-1-tr itylim id a zole (38). A mixture of 1-tetralone

(0.73 g, 5 mmol), potassium tert-butylate (0.56 g, 5 mmol) and

4-chloromethyl-1-tritylimidazole (37; 1.8 g, 5 mmol) in toluene

(30 mL), was brought to reflux for 5 h. The solvents were then

evaporated, the residue taken up in a mixture of CH₂Cl₂/H₂O

(50 mL/50 mL), the organic phase separated, dried (MgSO₄)

and concentrated. The residual solid was purified by column

chromatography (SiO₂, cyclohexane/AcOEt ) 3/1) to afford 38

as a white solid (0.59 g, 25%). ¹H NMR (CDCl₃): δ 7.90 (d,

1H), 7.50 (t, 1H), 7.40-7.10 (m, 11H), 7.05 (m, 6H), 6.50 (s,

2H), 3.00 (t, 2H), 2.90 (AB system, 4H), 2.15 (t, 2H).

4-[(1,2,3,4-Tetr a h yd r on a p h th a len -1-ol-2-yl)m eth yl]-1-

tr itylim id a zole (39). A mixture of 38 (0.12 g, 0.25 mmol) and

NaBH₄(0.04 g, 1 mmol) in MeOH (12 mL) was stirred

overnight. Solvent was then evaporated, the residue taken up

in a mixture of Ether/H₂O (20 mL/20 mL), the organic phase

separated, dried (MgSO₄) and concentrated to afford 39 as a

mixture of two diastereoisomers (0.10 g, 93%). ¹H NMR

(CDCl₃): δ 7.65 (d, 1H), 7.35 (m, 11H), 7.15 (m, 8H), 6.60 (2s,

1H), 4.60 (2d, 1H), 2.90-2.70 (m, 4H), 2.05 (m, 1H), 1.90 (m,

1H), 1.70 (m, 1H).

4(5)-[(3,4-Dih yd r on a p h t h a len -2-yl)m et h yl]im id a zole,

F u m a r a te (5). To a solution of 39 (0.61 g, 1.3 mmol) in CH₂-

Cl₂(30 mL), CF₃CO₂H (1 mL) in CH₂Cl₂(5 mL) was added

dropwise at 0 °C. The solution was stirred overnight, solvent

was then evaporated, the residue taken up in HCl (0.5 N, 100

mL), the aqueous phase washed with ether (2 × 100 mL),

basified with NaOH (38%) up to pH 14, extracted with CH₂-

Cl₂(2 × 100 mL), dried (MgSO₄) and concentrated. The

residual solid was purified by column chromatography (SiO₂,

CH₂Cl₂/EtOH/NH₄OH ) 95/4.5/0.5), dissolved in acetone (15

mL) and fumaric acid (0.12 g) in i-PrOH (2.5 mL) was added

and 5 was obtained by filtration as an off-white solid (0.24 g,

56%), mp 138.5-140.5 °C. ¹H NMR (DMSO-d₆): δ 7.70 (s, 1H),

7.10 (m, 3H), 6.95 (d, 1H), 6.85 (s, 1H), 6.60 (s, 2H), 6.25 (s,

1H), 4.00-3.00 (m, 2H), 3.40 (s, 2H), 2.70 (t, 2H), 2.20 (t, 2H).

Anal. (C₁₄H₁₄N₂‚C₄H₄O₄) H, N; C: calcd, 66.25; found, 65.73.

4(5)-(1,2,3,7b-Tetr a h yd r ocyclop r op a [a ]n a p h th a len -1a -

ylm eth yl)-4,5-d ih yd r oim id a zole, F u m a r a te (16a ). Eth yl

1-(1,2,3,7b -Tet r a h yd r ocyclop r op a [a ]n a p h t h a len -1a -yl)-

a ceta te (40). A solution of Et₂Zn in hexane (1 M, 200 mL)

and a solution of ICH₂Cl (71 g, 400 mmol) in 1,2-dichloroethane

2-Am in o-5-[(7-m e t h yl-3,4-d ih yd r on a p h t h a le n -2-yl)-

m eth yl]-4,5-d ih yd r ooxa zole, F u m a r a te (8c). The com-

pound was obtained as described for 8a , as a white powder

1

(24%), mp 190-192 °C. H NMR (DMSO-d₆): δ 7.00 (m, 1H),

6.90 (d, 1H), 6.85 (s, 1H), 6.45 (s, 2H), 6.30 (s, 1H), 5.20 (m,

1H), 3.85 (t, 1H), 3.45 (m, 1H), 2.65 (m, 4H), 2.20 (m, 5H).

Anal. (C₁₅H₁₈N₂O‚C₄H₄O₄) C, H, N.

2-Am in o-5-[(6-m e t h yl-3,4-d ih yd r on a p h t h a le n -2-yl)-

m eth yl]-4,5-dih ydr ooxazole, Hem ifu m ar ate (8d). The com-

pound was obtained as described for 8a , as a white powder

1

(31%), mp 214-215 °C. H NMR (DMSO-d₆): δ 6.95 (d, 3H),

6.40 (s, 2H), 6.30 (s, 1H), 5.05 (m, 1H), 3.80 (t, 1H), 3.35 (dd,

1H), 2.70 (t, 2H), 2.55 (t, 2H), 2.25 (m, 5H). Anal. (C₁₅H₁₈

-

ClN₂O‚0.5C₄H₄O₄) C, H, N.

4(5)-[(1,2,3,4-Tetr a h yd r on a p h th a len -2-yl)m eth yl]-4,5-

d ih yd r oim id a zole, Su ccin a te (10a ). A solution of 4a (1 g,

3 mmol) in EtOH (20 mL) was hydrogenated in the presence

of Pd/C (10%, 100 mg) under 1 atm. After 2 h, the catalyst

was filtered through glass fibers and the solvent evaporated

under reduced pressure. The waxy residue was concentrated

through scratching in acetone (10 mL); compound 10a was

obtained as a white powder (0.99 mg, 98%), mixture (45/55)

of the two diastereoisomers, mp 158-159 °C. ¹H NMR (DMSO-

d₆): δ 8.15 (s, 1H), 7.05 (m, 4H), 4.30 (m, 1H), 3.90-3.40 (m,

2H), 2.80 (dd, 3H), 2.40 (dd, 1H), 2.25 (s, 4H), 1.85 (m, 2H),

1.70-1.40 (m, 3H). Anal. (C₁₄H₁₈N₂‚C₄H₆O₄) C, H, N.

Meth od B: 4(5)-(8-Ch lor o-2-n a p h th ylm eth yl)-4,5-d ih y-

d r oim id a zole, F u m a r a te (9b). 8-Ch lor o-2-m eth yl-1,2,3,4-

tetr a h yd r on a p h th a len -2-ol (32). To a cooled (-40 °C)

solution of TiCl₄(1 M, 90 mL) in CH₂Cl₂, MeMgBr (3 M, 30

mL) in THF was added over 30 min. To the resulting mixture,

8-chloro-2-tetralone (31; 13.5 g, 74.8 mmol) dissolved in CH₂-

Cl₂(60 mL) was added over 30 min. The resulting mixture

was then warmed to 0 °C. After 3 h, the suspension was poured

over ice (300 g), the layers were separated, the organic phase

was washed with HCl (2 N, 100 mL) and brine (100 mL), dried

(MgSO₄) and concentrated to afford 32 as a brown solid (14.1

g, 96%) used without further purification. ¹H NMR (CDCl₃):

δ 7.30-7.00 (m, 3H), 3.15-2.70 (m, 4H), 2.00-1.65 (m, 2H),

1.60 (m, 1H), 1.40 (s, 3H).

1-Ch lor o-7-m eth yln a p h th a len e (33). A mixture of 32

(14.2 g, 72 mmol), trityl-OH (21.9 g, 84 mmol) and CF₃CO₂H

(54 mL) was stirred at room temperature for 2 days. The

mixture was then extracted with cyclohexane (3 × 100 mL),

the pooled organic phases were washed with H₂O (100 mL),

NaHCO₃(5%, 100 mL) and brine (100 mL), dried (MgSO₄) and

concentrated to give a brown oil which was purified by flash

column chromatography (SiO₂, cyclohexane/AcOEt ) 95/5) to

1

afford 33 as a colorless oil (10.5 g, 85%). H NMR (CDCl₃): δ

8.05 (d, 1H), 7.75 (d, 1H), 7.70 (dd, 1H), 7.55 (m, 1H), 7.35

(dd, 1H), 7.25 (m, 1H), 2.55 (s, 3H).

1-Ch lor o-7-br om om eth yln a p h th a len e (34). A solution of

33 (10.8 g, 61.2 mmol), NBS (11.4 g, 64 mmol) and AIBN (0.8

800 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

(125 mL) were added successively dropwise to a solution of

25a (7.2 g, 33 mmol) in 1,2-dichloroethane (75 mL) cooled at

-25 °C. The temperature of the reaction mixture was brought

to 10 °C and maintained at that temperature under stirring

for 4 h. After cooling to 0 °C, the mixture was treated with

saturated NH₄Cl (50 mL) then water (100 mL) and extracted

with ether (3 × 200 mL). The pooled organic phases were

washed with brine, dried (MgSO₄) and concentrated to afford

40 as an oil (7.4 g, 98%) which was used without further

concentrated. To a solution of pyridine (11.4 mL, 140 mmol)

in CH₂Cl₂(150 mL) at 0 °C under a N₂atmosphere was added

CrO₃(7.25 g, 72.7 mmol). After stirring for 1 h at room

temperature, alcohol prepared from 42 dissolved in CH₂Cl₂

(100 mL) was added and the mixture was stirred at room

temperature for 3 h. The reaction mixture was then filtered

and the filtrate evaporated. The residue was diluted with Et₂O,

washed with 1 N NaOH, 1 N HCl and brine, dried (MgSO₄)

and concentrated to give the pure aldehyde 43 (1.63 g, 79%)

1

purification. H NMR (CDCl₃): δ 7.20 (m, 1H), 7.15 (m, 1H),

as an oil. H NMR (CDCl₃): δ 9.35 (d, 1H), 7.25 (m, 1H), 7.15

7.10 (m, 1H), 7.00 (m, 1H), 4.45 (q, 2H), 2.75-2.45 (m, 2H),

2.60 (d, 1H), 2.35 (d, 1H), 2.20 (m, 1H), 1.80 (m, 1H), 1.65 (m,

1H), 1.25 (t, 3H), 1.15 (m, 1H), 0.90 (m, 1H).

(m, 2H), 7.00 (m, 1H), 2.75-2.60 (m, 2H), 2.50 (m, 1H), 2.40

(m, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 1.90 (m, 1H).

4(5)-(1a ,2,3,7b-Tetr a h yd r o-1H-cyclop r op a [a ]n a p h th a -

len -1-yl)-4,5-d ih yd r oim id a zole, F u m a r a te (17). Starting

from the aldehyde 43, the compound was obtained as described

for 4a , as a mixture of diastereoisomers (55/45) which was

salified as the fumarate and crystallized from a mixture of

1-(1,2,3,7b -Tet r a h yd r ocyclop r op a [a ]n a p h t h a len -1a -

yl)a ceta ld eh yd e (41). A solution of compound 40 (5 g, 21.5

mmol) in anhydrous THF (75 mL) was added dropwise to a

suspension of LiAlH₄(0.97 g, 25 mmol) in anhydrous THF (75

mL) cooled at 0 °C. After 2 h stirring at room temperature,

the reaction mixture was hydrolyzed by the cautious addition

of NaOH (1 N, 7 mL), followed by ether (250 mL). The

suspension was stirred for 2 h, filtered and the filtrate

concentrated. To a solution of pyridine (18.5 mL, 226.5 mmol)

in CH₂Cl₂(360 mL) at 0 °C under a N₂atmosphere, was added

CrO₃(11.60 g, 116.2 mmol). After stirring for 1 h at room

temperature, alcohol obtained from 40 (3.64 g, 19.4 mmol) in

solution in CH₂Cl₂(80 mL) was added and the mixture was

stirred at room temperature for 3 h. The reaction mixture was

then filtered and the filtrate evaporated The residue was

diluted with Et₂O, washed with 1 N NaOH, 1 N HCl and brine,

dried (MgSO₄) and concentrated to give the pure aldehyde 41

(3.05 g, 79%) as an oil. ¹H NMR (CDCl₃): δ 9.85 (s, 1H), 7.30-

6.95 (m, 4H), 2.80-2.35 (m, 4H), 2.15 (m, 1H), 1.85 (dd, 1H),

1.65 (m, 1H), 1.25 (m, 1H), 0.90 (m, 1H).

4(5)-(1,2,3,7b-Tetr a h yd r ocyclop r op a [a ]n a p h th a len -1a -

ylm eth yl)-4,5-d ih yd r oim id a zole, F u m a r a te (16a ,b). Start-

ing from the aldehyde 41, the compound was obtained as

described for 4a , as a mixture of diastereoisomers (50/50)

which were separated by column chromatography (SiO₂, CH₂-

Cl₂/MeOH/NH₄OH ) 95/4.5/0.5). Each diastereoisomer was

salified as the fumarate and crystallized from a mixture of

i-PrOH/acetone as a white powder. Diastereoisomer 1, 16a

(12%), mp 192 °C. ¹H NMR (DMSO-d₆): δ 8.20 (s, 1H), 7.20

(dd, 1H), 7.15-7.00 (m, 3H), 6.45 (s, 2H), 4.35 (m, 1H), 2.60

(m, 1H), 2.50 (m, 1H), 2.05 (m, 1H), 1.90 (m, 1H), 1.80-1.65

(m, 2H), 1.50 (m, 1H), 1.05 (m, 1H), 0.80 (m, 1H). Anal.

(C₁₅H₁₈N₂‚C₄H₄O₄) C, H, N. Diastereoisomer 2, 16b (10%), mp

204 °C. ¹H NMR (DMSO-d₆): δ 7.95 (s, 1H), 7.20 (m, 1H),

7.15-6.95 (m, 3H), 6.40 (s, 2H), 4.25 (m, 1H), 3.85 (m, 1H),

3.40 (m, 1H), 2.70-2.35 (m, 2H), 2.10 (m, 1H), 1.95 (m, 1H),

1.75 (m, 1H), 1.60 (m, 1H), 1.50 (m, 1H), 1.05 (m, 1H), 0.85

(m, 1H). Anal. (C₁₅H₁₈N₂‚C₄H₄O₄) C, H, N.

1

i-PrOH/acetone as a white powder (61%), mp 95 °C. H NMR

(DMSO-d₆): δ 8.30 (s, 1H), 7.30-7.25 (2d, 1H), 7.15-6.95 (m,

3H), 6.45 (s, 2H), 3.90 (m, 2H), 3.55-3.45 (2m, 1H), 2.65-2.35

(m, 2H), 2.10-2.00 (2m, 2H), 1.65-1.55 (m, 3H). Anal.

(C₁₄H₁₆N₂‚C₄H₄O₄) C, H, N.

4(5)-(1a ,2,7,7a -Tetr a h yd r o-1H-cyclop r op a [b]n a p h th a -

len -1-yl)-4,5-d ih yd r oim id a zole, F u m a r a te (18a ,b). 1a ,2,7,-

7a -Tetr a h yd r o-1H-cyclop r op a [b]n a p h th a len e-1-ca r box-

ylic Acid , E t h yl E st er (44a ,b ). To a solution of 1,4-

dihydronaphthalene (4.32 g, 33 mmol) and Rh(AcO)₄(73 mg,

0.17 mmol) in ether (100 mL), N₂CHCO₂Et (3.8 g, 33 mmol)

dissolved in ether (21.5 mL) was added, at room temperature,

at the rate of 4 mL/h. The reaction mixture was filtered over

Al₂O₃(10 g), the solids rinsed with ether (100 mL) and the

pooled filtrates concentrated. The oily residue was purified by

column chromatography (SiO₂, cyclohexane/AcOEt: 1%) to

1

afford the isomers anti (44a ; 1.4 g, 20%). H NMR (CDCl₃): δ

7.10 (m, 2H), 7.00 (m, 2H), 4.10 (q, 2H), 3.20-3.00 (m, 4H),

2.00 (m, 2H), 1.50 (m, 1H), 1.25 (m, 3H). And syn (44b; 1.97 g,

28%). ¹H NMR (CDCl₃): δ 7.05 (m, 4H), 3.75 (q, 4H), 3.20-

3.00 (m, 4H), 1.85-1.65 (m, 3H), 1.10 (t, 3H).

1a ,2,3,7b-Tetr a h yd r o-1H-cyclop r op a [a ]n a p h th a len e-1-

ca r ba ld eh yd e (45a ). A solution of compound 44a (1.4 g, 6.5

mmol) in anhydrous THF (50 mL) was added dropwise to a

suspension of LiAlH₄(0.37 g, 9.8 mmol) in anhydrous THF

(50 mL) cooled at 0 °C. After 2 h stirring at room temperature,

the reaction mixture was hydrolyzed by the cautious addition

of NaOH (1 N, 0.4 mL), followed by ether (100 mL). The

suspension was stirred for 2 h, filtered and the filtrate

concentrated. To a solution of pyridine (6.15 mL, 75 mmol) in

CH₂Cl₂(100 mL) at 0 °C under a N₂atmosphere was added

CrO₃(3.92 g, 39 mmol). After stirring for 1 h at room

temperature, alcohol prepared from 44a dissolved in CH₂Cl₂

(25 mL) was added and the mixture was stirred at room

temperature for 3 h. The reaction mixture was then filtered

and the filtrate evaporated The residue was diluted with Et₂O,

washed with 1 N NaOH, 1 N HCl and brine, dried (MgSO₄)

and concentrated to give the pure aldehyde 45a (0.62 g, 55%)

as an oil. ¹H NMR (CDCl₃): δ 7.15-7.00 (m, 4H), 3.50 (d, 2H),

3.05 (m, 4H), 1.25 (bd, 1H), 1.20 (m, 2H), 0.90 (m, 1H).

4(5)-(1a ,2,7,7a -Tetr a h yd r o-1H-cyclop r op a [b]n a p h th a -

len -1-yl)-4,5-d ih yd r oim id a zole, F u m a r a te (18a ). Starting

from the aldehyde 45a , the compound was obtained as

described for 4a , salified as the fumarate and crystallized from

a mixture of i-PrOH/acetone as a white powder (61%), mp 194

°C. ¹H NMR (DMSO-d₆): δ 7.70 (s, 1H), 7.15-7.00 (m, 4H),

6.35 (s, 2H), 3.80-3.60 (m, 2H), 3.30 (m, 1H), 3.10-2.85 (m,

4H), 1.30 (m, 2H), 0.60 (m, 1H). Anal. (C₁₄H₁₆N₂‚C₄H₄O₄) H,

N; C: calcd 69.86; found 69.41.

4(5)-(1a ,2,3,7b-Tetr a h yd r o-1H-cyclop r op a [a ]n a p h th a -

len -1-yl)-4,5-d ih yd r oim id a zole, F u m a r a te (17). 1a ,2,3,7b-

Tet r a h yd r o-1H -cyclop r op a [a ]n a p h t h a len e-1-ca r b oxyl-

ic Acid , E t h yl E st er (42). To a solution of 1,2-dihydro-

naphthalene (6.5 g, 50 mmol) and Rh₂(AcO)₄(51 mg, 0.11

mmol) in ether (30 mL), N₂CHCO₂Et (5.7 g, 50 mmol) dissolved

in ether (15 mL) was added, at room temperature, at the rate

of 2.5 mL/h. The reaction mixture was filtered over Al₂O₃(10

g), the solids rinsed with ether (100 mL) and the pooled

filtrates concentrated. The oily residue was purified by column

chromatography (SiO₂, cyclohexane/AcOEt ) 1.25%) to afford

the isomers syn (2.7 g, 25%) and anti (42; 3.68 g, 34%). ¹H

NMR (CDCl₃): 7.35-6.90 (m, 4H), 6.15 (q, 2H), 2.80-2.30 (m,

3H), 2.30-2.10 (m, 2H), 2.05 (m, 1H), 1.90-1.60 (m, 1H), 1.25

(t, 3H).

1a ,2,3,7b-Tetr a h yd r o-1H-cyclop r op a [a ]n a p h th a len e-1-

ca r boxa ld eh yd e (43). A solution of compound 42 (2.6 g, 12

mmol) in anhydrous THF (75 mL) was added dropwise to a

suspension of LiAlH₄(0.7 g, 18 mmol) in anhydrous THF (75

mL) cooled at 0 °C. After 2 h stirring at room temperature,

the reaction mixture was hydrolyzed by the cautious addition

of NaOH (1 N, 7 mL), followed by ether (250 mL). The

suspension was stirred for 2 h, filtered and the filtrate

4(5)-(1a ,2,7,7a -Tetr a h yd r o-1H-cyclop r op a [b]n a p h th a -

len -1-yl)-4,5-d ih yd r oim id a zole, F u m a r a te (18b). Starting

from the ester 44b, the compound was obtained as described

for 18a , salified as the fumarate and crystallized from a

mixture of i-PrOH/acetone as a white powder (41%), mp 185-

187 °C. ¹H NMR (DMSO-d₆): δ 8.10 (s, 1H), 7.05 (m, 4H), 6.45

(s, 1H), 3.70 (m, 1H), 3.55-3.30 (m, 2H), 3.25-2.65 (m, 4H),

1.45 (m, 2H), 1.15 (m, 1H). Anal. (C₁₄H₁₆N₂‚C₄H₄O₄) C, H, N.

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 801

4(5)-{Sp ir o[cyclop r op a n e -2′:2′′-(1′′,2′′,3′′,4′′-t e t r a h y-

d r on a p h th a len e)]-1′-yl}-4,5-d ih yd r oim id a zole, F u m a r a te

(19a ). (1-Oxo-1,2,3,4-t et r a h yd r on a p h t h a len -2-yl)p h os-

p h on ic Acid , Dieth yl Ester (48). A solution of 1-tetralone

(10 g, 68 mmol) in anhydrous THF (120 mL) was added

dropwise to a stirred 1 M solution of lithium diisopropylamide

(75 mmol, 75 mL) at -65 °C under N₂. After stirring for 45

min, the resulting enolate was treated with diethyl chloro-

phosphate (12.90 g, 75 mmol) and the mixture was allowed to

warm to 0 °C over the course of 50 min. After this mixture

was cooled to -70 °C, it was transferred to a 2 M solution of

lithium diisopropylamide (150 mmol, 75 mL). The resulting

solution was allowed to warm to 10 °C over 2 h and was treated

with a solution of acetic acid (272 mmol, 15.5 mL) in Et₂O (250

mL). The resulting mixture was filtered and the filtrate

concentrated. The oily residue was purified by flash chroma-

tography (SiO₂, cyclohexane/EtOAc ) 60/40) to give the

phosphonate 48 (13.5 g, 70%) as a brown oil. ¹H NMR

(CDCl₃): δ 8.05 (d, 1H), 7.50 (td, 1H), 7.40-7.20 (m, 2H), 4.30-

4.00 (m, 4H), 3.40-3.10 (m, 2H), 3.00-2.60 (m, 1H), 2.60-

2.30 (m, 2H), 1.40-1.10 (2t, 6H).

as an oil. ¹H NMR (CDCl₃): δ 9.50 (d, 1H), 7.05 and 6.95 (2m,

4H), 3.00-2.60 (m, 4H), 2.10-1.80 (m, 3H), 1.20 and 1.50 (2m,

2H).

1-{Spir o[cyclopr opan e-2′:2′′-(1′′,2′′,3′′,4′′-tetr ah ydr on aph -

th a len e)]-1′-yl}eth a n e-1,2-d ia m in e (54a ,b). Starting from

the aldehyde 53a , the compounds were obtained as described

for 4a , as a mixture of two diastereoisomers (50/50) 54a /54b

(0.905 g, 36%) as a brown oil. The two diastereoisomers were

separated by HPLC (Kromasil 100.5 C18, 265 nm, CH₃OH/

H₂O/CF₃COOH ) 350/650/5). 54a : ¹H NMR (CDCl₃): δ 7.20-

7.00 (2m, 4H), 3.05 and 2.80 (m, 2H), 2.90 (m, 3H), 2.70 (m,

1H), 2.45 (m, 1H), 2.00 (m, 1H), 1.65 (m, 1H), 1.60 (m, 4H),

0.75 (m, 1H), 0.60 (m, 1H), 0.25 (m, 1H). 54b: ¹H NMR

(CDCl₃): δ 7.20-7.00 (2m, 4H), 3.00 and 2.20 (m, 2H), 2.90

(m, 3H), 2.65 (m, 1H), 2.45 (m, 1H), 1.90 (m, 1H), 1.60 (m,

1H), 1.60 (m, 4H), 0.75 (m, 1H), 0.65 (m, 1H), 0.30 (m, 1H).

4(5)-{Sp ir o[cyclop r op a n e -2′:2′′-(1′′,2′′,3′′,4′′-t e t r a h y-

d r on a p h th a len e)]-1′-yl}-4,5-d ih yd r oim id a zole, F u m a r a te

(19a ). A mixture of the above diamine 54a (0.17 g, 0.8 mmol)

and formamidine acetate (0.094 g, 0.9 mmol) in EtOH (5 mL)

was stirred at 20 °C under N₂for 12 h. The solvent was

evaporated and the residue taken up in 1 N HCl. The acidic

phase was washed with Et₂O and rendered basic with aqueous

NaOH (35%); the mixture was extracted with CH₂Cl₂and the

organic layer washed with brine, dried (MgSO₄) and evapo-

rated. The solid residue was dissolved in acetone (10 mL) and

treated with a solution of fumaric acid (0.082 g, 0.7 mmol) in

i-PrOH (4 mL). After evaporation and crystallization of the

residue from acetone/i-PrOH, the derivative 19a was obtained

as a white powder (0.068 g, 65%), mp 149 °C. ¹H NMR (DMSO-

d₆): δ 8.20 (s, 1H), 7.10 (m, 3H), 7.00 (d, 1H), 3.90 (m, 1H),

3.90 and 3.55 (m, 2H), 2.95 and 2.80 (m, 2H), 2.90 and 2.25

(m, 2H), 2.00 and 1.55 (m, 2H), 1.05 (m, 1H), 0.55 (m, 1H),

0.30 (m, 1H). Anal. (C₁₅H₁₈N₂‚C₄H₄O₄) C, H, N.

4(5)-{Sp ir o[cyclop r op a n e -2′:2′′-(1′′,2′′,3′′,4′′-t e t r a h y-

d r on a p h th a len e)]-1′-yl}-4,5-d ih yd r oim id a zole, F u m a r a te

(19b). Compound 19b was prepared according to the procedure

described for 19a and obtained as a white solid, mp 164 °C.

¹H NMR (DMSO-d₆): δ 8.25 (s, 1H), 7.10 (m, 3H), 7.05 (d, 1H),

3.95 (m, 1H), 3.95 and 3.35 (m, 2H), 2.80 and 2.45 (m, 2H),

2.80 (m, 2H), 1.75 and 1.65 (m, 2H), 0.97 (m, 1H), 0.65 (m,

1H), 0.55 (m, 1H). Anal. (C₁₅H₁₈N₂‚C₄H₄O₄) C, H; N: calcd,

8.18; found, 7.65.

4(5)-[Sp ir o(cyclop r op a n e-2′:2′′-in d a n )-1′-yl]-4,5-d ih y-

d r oim id a zole, F u m a r a te (20a ). {Sp ir o[cyclop r op a n e-2:

2′-(1′-in d a n on e)]-1-yl}ca r boxylic Acid , Eth yl Ester (50).

Solid NaH (3.43 g, 140 mmol) was added portionwise to a

solution of 1-indanone (20 g, 120 mmol) and ethyl 2-[(diethoxy-

phosphoryl)oxy]acrylate (36 g, 140 mmol) in anhydrous THF

(260 mL) in such a way that the temperature did not exceed

35 °C. At the end of the addition the reaction vessel was

plunged into an oil bath at 50 °C, the reaction mixture

temperature climbed to 60 °C, afterward it was kept stirring

at 45 °C for 1 h. The reaction mixture was poured on a mixture

of ice (1 L) and HCl (1 N, 1 L), extracted with AcOEt (3 × 600

mL), dried (MgSO₄), and concentrated. The residue was

purified by column chromatography (SiO₂, cyclohexane/AcOEt

) 93/7) to yield 50 as a colorless oil (3.8 g, 26%). ¹H NMR

(CDCl₃): δ 7.80 (m, 1H), 7.65 (m, 1H), 7.50 (m, 1H), 7.40 (m,

1H), 4.20 (m, 2H), 3.30 (s, 1H), 2.50 (m, 1H), 1.75 (m, 2H)1.25

(t, 3H).

2-Oxir a n ylm eth oxytetr a h yd r op yr a n (46). A solution of

glycidol (5 g, 67.5 mmol), dihydropyran (28.4 g, 337.5 mmol)

and pyridinium tosylate (1.70 g, 6.7 mmol) in CH₂Cl₂(300 mL)

was stirred for 4 h at 20 °C. The solution was then washed

once with saturated aqueous NaCl, dried (MgSO₄) and con-

centrated in vacuo. The residue was purified by flash chro-

matography (SiO₂, cyclohexane/EtOAc ) 50/50) to give the

1

epoxyde 46 (3.78 g, 35%) as a colorless oil. H NMR (CDCl₃):

δ 4.65 (m, 1H), 3.85 and 3.50 (2m, 2H), 3.95, 3.70 and 3.40

(3m, 2H), 3.20 (m, 1H), 2.80, 2.70 and 2.60 (3m, 2H), 2.00-

1.40 (m, 6H).

2′-(Tet r a h yd r op yr a n -2-yloxym et h yl)sp ir o[1′.2]cyclo-

p r op a n e-3,4-d ih yd r o-1-oxon a p h th a len e (49). A solution of

phosphonate 48 (27 g, 95 mmol) in toluene (60 mL) was added

to a suspension of NaH (4.40 g, 109.2 mmol) in toluene (160

mL) at 20 °C under N₂. The reaction mixture was stirred at

ambient temperature for 1 h and epoxyde 46 (30 g, 190 mmol)

was added. After refluxing for 4 days, the solution was cooled,

hydrolyzed with water and extracted with Et₂O (3 × 100 mL).

The organic layer was then washed with saturated aqueous

NaCl, dried (MgSO₄) and concentrated in vacuo. The residue

was purified by flash chromatography (SiO₂, cyclohexane/

EtOAc ) 80/20) to give the compound 49 (19 g, 70%) as a pale

1

red oil. H NMR (CDCl₃): δ 8.00 (d, 1H), 7.50 (t, 1H), 7.40-

7.20 (m, 2H), 4.65 (2m, 1H), 4.05, 3.75, 3.65 and 3.40 (4m, 2H),

3.85 and 3.55 (2m, 2H), 3.30-2.90 (m, 2H), 2.20-2.00 (m, 3H),

1.70-1.40 (m, 7H), 0.70 (m, 1H).

{Sp ir o[cyclop r op a n e-2:2′-(1′,2′,3′,4′-t et r a h yd r on a p h -

th a len e)]-1-yl}m eth a n ol (52a ). To a solution of compound

49 (2.50 g, 8.7 mmol) in 1,2-dichloroethane (45 mL) at room

temperature under N₂were added solid ZnI₂(4.16 g, 13 mmol)

and NaBH₃CN (4.10 g, 62.2 mmol). The reaction mixture was

heated at 80-85 °C for 3 h. It was then cooled and poured

into an ice cold mixture of saturated aqueous NH₄Cl containing

10 vol % of 5 N HCl (180 mL). The mixture was extracted with

EtOAc (3 × 80 mL) and the combined extracts were dried

(MgSO₄) and evaporated to dryness. The residue was purified

by flash chromatography (SiO₂, cyclohexane/EtOAc ) 70/30)

to give the alcohol 52a (760 mg, 46%) as a colorless oil. ¹H

NMR (CDCl₃): δ 7.05 (m, 4H), 3.70 (t, 2H), 2.90 (t, 2H), 2.80

and 2.55 (2d, 2H), 1.80 (m, 2H), 1.20 (m, 2H), 0.65 and 0.30

(2dd, 2H).

{Sp ir o[cyclop r op a n e-2:2′-(1′,2′,3′,4′-t et r a h yd r on a p h -

t h a len e)]-1-yl}ca r b oxa ld eh yd e (53a ). To a solution of

pyridine (18.5 mL, 226.5 mmol) in CH₂Cl₂(360 mL) at 0 °C

under N₂was added CrO₃(11.60 g, 116.2 mmol). After stirring

for 1 h at room temperature, alcohol 52 (3.64 g, 19.4 mmol) in

solution in CH₂Cl₂(80 mL) was added and the mixture was

stirred at room temperature for 2 h. The reaction was then

filtered and the filtrate evaporated in vacuo. The residue was

diluted with Et₂O, washed with 1 N NaOH, 1 N HCl and

saturated aqueous NaCl, dried (MgSO₄) and evaporated under

reduced pressure to give the pure aldehyde 53a (3.05 g, 85%)

[Sp ir o(cyclop r op a n e-2:2′-in d a n )-1-yl]ca r boxylic Acid ,

Eth yl Ester (51). Compound 50 (24.2 g, 90 mmol) was added

dropwise under mechanical stirring, to a suspension of NaBH₃-

CN (42.7 g, 680 mmol) and ZnI₂(41.5 g, 130 mmol) in 1,2-

dichoroethane (500 mL). The suspension was brought to reflux

under stirring for 14 h. The inorganic salts were filtered and

the filtrate was hydrolyzed by NH₄Cl (10%, 1 L) and HCl (6

N, 180 mL). The aqueous phase was extracted with AcOEt (2

× 500 mL), the salts were hydrolyzed in the same aqueous

phase which was extracted one more time with AcOEt (2 ×

300 mL). The pooled organic phases were washed with Na₂-

CO₃(10%, 500 mL) and brine (500 mL), dried (MgSO₄) and

concentrated. The residue was purified by column chromatog-

802 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

raphy (SiO₂, cyclohexane/AcOEt ) 95/5) to yield 51 as a

colorless oil (3.8 g, 26%). ¹H NMR (CDCl₃): δ 7.25-7.10 (m,

4H), 4.15 (m, 2H), 3.25-2.80 (m, 4H), 1.85 (m, 1H), 1.35 (m,

1H), 1.25 (m, 3H), 1.20 (m, 1H).

3.75 (m, 2H), 3.45-3.15 (m, 2H), 2.80 (m, 2H), 1.35 (m, 1H),

0.95 (m, 1H), 0.60 (m, 1H). Anal. (C₁₄H₁₆N₂‚0.5C₄H₄O₄) C, H,

N.

4(5)-[Sp ir o(cyclop r op a n e-2′:2′′-in d a n )-1′-yl]-4,5-d ih y-

d r oim id a zole, F u m a r a te (d ia ster eom er 2, 20b). Starting

from the diamine 55d (diastereomer 2), the compound was

obtained as described for 20a , 20b (68%), mp 178 °C. ¹H NMR

(DMSO-d₆): δ 8.25 (s, 1H), 7.30-7.10 (m, 4H), 6.45 (s, 1H),

3.95 (m, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 3.15-2.65 (m, 4H),

1.20 (m, 1H), 0.90 (m, 1H), 0.70 (m, 1H). Anal. (C₁₄H₁₆N₂‚

C₄H₄O₄) C, H, N.

[Sp ir o(cyclop r op a n e-2:2′-in d a n )-1-yl]ca r bin ol (52b). A

solution of compound 51 (13.9 g, 53 mmol) in anhydrous THF

(250 mL)was added dropwise to a suspension of LiAlH₄(3.1

g, 82 mmol) in anhydrous THF (250 mL) cooled at -18 °C.

After 3 h stirring at room temperature, the reaction mixture

was hydrolyzed by the successive cautious additions of water

(3.1 mL), NaOH (3.1 mL) and water (6.2 mL). The resulting

suspension was stirred overnight, filtered and the filtrate

concentrated. Compound 52b was used without further puri-

fication. ¹H NMR (CDCl₃): δ 7.20 (m, 4H), 3.80-3.50 (m, 2H),

3.20-2.75 (m, 4H), 1.30 (m, 2H), 0.85 (m, 1H), 0.50 (m, 1H).

[S p ir o (c y c lo p r o p a n e -2:2′-in d a n )-1-y l]c a r b o x a ld e -

h yd e (53b). A solution of compound 52b (14.3 g, 68 mmol) in

CH₂Cl₂(140 mL)was added dropwise to a suspension of

pyridinium chromate prepared at 0 °C from pyridine (68 mL,

670 mmol) and CrO₃(42 g, 420 mmol) in CH₂Cl₂(1 L). After

5 h stirring, the solids were filtered, washed with ether (100

mL) and the filtrates concentrated. The residue was taken up

in ether (1 L), the insoluble material filtered, the filtrate

washed successively with NaOH (1 N, 1 L), HCl (1 N, 2 × 750

mL), NaHCO₃(10%, 2 × 500 mL), brine (500 mL), dried

(MgSO₄) and concentrated to afford compound 53b which was

used without further purification. ¹H NMR (CDCl₃): δ 9.40

(d, 1H), 7.20 (m, 4H), 3.30-2.85 (m, 4H), 2.10 (m, 1H), 1.40

(m, 1H), 0.60 (m, 1H).

Sp ir o[(1,3-d ia za cyclop en t-1-en e)-5:2′-(tr a n s-1′,2′,3′,4′,-

4′a,9′,9′a,10′-octah ydr oan th r acen e)], Fu m ar ate (21a). 7-(2-

Br om oben zyl)-1,4-d ioxa sp ir o[4.5]d eca n -8-on e (56). To a

THF solution of lithium diisopropylamide (1 M, 150 mL) cooled

to -78 °C under N₂was added dropwise a solution of

1,4-cyclohexanedione monoethylene ketal (20 g, 128 mmol) in

THF (360 mL) and the cooling bath was removed. Stirring was

continued for 1 h to give a cream colored solution. This solution

was then cooled to -78 °C and 2-bromobenzyl bromide (35.2

g, 141 mmol) was added dropwise. After stirring for 30 min at

-78 °C, the reaction was then allowed to warm to 0 °C and

stirred 3 h at 0 °C before being partitioned between Et₂O and

H₂O. The solution was extracted with Et₂O (3 × 100 mL) and

the organic layer was washed with aqueous NaCl, dried

(MgSO₄) and concentrated in vacuo. The crude compound was

purified by flash chromatography (SiO₂, cyclohexane/EtOAc

) 80/20) to yield the compound 56 (20 g, 50%) as a white solid,

mp 123 °C. ¹H NMR (CDCl₃): δ 7.50 (m, 1H), 7.20 (m, 2H),

7.05 (m, 1H), 3.95 (m, 4H), 3.35 (dd, 1H), 3.05 (m, 1H), 2.65

(m, 1H), 2.55 (m, 1H), 2.40 (m, 1H), 2.10-1.85 (m, 3H), 1.80

(m, 1H).

2-Di(4-m et h oxyp h en yl)m et h yla m in o-2-[sp ir o(cyclo-

p r op a n e-2′:2′′-in d a n )-1′-yl]eth yla m in e (54c,d ). A solution

of compound 53b (12 g, 58 mmol) in CH₂Cl₂(250 mL) was

stirred for 2 h in the presence of di(4-methoxyphenyl)methy-

lamine (14 g, 58 mmol) and molecular sieves (4 Å, 18 g). Then,

TMSCN (6.3 g, 64 mmol) was added and the suspension stirred

for 14 h. The solids were filtered, the filtrate washed with

NaOH (0.1 N, 500 mL) and brine (250 mL), dried (MgSO₄) and

concentrated to afford the aminonitrile which was used

without further purification. A solution of the aminonitrile

(26.7 g, 68 mmol) in anhydrous THF (125 mL) was added

dropwise to a suspension of LiAlH₄(3.3 g, 87 mmol) in

anhydrous THF (500 mL) cooled at -10 °C. After 1 h stirring

at room temperature, the reaction mixture was hydrolyzed by

the successive cautious addition of water (3.3 mL), NaOH (3.3

mL) and water (6.6 mL). Ether (300 mL) was added and the

suspension was stirred 45 min, filtered and the filtrate

concentrated. The two diastereoisomers were separated by

column chromatography (SiO₂, CH₂Cl₂/EtOH/NH₄OH ) 90/9/

1).

7-(2-Br om ob en zyl)-8-m et h ylen e-1,4-d ioxa sp ir o[4.5]-

d eca n e (57). To a suspension of methyl(triphenyl)phospho-

nium iodide (25 g, 61.8 mmol) in toluene (50 mL) was added

a toluene solution of freshly prepared sodium t-pentoxide (70

mL of 1 M solution) and the mixture was stirred at room

temperature under N₂for 20 min. The ketone 56 (6.70 g, 20.6

mmol) in toluene (50 mL) was then added dropwise and the

mixture was refluxed for 3 h. After cooling, the reaction was

hydrolyzed with saturated aqueous NH₄Cl and extracted with

Et₂O (3 × 50 mL). The extract was washed with saturated

aqueous NaCl, water and dried (MgSO₄). Evaporation provided

an oil which was purified by flash chromatography (SiO₂,

toluene/cyclohexane ) 60/40) to give the pure alkene 57 (6 g,

1

90%) as a white powder, mp 68 °C. H NMR (CDCl₃): δ 7.55

(dd, 1H), 7.30-7.10 (m, 2H), 7.05 (m, 1H), 4.80 and 4.70 (2s,

2H), 4.00-3.80 (m, 4H), 3.20 (m, 1H), 2.85-2.60 (m, 2H), 2.50-

2.25 (m, 2H), 1.85-1.60 (m, 3H), 1.60-1.40 (m, 1H).

2-Dioxola n yl-t r a n s-1,2,3,4,4a ,9,9a ,10-oct a h yd r oa n -

th r a cen e (58). A solution of bromide 57 (5 g, 15.5 mmol),

AIBN (510 mg, 0.02 mmol) and Bu₃SnH (6.75 g, 23.2 mmol)

in toluene (750 mL) under N₂was refluxed for 5 h 30 min.

The solvent was removed under reduced pressure and the

residue was stirred rapidly for 3 h with a mixture of Et₂O (120

mL) and saturated aqueous KF solution (120 mL). Filtration

of the precipitate, extraction with Et₂O (3 × 40 mL), drying

(MgSO₄) and concentration in vacuo gave an oily residue which

was purified by flash chromatography (SiO₂, cyclohexane/Et₂O

) 80/20) to yield the trans-octahydroanthracenic compound 58

(2 g, 50%), as a white solid, mp 71 °C. ¹H NMR (CDCl₃): δ

7.10 (m, 4Η), 3.95 (m, 4H), 2.85 (m, 2H), 2.00-1.30 (m, 8H),

2.50 (m, 2H).

tr a n s-3,4,4a,9,9a,10-Hexah ydr o-1H-an th r acen -2-on e (59).

A solution of the acetal 58 (6 g, 24.6 mmol) in acetone (100

mL) and water (25 mL) containing pyridinium tosylate (1.85

g, 7.4 mmol) was refluxed for 4 h. Excess solvent was then

removed in vacuo, Et₂O (500 mL) was added and the mixture

was washed with saturated aqueous Na₂CO₃and saturated

aqueous NaCl. The organic layer was dried (MgSO₄) and the

solvent removed under reduced pressure. The residue was

purified by flash chromatography (SiO₂, cyclohexane/EtOAc

) 80/20) to give the ketone 59 (3.90 g, 80%) as a white solid,

mp 99 °C. ¹H NMR (CDCl₃): δ 7.10 (m, 4H), 2.95-2.65 (m,

2-Am in o-2-[spir o(cyclop r op a n e-2′:2′′-in d a n )-1′-yl]eth yl-

a m in e (d ia ster eom er 1, 55c). A solution of 54c (3.12 g, 6.7

mmol) in a mixture AcOH/H₂O (80/20, 200 mL) was plunged

for 45 min in an oil bath at 90 °C. The acetic acid was then

evaporated and the residue was dissolved in HCl (1 N, 100

mL), washed with ether (3 × 75 mL), basified with NaOH (9

N, 20 mL), extracted with CH₂Cl₂(3 × 75 mL), dried (K₂CO₃)

and concentrated. The residue was purified by column chro-

matography (SiO₂, CH₂Cl₂/EtOH/NH₄OH ) 90/9/1) to afford

1

the product 55c as an oil. H NMR (CDCl₃): δ 7.25-7.10 (m,

4H), 3.20-2.80 (m, 4H), 2.90 (dd, 1H), 2.70 (dd, 1H), 2.30 (m,

1H), 1.70-1.30 (m, 2H), 1.00-0.70 (m, 2H), 0.50 (m, 1H).

4(5)-[Sp ir o(cyclop r op a n e-2′:2′′-in d a n )-1′-yl]-4,5-d ih y-

d r oim id a zole, Hem ifu m a r a te (d ia ster eom er 1, 20a ). A

solution of compound 55c (1.5 g, 6.3 mmol) and formamidine

acetate (654 mg, 6.3 mmol) in EtOH (100 mL) was stirred for

14 h at room temperature. EtOH was then evaporated under

reduced pressure and the white solid was taken up in acetone

(75 mL) and i-PrOH (10 mL). The solution was filtered and

fumaric acid (694 mg, 6.3 mmol), dissolved by gentle warming

in acetone (25 mL) and i-PrOH (10 mL), was added. The solid

20a was collected by filtration and dried under vacuum as a

1

white powder (66%), mp 212 °C. H NMR (DMSO-d₆): δ 8.20

(s, 1H), 7.25-7.10 (m, 4H), 6.65 (s, 1H), 4.10 (m, 1H), 3.95-

Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 803

2H), 3.05-2.55 (m, 2H), 2.60 (m, 2H), 2.60 and 2.20 (m, 2H),

20 °C under N₂. The mixture was stirred for 1 h 30 min before

being hydrolyzed by addition of H₂O (21 mL), 35% aqueous

NaOH (43 mL) and H₂O (45 mL). The resulting suspension

was filtered and the filtrate evaporated to give the diol (5.79

g, 85%) as a white solid, used without further purification, mp

109 °C. ¹H NMR (CDCl₃): δ 7.15 (m, 4H), 3.75 (d, 4H), 2.85

(s, 4H), 2.35 (s, 2H). To a solution of diol (5.53 g, 27.4 mmol)

in pyridine (20 mL) under N₂at 0 °C was added p-toluene-

sulfonyl chloride (13 g, 68.5 mmol). After stirring for 4 h at 20

°C, the mixture was filtered and the precipitate washed with

1 N HCl and Et₂O to give the ditosylate (14 g, 100%) as a white

solid, mp 135 °C. ¹H NMR (CDCl₃): δ 7.75 (d, 4H), 7.40 (d,

4H), 7.10 (m, 4H), 3.95 (s, 4H), 2.75 (s, 4H), 2.50 (s, 6H). A

mixture of the ditosylate (14 g, 27.3 mmol) and LiBr (9.30 g,

109 mmol) in DMF (22 mL) under N₂was refluxed for 5 h and

added to approximately 40 mL of crushed ice. The reaction

was extracted with Et₂O (3 × 20 mL) and the organic layer

was washed with water and saturated aqueous NaCl, dried

(MgSO₄) and evaporated under reduced pressure to give the

pure compound 64 (7.20 g, 86%) as a white solid, mp 48.5 °C.

¹H NMR (CDCl₃): δ 7.15 (s, 4H), 3.70 (s, 4H), 3.05 (s, 4H).

Sp ir o[(1-a m in o-1-cya n ocyclobu ta n e)-3:2′-in d a n ] (65).

To a refluxing solution of NaH (2.30 g, 56 mmol), in anhydrous

THF (22 mL) was added dropwise a mixture of N-(diphenyl-

methylene)aminoacetonitrile (2.46 g, 11.2 mmol) and com-

pound 64 (3.4 g, 11.2 mmol) in anhydrous THF (22 mL). The

solution was refluxed for 24 h before being cooled and

hydrolyzed by addition of water. The mixture was extracted

with EtOAc (3 × 60 mL) and the organic layer was washed

with saturated aqueous NaCl, dried (MgSO₄) and evaporated

in vacuo. The residue was then treated with 1 N HCl (30 mL)

and Et₂O (30 mL) and vigorously stirred for 12 h at 20 °C.

The two layers were separated and the acidic phase was

washed with Et₂O, basified with 35% aqueous NaOH and

extracted with CH₂Cl₂(3 × 40 mL). The organic layer was

washed with saturated aqueous NaCl, dried (MgSO₄) and

evaporated to give the desired aminonitrile 65 as a brown oil.

¹H NMR (CDCl₃): δ 7.15 (m, 4H), 3.20 (s, 2H), 3.10 (s, 2H),

2.45 (m, 4H), 1.85 (m, 2H).

Sp ir o[(1-a m in ocyclob u t a n e )-3:2′-in d a n ]-1-m e t h yl-

a m in e (66). A solution of the above aminonitrile 65 (1.49 g,

7.1 mmol) in 2 N methanolic NH₃solution (140 mL) was

hydrogenated over 50% aqueous Raney Nil at room temper-

ature for 5 h. The reaction was filtered to remove the catalyst

and concentrated to give an oil which was purified by flash

chromatography (SiO₂, CH₂Cl₂/CH₃OH/NH₄OH ) 90/10/1),

providing the corresponding diamine 66 (1.04 g, 70%) as a pale

yellow oil. ¹H NMR (CDCl₃): δ 7.15 (m, 5H), 3.10 and 3.00

(2s, 4H), 2.80 (s, 2H), 2.15 and 1.95 (m, 4H).

Sp ir o{(1,3-d ia za cyclop en t -1-en e)-5:3′-[sp ir o(cyclob u -

ta n e-1′:2′′-in d a n )]}, F u m a r a te (22). A mixture of the above

diamine 66 (1.03 g, 4.8 mmol) and formamidine acetate (0.576

g, 5.5 mmol) in EtOH (20 mL) was stirred at 20 °C under N₂

for 12 h. The solvent was evaporated and the residue taken

up in 1 N HCl. The acidic phase was washed with Et₂O and

basified with 35% aqueous NaOH; the mixture was extracted

with CH₂Cl₂and the organic layer washed with saturated

aqueous NaCl, dried (MgSO₄) and evaporated. The solid

residue was dissolved in EtOH (20 mL) and treated with a

solution of fumaric acid (557 mg, 4.8 mmol) in EtOH (20 mL).

After evaporation and recrystallization of the residue from

EtOH, the derivate 22 was obtained as a white powder (1.26

g, 80%), mp 189 °C. ¹H NMR (DMSO-d₆): δ 8.05 (s, 1H), 7.20-

7.00 (m, 4H), 6.45 (s, 2H), 3.95 (s, 2H), 3.00 (s, 4H), 2.35 (m,

4H). Anal. (C₁₄H₁₆N₂‚C₄H₄O₄) C, H, N.

1.70 (m, 2H), 2.25 and 1.56 (m, 2H).

2-Am in o-tr a n s-1,2,3,4,4a ,9,9a ,10-octa h yd r oa n th r a cen e-

2-ca r bon itr ile (60). To a vigorously stirred solution, main-

tained under N₂and containing the above ketone 59 (1.25 g,

6.2 mmol), MeOH (30 mL) and water (15 mL) were added KCN

(410 mg, 6.3 mmol) and NH₄Cl (340 mg, 6.3 mmol) succes-

sively. After stirring for 12 h at 20 °C, the solution was diluted

in CH₂Cl₂and extracted with CH₂Cl₂(3 × 30 mL). The organic

phase was washed with saturated aqueous NaCl, dried (Mg-

SO₄) and evaporated. The residue was then treated with 7 N

methanolic NH₃solution (25 mL) and stirred in a closed vessel

for 12 h at 20 °C. Evaporation under reduced pressure provided

the desired aminonitrile 60 (1.39 g, 100%) as a white solid,

1

mp 128 °C. H NMR (CDCl₃): δ 7.10 (m, 4H), 2.90-2.85 (2t,

2H), 2.60-2.45 (m, 2H), 2.20-1.25 (m, 8H), 1.90 (m, 2H).

2-Am in om et h yl-tr a n s-1,2,3,4,4a ,9,9a ,10-oct a h yd r oa n -

th r a cen -2-yla m in e (61). A solution of the above aminonitrile

60 (1.39 g, 6.1 mmol) in anhydrous THF (35 mL) was added

dropwise to a suspension of LiAlH₄(350 mg, 9.2 mmol) in

anhydrous THF (35 mL) at -20 °C under N₂. The mixture was

stirred for 1 h 30 min before hydrolysis by addition of H₂O

(2.3 mL), 35% aqueous NaOH (4.6 mL) and H₂O (4.9 mL). The

resulting suspension was filtered and the filtrate evaporated

to afford an oily residue which, after purification by flash

chromatography (SiO₂, CH₂Cl₂/CH₃OH/NH₄OH ) 90/10/1)

gave a mixture of two diastereoisomers (85/15) 61a /61b (0.505

g, 36%) as a white solid. The two diastereoisomers were

separated by HPLC (Kromasil 100.10 C18, 210 nm, CH₃CN/

H₂O/CF₃CO₂H ) 170/830/5). 61a : mp 123 °C. ¹H NMR

(CDCl₃): δ 8.50-7.00 (m, 4H), 7.05 (m, 4H), 3.00 (s, 2H), 2.75

(m, 2H), 2.70-2.30 (m, 2H), 2.00-1.30 (m, 8H). 61b: mp 183

°C. ¹H NMR (CDCl₃): δ 7.05 (m, 4H), 2.80 (m, 2H), 2.55 (s,

2H), 2.50 (m, 2H), 1.90-1.00 (m, 8H), 1.40 (m, 4H).

Sp ir o[(1,3-d ia za cyclop en t-1-en e)-5:2′-(tr a n s-1′,2′,3′,4′,-

4′a ,9′,9′a ,10′-octa h yd r oa n th r a cen e)], F u m a r a te (21a ). A

mixture of the above diamine 61a (0.495 g, 2.2 mmol) and

formamidine acetate (258 mg, 2.5 mmol) in EtOH (10 mL) was

stirred at 20 °C under N₂for 12 h. The solvent was evaporated

and the residue taken up in 1 N HCl. The acidic phase was

washed with Et₂O and basified with 35% aqueous NaOH; the

mixture was extracted with CH₂Cl₂(3 × 10 mL) and the

organic layer washed with saturated aqueous NaCl, dried

(MgSO₄) and evaporated. The solid residue was dissolved in

EtOH (10 mL) and treated with a solution of fumaric acid

(0.225 g, 1.9 mmol) in EtOH (10 mL). After evaporation and

recrystallization of the residue from EtOH, compound 21a was

obtained as a white powder (0.50 g, 65%), mp 233-237 °C. ¹H

NMR (TFA-d₁): δ 7.75 (s, 1H), 6.75 (s, 1H), 6.70 (m, 4H), 3.10

(s, 2H), 2.55 (m, 2H), 2.20 and 2.10 (m, 2H), 1.80 (m, 3H), 1.60

(m, 1H), 1.30 (m, 1H), 1.20 (m, 2H), 0.96 (m, 1H). Anal.

(C₁₆H₂₀N₂‚C₄H₄O₄) C, H, N.

Sp ir o[(1,3-d ia za cyclop en t-1-en e)-5:2′-(tr a n s-1′,2′,3′,4′,-

4′a ,9′,9′a ,10′-octa h yd r oa n th r a cen e)], F u m a r a te (21b). The

derivate 21b was prepared according to the procedure de-

1

scribed for 21a and obtained as a white solid, mp 215 °C. H

NMR (DMSO-d₆): δ 8.35 (s, 1H), 7.05 (m, 4H), 6.45 (s, 2H),

3.55 (s, 2H), 2.85-2.70 (m, 2H), 2.50-2.35 (m, 2H), 2.00-1.35

(m, 8H). Anal. (C₁₆H₂₀N₂‚C₄H₄O₄) C, H, N.

Sp ir o{(1,3-d ia za cyclop en t -1-en e)-5:3′-[sp ir o(cyclob u -

ta n e-1′:2′′-in d a n )]}, F u m a r a te (22). In d a n -2,2-d ica r boxy-

lic Acid , Dim eth yl Ester (63). A solution of 1,2-di(bromom-

ethyl)benzene (62; 30 g, 115 mmol), dimethyl malonate (15.20

g, 115 mmol) and K₂CO₃(31.50 g, 230 mmol) in ethylmethyl-

acetone (600 mL) under N₂was refluxed for 14 h. After cooling,

the reaction was filtered and the filtrate evaporated. The oily

residue was purified by flash chromatography (SiO₂, cyclo-

hexane/EtOAc ) 80/20) to give the diester 63 (16 g, 60%) as a

white solid. ¹H NMR (CDCl₃): δ 7.15 (m, 4H), 3.75 (s, 6H),

3.65 (s, 4H).

4(5)-[(3,4-Dih yd r on a p h th a len -2-yl)m eth yl]-4(5)-m eth -

yl-4,5-d ih yd r oim id a zole, F u m a r a t e (23). 1-(3,4-Dih y-

d r on a p h th a len -2-yl)p r op a n -2-on e (67). A vigorously stirred

suspension of 2-tetralone (13.15 g, 90 mmol), (2-oxopropyl)-

phosphonic acid diethyl ester (20.16 g, 104 mmol) and K₂CO₃

(24.9 g, 180 mmol) in H₂O (30 mL) was heated under reflux

for 3 h. After cooling (0 °C), the mixture was diluted with water

(30 mL) and extracted with ether (4 × 100 mL). The combined

extracts were dried and concentrated. The resulting oily

2,2-Bis(br om om eth yl)in d a n (64). A solution of the diester

63 (8 g, 34.2 mmol) in anhydrous THF (25 mL) and Et₂O (50

mL) was added dropwise to a suspension of LiAlH₄(3.25 g,

85.5 mmol) in anhydrous THF (10 mL) and Et₂O (20 mL) at

804 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5

Cordi et al.

residue was purified by column chromatography (SiO₂, cyclo-

hexane/AcOEt: 95/5) to afford 67 as a colorless oil (9 g, 54%).

¹H NMR (CDCl₃): δ 7.20-6.95 (m, 4H), 6.35 (s, 1H), 3.30 (s,

1H), 2.55 (t, 2H), 2.30 (t, 2H), 2.20 (s, 3H).

Ack n ow led gm en t. The authors thank the expert

technical assistance of Michele Hipeaux, Pascale Cado-

ret, and Pascal Vrillaud and also Stephane Mabic for

assistance in preparation of the manuscript.

4(5)-[(3,4-Dih yd r on a p h th a len -2-yl)m eth yl]-4(5)-m eth -

yl-4,5-d ih yd r oim id a zole, F u m a r a te (23). Starting from the

ketone 67, the compound was obtained as described for 4a , as

Refer en ces

1

a white powder (75%), mp 146-148 °C. H NMR (DMSO-d₆):

(1) Schildkraut, J . J . The Catecholamine Hypothesis of Affective

Disorders: a Review of Supporting Evidence. Am. J . Psychiatr.

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(2) Delgado, P.; Moreno, F. Antidepressants and the Brain. Intern.

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(3) Frazer, A. Antidepressants. J . Clin. Psychiatr. 1997, 58 (Suppl.

6), 9-25.

(4) Limberger, N.; Funk, L.; Trendelenburg, A. U.; Starke, K.

Subclassification of Presynaptic R₂-Adrenoceptors: R₂-Autore-

ceptors in Rabbit Atria and Kidney. Naunyn-Schmiedeberg’s

Arch. Pharmacol. 1995, 352, 31-42.

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Extracellular Noradrenaline and Serotonin Levels in Guinea Pig

Hypothalamus. J . Neurochem. 1997, 69, 815-822.

δ 8.10 (s, 1Η), 7.20-6.95 (m, 4H), 6.40 (s, 2H), 6.35 (s, 1H),

3.55 (AB system, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.20 (s, 3H),

2.30 (m, 2H), 1.35 (s, 3H). Anal. (C₁₅H₁₈N₂‚C₄H₄O₄) C, H, N.

4(5)-[(2-Me t h yl-1,2,3,4-t e t r a h yd r on a p h t h a le n -2-yl)-

m eth yl]-4,5-d ih yd r oim id a zole, F u m a r a te (24a ,b). Eth yl

(2-Met h yl-1,2,3,4-t et r a h yd r on a p h t h a len -1-on -2-yl)a ce-

ta te (68). To a solution of 2-methyl-1-tetralone (1 g, 6.25 mmol)

in anhydrous THF (50 mL), KO-t-Bu (0.77 g, 6.9 mmol) was

added portionwise at -60 °C under a N₂atmosphere. The

reaction mixture was brought to 0 °C, stirred 1 h at that

temperature and cooled again to -60 °C, when a solution of

ethyl iodoacetate (1.47 g, 6.9 mmol) in anhydrous THF (2 mL)

was added dropwise. The solution was maintained at -60 °C

under stirring and brought to room temperature overnight.

The reaction mixture was quenched by dropwise addition of

water (50 mL), extracted with ether (2 × 100 mL), the pooled

organic phases were washed with brine, dried (MgSO₄) and

concentrated to afford 68 as a brown oil which was purified

through column chromatography (SiO₂, cyclohexane/AcOEt )

90/10) and used without further purification. ¹H NMR

(CDCl₃): δ 8.05 (m, 1H), 7.45 (m, 1H), 7.30 (m, 1H), 7.25 (m,

1H), 4.15 (q, 2H), 3.20-2.85 (d + m, 2H), 2.55-2.35 (m, 1H),

1.95 (m, 1H), 1.25 (s, 3H), 1.20 (t, 3H).

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Combining Pindolol and Paroxetine in an Animal Model of

Chronic Antidepressant Action-Can Early Action be Detected.

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of the Fluoxetine-Induced Increase in Dialysate Levels of Sero-

tonin (5-HT) in the Frontal Cortex of Freely Moving Rats by

Combined Blockade of 5-HT_1Aand 5-HT_1BReceptors with WAY

100,635 and GR 127,935. J . Neurochem. 1997, 68, 1159-1163.

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Antidepressant Therapy. Br. J . Psychiatr. 1998, 173, 203-208.

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149-153.

(2-Meth yl-1,2,3,4-tetr a h yd r on a p h th a len -2-yl)a ceta ld e-

h yd e (69). A suspension of 68 (15.3 g, 62 mmol), NaBH₃CN

(29.5 g, 470 mmol) and ZnI₂(29.7 g, 93 mmol) in (CH₂Cl)₂(375

mL) was heated to reflux overnight under a N₂atmosphere.

Insoluble materials were dissolved by addition of a mixture

of NH₄Cl (10%, 1 L) and HCl (0.5 N, 100 mL), the aqueous

phase was extracted with AcOEt (3 × 250 mL), the pooled

organic phases were washed with Na₂CO₃(10%), dried (Mg-

SO₄) and concentrated to afford a mixture of ethyl (2-methyl-

1,2,3,4-tetrahydronaphthalen-2-yl)acetate and the correspond-

ing alcohol (1/1) which was dissolved in anhydrous THF (100

mL) and added dropwise to a suspension of LiAlH₄(1.5 g, 41

mmol) in THF (400 mL) kept at -10 °C. At the end of the

addition, the temperature was raised to room temperature and

the mixture stirred for 1 h. The reaction mixture was then

quenched by the successive cautious additions of water (1.5

mL), NaOH (1 N, 1.5 mL) and water (3 mL). Ether (250 mL)

was added and the suspension was stirred for 1.5 h, filtered

and the filtrate concentrated to give 2-(2-methyl-1,2,3,4-

tetrahydronaphthalen-2-yl)ethanol (9.2 g, 75%). To a solution

of this alcohol (8.6 g, 45 mmol) in THF (175 mL), IBX (13.95

g, 49 mmol) was added portionwise. The suspension was

heated under reflux for 2 h, cooled and filtered. The solid was

washed with THF (100 mL), the filtrates concentrated, the

residue dissolved in ether (350 mL), the organic solution

washed with Na₂CO₃(10%, 100 mL) and brine (100 mL), dried

(MgSO₄) and concentrated to afford 69 as colorless oil (8.41 g,

99%) used without further purification. ¹H NMR (CDCl₃): δ

7.20-7.00 (m, 4H), 4.15 (q, 2H), 2.85 (m, 2H), 2.65 (AB system,

2H), 2.30 (AB system, 2H), 1.85-1.55 (m, 2H), 1.25 (t, 3H),

1.10 (s, 3H).

(10) Debonnel, G.; Gobbi, G.; Turcotte, J .; Boucher, N.; He´bert, C.;

de Montigny, C.; Blier, P. Comparative Study of the Therapeutic

Effects of R₂-Adrenergic Antagonism, Serotonin Reuptake Inhi-

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L.; Gorissen, H.; Calderon, P.; Remacle, M. D.; J anssens de

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4(5)-[(2-Me t h yl-1,2,3,4-t e t r a h yd r on a p h t h a le n -2-yl)-

m eth yl]-4,5-d ih yd r oim id a zole, F u m a r a te (24a ,b). Starting

from the aldehyde 69, the compounds were obtained as

1

described for 20a . Diastereomer 1, 24a (83%), mp 154 °C. H

NMR (DMSO-d₆): δ 8.10 (s, 1H), 7.05 (m, 4H), 6.40 (s, 2H),

4.25 (m, 1H), 3.95 (m, 1H), 3.30 (m, 1H), 2.75 (m, 2H), 2.50

(AB system, 2H), 1.75-1.50 (m, 4H), 0.95 (s, 3H). Anal.

(C₁₅H₂₀N₂‚C₄H₄O₄) C, H, N. Diastereomer 2, 24b (88%), mp

152 °C. ¹H NMR (DMSO-d₆): δ 8.15 (s, 1H), 7.05 (m, 4H), 6.45

(s, 2H), 4.25 (m, 1H), 4.00 (m, 1H), 3.35 (m, 1H), 2.75 (m, 2H),

2.55 (AB system, 2H), 1.75-1.45 (m, 4H), 0.95 (s, 3H). Anal.

(C₁₅H₂₀N₂‚C₄H₄O₄) H, N; C: calcd, 66.36; found, 65.72.

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Potential Antidepressants

J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 805

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J M001040G

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Potential antidepressants displayed combined α2-adrenoceptor antagonist and monoamine uptake inhibitor properties

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