Synthesis and pharmacological evaluation of a series of the agomelatine analogues as melatonin MT1/MT2 agonist and 5-HT 2C antagonist

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DOI: 10.1002/cmdc.201300294

Synthesis and Pharmacological Evaluation of a series of

the Agomelatine Analogues as Melatonin MT /MT Agonist

1

2

and 5-HT Antagonist

2

C

[a]

Mohamed Ettaoussi,* Ahmed Sabaouni, Basile Pꢀrꢁs, Elodie Landagaray,

[

b]

[b]

[c]

Olivier Nosjean, Jean A. Boutin, Daniel-Henri Caignard, Philippe Delagrange,

[a]

Pascal Berthelot, and Sa ¨ı d Yous

Agomelatine is a naphthalenic analogue of melatonin that is in

clinical use for the treatment of major depressive disorders. In-

terestingly, while agomelatine exhibits potent affinity for mela-

tonin receptors, it binds with only moderate affinity to the se-

rotonin 5-HT₂_Creceptor. Optimization of agomelatine toward

this target could further potentiate its clinical efficacy. To ex-

plore this hypothesis and to access derivatives in which a key

point of agomelatine metabolism is blocked, a series of naph-

thalenic derivatives was designed and synthesized as novel an-

alogues of agomelatine. Most of the prepared compounds ex-

hibited good binding affinity at the melatonin MT and MT re-

1

2

ceptor subtypes. Two compounds, an acetamide and an acryl-

amide derivative, exhibited good binding affinities at both the

human melatonin (MT) receptors and the serotonin 5-HT₂_Cre-

ceptor subtype, with pK values of 7.96 and 7.95 against MT ,

i

1

7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5-HT ,

2

C

respectively.

Introduction

Agomelatine (S20098), the naphthalenic analogue of melato-

the mechanism of action of the complex relationship linking al-

terations in circadian rhythms to depressive disorders is still

unknown.

[

1]

nin is an antidepressant approved by the European Union

Agency for Medicines (EU-EMEA) in 2009 for the treatment of

major depressive disorders and marketed under the name Val-

doxan. It belongs to a new class of antidepressants with mela-

toninergic receptor agonist (MT /MT ) and serotoninergic (5-

Previously, different alternative therapeutic strategies that

combine biological clock resynchronization and medical treat-

ment of depressed patients were reported. A combination of

the sleep deprivation method and a selective serotonin reup-

take inhibitor (SSRI) therapy has been reported to produce

a more rapid improvement of depressive symptoms than

1

2

[

2,3]

HT ) receptor antagonist activities.

This resynchronizing

2C

agent of the biological clock provides new evidence for the ex-

istence of a relationship between circadian rhythm disturban-

ces and depressive disorders. Moreover, clinical observations of

depressive patients have shown that mood, anxiety, and sever-

al physiological functions are affected by a number of circadi-

an abnormalities in depression (sleep–wake cycle disorder,

body temperature, blood pressure, immune response and cor-

[5]

a single treatment with an SSRI. With a view to developing

novel therapeutic agents for depression, intense research activ-

ity has been focused on the development of new chronothera-

peutic agents. Agomelatine, with its novel pharmacological

profile, represents this new family of chronotherapeutic antide-

pressants. Results from several clinical trials with agomelatine

have shown its efficacy in the treatment of major depressive

[

4]

tisol secretion). Despite the existence of many indications,

[6–9]

disorders.

Agomelatine is well tolerated, improves subjec-

+

[

a] Dr. M. Ettaoussi, Dr. A. Sabaouni, Dr. B. Pꢀrꢁs, E. Landagaray,

tive sleep in patients suffering from major depressive disorders,

Prof. P. Berthelot, Dr. S. Yous

Universitꢀ Lille Nord de France

[10,11]

and had no deleterious effect on sexual functioning.

The

and

melatoninergic component is involved in the improvement of

UDSL, EA GRIIOT, UFR Pharmacie

Universitꢀ du Droit et de la Santꢀ de Lille, 59000 Lille (France)

E-mail: m.ettaoussi@yahoo.fr

[12]

sleep quality without daytime sedation and resynchroniza-

[13]

tion of circadian rhythms,

^w^h^e^r^e^a^s^t^h^e^s^e^r^o^t^oⁿⁱⁿ^e^r^gⁱ^c⁵^-^H^T2C

antagonism is implicated in the release of norepinephrine and

[

b] Dr. O. Nosjean, Dr. J. A. Boutin

[14]

Biotechnologies, Pharmacologie Molꢀculaire et Cellulaire

Institut de Recherches Servier

dopamine in the frontal cortex. Nevertheless, the agomela-

tine mechanism of action is probably due to a synergic effect

between the activities at the three receptors: MT , MT , and 5-

1

25 Chemin de Ronde, 78290 Croissy-sur-Seine (France)

1

2

[

c] Dr. D.-H. Caignard, Dr. P. Delagrange

Unitꢀ de Recherches et Dꢀcouvertes en Neurosciences

Institut de Recherches Servier

[15]

HT .

2

C

Moreover, additional studies have shown that agomelatine

1

25 Chemin de Ronde, 78290 Croissy-sur-Seine (France)

has general efficacy for the treatment of depression, anxiety,

+

[16,17]

[

] These authors contributed equally to this work.

and seasonal affective disorders.

Agomelatine has a high

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affinity for both MT and MT receptors (MT : pK =9.92; MT :

ligands were evaluated for their binding affinity on CHO cells

1

2

1

i

2

[

18a,19]

3

pK =9.24) but its affinity at 5-HT is lower (pK =6.2).

stably transfected with 5-HT₂_Creceptors, using [ H]mesulergine

i

2C

i

Therefore, an improvement in serotoninergic 5-HT₂_Caffinity

might improve the efficacy of agomelatine. Obviously, it was

difficult to explain why agomelatine has affinity at the 5-HT₂_C

receptor whereas melatonin has no affinity for this receptor.

This is the reason why we launched, in parallel, a large screen-

ing campaign with already synthesized melatoninergic ligands

against the 5-HT₂_Creceptor and a wide pharmacomodulation

program on the lead, agomelatine, using different strategies.

The blockade of the metabolic sites of agomelatine was one of

as radioligand. All the relevant molecules were evaluated in

functional assays against MT , MT and 5-HT , and chiral com-

1

2

2C

pounds were evaluated as racemic mixtures.

Chemistry

Scheme 1 describes the synthesis of compounds 5a,b from (7-

[21]

methoxynaphthalen-1-yl)acetonitrile (A). First, the reaction of

this nitrile with dimethyl carbonate (DMC) or methyl bromoa-

cetate led to cyanoesters 1 and 2, respectively, in good

[

18a,b]

the pathways adopted.

This explains why we carried out

the present medicinal chemistry strategy based on the intro-

duction of different structural changes at the beta-position of

the ethyl amido side chain. This position was reported to be

metabolized only by CYP2C9 into beta-hydroxy-agomelatine.

Furthermore, at this position in vitro and in vivo, metabolic ac-

tivity was reported to be in reasonable agreement with activi-

[

18b]

ties measured in human liver microsomes.

By performing

these chemical modifications we aimed first to block this

known metabolic position of agomelatine and to improve the

5-HT₂_Cbinding affinity. Herein we report the synthesis and bio-

logical results of new series of compounds arising from the dif-

ferent modifications (Figure 1).

Scheme 1. Synthesis of compounds 5a,b. Reagents and conditions: a) 1. NaH,

DMC, THF, reflux, 30 min; 2. BrCH

2

CO

, R X, acetone, reflux, 2 h; c) aq NaOH (1.5n), reflux, 20 h; d) H

Raney nickel, Ac O, 608C, 2 h.

2 3 2 3

CH , K CO , TBAB, acetone, reflux, 24 h;

2

b) K

2

CO

3

2

,

2

[22,23]

yields.

C-Alkylation of compound 1 by methyl iodide or

ethyl bromide afforded intermediates 3a,b, which were then

decarboxylated according to previously reported condi-

[24,25]

tions

to give compounds 4a,b. Next, reductive acylation of

the nitriles over Raney nickel in acetic anhydride furnished de-

sired compounds 5a,b (Scheme 1). Synthesis and evaluation

on melatonin receptors of compound 5a was previously re-

[26]

ported.

Figure 1. Structures of melatonin, agomelatine, a previously prepared 3-allyl

[

18a]

derivative,

and an example of the compounds prepared here. Also shown

) of each agent against the 5-HT2C receptor.

Compounds 8a,b and 10 were also prepared from (7-me-

thoxynaphthalen-1-yl)acetonitrile as reported in Scheme 2. The

treatment of this nitrile with an excess of methyl iodide or 1,3-

dibromopropane gave compounds 6 and 9, respectively, in

good yields. Chemical reduction of nitrile 6 with a mixture of

lithium aluminum hydride and aluminum chloride gave amine

7, which was subsequently treated with ethyl fluoroacetate or

methyl difluoroacetate to give fluoroacetamides 8a and 8b,

is the binding affinity (pK

i

Results and Discussion

Different lipophilic and hydrophilic groups were introduced in

the beta-position of the lateral amido side chain, one of the

metabolic sites of agomelatine. Hence, substituents such as

methyl, ethyl, dimethyl, cyclobutyl, fluorine, ketone, oximes,

and hydroxymethyl were inserted. The synthesis of these dif-

ferent compounds and their pharmacological binding results

are reported herein. These compounds were evaluated first for

their binding affinities at human MT and MT receptors stably

[27]

respectively. Acetamide 10 was then obtained by catalytic

hydrogenation over Raney nickel of nitrile 9 in acetic anhy-

dride at 608C (Scheme 2).

With the aim of synthesizing agomelatine analogues con-

taining groups such as ketones, oximes, or fluorine, we first

prepared aldehyde 11 from 7-methoxynaphthyl acetic acid by

1

2

transfected in Chinese hamster ovarian (CHO) cells, using 2-

125

[20]

[28]

[

I]iodomelatonin as radioligand. Then the most interesting

oxidative decarboxylation as reported by Santanielo. Next,

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To achieve the synthesis of

amidoalcohols 21–24, we estab-

lished the synthetic route depict-

ed in Scheme 4. Chemical reduc-

tion of cyanoesters 1 and 2 pre-

viously prepared (Scheme 1)

with a mixture of lithium alumi-

num hydride and aluminum

chloride afforded the corre-

sponding derivatives 19 and

[32]

2

0. N-Acylation of 19 and 20

according to a variant of the

Scheme 2. Synthesis of compounds 8a,b and 10. Reagents and conditions: a) K

2

CO

3

, CH

3

I, acetone, reflux, 2 h;

Me, CF CH OH, reflux,

[33]

Schotten–Baumann reaction

afforded desired compounds

1a–d and 22a,b (Scheme 4).

However, attempts to apply the

b) LiAlH

4

, AlCl

3

, Et

2

O, RT, 20 min, HCl(g), Et

2

O; c) K

2

CO

3

, EtOAc/H

2

O, FCH

2

CO

2

Et or F

2

CHCO

2

3

2

12 h; d) Br(CH

2

)

3

Br, NaH, DMSO/Et

2

O, RT, 2 h; e) H

2

, Raney nickel, Ac

2

O, 608C, 2 h.

2

the reaction of this aldehyde with trimethylsilyl cyanide in the

same reaction conditions with vinyl acetic acid chloride and 19

were unsuccessful. Hence, compound 21e was prepared by

coupling amine 19 with the but-3-enoic acid in the presence

presence of methyl triphenylphosphine iodide led to O-silylat-

[

29]

ed cyanhydrin 12. This latter compound was then reduced

to the corresponding aminoalcohol (13) by treatment with lith-

ium aluminum hydride and then N-acetylated to form amidoal-

cohol 14 (Scheme 3). Fluoro derivative 15 was then prepared

from 14 by treatment with diethylaminosulfur trifluoride

[34,35]

of N-(3-dimethylamino)-N’-ethylcarbodiimide (EDCI).

Fluo-

roacetamides 21 f and 22c were prepared according to a previ-

ously described procedure (Scheme 2). Condensation of the

corresponding free amines 19 or 20 with urea or isocyanate in

the presence of triethylamine afforded ureas 21h–j and 22d–

[

30a]

(DAST).

This reaction was carried out in dichloromethane at

[36]

0

8C and also led to the formation of the cyclized compound

e. On the other hand, compounds 24a,b were prepared in

three steps starting from cyanoester 1 (Scheme 4). In fact, cata-

lytic hydrogenation of intermediates 2a,b, described in

Scheme 1, in acetic anhydride afforded acetamido esters

23a,b, which were then selectively reduced by lithium alumi-

num hydride to give the desired compounds (24a,b).

[

30,31]

(

16).

Intermediate 14 was also oxidized into ketone 17 by

reaction with pyridinium chlorochromate (PCC) as reported in

[

30b]

the literature.

Finally, oximes 18a–d were prepared from 17

by condensation with the hydroxylamine or O-methylhydroxyl-

amine hydrochlorides. Both E and Z isomers were isolated and

identified by NMR studies.

Scheme 5 illustrates the synthesis of compounds 25–31.

Ether 25 and ester 26 were prepared by treatment of

[37]

2

1a with methyl iodide or acetic anhydride, respec-

tively, in hydrobromic medium. Next, compounds 28

and 29 were synthesized from the resulting mesyl in-

[38]

termediate (27) by treatment with tetrabutylammo-

[39]

nium fluoride (TBAF).

Fluoropropyl acetamide 28

was isolated in a low yield (5%) because, under these

conditions, two other products are also formed: the

acetamide (21a) and the vinyl (29) resulting from the

elimination of the methanesulfonic group as previ-

[40]

ously described by Badone et al.

Finally, thiol 31

was prepared in good yield over two steps: treatment

of mesyl 27 with potassium thioacetate followed by

saponification of the formed thioester (30) with an

aqueous solution of sodium hydroxide.

The next modification to the hydroxy group of 21a

was its substitution for amides (34a–d) and a morpho-

line group (35). Starting from previously prepared

mesyl 27, nucleophilic substitution of the O-mesyl

group with sodium azide or morpholine led to com-

pounds 32 and 35, respectively (Scheme 6). Azide 32

was then catalytically hydrogenated into the corre-

sponding amine (33) and transformed into the dia-

mide compounds (34a–d) under the conditions de-

scribed above for compounds 21a–d (Scheme 4).

Scheme 3. Synthesis of compounds 15–18. Reagents and conditions: a) TMSCN,

CH

8C, 15 min; d) DAST, CH

MeOH, reflux, 3 h.

3

PPh

3

I, CH

2

Cl

2

, RT, 72 h; b) LiAlH

4

, THF/Et

Cl , 08C; e) PCC, AcOK, CH

2

O, RT, 1 h; c) K

2

CO

3

, EtOAc/H

2

O, CH

3

COCl,

3

0

2

Cl , RT, 2 h; f) R ONH

2

·HCl, pyridine,

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Finally, selective reduction of the ester function af-

forded desired compound 39.

Biological results

Investigations of new melatoninergic ligands based

on agomelatine revealed that introduction of

a methyl (5a), an ethyl (5b) or a dimethyl group

(

8a,b) afforded compounds with excellent melatoni-

nergic binding affinities at both MT and MT recep-

1

2

tor subtypes. In addition, difluoroacetamide deriva-

tive 8b represents the most interesting compound of

this series exhibiting binding affinities at MT₁and

MT higher than the binding affinity of agomelatine

2

itself (Table 1). In contrast, the introduction of a bulki-

er cyclobutyl group (10) gave rise to a compound

with decreased affinities for both melatonin MT and

1

Scheme 4. Synthesis of compounds 21–24. Reagents and conditions: a) LiAlH

4

, AlCl

CO)

H, EDCI, CH

, R X, acetone, reflux,

3

, Et

O,

Cl ,

2 2

2

O,

MT receptors. Finally, introduction of a fluorine sub-

2

1

RT, 20 min HCl(g), Et

Et N, THF, RT (21g); FCH

RT (21e, 21g); R N=C=O, Et

h; d) H , Raney nickel, Ac O, 608C, 2 h; e) LiAlH

2

O; b) EtOAc/H

CO Et, CF

N, THF, RT (21h–j, 22d–e); c) K

, THF, 08C, 1 h.

2

O, K

2

CO

3

, R COCl, 08C (21a–d, 22a–b); (CF

3

2

stituent (15) did not significantly alter the ability of

3

2

3

CH

2

OH, reflux (22c); CH

2

=CHCH

2

CO

2

1

the compound to bind at MT and MT in comparison

3

2

CO

3

1

2

4

with agomelatine.

Compounds in which hydrophilic groups were in-

troduced (17–24) exhibited a decrease in the melato-

Scheme 6. Synthesis of compounds 33–35. Reagents and conditions: a) NaN

3

,

TBAB, DMF, 708C, 2 h; b) morpholine, THF, reflux, 24 h HCl(g), Et O; c) H , Pd/

2

Scheme 5. Synthesis of compounds 25–31. Reagents and conditions:

a) K CO , CH I, acetone or Ac O, HBr, reflux, 40 min; b) MsCl, Et N, CH

8C, 12 h; c) TBAF, THF, 608C, 12 h; d) CH COSK, acetone, reflux, 3 h;

e) NaOH(aq), acetone, RT, 2 h.

2 3 2

C, MeOH, RT, 2 h; d) K CO , EtOAc/H O, R COCl, 08C, 15 min.

2

3

2

3

2 2

Cl ,

0

3

ninergic receptor binding affinities. Only ketone 17 conserved

binding affinities at MT and MT similar to those of agomela-

1

2

Finally, the position isomer of 21a, amidoalcohol 39, was

prepared from aldehyde 11 as shown in Scheme 7. First, treat-

ment of this aldehyde with sodium borohydride afforded alco-

hol 36, which was then transformed into the chloride deriva-

tive by reaction with thionyl chloride in chloroform. Reaction

of this chloro derivative with diethyl acetamidomalonate in the

tine. However, insertion of a hydroxymethyl group (21a) led to

a decrease in MT binding affinity of about 78-fold and in MT

1

2

binding affinity of 10-fold (Table 1). Compound 21a was also

previously used by our group to perform a CoMFA study

aimed to generate an agonist model for melatonin MT and

1

[42]

MT receptors. Despite the length, and because methyl or

2

[41]

presence of sodium hydride furnished intermediate 37. De-

carboxylation of 37 with lithium bromide in the presence of

ethyl insertion (5a,b and 8a,b) has a positive effect on the

melatoninergic binding affinity, we then introduced methyl

and ethyl moieties into the beta position of 21a giving com-

[

25]

water according to Krapcho conditions led to amidoester 38.

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Table 2. Binding affinity of compounds 21a–j and 22a–e for human mel-

atoninergic receptors.

1

[a]

Compd

R

pK

i

h-MT

1

h-MT

2

1a

1b

1c

1d

1e

1 f

1g

1h

1i

CH

C H

3 7

3

7.96Æ0.10 (2)

8.18Æ0.08 (2)

8.18Æ0.10 (2)

7.19Æ0.18 (2)

7.95Æ0.06 (2)

8.61Æ0.03 (2)

7.59Æ0.05 (2)

6.99Æ0.17 (3)

6.36Æ0.17 (2)

6.50Æ0.09 (4)

8.02Æ0.18 (3)

8.13Æ0.02 (2)

7.73Æ0.04 (2)

6.52Æ0.21 (2)

5.94Æ0.15 (2)

7.86Æ0.03 (2)

8.43Æ0.15 (3)

7.81Æ0.14 (2)

7.38Æ0.21 (4)

8.68Æ0.03 (2)

9.33Æ0.18 (2)

8.79Æ0.26 (2)

8.02Æ0.12 (3)

7.68Æ0.15 (3)

7.62Æ0.06 (4)

8.09Æ0.06 (5)

8.87Æ0.04 (3)

8.59Æ0.05 (3)

7.95Æ0.04 (2)

7.73Æ0.02 (2)

c-C

OC

vinyl

CF

allyl

NH

3 5

H

2

H

5

3

2

4

Scheme 7. Synthesis of compound 39. Reagents and conditions: a) NaBH ,

NHC

CH

3

2

3

H

5

MeOH, RT, 30 min; b) SOCl

2

, CHCl

3

, RT, NaH, diethyl acetamidomalonate,

, THF/Et O, RT, 2 h.

1j

7

DMF, 808C, 1 h; c) LiBr, H O, DMF, 1508C, 16 h; d) LiAlH

2

4

2

2a

2b

2c

2 5

C H

2

CH F

NHC

Table 1. Binding affinity of agomelatine and selected compounds for

human melatoninergic receptors.

22d

22e

2

3

H

5

7

[

a] Data represent the meanÆSEM of n independent experiments per-

formed in duplicate, where n is given in parentheses.

tion was substituted for alkyl, carbamate, fluoroalkyl, or ureas

1

2

3

[a]

Compd

R

pK

i

(

21b–j). Substitution of the acetamide by trifluoroacetamide

21 f) improved melatoninergic binding affinities in comparison

h-MT

1

h-MT

2

Agomelatine

9.92Æ0.00 (2)

10.07Æ0.14 (2)

9.84Æ0.14 (2)

9.55Æ0.11 (3)

10.11Æ0.16 (3)

7.64Æ0.15 (2)

8.53Æ0.14 (2)

8.65Æ0.06 (3)

6.66Æ0.12 (2)

8.14Æ0.20 (2)

7.52Æ0.08 (2)

7.96Æ0.10 (2)

7.34Æ0.14 (2)

7.83Æ0.03 (2)

9.42Æ0.06 (3)

with parent compound 21a (Table 2). Also, we extended the

hydroxymethyl to a hydroxyethyl group and prepared com-

pounds 22a–e. This modification did not have a strong effect

on the MT and MT binding affinities of these derivatives. Fur-

5

8

1

a

b

a

b

0

5

7

CH

3

2

CH

3

H

CH

10.06Æ0.04 (2)

9.87Æ0.09 (2)

9.87Æ0.11 (2)

10.17Æ0.05 (3)

8.63Æ0.09 (3)

9.56Æ0.22 (2)

9.21Æ0.04 (3)

7.94Æ0.02 (2)

9.09Æ0.02 (2)

8.69Æ0.18 (3)

7.86Æ0.03 (2)

7.88Æ0.09 (2)

7.59Æ0.19 (2)

C

2

H

5

F

CH

3

CHF

2

3

1

2

CH

3

cyclobutyl

H

thermore, in these two series, we noted that replacement of

the acetamide entity by a urea (21h–j and 22d–e) led to MT₂

selectivity (Table 2).

F

=O

Z-18a

E-18b

Z-18c

=NÀOH

These results led us to modulate the hydroxy group of com-

pound 21a. In fact, its substitution by a fluorine atom (28) no-

tably improved the binding affinities at both MT and MT mel-

=NOCH

3

21a

24a

24b

H

CH

2

OH

2

OH

2

OH

1

2

3

C

2

H

5

atonin receptors compared with compound 21a. Moreover,

vinyl 29 showed the most interesting binding results of this

series. Replacement of the hydroxy group by a thiol led to an

increase of both MT and MT binding affinities. Unfortunately,

[

a] Data represent the meanÆSEM of n independent experiments per-

formed in duplicate, where n is given in parentheses.

1

2

substitution of the hydroxy group of 21a by amines (33 and

35) or amides (34a–d) led to a decrease in melatoninergic

pounds 24a,b. This modification confirms the decrease in MT₁

and MT binding affinities observed with compound 21a.

binding affinity, particularly toward the MT receptor (Table 3).

2

1

Finally, all compounds tested on melatonin (MT /MT ) recep-

Furthermore, as observed from the binding assays, displace-

ment of the hydroxymethyl from the beta to the alpha posi-

tion of the acetamide was not a favorable structural modula-

tion because the resulting compound (39) exhibited a noticea-

ble decrease in melatoninergic binding affinity, particularly at

MT receptor leading to poor MT selectivity (Table 3).

1

2

tors (Table 1) were then evaluated at the human cloned 5-HT₂_C

receptor subtype using CHO cell lines stably expressing the re-

[

20]

ceptor. Most of the compounds exhibited 5-HT₂_Cbinding af-

finity in the micromolar range except compound 21a, which

showed good affinity (pK =6.64Æ0.14).

i

1

2

Compound 21a was then considered for additional pharma-

comodulations with the aim of improving melatoninergic and

serotoninergic binding affinities. Consequently, the amide func-

Table 4 shows those compounds that exhibit good binding

affinities at both melatonin (MT /MT ) and serotonin 5-HT re-

1

2

2C

ceptor subtypes. Only compounds 21a, 21b, 21d, 21e, 21 f,

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Table 3. Binding affinity of selected compounds for human melatoninergic

receptors.

Table 5. pEC50 and Emax data of compounds 21a–j determined against

human melatoninergic receptors.

[a]

Compd h-MT

1

h-MT

2

pEC50

E

max [%]

pEC50

Emax [%]

Agomelatine 9.70Æ0.01 (2) 96Æ11 (2) 10.16Æ0.06 (2)

96Æ1 (2)

48Æ6 (2)

92Æ14 (3)

87Æ17 (2)

95Æ12 (2)

21a

21b

21c

21d

21e

21 f

7.14Æ0.05 (2) 69Æ5 (2)

7.10Æ0.02 (2) 55Æ8 (2)

6.82Æ0.15 (2) 67Æ4 (2)

6.44Æ0.09 (2) 40Æ2 (2)

6.90Æ0.12 (2) 86Æ14 (2)

7.64Æ0.08 (2) 88Æ20 (2)

6.78Æ0.10 (2) 83Æ21 (2)

6.75Æ0.16 (2) 91Æ8 (2)

6.70Æ0.09 (2) 61Æ1 (2)

6.84Æ0.16 (2)

8.92Æ0.15 (3)

8.42Æ0.08 (2)

8.45Æ0.10 (2)

2

[a]

Compd

R

pK

i

8.15Æ0.18 (3) 128Æ48 (3)

h-MT

1

h-MT

2

8.49Æ0.11 (2)

8.31Æ0.05 (2)

7.29Æ0.01 (2)

8.52Æ0.07 (3)

7.54Æ0.07 (2)

80Æ7 (2)

76Æ10 (2)

65Æ5 (2)

95Æ4 (3)

76Æ10 (2)

2

3

1a

5

6

8

9

1

3

4a

4b

4c

4d

5

OH

OCH

OCOCH

3

7.96Æ0.10 (2)

8.20Æ0.05 (2)

6.74Æ0.13 (2)

9.94Æ0.06 (2)

10.56Æ0.04 (2)

8.68Æ0.14 (3)

6.32Æ0.11 (2)

6.25Æ0.01 (2)

6.42Æ0.13 (3)

6.42Æ0.05 (2)

6.46Æ0.12 (3)

6.82Æ0.03 (2)

6.46Æ0.10 (3)

7.86Æ0.03 (2)

8.69Æ0.08 (2)

8.21Æ0.18 (3)

9.67Æ0.05 (3)

9.90Æ0.10 (2)

9.08Æ0.06 (3)

6.23Æ0.20 (2)

7.07Æ0.02 (2)

7.66Æ0.03 (3)

7.64Æ0.03 (3)

7.77Æ0.05 (3)

7.55Æ0.10 (3)

7.57Æ0.06 (3)

21g

21h

21i

3

CH

–

2

F

21j

–

[

a] Data represent the meanÆSEM of n independent experiments per-

SH

formed in duplicate, where n is given in parentheses.

NH

2

·HCl

NHCOCH

NHCOC

NHCOc-C H

3 5

N-Morpholine

–

3

2

H

5

7

3

Table 6. Evaluation of select compounds 21 against the 5-HT2C recep-

tor.

[

a]

9

[

a] Data represent the meanÆSEM of n independent experiments per-

Compd

pK

B

Imax [%]

formed in duplicate, where n is given in parentheses.

Agomelatine

6.1Æ0.1 (2)

6.4Æ0.2 (2)

6.5Æ0.2 (2)

6.4Æ0.1 (2)

107Æ13 (2)

104Æ4 (2)

94.8Æ3.1 (2)

108Æ3 (2)

21a

21e

21 f

Table 4. Binding affinity results for select compounds 21 for human mel-

atoninergic and the 5-HT2C receptors.

[

a] Data represent the meanÆSEM of n independent experiments per-

[

a]

formed in duplicate, where n is given in parentheses.

Compd

pK

h-MT

i

h-MT

1

2

h-5-HT2C

cological profiles were obtained. In addition, compounds 21a,

Agomelatine

9.92Æ0.00 (2)

7.96Æ0.10 (2)

8.18Æ0.08 (2)

7.19Æ0.18 (2)

7.95Æ0.06 (2)

8.61Æ0.03 (2)

6.50Æ0.09 (4)

9.42Æ0.06 (3)

7.86Æ0.03 (2)

8.43Æ0.15 (3)

7.38Æ0.21 (4)

8.68Æ0.03 (2)

9.33Æ0.18 (2)

7.62Æ0.06 (4)

6.15Æ0.04 (3)

6.64Æ0.14 (2)

6.08Æ0.07 (3)

6.19Æ0.14 (2)

6.44Æ0.14 (3)

6.12Æ0.06 (2)

6.16Æ0.05 (3)

21b, 21d, 21e, 21 f, and 21j showed good binding affinities

21a

21b

21d

21e

21 f

21j

at both melatonin (MT /MT ) and serotonin (5-HT ) receptor

1

2

2C

subtypes. Moreover, acetamide 21a and acrylamide 21e be-

haved as MT /MT agonists and 5-HT antagonists. The selec-

1

2

2C

^tⁱ^vⁱ^t^y^o^f^t^h^e^s^e^c^o^m^p^o^uⁿ^d^s^t^o^w^a^r^d⁵^-^H^T2A ^aⁿ^d⁵^-^H^T2B receptor

subtypes is currently under investigation.

[

a] Data represent the meanÆSEM of n independent experiments per-

formed in duplicate, where n is given in parentheses.

and 21j showed binding affinities in the low micromolar range

when evaluated against the human cloned 5-HT₂_Creceptor

subtype.

Experimental Section

Chemistry

A number of the synthesized compounds, especially those

exhibiting good binding affinities, were evaluated in functional

assays to determine their agonist activities at MT and MT ,

Melting points (mp) were determined on a Bꢃchi SMP-20 capillary

apparatus and are uncorrected. IR spectra were recorded on

1

2

1

13

a Thermo Nicolet Avatar 320 FT-IR spectrometer. H and C NMR

spectra were recorded on AC300 Bruker spectrometer. Chemical

shifts (d) are reported in parts per million (ppm) relative to (CH ) Si,

and their antagonist activity at 5-HT ; their pEC values are

2C

50

reported in Tables 5 and 6. Several compounds were potent

agonists of the MT and MT receptors, and full antagonists of

3

4

and coupling (J) values are reported in hertz (Hz). Purity of all final

products was determined to be >95% by analytical reverse-phase

HPLC (Lichrospher 100 RP-18 column, 4.6 mmꢄ150 mm, 12 mm). El-

emental analyses of new compounds were performed by CNRS

Laboratories (Vernaison, France), and the results obtained were

within 0.4% of the theoretical values. Mass spectrometry (MS) was

performed on a Surveyor MSQ Thermoelectron spectrometer (+

cAPCI corona sid=30.00; det=1400.00; full mass range: 100.00–

1000.00). All anhydrous solvents were dried and purified by stan-

dard techniques just before use.

1

2

the 5-HT₂_Creceptor, similar to agomelatine.

Conclusions

We synthesized a variety of naphthalenic analogues of agome-

^l^a^tⁱⁿ^e^t^oⁱ^m^p^r^o^v^e^t^h^e⁵^-^H^T²C binding affinity. By introducing

different lipophilic and hydrophilic groups in the b-position of

the ethyl amide side chain, compounds with different pharma-

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2

-Cyano-2-(7-methoxynaphthalen-1-yl)methyl acetate (1): (7-Me-

in vacuo, and the residue obtained was taken up in water (20 mL)

thoxynaphthalen-1-yl)acetonitrile (20 g, 101.4 mmol) was dissolved

in dry THF (150 mL) and treated with NaH (8.32 g, 202.8 mmol;

and extracted with Et O (2ꢄ40 mL). The organic layers were then

2

washed with 1n aq NaOH, dried (MgSO ), filtered, and concentrat-

4

6

0% dispersion in mineral oil). The mixture was heated at reflux

ed in vacuo.

for 30 min. Dimethyl carbonate (12mL, 142.5 mmol) was then

added, and the reaction mixture was maintained at reflux for an

additional 30 min, then poured into ice-cold water (100 mL) and

acidified with 37% HCl (21 mL). The aqueous phase was extracted

with EtOAc (2ꢄ100 mL), and the organic layer was washed with

2

-(7-Methoxynaphthalen-1-yl)propionitrile (4a): Recrystallized

from toluene to give the desired product as a white solid (2.95 g,

1

7

0%): mp: 68–698C; H NMR (300 MHz, CDCl ): d=2.28 (d, J=

.1 Hz, 3H), 3.98 (s, 3H), 4.55 (q, J=7.1 Hz, 1H), 7.18–7.27 (m, 2H),

.38–7.42 (m, 1H), 7.67–7.72 (m, 1H), 7.79–7.82 (m, 1H), 7.84 ppm

3

water (50 mL), dried (MgSO ), filtered, and concentrated in vacuo.

4

À1

(d, J=8.8 Hz, 1H); IR (KBr): n˜ =2240 cm ; MS (APCI+, 30 V): m/z

After recrystallization from toluene, the desired product was ob-

+

1

(%): 212.30 [M+H] .

tained as a white solid (20.37 g, 80%): mp: 81–828C; H NMR

(

7

1

300 MHz, CDCl ): d=3.80 (s, 3H), 3.97 (s, 3H), 5.28 (s, 1H), 7.23

dd, J=2.4, 9.0 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.39–7.42 (m, 1H),

3

2

-(7-Methoxynaphthalen-1-yl)butyronitrile (4b): Recrystallized

from toluene to give the desired product as a white solid (3.15 g,

70%): mp: 78–798C; H NMR (300 MHz, CDCl ): d=1.19 (t, J=

.66–7.70 (m, 1H), 7.80–7.88 ppm (m, 2H); IR (KBr): n˜ =2246,

1

À1

+

3

736 cm ; MS (APCI+, 30 V): m/z (%): 256.19 [M+H] .

7

.4 Hz, 3H), 2.28–2.35 (m, 2H), 3.98 (s, 3H), 4.55 (dd, J=6.0, 8.0 Hz,

3

-Cyano-2-(7-methoxynaphthalen-1-yl)methyl propanoate (2):

1H), 7.18–7.27 (m, 2H), 7.38–7.42 (m, 1H), 7.67–7.73 (m, 1H), 7.79–

À1

(

7-Methoxynaphthalen-1-yl)acetonitrile (10 g, 50.7 mmol) and TBAB

0.35 g, 1.3 mmol) were dissolved in acetone (100 mL). K CO (21 g,

7.83 (m, 1H), 7.84 ppm (d, J=8.8 Hz, 1H); IR (KBr): n˜ =2234 cm

;

+

(

MS (APCI+, 30 V): m/z (%): 226.31 [M+H] .

2

3

1

52.1 mmol) was added portionwise, and the reaction mixture was

heated at reflux for 30 min. Methyl bromoacetate (7 mL, 76 mmol)

was added cautiously, and the reaction mixture maintained at

reflux for a further 24 h. After cooling, the reaction mixture was

added to 1n aq HCl (100 mL), and the organic phase was washed

General procedure for the preparation of compounds 5a,b: Ni-

trile 4 (6.0 mmol) was dissolved in Ac O (80 mL) and Raney nickel

(1 g) was added. The mixture was placed under H (50 bars) and

2

heated at 608C for 2 h. After cooling, the catalyst was removed by

with water (50 mL), dried (MgSO ), filtered, and concentrated in

filtration, the filtrate was concentrated in vacuo. The residue ob-

4

vacuo to furnish the desired product as a white solid (10.23 g,

tained was then taken up in water (20 mL) and extracted with Et

(2ꢄ40 mL). The organic phase was washed with 1n aq NaHCO

(50 mL), brine (50 mL) and water (50 mL), then dried (MgSO ), fil-

tered, and concentrated in vacuo. The residue obtained was taken

up with petroleum ether, and the precipitate formed was filtered

and recrystallized.

2

O

1

7

5

3

1

5%): mp: 112–1148C; H NMR (300 MHz, CDCl ): d=3.03 (dd, J=

3

.2, 16.5 Hz, 1H), 3.15 (dd, J=9.1, 16.5 Hz, 1H), 3.78 (s, 3H), 4.02 (s,

H), 4.98 (dd, J=5.2, 9.1 Hz, 1H), 7.29–7.37 (m, 2H), 7.53–7.55 (m,

H), 7.70–7.72 (m, 1H), 7.75–7.90 ppm (m, 2H); IR (KBr): n˜ =2241,

4

À1

+

726 cm ; MS (APCI+, 30 V): m/z (%): 270.19 [M+H] .

General procedure for alkylation to give 3a,b: Compound

N-[2-(7-Methoxynaphthalen-1-yl)propyl]acetamide (5a): Recrys-

1

2

⁽²⁰^.⁰^m^m^o^l⁾^w^a^s^dⁱ^s^s^o^l^v^e^dⁱⁿ^a^c^e^t^oⁿ^e⁽⁵⁰^m^L⁾^,^t^h^eⁿ^K^C^O3

tallized from cyclohexane to give the desired product as a white

1

(

8.292 g, 60.0 mmol) was added, and the mixture was heated at

solid (0.58 g, 38%): mp: 76–788C; H NMR (300 MHz, CDCl ): d=

3

reflux for 30 min. Methyl or ethyl iodide (24.0 mmol) was added

dropwise, and the reaction mixture was heated at reflux for an ad-

ditional 2 h. After cooling, the solid was removed by filtration and

discarded, and the filtrate was concentrated in vacuo. The residue

1.43 (d, J=6.9 Hz, 3H), 1.90 (s, 3H), 3.79–3.61 (m, 2H), 3.82–3.92

(m, 1H), 4.00 (s, 3H), 5.49 (brs, 1H), 7.18 (dd, J=8.9, 2.3 Hz, 1H),

7.34–7.39 (m, 2H), 7.55 (d, J=2.0 Hz, 1H), 7.70 (dd, J=9.0, 2.0 Hz,

13

1

H), 7.79 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz, [D ]DMSO): d=

6

obtained was taken up in water (25 mL) and extracted with Et O

2

18.3, 23.1, 34.0, 46.6, 55.7, 102.7, 118.4, 123.5, 123.6, 126.8, 129.3,

À1

(

2ꢄ100 mL). The organic phase was washed with water (50 mL),

1

30.6, 133.2, 139.6, 157.9, 170.0 ppm; IR (KBr): n˜ =3289, 1645 cm

;

+

dried (MgSO ), filtered, and concentrated in vacuo.

4

MS (APCI+, 30 V): m/z (%): 258.40 [M+H] .

Methyl 2-cyano-2-(7-methoxynaphthalen-1-yl)propionate (3a):

N-[2-(7-Methoxynaphthalen-1-yl)butyl]acetamide (5b): Recrystal-

Recrystallized from toluene to give the desired product as a white

lized from toluene/cyclohexane (1:3) to give the desired product as

1

solid (4.84 g, 90%): mp: 81–828C; H NMR (300 MHz, CDCl ): d=

1

3

a white solid (1.0 g, 62%): mp: 101–1038C; H NMR (300 MHz,

2

7

.28 (s, 3H), 3.78 (s, 3H), 3.94 (s, 3H), 7.22 (dd, J=8.8, 2.3 Hz, 1H),

.36 (d, J=2.3 Hz, 1H), 7.41–7.45 (m, 1H), 7.67–7.70 (m, 1H), 7.83

CDCl ): d=0.86–0.91 (t, J=7.2 Hz, 3H), 1.75–2.12 (m, 5H), 3.36–

3

5

.48 (m, 1H), 3.60–3.71 (m, 1H), 3.73–3.86 (m, 1H), 3.98 (s, 3H),

.38 (brs, 1H), 7.19 (dd, J=9.0, 2.4 Hz, 1H), 7.34–7.38 (m, 2H), 7.47

(

1

d, J=8.8 Hz, 1H), 7.88–7.92 ppm (m, 1H); IR (KBr): n˜ =2240,

749 cm ; MS (APCI+, 30 V): m/z (%): 270.38 [M+H] .

À1

+

(

d, J=2.4 Hz, 1H), 7.67–7.74 (m, 1H), 7.79 ppm (d, J=9.0 Hz, 1H);

1

3

C NMR (75 MHz, [D ]DMSO): d=12.2, 23.1, 24.9, 39.9, 45.3, 55.6,

Methyl 2-cyano-2-(7-methoxynaphthalen-1-yl)butanoate (3b):

6

1

02.7, 118.2, 123.6, 124.0, 126.7, 129.4, 130.6, 134.1, 137.9, 157.8,

Recrystallized from toluene to give the desired product as a white

À1

1

170.0 ppm; IR (KBr): n˜ =3300, 1642 cm ; MS (APCI+, 30 V): m/z

solid (5.09 g, 90%): mp: 76–788C; H NMR (300 MHz, CDCl ): d=

3

+

(%): 272.37 [M+H] .

1

7

1

2

.23 (t, J=7.4 Hz, 3H), 2.65–2.71 (m, 2H), 3.78 (s, 3H), 3.94 (s, 3H),

.21 (dd, J=9.0, 2.3 Hz, 1H), 7.39–7.42 (m, 1H), 7.45 (d, J=2.3 Hz,

H), 7.70–7.76 (m, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.84–7.90 ppm (m,

2

-(7-Methoxynaphthalen-1-yl)-2-methylpropionitrile (6): Pre-

pared from compound A (3.94 g, 20.0 mmol) and CH I (3 mL,

48.0 mmol) according to the procedure described for compounds

a,b. Recrystallized from toluene to give the desired product as

À1

3

H); IR (KBr): n˜ =2220, 1742 cm ; MS (APCI+, 30 V): m/z (%):

+

84.32 [M+H] .

3

1

General procedure for decarboxylation to give 4a,b: Cyanoester

(20.0 mmol) was dissolved in EtOH (30 mL) and then treated with

.5n aq NaOH (20 mL, 30.0 mmol). The mixture was stirred at RT

a yellow solid (3.36 g, 75%): mp: 73–758C; H NMR (300 MHz,

3

1

CDCl ): d=1.99 (s, 6H), 4.01 (s, 3H), 7.22 (dd, J=9.3, 2.7 Hz, 1H),

3

7.33 (t, J=7.8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.76–7.84 ppm (m,

À1

for 20 h, then treated with 37% HCl (3.34 mL, 40.0 mmol) and

heated at reflux for 2 h. The solvent was then evaporated in vacuo

3H); IR (KBr): n˜ =2227 cm ; MS (APCI+, 30 V): m/z (%): 225.20

+

[M+H] .

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À1

2

-(7-Methoxynaphthalen-1-yl)-2-methylpropylamine hydrochlo-

7.84 ppm (m, 2H); IR (KBr): n˜ =2225 cm ; MS (APCI+, 30 V): m/z

(%): 238.31 [M+H] .

+

ride (7): A solution of AlCl (5.33 g, 40.0 mmol) in dry Et O (50 mL)

3

2

was added dropwise to a suspension of LiAlH (1.51 g, 40.0 mmol)

4

at 08C in dry Et O (100 mL). After 10 min of stirring, a solution of

N-{[1-(7-Methoxynaphthalen-1-yl)cyclobutyl]methyl}acetamide

(10): Prepared from compound 9 according to the procedure de-

2

compound 6 (2.24 g, 10.0 mmol) in dry Et O (100 mL) was added.

2

The reaction mixture was stirred for an additional 30 min, and then

hydrolyzed with 15n aq NaOH (10 mL, 150.0 mmol). After filtration

and evaporation, the residue was dissolved in water (50 mL) and

extracted with CH Cl (3ꢄ40 mL). The organic phase was washed

scribed for 5a,b. Recrystallized from iPr O to give the desired prod-

uct as a white solid (0.61 g, 36%): mp: 107–1098C; H NMR

2

1

(300 MHz, CDCl ): d=1.85–2.70 (m, 11H), 3.90 (s, 3H), 5.05 (brs,

3

1H), 7.12–7.20 (m, 3H), 7.33 (dd, J=7.0, 8.2 Hz, 1H), 7.69 (d, J=

2

13

with water (50 mL), dried (MgSO ), filtered, and concentrated in

8.2 Hz, 1H), 7.80 ppm (d, J=8.8 Hz, 1H); C NMR (75 MHz, CDCl₃):

d=16.3, 23.4, 32.4, 46.3, 47.5, 55.3, 103.8, 118.1, 122.9, 125.0, 127.2,

129.8, 130.6, 131.6, 141.5, 157.1, 170.4 ppm; IR (KBr): n˜ =3309,

4

vacuo. The oily residue was then treated with HCl₍_g₎and recrystal-

lized from CH CN to give the desired product as a white solid

3

1

À1

+

(

1.32 g, 50%): mp: 177–1798C; H NMR (300 MHz, [D ]DMSO): d=

1647 cm ; MS (APCI+, 30 V): m/z (%): 284.31 [M+H] ; Anal. calcd

6

1

7

1

.63 (s, 6H), 3.39 (s, 2H), 3.93 (s, 3H), 7.23 (dd, J=9.0, 2.4 Hz, 1H),

.32 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.54 (d, J=2.1 Hz,

for C H NO : C 76.29, H 7.47, N 4.94, found: C 76.61, H 7.55, N

4.62.

18

21

2

H), 7.80 (d, J=8.1 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 8.00 ppm (brs

À1

exchangeable in D O, 3H); IR (KBr): n˜ =2884, 1623 cm ; MS

(7-Methoxynaphthalen-1-yl)carbaldehyde (11): Tetrabutylammo-

nium periodate (15 g, 34.6 mmol) was added dropwise to a solution

of (7-methoxynaphthalen-1-yl) acetic acid (7.5 g, 34.6 mmol) in di-

oxane (150 mL), and the mixture was heated at reflux for 16 h, and

then concentrated in vacuo. The residue obtained was dissolved in

2

+

(

APCI+, 30 V): m/z (%): 266.81 [M+H] .

Preparation of fluoroacetamides 8a,b: Ethyl fluoroacetate or

methyl difluoroacetate (10.0 mmol) was added to a solution of the

free base of compound 7 (1.15 g, 5.0 mmol) in 2,2,2-trifluoroetha-

nol (40 mL), and the reaction mixture was heated at reflux for 12 h.

After cooling, the reaction mixture was diluted with water (50 mL),

water (100 mL) and extracted with Et O (2ꢄ100 mL). The organic

2

phase was washed with water (80 mL), dried (MgSO ), filtered, and

4

concentrated in vacuo. Purification using a silica gel column

and the aqueous phase was extracted with Et O (2ꢄ60 mL). The

(EtOAc/cyclohexane, 1:9) and recrystallization from iPr O gave the

2

organic phase was washed with water (40 mL), dried (MgSO ), fil-

tered, and concentrated in vacuo. The solid obtained was then re-

desired compound as a white solid (2.89 g, 45%): mp: 61–638C;

4

1

H NMR (300 MHz, CDCl ): d=3.95 (s, 3H), 7.26 (dd, J=2.1, 9.0 Hz,

3

crystallized from iPr O to give the desired product.

1H), 7.51–7.60 (m, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.97–8.00 (m, 1H),

2

8

.05–8.08 (m, 1H), 8.78 (d, J=9.0 Hz, 1H), 10.45 ppm (s, 1H); IR

À1

+

2

-Fluoro-N-[2-(7-methoxynaphthalen-1-yl)-2-methylpropyl]aceta-

(KBr): n˜ =1686 cm ; MS (APCI+, 30 V): m/z (%): 187.11 [M+H] .

1

mide (8a): White solid (0.86 g, 60%): mp: 74–768C; H NMR

(

8

300 MHz, [D ]DMSO): d=1.48 (s, 6H), 3.71 (d, J=6.0 Hz, 2H), 3.98

s, 3H), 4.89 (d, J=47.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.28 (t, J=

(7-Methoxynaphthalen-1-yl)trimethylsilylanoyloxy

acetonitrile

6

(12): Methyl triphenyl-phosphonium iodide (2.3 g, 5.7 mmol) was

dissolved in dry CH Cl (250 mL) under an inert atmosphere, and

.1 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.85 (d,

2

13

J=8.7 Hz, 1H), 8.06 (s, 1H), 8.32 ppm (brs, 1H); C NMR (75 MHz,

CDCl ): d=18.3, 35.8, 45.8, 55.7, 80.5 ( J =180 Hz), 102.7, 118.4,

TMSCN (22.8 mL, 170.8 mmol) and aldehyde 11 (10.6 g, 56.9 mmol)

were added. The reaction mixture was stirred at RT for 72 h, then

water (200 mL) was added and the two phases were separated.

The aqueous phase was extracted with CH Cl (3ꢄ50 mL), and the

1

3

CF

1

(

23.4, 123.7, 126.9, 129.3, 130.7, 133.1, 139.4, 158.0, 168.0 ppm

2

À1

J =18 Hz); IR (KBr): n˜ =3339, 3320, 1673 cm ; MS (APCI+,

0 V): m/z (%): 290.39 [M+H] .

CF

2

+

3

organic phase was dried (MgSO ), filtered, and concentrated in

4

vacuo. Recrystallization from cyclohexane gave the desired product

1

2

,2-Difluoro-N-[2-(7-methoxynaphthalen-1-yl)-2-methylpropyl]a-

as a white solid (12.50 g, 77%): mp: 123–1258C; H NMR (300 MHz,

1

cetamide (8b): White solid (0.61 g, 40%): mp: 103–1058C; H NMR

CDCl ): d=0.20 (s, 9H), 4.00 (s, 3H), 6.00 (s, 1H), 7.24 (dd, J=9.1,

3

(

7

1

300 MHz, [D ]DMSO): d=1.48 (s, 6H), 4.74 (d, J=6.6 Hz, 2H), 3.98

s, 3H), 6.28 (t, J=52.5, 53.7 Hz, 1H), 7.18 (dd, J=9.0, 2.4 Hz, 1H),

.29 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz,

2.5 Hz, 1H), 7.36 (dd, J=7.3, 8.0 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H),

7.65 (d, J=7.3 Hz, 1H), 7.80–7.88 ppm (m, 2H); IR (KBr): n˜ =

2230 cm ; MS (APCI+, 30 V): m/z (%): 286.40 [M+H] .

6

À1

+

H), 7.86 (d, J=9.0 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 8.98 ppm (brs,

À1

H); IR (KBr): n˜ =3300, 3298, 1665 cm ; MS (APCI+, 30 V): m/z

2-Amino-1-(7-methoxynaphthalen-1-yl)ethanol

hydrochloride

+

(

%): 308.38 [M+H] .

(13): LiAlH₄(1.41 g, 37.1 mmol) was suspended in dry Et O

2

(200 mL) under an inert atmosphere, and then a solution of com-

1

-(7-Methoxynaphthalen-1-yl)cyclobutanecarbonitrile (9): 1,3-Di-

pound 12 (18.6 mmol) in dry THF (50 mL) was added dropwise

over 15 min. The reaction mixture was stirred at RT for 1 h, and

then hydrolyzed by addition of water (1.4 mL), 15% aq NaOH

(1.4 mL), then with water (4.2 mL). The mineral formed was filtered,

washed with THF (50 mL) and discarded. The combined filtrates

bromopropane (2.5 mL, 25.6 mmol) was added to a solution of (7-

methoxynaphthalen-1-yl)acetonitrile (5 g, 25.4 mmol) in DMSO/

Et O (1:1, 150 mL). The mixture was stirred and added dropwise to

a suspension of NaH (3.05 g, 76.1 mmol; 60% dispersion in mineral

oil) in DMSO (50 mL) at RT. The reaction mixture was stirred for 2 h,

then poured into water (100 mL). The aqueous mixture was acidi-

fied with 0.1n aq HCl (5 mL) and extracted with EtOAc (3ꢄ50 mL).

2

were dried (MgSO ), filtered, and concentrated in vacuo. The

4

yellow oil obtained was solubilized in Et O and treated with HCl .

2

(g)

Recrystallization from CH CN gave the desired product as a white

3

1

The organic phase was washed with water, dried (MgSO ), filtered,

solid (4.64 g, 98%): mp: 207–2098C; H NMR (300 MHz, [D ]DMSO):

4

6

and concentrated in vacuo. The residue obtained was then chro-

matographed on silica gel (EtOAc/cyclohexane, 1:9), and recrystal-

d=2.80–2.86 (m, 1H), 3.10–3.22 (m, 1H), 3.95 (s, 3H), 5.70 (d, J=

9.0 Hz, 1H), 6.20 (brs exchangeable in D O, 1H), 7.18 (d, J=8.8 Hz,

2

lized from iPr O to give the desired product as a white solid

1H), 7.38 (t, J=7.6 Hz, 1H), 7.52 (s, 1H), 7.70 (d, J=6.9 Hz, 1H),

2

1

(

3.73 g, 62%): mp: 99–1018C; H NMR (300 MHz, CDCl ): d=2.10–

7.80 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.43 ppm (brs ex-

3

À1

2

.12 (m, 1H), 2.60–2.64 (m, 1H), 2.85–2.88 (m, 2H), 3.10–3.18 (m,

H), 4.00 (s, 3H), 7.19–7.24 (m, 2H), 7.30–7.40 (m, 2H), 7.74–

changeable in D O, 3H); IR (KBr): n˜ =3512, 3200–2600 cm ; MS

(APCI+, 30 V): m/z (%): 255.70 [M+H] .

2

+

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N-[2-Hydroxy-2-(7-methoxynaphthalen-1-yl)ethyl]acetamide (14):

K₂CO₃(8.29 g, 60.0 mmol) was added to a suspension of com-

pound 13 (5.07 g, 20.0 mmol) in water/EtOAc (100 mL, 1:1). The re-

action mixture was cooled at 08C in an ice bath and acetyl chloride

General procedure for the preparation of oximes 18a–d: Hydrox-

ylamine or O-methylhydroxylamine hydrochlorides (16.8 mmol)

and pyridine (1.7 mL, 21.1 mmol) were added to a solution of com-

pound 17 (1.08 g, 4.2 mmol) in MeOH (250 mL). The reaction mix-

ture was heated at reflux for 3 h, cooled and hydrolyzed with

water (150 mL). The precipitate formed was filtered and recrystal-

lized leading to the desired product.

(

1.85 mL, 26.0 mmol) was added. The mixture was stirred for

5 min, and the organic phase was washed with 1n aq HCl

20 mL) and water (20 mL), dried (MgSO ), filtered, and concentrat-

1

(

4

ed in vacuo. Recrystallization from CH CN gave the desired product

as a white solid (3.73 g, 72%): mp: 173–1758C; H NMR (300 MHz,

3

1

N-[(2 Z)-2-(Hydroxyimino)-2-(7-methoxynaphthalen-1-yl)ethyl]a-

cetamide (18a): Recrystallized from CH CN to give the desired

3

[

D ]DMSO): d=1.90 (s, 3H), 2.75–2.82 (m, 1H), 3.70 (dd, J=11.7,

6

1

product as a white solid (0.24 g, 21%): mp: 157–1598C; H NMR

6

.4 Hz, 1H), 3.95 (s, 3H), 5.35–3.38 (m, 1H), 6.20 (brs exchangeable

(

300 MHz, [D ]DMSO): d=1.73 (s, 3H), 3.85 (s, 3H), 4.15 (d, J=

6

in D O, 1H), 7.16 (dd, J=9.0, 2.3 Hz, 1H), 7.35 (dd, J=7.0, 8.0 Hz,

2

6

7

.0 Hz, 2H), 7.06 (d, J=2.5 Hz, 1H), 7.17 (dd, J=8.9, 2.5 Hz, 1H),

.25 (dd, J=6.9, 1.2 Hz, 1H), 7.35 (dd, J=6.9, 8.0 Hz, 1H), 7.78–7.88

1

2

H), 7.67 (d, J=7.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.80 (d, J=

.3 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 8.32 ppm (brs, 1H); IR (KBr):

1

3

À1

(m, 2H), 8.17 (t, J=6.0 Hz, 1H), 10.80 ppm (brs, 1H); C NMR

n˜ =3400–3200, 1637 cm ; MS (APCI+, 30 V): m/z (%): 260.36

+

(75 MHz, [D ]DMSO): d=22.9, 43.5, 55.6, 104.8, 118.8, 123.4, 125.5,

6

[M+H] ; Anal. calcd for C H NO : C 69.49, H 6.61, N 5.40, found:

15 17 3

1

28.3, 128.8, 130.1, 131.5, 132.1, 153.8, 157.8, 169.8 ppm; IR (KBr):

C 69.49, H 6.53, N 5.31.

À1

n˜ =3313, 2839, 1624 cm ; MS (APCI+, 30 V): m/z (%): 273.31

[M+H] ; Anal. calcd for C15

+

General procedure for the preparation of compounds 15 and

6: DAST (2.24 g, 13.9 mmol) was cautiously added dropwise to

a solution of compound 14 (1.81 g, 7.0 mmol) in dry CH Cl₂

H N O : C 66.16, H 5.92, N 10.29,

16 2 3

1

found: C 65.93, H 5.85, N 10.21.

2

N-[(2 E)-2-(Hydroxyimino)-2-(7-methoxynaphthalen-1-yl)ethyl]a-

cetamide (18b): Recrystallized from toluene to give the desired

(

25 mL) at 08C. The reaction mixture was allowed to warm to RT

and poured into water (100 mL), then acidified with 1n aq HCl

5 mL) and extracted with CH Cl (2ꢄ100 mL). The organic phase

1

product as a white solid (0.12 g, 11%): mp: 136–1388C; H NMR

(

2

(

300 MHz, [D ]DMSO): d=1.52 (s, 3H), 3.84 (s, 3H), 4.43 (d, J=

6

was washed with water (50 mL), dried (MgSO ), filtered, and con-

4

6

.0 Hz, 2H), 7.16 (dd, J=8.9, 2.5 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H),

centrated in vacuo to give the desired product.

7

.30–7.35 (m, 2H), 7.80–7.91 (m, 3H), 11.40 ppm (brs exchangeable

13

in D O, 1H); C NMR (75 MHz, [D ]DMSO): d=22.7, 37.2, 54.5,

N-[2-Fluoro-2-(7-methoxynaphthalen-1-yl)ethyl]acetamide (15):

2

6

1

04.6, 118.7, 123.1, 127.7, 128.7, 129.0, 130.2, 132.2, 133.2, 157.0,

Recrystallized from toluene/cyclohexane (1:1) to give the desired

product as a white solid (1.09 g, 60%): mp: 149–1518C; H NMR

À1

1

57.8, 170.0 ppm; IR (KBr): n˜ =3283, 1654 cm ; MS (APCI+, 30 V):

+

m/z (%): 273.29 [M+H] .

(

300 MHz, [D ]DMSO): d=1.95 (s, 3H), 3.25–3.35 (m, 1H), 3.70–4.05

m, 4H), 6.25 (dd, J=47.9, 7.9 Hz, 1H), 7.20 (dd, J=9.0, 2.3 Hz, 1H),

6

N-[(2 Z)-2-(Methoxyimino)-2-(7-methoxynaphthalen-1-yl)ethyl]a-

cetamide (18c): Recrystallized from iPr O to give the desired prod-

uct as a white solid (0.60 g, 50%): mp: 110–1128C; H NMR

7

2

.38 (dd, J=7.0, 7.6 Hz, 1H), 7.53 (d, J=7.0 Hz, 1H), 7.63 (d, J=

13

2

.3 Hz, 1H), 7.80–7.92 (m, 2H), 8.58 ppm (brs, 1H); C NMR

1

2

(

75 MHz, [D ]DMSO): d=22.9, 45.4 ( J =24 Hz), 55.9, 90.4, 92.7

6 CF

(300 MHz, CDCl ): d=2.05 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 4.35 (d,

1

3

J =171.0 Hz), 102.4, 119.0, 123.1, 123.2, 128.9, 130.9, 132.7, 133.0

CF

J=5.0 Hz, 2H), 6.25 (brs, 1H), 6.94 (d, J=2.5 Hz, 1H), 7.18 (dd, J=

À1

(J=18.0 Hz), 158.2, 170.8 ppm; IR (KBr): n˜ =3243, 1643 cm ; MS

9

7

2

1

.1, 2.5 Hz, 1H), 7.27 (dd, J=7.0, 1.0 Hz, 1H), 7.36 (dd, J=7.0,

.5 Hz, 1H), 7.75–7.83 ppm (m, 2H); C NMR (75 MHz, CDCl ): d=

+

(

APCI+, 30 V): m/z (%): 262.32 [M+H] ; Anal. calcd for C H FNO :

15

16

2

13

3

C 68.95, H 6.17, N 5.36, found: C 68.40, H 6.14, N 5.19.

3.2, 44.0, 55.4, 62.3, 103.6, 119.1, 122.8, 125.1, 128.9, 129.2, 130.0,

À1

30.1, 130.7, 153.1, 158.3, 170.0 ppm; IR (KBr): n˜ =3260, 1670 cm

;

5

-(7-Methoxynaphthalen-1-yl)-2-methyl-4,5-dihydro-oxazole

+

MS (APCI+, 30 V): m/z (%): 287.40 [M+H] ; Anal. calcd for

C H N O : C 67.12, H 6.34, N 9.78, found: C 67.11, H 6.34, N 9.53.

(16): Recrystallized from toluene/cyclohexane (1:1) to give the de-

sired product as a white solid (0.33 g, 20%): mp: 169–1718C;

16 18

2

3

1

H NMR (300 MHz, [D ]DMSO): d=2.05 (s, 3H), 3.50 (m, 1H), 3.90 (s,

6

N-[(2 E)-2-(Methoxyimino)-2-(7-methoxynaphthalen-1-yl)ethyl]a-

cetamide (18d): Purified on a silica gel column (cyclohexane/

EtOAc 1:1) as a yellow oil (0.55 g, 46%): H NMR (300 MHz, CDCl ):

d=1.80 (s, 3H), 3.92 (s, 3H), 4.09 (s, 3H), 4.63 (d, J=6.6 Hz, 2H),

3

1

H), 4.50–4.65 (m, 1H), 6.18 (t, J=8.9 Hz, 1H), 7.14 (d, J=2.3 Hz,

H), 7.23 (dd, J=9.0, 2.3 Hz, 1H), 7.34 (dd, J=7.0, 8.0 Hz, 1H), 7.45

1

3

(

1

d, J=7.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.90 ppm (d, J=9.0 Hz,

À1

H); IR (KBr): n˜ =1677 cm ; MS (APCI+, 30 V): m/z (%): 242.30

5

.84 (brs, 1H), 7.17 (dd, J=8.9, 2.5 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H),

+

[M+H] .

7

.36 (t, J=7.2 Hz, 1H), 7.51 (dd, J=7.2, 1.0 Hz, 1H), 7.74–7.84 ppm

À1

(m, 2H); IR (KBr): n˜ =3291, 1655 cm ; MS (APCI+, 30 V): m/z (%):

N-[2-(7-Methoxynaphthalen-1-yl)-2-oxo-ethyl]acetamide (17): A

solution of compound 14 (2 g, 7.7 mmol) in dry CH Cl (200 mL)

+

2

87.39 [M+H] .

2

was added to a suspension of PCC (2.5 g, 11.6 mmol) and AcOK

0.23 g, 2.3 mmol) in dry CH Cl (50 mL). The mixture was stirred at

RT for 2 h then filtered through celite. The filtrate was washed with

3

-Hydroxy-2-(7-methoxynaphthalen-1-yl)propylamine

hydro-

(

2

chloride (19): Prepared from cyanoester 1 according to the experi-

mental procedure described for compound 7. Recrystallized from

CH CN to give the desired product as a white solid (1.73 g, 65%):

mp: 164–1668C; H NMR (300 MHz, [D ]DMSO): d=3.19–3.26 (m,

1

water (25 mL), dried (MgSO ), filtered, and concentrated in vacuo.

4

3

The residue obtained was taken up in Et O (5 mL), and the precipi-

1

2

6

tate formed was filtered and recrystallized from iPr O to give the

2

H), 3.41–3.45 (m, 1H), 3.71–3.78 (m, 2H), 3.92–4.02 (m, 4H), 5.31

desired product as a white solid (0.93 g, 47%): mp: 122–1248C;

(brs, 1H), 7.22 (dd, J=2.0, 9.1 Hz, 1H), 7.34–7.36 (m, 1H), 7.46–7.48

1

H NMR (300 MHz, [D ]DMSO): d=1.90 (s, 3H), 3.90 (s, 3H), 4.60 (d,

6

(m, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.78–7.81 (m, 1H), 7.88 (d, J=

J=5.6 Hz, 2H), 7.26 (dd, J=9.1, 2.5 Hz, 1H), 7.45 (dd, J=7.6,

À1

9

.1 Hz, 1H), 7.99 ppm (brs, 3H); IR (KBr): n˜ =3330–2800 cm ; MS

7

.8 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 8.80–8.14 (m, 3H), 8.36 ppm

+

(APCI+, 30 V): m/z (%): 268.61 [M+H] .

À1

(

brs, 1H); IR (KBr): n˜ =3316, 1673, 1641 cm ; MS (APCI+, 30 V): m/

+

z (%): 258.32 [M+H] ; Anal. calcd for C H NO : C 70.02, H 5.88, N

4-Amino-3-(7-methoxynaphthalen-1-yl)butan-1-ol hydrochloride

15

3

5

.44, found: C 69.73, H 5.77, N 5.07.

(20): Prepared from 2 according to the procedure described for 7.

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Recrystallized from CH CN to give the desired product as a white

for C H NO : C 67.31, H 6.98, N 4.62, found: C 67.29, H 7.20, N

4.50.

3

17 21

4

1

solid (1.83 g, 65%): mp: 168–1698C; H NMR (300 MHz, [D ]DMSO):

6

d=1.86–1.89 (m, 1H), 2.07–2.11 (m, 1H), 3.21–3.26 (m, 2H), 3.36–

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]acrylamide

21e): Ethyl carbodiimide (0.91 g, 6.0 mmol) was added to a solu-

tion of acrylic acid (0.35 mL, 5.0 mmol) in CH Cl (40 mL) at 08C.

3

2

8

.38 (m, 3H), 3.94 (s, 3H), 4.06–4.18 (m, 1H), 7.19 (dd, J=9.0,

.1 Hz, 1H), 7.36–7.38 (m, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.60 (d, J=

.1 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H),

(

2

À1

The reaction mixture was stirred for 30 min at 08C, then a solution

of amine 19 (1.50 g, 5.6 mmol) in CH Cl (20 mL) was added drop-

.15 ppm (brs, 3H); IR (KBr): n˜ =3356–3216, 2982–2897 cm ; MS

+

(

APCI+, 30 V): m/z (%): 282.70 [M+H] .

2

wise while maintaining the temperature at 08C for an additional

30 min. The reaction mixture was then added to water (60 mL),

and the organic phase was washed with 1n aq HCl (15 mL) and

General procedure for the preparation of 21a–d: K CO (8.3 g,

2

3

6

0.0 mmol) was added to a suspension of compound 19 (5.35 g,

2

0.0 mmol) in water/EtOAc (100 mL, 1:1). The reaction mixture was

then water (15 mL), dried (MgSO ), filtered, and concentrated in

4

then cooled to 08C in an ice bath, the corresponding acyl chloride

26.0 mmol) was added, and the mixture was stirred at RT for

5 min. The organic phase was then washed with 1n aq HCl

50 mL) and water (50 mL), dried (MgSO ), filtered, and concentrat-

vacuo. The crude material was then recrystallized from toluene to

(

1

(

give the desired product as a white solid (1.35 g, 85%): mp: 150–

1

1528C; H NMR (300 MHz, [D

]acetone): d=3.62–4.07 (m, 8H), 4.28

6

(brs, 1H), 5.59 (dd, Jgem =4.0 Hz, Jcis =8.2 Hz, 1H), 6.23–6.29 (m,

2H), 7.16 (dd, J=9.0, 2.1 Hz, 1H), 7.31 (dd, J=7.3, 8.0 Hz, 1H), 7.54

4

ed in vacuo to give the desired product.

(

dd, J=1.2, 7.3 Hz, 1H), 7.59 (brs, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.72

d, J=8.0 Hz, 1H), 7.81 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz,

13

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]acetamide

(

21a): Recrystallized from CH CN to give the desired product as

3

[D ]DMSO): d=41.7, 42.2, 55.6, 63.3, 102.8, 118.2, 123.6, 124.7,

6

1

a white solid (4.37 g, 80%): mp: 136–1388C; H NMR (300 MHz,

D ]DMSO): d=1.76 (s, 3H), 3.35–3.46 (m, 2H), 3.65–3.85 (m, 3H),

1

25.5, 126.8, 129.4, 130.6, 132.2, 133.8, 136.6, 157.8, 165.5 ppm; IR

À1

[

3

6

(KBr): n˜ =3300–3180, 1660 cm ; MS (APCI+, 30 V): m/z (%): 286.19

+

.96 (s, 3H), 4.73 (brs, 1H), 7.17 (dd, J=2.0, 9.1 Hz, 1H), 7.31–7.36

[M+H] ; Anal. calcd for C H NO : C 71.56, H 6.71, N 4.91, found:

17 19 3

(

1

m, 1H), 7.45–7.48 (m, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.71–7.76 (m,

H), 7.83 (d, J=9.1 Hz, 1H), 7.96 ppm (brs, 1H); C NMR (75 MHz,

C 71.37, H 6.81, N 4.82.

13

[

1

3

D ]DMSO): d=23.0, 41.4, 42.2, 55.3, 63.7, 123.8, 124.4, 125.8, 126.0,

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)-propyl]trifluoro-

acetamide (21 f): Trifluoroacetic acid anhydride (0.66 mL,

5.0 mmol) was added dropwise to a solution of compound 19

6

26.3, 127.0, 129.1, 132.6, 133.8, 138.0, 170.1 ppm; IR (KBr): n˜ =

À1

+

280, 3199, 1645 cm ; MS (APCI+, 30 V): m/z (%): 274.31 [M+H] .

(

1.50 g, 5.6 mmol) and Et N (1.56 mL, 11.4 mmol) in THF (40 mL).

3

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]butanamide

21b): Recrystallized from toluene to give the desired product as

The reaction mixture was stirred for 10 min at RT. The mixture was

concentrated in vacuo and added to water (50 mL). The aqueous

(

1

a white solid (4.21 g, 70%): mp: 94–958C; H NMR (300 MHz,

D ]DMSO): d=0.77 (t, J=7.1 Hz, 3H), 1.44–1.46 (m, 2H), 1.98 (t,

phase was extracted with Et O (2ꢄ60 mL). The organic phase was

2

[

washed with 1n aq HCl (40 mL) and then water (40 mL), dried

6

J=7.1 Hz, 2H), 3.42–3.48 (m, 2H), 3.67–3.83 (m, 3H), 3.95 (s, 3H),

(MgSO ), filtered, and concentrated in vacuo. The oily residue was

4

7

.75 (brs, 1H), 7.16 (dd, J=2.1, 9.0 Hz, 1H), 7.30–7.36 (m, 1H),

.44–7.48 (m, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.70–7.76 (m, 1H), 7.82

taken up in Et O/petroleum ether (1:1) to form a solid, which was

2

recrystallized from toluene to give the desired product as a white

13

1

(

d, J=9.0 Hz, 1H), 7.87 ppm (brs, 1H);

C NMR (75 MHz,

solid (1.28 g, 70%): mp: 138–1408C; H NMR (300 MHz, [D ]DMSO):

6

[

1

D ]DMSO): d=14.0, 19.2, 37.8, 41.5, 42.3, 55.7, 63.2, 102.8, 118.1,

d=3.60–3.65 (m, 2H), 3.78–3.82 (m, 2H), 3.88–4.02 (m, 4H), 4.88

(brs, 1H), 7.19 (dd, J=9.0, 2.1 Hz, 1H), 7.31–7.35 (m, 1H), 7.44–7.48

6

23.5, 124.7, 126.7, 129.3, 130.6, 133.8, 136.7, 157.8, 172.9 ppm; IR

À1

(

KBr): n˜ =3460–3310, 1646 cm ; MS (APCI+, 30 V): m/z (%): 302.21

(m, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.73–7.76 (m, 1H), 7.84 (d, J=

+

À1

[M+H] ; Anal. calcd for C H NO : C 71.73, H 7.69, N 4.64, found:

9.0 Hz, 1H), 9.47 ppm (brs, 1H); IR (KBr): n˜ =3425, 3216, 1701 cm

MS (APCI+, 30 V): m/z (%): 328.20 [M+H] .

;

18

23

3

+

C 71.77, H 7.89, N 4.59.

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]cyclopropa-

namide (21c): Recrystallized from toluene to give the desired

product as a white solid (4.78 g, 80%): mp: 153–1548C; H NMR

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]allylamide

(21g): Prepared from free amine 19 according to the procedure

described above for compound 21e. Recrystallized from toluene to

1

(

300 MHz, [D ]DMSO): d=0.62–0.86 (m, 4H), 1.49–1.52 (m, 1H),

give the desired product as a white solid (1.0 g, 60%): mp: 86–

6

1

3

7

8

4

1

.47–3.52 (m, 2H), 3.70–3.80 (m, 3H), 3.93 (s, 3H), 4.77 (brs, 1H),

.16 (dd, J=2.1, 9.0 Hz, 1H), 7.30–7.36 (m, 1H), 7.44–7.48 (m, 1H),

.60 (d, J=9.0 Hz, 1H), 7.70–7.76 (m, 1H), 7.82 (d, J=2.1 Hz, 1H),

888C; H NMR (300 MHz, [D ]DMSO): d=2.83 (d, J=7.0 Hz, 2H),

6

3.44–3.46 (m, 2H), 3.70–3.85 (m, 3H), 3.94 (s, 3H), 4.75 (brs, 1H),

4.88–5.09 (m, 2H), 5.81 (ddt, J=7.0 Hz, J =10.2 Hz, J =17.1 Hz,

cis

trans

13

.14 ppm (brs, 1H); C NMR (75 MHz, [D ]DMSO): d=6.7, 14.1,

1H), 7.17 (dd, J=2.1, 9.0 Hz, 1H), 7.31–7.36 (m, 1H), 7.44–7.47 (m,

6

1.7, 42.5, 55.7, 63.3, 102.9, 118.1, 123.6, 124.7, 126.8, 129.4, 130.6,

1H), 7.60 (d, J=2.1 Hz, 1H), 7.70–7.75 (m, 1H), 7.82 (d, J=9.0 Hz,

À1

13

33.8, 136.7, 157.8, 173.5 ppm; IR (KBr): n˜ =3410–3160, 1646 cm

;

1H), 7.93 ppm (brs, 1H); C NMR (75 MHz, [D ]DMSO): d=41.1,

6

+

MS (APCI+, 30 V): m/z (%): 300.20 [M+H] ; Anal. calcd for

41.7, 42.2, 55.7, 63.2, 102.8, 117.7, 118.1, 123.5, 124.7, 126.8, 129.4,

C H NO : C 72.22, H 7.07, N 4.68, found: C 72.38, H 7.28, N 4.53.

130.6, 133.3, 133.8, 136.6, 157.8, 170.7 ppm; IR (KBr): n˜ =3330–

1

8

21

3

À1

+

3

100, 1650 cm ; MS (APCI+, 30 V): m/z (%): 300.19 [M+H] .

3

-Ethoxycarbonylamino-2-(7-methoxynaphthalen-1-yl)propanol

(

21d): Recrystallized from toluene/cyclohexane (1:3) to give the de-

[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]urea

(21h):

1

sired product as a white solid (4.85 g, 80%): mp: 74–758C; H NMR

300 MHz, CDCl ): d=1.23 (t, J=7.1 Hz, 3H), 3.22 (brs, 1H), 3.50–

37% HCl (0.1 mL, 8.9 mmol) was added to a solution of free amine

19 (0.92 g, 4.0 mmol) and urea (0.48 g, 8.0 mmol) in water (8 mL),

and the mixture was heated at reflux for 3.5 h. After cooling, the

reaction mixture was hydrolyzed with water (15 mL) and extracted

with EtOAc (3ꢄ50 mL). The organic phase was washed with water

(

3

4

1

.07 (m, 8H), 4.13 (q, J=7.1 Hz, 2H), 4.98 (brs, 1H), 7.05–7.49 (m,

13

H), 7.61–7.90 ppm (m, 2H); C NMR (75 MHz, [D ]DMSO): d=15.1,

6

2.6, 43.2, 55.6, 60.0, 63.2, 102.8, 118.1, 123.6, 124.8, 126.8, 129.4,

30.6, 133.8, 136.6, 156.9, 157.8 ppm; IR (KBr): n˜ =3500–3200,

(50 mL), dried (MgSO ), filtered, and concentrated in vacuo to give

4

À1

+

698 cm ; MS (APCI+, 30 V): m/z (%): 304.22 [M+H] ; Anal. calcd

the desired product, after recrystallization from toluene, as a white

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1

solid (0.15 g, 14%): mp: 138–1398C; H NMR (300 MHz, [D ]DMSO):

(1 mL, 10.3 mmol) and heating at reflux for 12 h. After cooling, the

reaction mixture was dissolved in water (60 mL) and the aqueous

6

d=3.42–3.48 (m, 2H), 3.73–3.76 (m, 3H), 3.94 (s, 3H), 4.83 (brs,

1

7

1

H), 5.40 (brs, 2H), 6.00 (brs, 1H), 7.18 (dd, J=2.1, 9.0 Hz, 1H),

.31 (d, J=2.1 Hz, 1H), 7.44 (dd, J=1.5, 7.4 Hz, 1H), 7.58 (d, J=

phase extracted with Et O (2ꢄ60 mL). The organic phase was

2

washed with water (50 mL), dried (MgSO ), filtered, and concentrat-

4

.5 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.83 ppm (d, J=9.0 Hz, 1H); IR

ed in vacuo. The residue obtained was dissolved in MeOH/water

(40 mL, 3:1), then NaOH (0.33 g, 8.2 mmol) was added, and the

mixture was heated at 408C for 30 min. After cooling, the mixture

was dissolved in water (60 mL) and neutralized with 1n aq HCl

À1

(

KBr): n˜ =3424, 3301–3222, 1658 cm ; MS (APCI+, 30 V): m/z (%):

+

2

75.11 [M+H] .

1

(

-Ethyl-3-[3-hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]urea

21i): Ethyl isocyanate (6.25 mL, 7.8 mmol) was added to a solution

of free base 19 (7.1 mmol) in CH Cl (60 mL) at 08C, and the mix-

(

15 mL), and the aqueous phase was extracted with Et O (2ꢄ

2

6

0 mL). The organic phase was washed with water (50 mL), dried

2

(

MgSO ), filtered, and concentrated in vacuo. The desired product

4

ture was stirred for 2 h at RT. The solid formed was filtered,

washed with Et O, and recrystallized from CH CN to give the de-

precipitated from a mixture of Et O/petroleum ether (4:6), and fur-

2

3

ther recrystallization from toluene gave a white solid (0.71 g, 42%):

sired product as a white solid (1.50 g, 70%): mp: 120–1228C;

1

mp: 96–988C; H NMR (300 MHz, [D ]DMSO): d=1.90–1.92 (m, 2H),

6

1

H NMR (300 MHz, [D ]DMSO): d=0.95 (t, J=7.0 Hz, 3H), 2.99–3.11

6

3

.10–3.55 (m, 4H), 3.70–4.00 (m, 4H), 4.45 (t, J=5.0 Hz, 1H), 4.90

(

m, 2H), 3.42–3.46 (m, 2H), 3.60–3.85 (m, 3H), 3.94 (s, 3H), 4.83

brs, 1H), 5.85 (brs, 2H), 7.18 (dd, J=2.1, 9.0 Hz, 1H), 7.31–7.35 (m,

(d, J=47.0 Hz, 2H), 7.16 (dd, J=2.1, 9.0 Hz, 1H), 7.32 (dd, J=7.3,

7

9

3

1

.8 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.67–7.76 (m, 2H), 7.84 (d, J=

1

7

3

1

H), 7.44–7.49 (m, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.70–7.75 (m, 1H),

13

.0 Hz, 1H), 8.35 ppm (brs, 1H); C NMR (75 MHz, [D ]DMSO): d=

6

13

.83 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz, [D ]DMSO): d=16.1,

1

6

5.8, 44.5, 44.9, 55.6, 59.1, 81.7 ( J =180 Hz), 102.0, 118.3, 123.6,

24.3, 126.8, 129.4, 130.6, 133.8, 137.9, 157.8, 167.9 ppm ( J =

8 Hz); IR (KBr): n˜ =3375–3227, 1672 cm ; MS (APCI+, 30 V): m/z

CF

4.5, 42.2, 43.1, 55.6, 63.4, 102.9, 118.1, 123.6, 124.7, 126.7, 129.4,

2

CF

30.6, 133.8, 137.0, 157.8, 158.8 ppm; IR (KBr): n˜ =3419, 3296,

À1

+

645 cm ; MS (APCI+, 30 V): m/z (%): 303.21 [M+H] ; Anal. calcd

+

(%): 306.29 [M+H] ; Anal. calcd for C H FNO : C 66.87, H 6.60, N

17

20

3

for C H N O : C 67.53, H 7.33, N 9.26, found: C 67.47, H 7.21, N

1

7

22

2

3

4

.95, found: C 66.44, H 6.56, N 4.59.

9

.17.

1

-[4-Hydroxy-2-(7-methoxynaphthalen-1-yl)butyl]-3-ethylurea

1

-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)propyl]-3-propylurea

(22d): Synthesized from free base 20 according to procedure de-

(21j): Prepared from free amine 19 according to the procedure de-

scribed above for 21i. Recrystallized from toluene to give the de-

sired product as a white solid (1.63 g, 73%): mp: 78–798C; H NMR

scribed above for compound 21i. Recrystallized from CH CN to

give the desired product as a white solid (1.05 g, 47%): mp: 74–

1

3

(300 MHz, [D ]DMSO): d=0.97–1.00 (m, 3H), 2.03–2.08 (m, 2H),

1

6

7

1

2

7

58C; H NMR (300 MHz, CDCl ): d=0.90 (t, J=7.0 Hz, 3H), 1.50–

.85 (m, 2H), 3.05–3.12 (m, 2H), 3.60–3.65 (m, 2H), 3.85–3.87 (m,

3

.01–3.03 (m, 2H), 3.41–3.44 (m, 1H), 3.59–3.66 (m, 1H), 3.71–3.74

(m, 1H), 3.85 (brs, 1H), 3.91–3.92 (m, 2H), 3.93 (s, 3H), 4.38 (brs,

H), 3.90–4.00 (m, 4H), 4.50 (brs, 2H), 5.20 (brs, 1H), 7.20 (dd, J=

1

7

3

1

H), 4.50 (brs, 1H), 7.15 (dd, J=9.0, 2.1 Hz, 1H), 7.20–7.23 (m, 1H),

.1, 9.0 Hz, 1H), 7.31–7.44 (m, 3H), 7.65 (dd, J=2.1, 7.0 Hz, 1H),

.75 ppm (d, J=9.0 Hz, 1H); IR (KBr): n˜ =3421, 3297, 1649 cm

.34–7.38 (m, 1H), 7.49–7.55 (m, 1H), 7.66 (dd, J=7.0, 2.1 Hz, 1H),

.75 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz, [D ]DMSO): d=16.2,

4.5, 36.5, 45.4, 55.6, 59.3, 103.1, 118.3, 123.7, 126.6, 129.5, 130.6,

34.0, 138.8, 157.8, 158.7 ppm; IR (KBr): n˜ =3464–3313, 1636 cm

À1

;

13

+

6

MS (APCI+, 30 V): m/z (%): 317.20 [M+H] .

À1

;

Preparation of compounds 22a,b: These compounds were pre-

pared from 20 according to the procedure described for 21a.

+

MS (APCI+, 30 V): m/z (%): 317.21 [M+H] .

1

(

2

-[4-Hydroxy-2-(7-methoxynaphthalen-1-yl)butyl]-3-propylurea

22e): Prepared from 20 according to the procedure described for

1i. Recrystallized from toluene to give the desired product as

N-[4-Hydroxy-2-(7-methoxynaphthalen-1-yl)butyl]acetamide

(

22a): Recrystallized from EtOH at 958 to give the desired product

1

as a white solid (0.86 g, 15%): mp: 143–1458C; H NMR (300 MHz,

D ]DMSO): d=1.77 (s, 3H), 1.97–2.01 (m, 2H), 3.19–3.25 (m, 2H),

1

a white solid (1.71 g, 73%): mp: 74–758C; H NMR (300 MHz,

D ]DMSO): d=0.81–0.85 (m, 3H), 1.36–1.40 (m, 2H), 2.06–2.09 (m,

[

6

[

6

3

7

.39–3.42 (m, 2H), 3.67–3.70 (m, 1H), 3.96 (s, 3H), 4.48 (brs, 1H),

2

3

H), 2.94–3.00 (m, 2H), 3.43–3.47 (m, 1H), 3.60–3.66 (m, 1H), 3.73–

.76 (m, 1H), 3.85 (brs, 1H), 3.91–3.92 (m, 2H), 3.93 (s, 3H), 4.36

.18 (dd, J=2.1, 9.0 Hz, 1H), 7.25–7.45 (m, 2H), 7.62–7.75 (m, 2H),

13

.82 (d, J=9.0 Hz, 1H), 8.02 ppm (brs, 1H); C NMR (75 MHz,

(brs, 1H), 4.48 (brs, 1H), 7.15 (dd, J=9.0, 2.1 Hz, 1H), 7.20–7.22 (m,

[

D ]DMSO): d=22.3, 34.5, 36.5, 45.4, 55.6, 59.3, 103.1, 118.3, 123.5,

6

1

7

2

1

3

H), 7.28–7.30 (m, 1H), 7.34–7.37 (m, 1H), 7.50–7.56 (m, 1H),

1

3

26.6, 129.4, 130.6, 134.0, 138.8, 157.7, 160.0 ppm; IR (KBr): n˜ =

300–3100, 1630 cm ; MS (APCI+, 30 V): m/z (%): 288.11 [M+H] .

13

À1

+

.75 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz, [D ]DMSO): d=11.8,

6

3.7, 36.5, 41.6, 45.5, 55.5, 59.3, 103.0, 118.3, 123.7, 126.6, 129.4,

N-[4-Hydroxy-2-(7-methoxynaphthalen-1-yl)butyl]propionamide

22b): Recrystallized from toluene to give the desired product as

30.5, 134.0, 138.7, 157.2, 157.8, 158.7 ppm; IR (KBr): n˜ =3457–

À1

+

(

314, 1633 cm ; MS (APCI+, 30 V): m/z (%): 331.33 [M+H] .

1

a white solid (3.49 g, 58%): mp: 123–1258C; H NMR (300 MHz,

CDCl ): d=1.00 (t, J=7.6 Hz, 3H), 1.90–2.20 (m, 5H), 3.60–3.64 (m,

Methyl 3-(acetylamino)-2-(7-methoxynaphthalen-1-yl)-2-methyl-

3

2

7

1

3

H), 3.70–4.10 (m, 6H), 5.55 (brs, 1H), 7.18 (dd, J=9.0, 2.3 Hz, 1H),

propanoate (23a): Prepared from 3a according to the procedure

.30–7.41 (m, 2H), 7.50 (d, J=2.3 Hz, 1H), 7.70 (dd, J=7.0, 2.1 Hz,

described for 5a. Recrystallized from iPr

product as a white solid (0.52 g, 28%): mp: 161–1638C; H NMR

(300 MHz, CDCl ): d=1.80 (s, 3H), 2.00 (s, 3H), 3.60 (s, 3H), 3.85–

2

O to give the desired

13

1

H), 7.90 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz, [D ]DMSO): d=

6

0.4, 29.0, 36.1, 36.6, 45.0, 55.6, 59.2, 103.0, 118.2, 123.6, 124.3,

3

26.7, 129.4, 130.5, 133.9, 138.3, 157.7, 173.6 ppm; IR (KBr): n˜ =

3.95 (m, 4H), 4.15 (dd, J=14.0, 5.6 Hz, 1H), 5.95 (brs, 1H), 7.10–

7.20 (m, 2H), 7.37 (dd, J=7.2, 7.7 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H),

À1

+

277, 1639 cm ; MS (APCI+, 30 V): m/z (%): 302.22 [M+H] ; Anal.

À1

calcd for C H NO : C 71.73, H 7.69, N 4.65, found: C 71.70, H 7.66,

N 4.54.

7.75–7.85 ppm (m, 2H); IR (KBr): n˜ =3283, 1719, 1647 cm ; MS

1

8

23

3

+

(APCI+, 30 V): m/z (%): 316.40 [M+H] .

2

-Fluoro-N-[4-hydroxy-2-(7-methoxynaphthalen-1-yl)butyl]aceta-

mide (22c): Prepared from free amine 20 (1.37 g, 5.6 mmol) in

,2,2-trifluoroethanol (40 mL), by addition of ethyl fluoroacetate

Methyl 2-[(acetylamino)methyl]-2-(7-methoxynaphthalen-1-yl)-

butanoate (23b): Prepared from 3b according to the procedure

2

described for compound 5a: Recrystallized from iPr O to give the

2

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11

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CHEMMEDCHEM

FULL PAPERS

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desired product as a white solid (0.25 g, 13%): mp: 147–1498C;

product was obtained after recrystallization from iPr O as a white

2

1

H NMR (300 MHz, CDCl ): d=1.80 (t, J=7.5 Hz, 3H), 1.90 (s, 3H),

solid (2.52 g, 80%): mp: 94–968C; H NMR (300 MHz, [D ]DMSO):

3

6

2

7

.30–2.34 (m, 2H), 3.70 (s, 3H), 3.75–4.05 (m, 4H), 4.15 (dd, J=14.0,

.7 Hz, 1H), 5.30 (brs, 1H), 7.14–7.19 (m, 2H), 7.37 (dd, J=6.4,

.7 Hz, 1H), 7.46 (d, J=6.4 Hz, 1H), 7.75–7.85 ppm (m, 2H);

d=1.78 (s, 3H), 1.83 (s, 3H), 3.44–3.46 (m, 2H), 3.84 (m, 1H), 3.94

(s, 3H),), 4.28 (d, J=6.3 Hz, 2H), 7.10 (dd, J=2.1, 9.0 Hz, 1H), 7.24–

7.28 (m, 1H), 7.32–7.42 (m, 2H), 7.68–7.71 (m, 1H), 7.78 (d, J=

1

3

À1

C NMR (75 MHz, [D ]DMSO): d=9.0, 23.0, 25.7, 41.6, 52.5, 54.2,

9.0 Hz, 1H), 8.10 ppm (brs, 1H); IR (KBr): n˜ =3380, 1718, 1657 cm

MS (APCI+, 30 V): m/z (%): 316.27 [M+H] .

;

6

+

5

1

5.4, 102.8, 117.8, 123.3, 125.9, 128.2, 129.7, 131.3, 132.4, 135.6,

57.6, 170.1, 176.6 ppm; IR (KBr): n˜ =3282, 1715, 1642 cm ; MS

À1

+

General procedure for the preparation of N-[3-methanesulfony-

(

APCI+, 30 V): m/z (%): 330.30 [M+H] .

loxy-2-(7-methoxynaphthalen-1-yl)propyl]acetamide (27): Et N

3

(

1

2.3 mL, 16.8 mmol) was added to a solution of 21a (3.0 mg,

N-[3-Hydroxy-2-(7-methoxynaphthalen-1-yl)-2-methylpropyl]ace-

tamide (24a): Prepared from 23a according to the procedure de-

scribed for compound 13: Recrystallized from toluene to give the

0.9 mmol) in CH Cl (160 mL), and the mixture was cooled to 08C.

2

MsCl (1.3 mL, 16.8 mmol) was then added dropwise, and the reac-

tion mixture was stirred at RT for 15 min. After hydrolysis, the or-

desired product as a white solid (2.88 g, 54%): mp: 154–1568C;

1

H NMR (300 MHz, [D ]DMSO): d=1.40 (s, 3H), 1.90 (s, 3H), 3.50

^g^aⁿⁱ^c^p^h^a^s^e^w^a^s^w^a^s^h^e^d^wⁱ^t^h²ⁿ^a^q^H^C^l⁽⁵⁰^m^L⁾^,⁵^%^a^q^N^a^H^C^O3

6

(

50 mL) and then water (80 mL), dried (MgSO ), filtered, and con-

(

dd, J=13.7, 5.7 Hz, 1H), 3.70–4.00 (m, 6H), 4.90 (t, exchangeable

4

centrated in vacuo without heating to give the desired product as

in D O, J=5.6 Hz, 1H), 7.14 (dd, J=9.0, 2.2 Hz, 1H), 7.27 (t, J=

2

a white solid after precipitation in Et O and filtration (3.06 g, 80%):

7

.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.83 (d,

2

1

13

mp: 104–1068C; H NMR (300 MHz, CDCl ): d=1.98 (s, 3H), 3.02 (s,

J=9.0 Hz, 1H), 7.93 (brs, 1H), 7.99 ppm (d, J=2.2 Hz, 1H); C NMR

75 MHz, [D ]DMSO): d=21.4, 23.0, 43.7, 45.9, 55.8, 66.9, 106.1,

3

6

7

1

H), 3.80–3.86 (m, 2H), 4.02 (s, 3H), 4.20–4.24 (m, 1H), 4.46 (dd, J=

.6, 10.5 Hz, 1H), 4.71–4.76 (m, J=5.0, 10.5 Hz, 1H), 5.80 (brs, 1H),

.21 (dd, J=2.0, 9.0 Hz, 1H), 7.34–7.36 (m, 1H), 7.39–7.41 (m, 1H),

.54 (d, J=2.0 Hz, 1H), 7.76–7.78 (m, 1H), 7.80 ppm (d, J=9.0 Hz,

(

6

117.5, 123.3, 126.9, 127.8, 130.4, 131.4, 132.9, 139.5, 156.6,

À1

1

71.0 ppm; IR (KBr): n˜ =3380, 3292, 1665 cm ; MS (APCI+, 30 V):

+

m/z (%): 288.38 [M+H] .

À1

H); IR (KBr): n˜ =3353, 1644, 1344 cm ; MS (APCI+, 30 V): m/z

+

N-[2-(Hydroxymethyl)-2-(7-methoxynaphthalen-1-yl)butyl]aceta-

mide (24b): Prepared from 23b according to the procedure de-

scribed for compound 13. Recrystallized from toluene to give the

(%): 352.40 [M+H] .

Preparation of compounds 28 and 29: Compound 27 (1.75 g,

5

.0 mmol) and TBAF (15 mL, 15.0 mmol, 1m in THF) were placed in

desired product as a white solid (2.80 g, 50%): mp: 139–1418C;

1

a sealed tube and heated at 708C for 12 h. The reaction mixture

H NMR (300 MHz, [D ]DMSO): d=0.40 (t, J=7.5 Hz, 3H), 1.80–1.90

6

was then dissolved in water (20 mL) and extracted with Et O (2ꢄ

2

(

m, 4H), 2.30–2.34 (m, 1H), 3.55 (dd, J=13.9, 5.4 Hz, 1H), 3.70–3.73

m, 1H), 3.90 (s, 3H), 4.10–4.18 (m, 2H), 4.90 (t, exchangeable in

4

0 mL). The combined organic layers were washed with brine

(

25 mL), dried (MgSO ), filtered, and concentrated in vacuo. The

4

D O, J=5.8 Hz, 1H), 7.15 (dd, J=8.8, 2.0 Hz, 1H), 7.27 (t, J=7.8 Hz,

1

7

2

oily product was chromatographed on silica gel (EtOAc/cyclohex-

ane, 1:9) to give compounds 21a, 28, and 29.

H), 7.44 (d, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.71 (d, J=

13

.8 Hz, 1H), 7.81–7.90 ppm (m, 3H); C NMR (75 MHz, [D ]DMSO):

6

d=9.2, 23.0, 25.0, 42.6, 49.0, 55.7, 64.7, 105.4, 117.3, 123.3, 123.4,

N-[3-Fluoro-2-(7-methoxynaphthalen-1-yl)propyl]acetamide (28):

1

3

27.8, 130.2, 131.4, 133.3, 137.1, 156.8, 171.4 ppm; IR (KBr): n˜ =

424, 3280, 1640 cm ; MS (APCI+, 30 V): m/z (%): 302.42 [M+H] .

Recrystallized from cyclohexane to give the desired product as

À1

+

1

a white solid (0.31 g, 23%): mp: 87–898C; H NMR (300 MHz,

CDCl ): d=1.94 (s, 3H), 3.53–3.56 (m, 2H), 4.02 (s, 3H), 4.10–4.16

3

N-[3-Methoxy-2-(7-methoxynaphthalen-1-yl)propyl]acetamide

25): Compound 21a (1.0 g, 3.6 mmol) was added to a suspension

of K CO (2.48 g, 18.0 mmol) in acetone (40 mL), and the mixture

(m, 1H), 4.81 (ddd, J=5.1, 9.4, 47.4 Hz, 1H), 4.86–5.16 (m, J=5.1,

(

9

.4, 47.4 Hz, 1H), 5.68 (brs, 1H), 7.21 (dd, J=2.1, 9.0 Hz, 1H), 7.34–

2

3

7

.36 (m, 1H), 7.45–7.49 (m, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.75–7.77

was heated at reflux for 10 min. CH I (0.33 mL, 7.3 mmol) was

3

13

(m, 1H), 7.79 ppm (d, J=9.0 Hz, 1H); C NMR (75 MHz, CDCl ): d=

3

added, and the reaction mixture was heated at reflux for a further

2

1

2

1

3.3, 33.9, 40.2 ( J =19 Hz), 55.6, 86.5 ( J =172 Hz), 101.6, 118.6,

CF CF

23.1, 124.5, 127.7, 129.4, 130.5, 133.2, 133.3, 158.4, 170.5 ppm; IR

3

0 min. After cooling, the residue was dissolved in water and ex-

tracted with Et O (2ꢄ50 mL). The organic phase was washed with

2

À1

(

[

KBr): n˜ =3278, 1642 cm ; MS (APCI+, 30 V): m/z (%): 276.31

M+H] .

water (40 mL), dried (MgSO ), filtered, and concentrated in vacuo

4

+

to give an oily product. After purification on a silica gel column

(

acetone/cyclohexane, 4:6) and recrystallization from cyclohexane,

N-[2-(7-Methoxynaphthalen-1-yl)allyl]acetamide (29): Recrystal-

the desired product was obtained as a white solid (0.36 g, 35%):

lized from iPr O to give the desired product as a white solid

2

1

mp: 82–848C; H NMR (300 MHz, CDCl ): d=1.92 (s, 3H), 3.42 (s,

3

(1.02 g, 80%): mp: 108–1108C; H NMR (300 MHz, [D ]DMSO): d=

6

3

9

2

H), 3.62–4.01 (m, 5H), 4.00 (s, 3H), 5.92 (brs, 1H), 7.18 (dd, J=2.1,

.0 Hz, 1H), 7.32–7.36 (m, 1H), 7.38–7.40 (m, 1H), 7.54 (d, J=

1

5

1

2

.92 (s, 3H), 3.95 (s, 3H), 4.26–4.31 (m, 2H), 5.23 (d, J=0.8 Hz, 1H),

.53 (d, J_g_e_m=0.8 Hz, 1H), 5.70 (brs, 1H), 7.18 (dd, J=2.1, 9.0 Hz,

H), 7.24–7.38 (m, 2H), 7.45 (d, J=2.1 Hz, 1H), 7.68–7.92 ppm (m,

.1 Hz, 1H), 7.71–7.76 (m, 1H), 7.79 ppm (d, J=9.0 Hz, 1H); IR

À1

13

(

KBr): n˜ =3339, 1647 cm ; MS (APCI+, 30 V): m/z (%): 288.23

H); C NMR (75 MHz, [D ]DMSO): d=23.0, 44.5, 55.7, 104.4, 113.7,

6

+

[M+H] ; Anal. calcd for C H NO : C 71.05, H 7.36, N 4.87, found:

17 21 3

118.9, 123.4, 126.2, 127.7, 129.1, 130.2, 132.6, 138.2, 146.9, 158.0,

C 70.77, H 7.57, N 4.78.

1

2

70.0 ppm; IR (KBr): n˜ =3243, 1654; MS (APCI+, 30 V): m/z (%):

+

56.18 [M+H] ; Anal. calcd for C H NO : C 75.27, H 6.71, N 5.49,

16

17

2

3

-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl acetate (26):

A solution of compound 21a (2.73 g, 10.0 mmol) in acetic acid

40 mL) was treated with 33% HBr (0.2 mL, 1.0 mmol), and the mix-

found: C 74.92, H 6.95, N 5.02.

(

N-[3-Acetylsulfanyl-2-(7-methoxynaphthalen-1-yl)propyl]aceta-

mide (30): Potassium thioacetate (0.4 g, 3.4 mmol) was added to

a solution of 27 (1.0 g, 2.8 mmol) in acetone (20 mL), and the reac-

tion mixture was heated at reflux for 3 h. After concentration in

vacuo, the residue was dissolved in water (50 mL) and extracted

with CH Cl (2ꢄ40 mL). The organic phase was washed with water

ture was stirred at RT for 12 h. The reaction mixture was then con-

centrated in vacuo. The residue obtained was dissolved in water

(

25 mL) and extracted with Et O (2ꢄ30 mL). The organic phase was

2

washed with 1m aq NaHCO (20 mL) and then with water (20 mL),

3

dried (MgSO ), filtered, and concentrated in vacuo. The desired

4

2

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ÞÞ

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13

(

30 mL), dried (MgSO ), filtered, and concentrated in vacuo. Purifi-

1H), 7.78–7.88 (m, 2H), 7.95 ppm (brs, 2H); C NMR (75 MHz,

4

cation on a silica gel column (EtOAc/cyclohexane, 8:2) and recrys-

[D ]DMSO): d=23.0, 40.0, 42.1, 55.8, 102.9, 118.4, 123.6, 124.0,

6

tallization from cyclohexane gave the desired product as a white

127.1, 129.4, 130.6, 133.9, 135.9, 158.0, 170.0 ppm; IR (KBr): n˜ =

3275, 1642 cm ; MS (APCI+, 30 V): m/z (%): 315.29 [M+H] ; Anal.

1

À1

+

solid (0.51 g, 56%): mp: 72–748C; H NMR (300 MHz, [D ]DMSO):

6

d=1.80 (s, 3H), 2.25 (s, 3H), 3.15–3.18 (m, 1H), 3.30–3.34 (m, 1H),

calcd for C H N O : C, 68.77%; H 7.05, N 8.91, found: C 68.67, H

18

22

2

3

9

7

1

.50–3.55 (m, 2H), 3.80–3.82 (m, 1H), 4.00 (s, 3H), 7.18 (dd, J=2.1,

.0 Hz, 1H), 7.32 (dd, J=7.6, 8.0 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H),

.67 (d, J=2.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.85 (d, J=9.0 Hz,

7.15, N 8.89.

N-[3-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl]propiona-

mide (34b): Recrystallized from CH CN as a white solid (5.25 g,

80%): mp: 148–1508C; H NMR (300 MHz, [D ]DMSO): d=0.92 (t,

J=7.6 Hz, 3H), 1.75 (s, 3H), 2.00 (q, J=7.6 Hz, 2H), 3.30–3.60 (m,

À1

H), 8.85 ppm (brs, 1H); IR (KBr): n˜ =3281, 1687, 1651 cm ; MS

3

1

+

(

APCI+, 30 V): m/z (%): 332.39 [M+H] .

6

N-[3-Mercapto-2-(7-methoxynaphthalen-1-yl)propyl]acetamide

31): A solution of 3n aq NaOH (12.6 mL, 3.1 mmol) was added

dropwise to a solution of thioester 30 (0.4 g, 1.3 mmol) in acetone

15 mL), and the mixture was stirred for 2 h at RT. After neutraliza-

tion with 1n aq HCl (25 mL), the mixture was extracted with

CH Cl (2ꢄ50 mL). The organic phase was washed with water

4

7

H), 3.85–3.90 (m, 1H), 3.97 (s, 3H), 7.19 (dd, J=2.1, 9.0 Hz, 1H),

(

.37–7.40 (m, 1H), 7.48–7.52 (m, 1H), 7.71–7.74 (m, 1H), 7.78–7.88

13

(m, 3H), 7.95 ppm (brs, 1H); C NMR (75 MHz, [D ]DMSO): d=10.4,

6

(

2

1

3.0, 30.0, 39.8, 42.0, 42.1, 55.8, 103.0, 118.5, 123.6, 124.1, 127.0,

29.4, 130.5, 133.9, 136.0, 158.0, 170.0, 173.6 ppm; IR (KBr): n˜ =

À1

2

3273, 3243, 1645–1635 cm ; MS (APCI+, 30 V): m/z (%): 329.30

[M+H] ; Anal. calcd for C H N O : C 69.49, H 7.37, N 8.53, found:

+

(

50 mL), dried (MgSO ), filtered, and concentrated in vacuo. Purifi-

4

19

24

2

3

cation on a silica gel column (EtOAc/cyclohexane, 7:3) and recrys-

tallization from cyclohexane gave the desired compound as

a white solid (0.15 g, 41%): mp: 109–1118C; H NMR (300 MHz,

C 69.74, H 7.46, N 8.42.

1

N-[3-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl]butana-

mide (34c): Recrystallized from CH CN as a white solid (5.47 g,

80%): mp: 150–1528C; H NMR (300 MHz, [D ]DMSO): d=0.75 (t,

J=7.6 Hz, 3H), 1.43–1.48 (m, 2H), 1.75 (s, 3H), 1.98 (t, J=7.6 Hz,

2H), 3.30–3.60 (m, 4H), 3.87–3.90 (m, 1H), 3.97 (s, 3H), 7.16 (dd, J=

CDCl ): d=1.50 (brs, J=7.9 Hz, 1H), 1.90 (s, 3H), 3.00–3.02 (m, 2H),

3

1

3

1

2

.65–3.77 (m, 1H), 3.80–3.84 (m, 1H), 3.90–4.15 (m, 4H), 5.45 (brs,

6

H), 7.10–7.50 (m, 4H), 7.68–7.88 ppm (m, 2H); IR (KBr): n˜ =3329,

À1

+

568, 1649 cm ; MS (APCI+, 30 V): m/z (%): 290.23 [M+H] .

2

1

.1, 9.0 Hz, 1H), 7.29–7.32 (m, 1H), 7.36–7.40 (m, 1H), 7.71–7.76 (m,

H), 7.78–7.88 (m, 3H), 7.95 ppm (brs, 1H); C NMR (75 MHz,

N-[3-Azido-2-(7-methoxynaphthalen-1-yl)propyl]acetamide (32):

TBAB (0.13 g, 0.4 mmol) was added to a suspension of NaN₃

13

[D ]DMSO): d=14.0, 19.1, 23.0, 37.8, 39.8, 41.9, 42.2, 55.8, 103.0,

6

(

1.66 g, 25.6 mmol) in DMF (10 mL), and the mixture was heated

for 30 min at 708C, then a solution of compound 27 (3.0 g,

.5 mmol) in DMF (10 mL) was added. After 2 h at 708C, the reac-

118.4, 123.5, 124.2, 127.0, 129.4, 130.6, 133.9, 136.0, 157.9, 169.9,

À1

1

72.7 ppm; IR (KBr): n˜ =3275, 3244, 1645–1635 cm ; MS (APCI+,

8

+

3

0 V): m/z (%): 343.41 [M+H] ; Anal. calcd for C H N O : C 70.15,

20

26

2

3

tion mixture was cooled, hydrolyzed with water (40 mL), and ex-

H 7.65, N 8.18, found: C 70.22, H 7.33, N 8.25.

tracted with Et O (3ꢄ60 mL). The organic phase was washed with

2

n aq HCl (30 mL) and water (30 mL), dried (MgSO ), filtered, and

N-[3-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl]cyclopro-

4

concentrated in vacuo to give the desired product as an orange oil

pionamide (34d): Recrystallized from CH CN as a white solid

3

1

(

1.52 g, 60%): H NMR (300 MHz, CDCl ): d=1.89 (s, 3H), 3.55–3.80

m, 4H), 3.90–4.10 (m, 4H), 5.51 (brs, 1H), 7.22 (dd, J=2.3, 9.0 Hz,

(5.44 g, 80%): mp: 175–1768C; H NMR (300 MHz, [D ]DMSO): d=

3

6

0.61–0.80 (m, 4H), 1.46–1.49 (m, 1H), 1.75 (s, 3H), 3.30–3.60 (m,

4H), 3.82–3.86 (m, 1H), 3.98 (s, 3H), 7.19 (dd, J=2.1, 9.0 Hz, 1H),

7.31–7.35 (m, 1H), 7.37–7.41 (m, 1H), 7.71–7.76 (m, 1H), 7.78 (d,

J=2.1 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 8.05 (brs, 1H), 8.34 ppm

1

7

2

H), 7.34–7.36 (m, 1H), 7.39–7.41 (m, 1H), 7.54 (d, J=2.3 Hz, 1H),

.76–7.78 (m, 1H), 7.80 ppm (d, J=9.0 Hz, 1H); IR (KBr): n˜ =3423,

À1

+

098, 1640 cm ; MS (APCI+, 30 V): m/z (%): 299.21 [M+H] .

13

(

brs, 1H); C NMR (75 MHz, [D ]DMSO): d=6.6, 14.0, 23.0, 39.8,

6

N-[3-Amino-2-(7-methoxynaphthalen-1-yl)propyl]acetamide hy-

drochloride (33): 10% Pd basis Pd/C (200 mg) was added to a solu-

tion of 32 (2.0 g, 6.5 mmol) in MeOH (50 mL), the mixture was

placed under hydrogen, and stirred at RT for 2 h. After filtration

and evaporation of the filtrate, the residue obtained was dissolved

in Et O (50 mL) and treated with HCl . Recrystallization from

4

1

2.1, 42.4, 55.8, 103.0, 118.4, 123.6, 124.1, 127.1, 129.4, 130.6, 133.9,

35.9, 158.0, 170.0, 173.3 ppm; IR (KBr): n˜ =3246, 3079, 1645–

À1

+

635 cm ; MS (APCI+, 30 V): m/z (%): 341.30 [M+H] ; Anal. calcd

for C H N O : C 70.57, H 7.11, N 8.23, found: C 70.48, H 7.32, N

20

24

2

3

8

.51.

2

(g)

CH CN/MeOH (8:2) gave the desired hydrochloride salt as a white

3

N-[2-(7-Methoxynaphthalen-1-yl)-3-morpholin-4-yl-propyl]aceta-

mide hydrochloride (35): Mesyl 27 (1.5 g, 4.2 mmol) and morpho-

line (3.7 mL, 42.3 mmol) were dissolved in dry THF (40 mL), and the

reaction was heated at reflux for 24 h. The mixture was concentrat-

ed in vacuo, and the residue obtained was taken up in water

1

solid (1.06 g, 60%): mp: 230–2318C; H NMR (300 MHz, [D ]DMSO):

6

d=1.85 (s, 3H), 3.05–3.68 (m, 4H), 3,98 (s, 3H), 4.08–4.15 (m, 1H),

7

8

1

.20 (dd, J=2.1, 9.0 Hz, 1H), 7.35–7.37 (m, 1H), 7.49–7.52 (m, 1H),

.71 (d, J=2.1 Hz, 1H), 7.79–7.81 (m, 1H), 7.87 (d, J=9.0 Hz, 1H),

.05 (brs, 3H), 8.34 ppm (brs, 1H); IR (KBr): n˜ =3238, 3200–2400,

(

40 mL) and extracted with Et O (2ꢄ50 mL). The organic layers

2

À1

+

630 cm ; MS (APCI+, 30 V): m/z (%): 273.28 [M+H] ; Anal. calcd

were then washed with 1n aq HCl (30 mL). The aqueous phase

was alkalinized with 15% aq NaOH (15 mL) and extracted with

Et O (2ꢄ50 mL). The combined organic phases were washed with

2

for C H ClN O : C 62.23, H 6.85, N 9.07, found: C 62.19, H 6.76, N

1

6

21

2

9

.21.

water (40 mL), dried (MgSO ), filtered, and concentrated in vacuo.

4

Preparation of compounds 34a–d: These compounds were pre-

pared from 33 according to the procedure described for com-

pound 21a.

Treatment with HCl₍_g₎and recrystallization from CH CN gave the

3

desired compound as a white solid (0.86 g, 60%): mp: 125–1268C;

1

H NMR (300 MHz, [D ]DMSO): d=1.79 (s, 3H), 2.85–3.48 (m, 6H),

6

N-[3-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl]aceta-

3.62–3.95 (m, 6H), 3.98 (s, 3H), 4.06–4.10 (m, 1H), 7.21 (dd, J=2.1,

9.0 Hz, 1H), 7.37–7.42 (m, 1H), 7.56–7.58 (m, 1H), 7.68 (d, J=

2.1 Hz, 1H), 7.79–7.81 (m, 1H), 7.87 (d, J=9.0 Hz, 1H), 8.35 (brs,

mide (34a): Recrystallized from CH CN as a white solid (5.02 g,

3

1

8

6

2

0%): mp: 199–2008C; H NMR (300 MHz, [D ]DMSO): d=1.75 (s,

H), 3.35–3.37 (m, 4H), 3.85–3.87 (m, 1H), 3.97 (s, 3H), 7.16 (dd, J=

.1, 9.0 Hz, 1H), 7.31–7.33 (m, 1H), 7.37–7.41 (m, 1H), 7.71–7.75 (m,

6

13

1H), 11.05 ppm (brs, 1H); C NMR (75 MHz, [D ]DMSO): d=23.0,

6

34.7, 51.3, 52.8, 55.9, 58.4, 63.4, 102.9, 118.7, 123.6, 125.1, 127.8,

ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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1

2

29.5, 130.8, 132.8, 135.3, 158.3, 170.7 ppm; IR (KBr): n˜ =3300–

400, 1623 cm ; MS (APCI+, 30 V): m/z (%): 343.30 [M+H] ; Anal.

drolyzed with water (50 mL). The organic phase was washed with

À1

+

water, dried (MgSO ), filtered, and concentrated in vacuo to give

4

calcd for C H ClN O : C 63.40, H 7.18, N 7.39, found: C 63.38, H

the desired product as a white solid after recrystallization from

2

0

27

2

3

1

7

.22, N 7.37.

CH CN (0.43 g, 50%): mp: 122–1248C; H NMR (300 MHz, CDCl₃):

3

d=1.88 (brs, 1H), 2.02 (s, 3H), 3.16–3.22 (m, 2H), 3.61–3.65 (m,

(

1

3

7-Methoxynaphthalen-1-yl)methanol (36): Aldehyde 11 (3.0 g,

⁶^.¹^m^m^o^l⁾^w^a^s^dⁱ^s^s^o^l^v^e^dⁱⁿ^M^e^O^H⁽⁷⁵^m^L⁾^aⁿ^d^N^a^B^H4 (1.22 g,

2.2 mmol) was added. The mixture was stirred at RT for 30 min,

2

H), 4.04 (s, 3H), 4.35–4.38 (m, 1H), 6.10 (brs, 1H), 7.16 (dd, J=2.1,

9.0 Hz, 1H), 7.26–7.29 (m, 1H), 7.33–7.37 (m, 1H), 7.70–7.74 (m,

13

1

3

1

H), 7.76–7.86 ppm (m, 2H); C NMR (75 MHz, [D ]DMSO): d=23.2,

6

and then concentrated in vacuo. The residue obtained was dis-

solved in 3n aq HCl (50 mL) and the aqueous solution was extract-

ed with Et O (2ꢄ50 mL). The organic layer was washed with water

5.1, 52.0, 55.8, 62.4, 103.4, 118.5, 123.4, 127.0, 128.3, 129.3, 130.5,

33.5, 134.4, 157.9, 169.7 ppm; IR (KBr): n˜ =3260, 3180, 1638 cm

MS (APCI+, 30 V): m/z (%): 274.20 [M+H] .

À1

;

+

2

(

40 mL), dried (MgSO ), filtered, and concentrated in vacuo. Recrys-

4

tallization from cyclohexane gave the desired product as a white

1

solid (2.27 g, 75%): mp: 70–728C; H NMR (300 MHz, CDCl ): d=

Pharmacology

3

1

.68 (brs, 1H), 3.95 (s, 3H), 5.12 (s, 2H), 7.22 (dd, J=2.1, 9.0 Hz,

H), 7.33–7.37 (m, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.49 (d, J=7.1 Hz,

H), 7.76 (d, J=7.1 Hz, 1H), 7.80 ppm (d, J=9.0 Hz, 1H); IR (KBr):

125

À1

Reagents and chemicals: 2-[ I]Iodomelatonin (2200 Cimmol ) was

purchased from NEN Life Science Products Inc. (Boston, USA).

Other drugs and chemicals were purchased from Sigma–Aldrich

À1

+

n˜ =3380 cm ; MS (APCI+, 30 V): m/z (%): 189.10 [M+H] .

(Saint Quentin, France).

2

-Acetylamino-2-[(7-methoxynaphthalen-1-yl)methyl]diethyl

125

Assays for MT₁and MT₂receptor subtypes: 2-[ I]Iodomelatonin

malonate (37): Compound 36 (3.0 g, 15.9 mmol) was dissolved in

competition binding assay conditions were essentially as previous-

ly described. Briefly, binding was initiated by addition of mem-

CHCl (75 mL) and cooled to À58C in an ice bath. Thionyl chloride

[19]

3

(

3.5 mL, 47.9 mmol) was added, and the reaction mixture was

brane preparations from transfected chinese hamster ovary (CHO)

cells stably expressing the human melatonin MT or MT receptor

stirred at RT for 1 h. The solvent was then evaporated in vacuo,

and the residue obtained was dissolved in 5% aq NaHCO₃

1

2

diluted in binding buffer (50 mm Tris–HCl buffer, pH 7.4, containing

mm MgCl ) to 2-[ I]iodomelatonin (20 pm for MT and MT re-

2 1 2

(

100 mL). The aqueous phase was extracted with Et O (2ꢄ50 mL),

125

2

5

and the combined organic layer was washed with water (40 mL),

dried (MgSO ), filtered, and concentrated in vacuo to give the

chloro intermediate after recrystallization from cyclohexane. Next,

NaH (0.7 g, 17.5 mmol, 60% dispersion in mineral oil) was cautious-

ly added portionwise to a solution of diethyl acetamidomalonate

ceptors expressed in CHO cells) and the test compound. Nonspe-

cific binding was defined in the presence of 1 mm of melatonin.

After 120 min incubation at 378C, the reaction was stopped by

rapid filtration through GF/B filters presoaked in 0.5% (v/v) polye-

thylenimine. Filters were washed three times with 1 mL of ice-cold

4

(

3.8 g, 17.5 mmol) in dry DMF (32 mL) under an inert atmosphere.

5

0 mm Tris–HCl buffer, pH 7.4.

The reaction mixture was stirred at RT for 30 min, and then a solu-

tion of the chloro intermediate (3.0 g, 14.5 mmol) in dry DMF

Data from the dose–response curves were analyzed using PRISM

(version 4.00, Graph Pad Software Inc., San Diego, USA) to yield

IC50 values. Binding affinities are expressed as pK

ÀLog10(K) and K =IC50/1+([L]/K ), where [L] is the concentration of

radioligand used in the assay and K is the dissociation constant of

(

1

10 mL) was added. The reaction mixture was heated at 808C for

h. After cooling, the mixture was hydrolyzed with water (100 mL),

, with pK =

i i

and the aqueous phase was acidified with 37% HCl (6 mL) and ex-

tracted with EtOAc (2ꢄ50 mL). The organic phase was washed

with water (30 mL), dried (MgSO ), filtered, and concentrated in

i

D

[44]

the radioligand characterizing the membrane preparation.

4

vacuo. Recrystallization from toluene/cyclohexane (1:9) gave the

35

The [ S]GTPgS binding assay was performed according to pub-

desired product as a white solid (5.54 g, 90%): mp: 98–1008C;

[19]

lished methodology. Briefly, membranes from transfected CHO

cells expressing MT₁and MT₂receptor subtypes and test com-

pound were diluted in binding buffer (20 mm HEPES, pH 7.4,

00 mm NaCl, 3 mm GDP, 3 mm MgCl , and 20 mgmL saponin). In-

cubation was started by the addition of 0.2 nm [ S]GTPgS to mem-

branes (20 mgmL ) and test compound, and followed for 1 h at

1

H NMR (300 MHz, CDCl ): d=1.32 (t, J=7.1 Hz, 6H), 1.81 (s, 3H),

3

7

1

.95 (s, 3H), 4.12 (s, 2H), 4.21 (q, J=7.1 Hz, 4H), 6.42 (brs, 1H),

.05–7.17 (m, 2H), 7.22–7.26 (m, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.69–

.71 (m, 1H), 7.73 ppm (d, J=9.0 Hz, 1H); IR (KBr): n˜ =3320, 1746,

À1

1

2

35

À1

+

653 cm ; MS (APCI+, 30 V): m/z (%): 388.41 [M+H] .

À1

room temperature. The reaction was stopped by rapid filtration

through GF/B filters followed by three successive washes with ice-

cold buffer.

2

(

-Acetylamino-3-(7-methoxynaphthalen-1-yl)ethyl propanoate

38): Compound 37 (6.2 g, 16.0 mmol) was dissolved in dry DMF

15 mL), and the solution was treated with LiBr (1.39 g, 16.0 mmol)

and water (16.0 mmol). The mixture was heated at 1508C for 16 h.

After cooling, the reaction mixture was diluted with water (30 mL),

and the solid formed was collected by filtration and recrystallized

35

Usual levels of [ S]GTPgS binding (expressed in dpm) for CHO–MT

2

membranes are: 2000 for basal activity, 8000 in the presence of

melatonin 1 mm, and 180 in the presence of GTPgS (10 mm), which

defined the nonspecific binding. Data from the dose–response

from toluene to give the desired product as a white solid (4.54 g,

1

9

7

3

9

0%): mp: 122–1248C; H NMR (300 MHz, CDCl ): d=1.05 (t, J=

3

curves were analyzed using PRISM to yield pEC₅₀values (pEC =

50

.1 Hz, 3H), 1.98 (s, 3H), 3.49–3.52 (m, 1H), 3.61–3.66 (m, 1H),

.95–4.15 (m, 5H), 5.01–5.06 (m, 1H), 6.10 (brs, 1H), 7.14–7.26 (m,

H), 7.54 (d, J=2.1 Hz, 1H), 7.70–7.73 (m, 1H), 7.76 ppm (d, J=

ÀLog (EC ), where the EC is the half maximal effective concen-

10

50

tration) and E (maximal effect) for agonists.

max

À1

^A^s^s^a^y^s^f^o^r⁵^-^H^T2C ^r^e^c^e^p^t^o^r^s^u^b^t^y^p^e^s^:^T^h^e^s^e^r^o^t^oⁿⁱⁿ⁵^-^H^T2C competi-

tion binding assay was performed according to the protocol previ-

ously reported in the literature.

.0 Hz, 1H); IR (KBr): n˜ =3330, 1741, 1660 cm ; MS (APCI+, 30 V):

+

m/z (%): 316.31 [M+H] .

[20]

Membranes from CHO cells

N-[1-Hydroxymethyl-3-(7-methoxynaphthalen-1-yl)ethyl]aceta-

stably expressing the human 5-HT₂_C₍_V_S_V₎receptor were incubated

for 60 min at 378C in binding buffer (50 mm Tris–HCl buffer,

pH 7.4, containing 10 mm MgCl₂and 0.1% BSA) containing the

mide (39): LiAlH (0.17 g, 4.7 mmol) was added dropwise to a solu-

4

tion of compound 38 (1.0 g, 3.2 mmol) in Et O/THF (150 mL,

2

3

8

5:15). The reaction mixture was stirred for 2 h at RT and then hy-

radioligand [ H]mesulergine (1 nm). Nonspecific binding was de-

ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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fined in the presence of 10 mm mianserine. The reaction was termi-

nated by rapid filtration through GF/B filters presoaked in 0.1% (v/

v) polyethylenimine. Filters were washed three times with 1 mL of

ice-cold 50 mm Tris–HCl buffer, pH 7.4. Residual radioactivity on fil-

ters was measured using a TopCount scintillation counter (Perki-

nElmer Life Sciences) after addition of Microscint 20. Isotherms

were analyzed using nonlinear regression to yield IC₅₀values (an-

tagonist concentration producing half maximal response). Binding

[4] a) F. W. Turek, Int. Clin. Psychorpharmacol. 2007 , 22 , S1–S8; b) D. De Ber-

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affinities are expressed as pK values.

i

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5

For the [ S]-GTPgS binding assay, compounds and membranes

À1

(

25 fmolmL ) were diluted in the binding buffer (20 mm Hepes,

2

008 , 28 , 329–333.

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pH 7.4, containing 100 mm NaCl, 10 mm MgCl , and 1 mm GDP) in

2

[

À1

the presence of 20 mgmL saponin to enhance the agonist-in-

1

duced stimulation level. In antagonist mode, a preincubation of

test compound and membranes with serotonin (100 nm) was per-

formed for 30 min at 208C, before addition of the radioligand. In-

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696.

35

cubation was started by the addition of 0.2 nm [ S]-GTPgS (Perki-

[13] a) G. Dagyte, A. Trentani, F. Postema, P. G. Luiten, J. A. Den Boer, C. Ga-

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nElmer, NEG030X) to membranes and ligands, and carried on for

6

0 min at room temperature in a final volume of 250 mL. Nonspe-

cific binding was assessed using non-radiolabeled GTPgS (10 mm).

Reactions were stopped by rapid filtration through GF/B unifilters

presoaked with distilled water, followed by three successive

washes with ice-cold Tris–HCl buffer (50 mm, pH 7.4). Data were

analyzed using PRISM. Antagonist potencies are expressed as pK_B,

with pK =ÀLog (K ) and K =IC /1+([Ago]/EC ago), where the

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14] M. J. Millan, A. Gobert, F. Lejeune, A. Dekeyne, A. Newman-Tancredi, V.

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10

B

50

587.

IC value is the antagonist concentration required to induce

5

0

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5

a 50% decrease of [ S]-GTPgS binding in the presence of a fixed

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Abbreviations

Bovine serum albumin (BSA); dimethyl carbonate (DMC); N-(3-di-

methylamino)-N’-ethylcarbodiimide

(EDCI);

dimethylsulfoxide

(

DMSO); diethylaminosulfur trifluoride (DAST); guanosine diphos-

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2

35

2C

3

5

(

[ S]GTPgS); selective serotonin reuptake inhibitor (SSRI); tetrabu-

tylammonium bromide (TBAB); tetrabutylammonium fluoride

TBAF); tetrahydrofuran (THF); trimethylsilyl cyanide (TMSCN).

[

(

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Received: July 3, 2013

Published online on && &&, 0000

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Selectively seeking subtypes: A series

of agomelatine analogues were synthe-

sized and biologically evaluated. Most

of the prepared compounds exhibited

good binding affinity at melatonin MT₁

M. Ettaoussi,* A. Sabaouni, B. Pꢀrꢁs,

E. Landagaray, O. Nosjean, J. A. Boutin,

D.-H. Caignard, P. Delagrange,

P. Berthelot, S. Yous

&& – &&

and MT receptor subtypes. Compounds

2

1a and 21e showed good binding af-

Synthesis and Pharmacological

Evaluation of a series of the

Agomelatine Analogues as Melatonin

MT /MT Agonist and 5-HT

finities and behaved as agonists at mel-

atonin (MT /MT ) receptors and as an-

1

2

tagonists at serotonin 5-HT₂_Creceptor

subtypes.

1

2

2C

Antagonist

ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Article Doi

Synthesis and pharmacological evaluation of a series of the agomelatine analogues as melatonin MT1/MT2 agonist and 5-HT 2C antagonist

DOI: 10.1002/cmdc.201300294

Source and publish data:

Authors:

Article abstract of DOI:10.1002/cmdc.201300294

Full text of DOI:10.1002/cmdc.201300294

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