Substituted oxygenated heterocycles and thio-analogues: Synthesis and biological evaluation as melatonin ligands

Article abstract of DOI:10.1016/S0968-0896(99)00265-5

A new series of substituted oxygenated heterocycles and thio-analogues were synthesized and evaluated as melatonin receptor ligands. The replacement of the indolic moiety of melatonin by heterocyclic skeleton such as 1,4- benzodioxin, 2,3-dihydro-1,4-benzodioxin, chroman, 2,3-dihydro-1,4- benzoxathiin, thiochroman, carrying the amidic chain on the aromatic ring, leads to compounds showing a weak affinity for melatonin receptors, except for the compounds 1cb and 1hb. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00265-5

Bioorganic & Medicinal Chemistry 8 (2000) 105±114
Substituted Oxygenated Heterocycles and Thio-Analogues:
Synthesis and Biological Evaluation as Melatonin Ligands
Isabelle Charton, a Ahmed Mamai, a Caroline Bennejean, b Pierre Renard, b
Edward H. Howell, c Beatrice Guardiola-Lemaõtre, d Philippe Delagrange, d
Peter J. Morgan, c Marie-Claude Viaud a,* and Gerald Guillaumet a
a
Â
Â
Â
Â
Institut de Chimie Organique et Analytique, associe au CNRS, Universite d'Orleans, BP 6759, 45067 Orleans Cedex 2, France
b
Â
A.D.I.R., 1, rue Carle Hebert, 92415 Courbevoie Cedex, France
cRowett Research Institute, Aberdeen, UK
d
Â
I.R.I. Servier, 6, place des Pleiades, 92415 Courbevoie Cedex, France
Received 20 January 1999; accepted 30 August 1999
AbstractÐA new series of substituted oxygenated heterocycles and thio-analogues were synthesized and evaluated as melatonin
receptor ligands. The replacement of the indolic moiety of melatonin by heterocyclic skeleton such as 1,4-benzodioxin, 2,3-dihydro-
1,4-benzodioxin, chroman, 2,3-dihydro-1,4-benzoxathiin, thiochroman, carrying the amidic chain on the aromatic ring, leads to
compounds showing a weak anity for melatonin receptors, except for the compounds 1cb and 1hb. # 2000 Elsevier Science Ltd.
All rights reserved.
Introduction
sites, mt1, MT2, and MT3,10 although the physiological
role of the last two receptors is still unclear.11,12 There-
fore, research on new molecules capable of mimicking
or antagonizing responses to melatonin has been con-
siderably developed. Such compounds represent impor-
tant tools for the understanding of the physiological
roles of melatonin. Thus, several indolic analogues13±20
of melatonin have been found to act as ligands and
many papers reported the synthesis of several non-
indolic bioisosteres.21±31
Since melatonin was isolated and identi®ed as N-acetyl-
5-methoxytryptamine by Lerner in 1958,1 the interest in
this hormone has been steadily growing. In vertebrates
this hormone has its primary sites of production in the
pineal gland and the photoreceptor cells of the retina,
where it is synthesized from serotonin via a two-steps
biochemical pathway.2,3 Melatonin plays a fundamental
role in a number of related actions. Its activity, medi-
ated through high-anity-G-protein-coupled receptors,
is mainly related to the regulation of the photoperiodic
responses,4 the entrainment of the mammalian circa-
dian-rhythms,5 the induction of sleep in humans,6 and
retinal physiology.7 Recently, the antitumoral proper-
ties of melatonin, its implication in the responsiveness of
the immune system,8 and its free radical scavenger
properties have also been described.9 Despite its poten-
tial involvement in the regulation in many possible
physiological processes, two problems limit its thera-
peutic use at the present time. Firstly, its very short
biological half-life (15±30 min), due to its rapid catabo-
lism to 6-hydroxymelatonin and N-acetylkynurenamines.
Secondly, the lack of selectivity of melatonin at its target
It is well known that some structural requirements are
in favor of a good anity for the melatonin receptors.
For example in phenylethyl amide series, the ortho and
meta positions of the methoxy group on the phenyl ring
are more optimal than the para positions.22,25,29 More-
over, the variable length of the side chain is able to
provide a good relative position to the methoxy group
and the N-acyl group of the ligands.29
Therefore, we decided to examine if these assessments
could be con®rmed in a series of heterocyclic com-
pounds, whose structure represents a conformational
restriction of the (2- or 3-methoxyphenyl)alkyl amides.
In order to mimic compounds described by Garratt et al.29
and Langlois et al.,25 which possess methoxy group in
ortho or meta position, we have synthesized 2,3-dihydro-
1,4-benzodioxinic and 2,3-dihydro-1,4-benzoxathiinic
Keywords: 1,4-benzodioxins; 2,3-dihydro-1,4-benzoxathiins; chro-
mans; thiochromans; melatonin ligands.
*Corresponding author. Tel.: +33-2-4736 7227; fax: +33-2-4736
7229; e-mail: mcviaud@univ-tours.fr
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00265-5

106
I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
structural families with variable N-acylalkyl side chain
on the aromatic ring, in ortho position of the oxygen or
sulfur atom of the heterocycle. 2,3-Insaturated analo-
gues were also prepared and, in the same way, 2,3-
dihydro-1,4-benzodioxinic, chromanic and thiochromanic
compounds, where an oxygen atom is intercalated
between the aromatic ring and the N-alkanamido side
chain.
In this paper, we report our results on the synthesis and
the biological evaluation of those new non-indolic mel-
atonin-ligands (Fig. 1).
Chemistry
The synthesis of amides 1a, 1e, 1i±1m required access to
a number of di€erent bromo derivatives 2a, 2e, 2i±2m.
Compound 2a was obtained by radical bromination of
5-methyl-2,3-dihydro-1,4-benzodioxin. Compounds 2i±
2m were generated by treatment of corresponding phe-
nols with appropriate dibromoalkanes in basic medium.
Bromo derivative 2e was prepared by heating of N-[2-
(3,4-dihydro-2H-1-benzothiopyran-8-yloxy)]-bromoethane
2m in anhydrous acetonitrile. Bromides 2a, 2e, 2i±2m
were smoothly substituted by potassium phthalimide in
N,N-dimethylformamide at re¯ux in the presence of
potassium iodide to provide the corresponding phthali-
mido compounds. The latter products were cleaved by
hydrazine hydrate in re¯uxing ethanol leading to amides
3a, 3e, 3i±3m in satisfactorily global yields. The acetyl-
ation of these amines with acetic anhydride in pyridine
gave amides 1a, 1e, 1i±1m in very good yields (Scheme 1).
Scheme 1.
and 2e (vide infra) or tosylate 432 with potassium cya-
nide in N,N-dimethylformamide gave required nitriles
5b, 5d and 5f. Reduction of these compounds was car-
ried out with lithium aluminum hydride in diethyl ether,
and the resulting amines 3b, 3d and 3f acylated with
acetic anhydride in pyridine to supply amides 1b, 1d, 1f
in good overall yield.
The syntheses of target compounds 1b, 1d and 1f are
depicted in Scheme 2. Treatment of either bromides 2a
The synthesis of the new amino derivatives 1c and 1h is
outlined in Scheme 3. The aldehyde 6 was synthesized
Figure 1. Compounds 1a±m synthesized.

I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
107
via route developed in our laboratories.33 The carbonyl
derivative 7 was obtained from 5-carboxy-1,4-benzo-
dioxin.34 Using the Horner±Emmons modi®cation of
the Wittig reaction, compounds 6 and 7 were converted
to propenenitriles 8c and 8h, which were reduced in
amines 3c and 3b by treatment with lithium aluminum
hydride. The acetylation of these amines with acetic
anhydride in pyridine gave acetamides 1ca and 1ha
whereas its condensation with butyryl chloride in the
presence of triethylamine in anhydrous methylene chlo-
ride a€orded butyramides 1cb and 1hb.
The synthesis of amido derivative 1g is shown in
Scheme 4. Aldehyde 932 permitted access to compound
5g, using successively a Horner±Emmons's reaction
with diethyl cyanomethylphosphonate in the presence of
sodium hydride followed by a catalytic hydrogenation
with 10% palladium on activated carbon of inter-
mediary unsaturated nitrile 8g. Compound 5g was
obtained and was submitted to a novel hydrogenation
reaction in a mixture of acetic anhydride and sodium
acetate in the presence of Raney nickel as catalyst to
give the amido derivative 1g in 47% yield.
Biological Results and Discussion
The anities of these new heterocyclic compounds for
melatonin binding sites were evaluated in vitro, on
ovine pars tuberalis membranes. The binding values are
summarized in Table 1. The best compounds were eval-
uated on chicken brain membranes (Table 2) in order to
con®rm the anity in another model, and to compare
with data published previously.
In addition to the binding data, bioassays are carried
out to characterize the activity of the reported com-
pounds on forskolin stimulated cAMP production,
according to the methodology described by Howell et
al.35 Indeed, melatonin at 1 nM inhibits (typically 80%)
this forskolin stimulated production of cAMP.
Scheme 2.
In each experiment the cAMP responses are normalized
against the response induced by forskolin (F) 10 mM
alone, which is taken as the 100% e€ect. The e€ect of
10 mM drug alone (D), with forskolin (F/D), and with
forskolin and melatonin (F/M/D) is compared to the
e€ect of forskolin and melatonin (F/M).
The indexed activity of melatonin (M) is de®ned from
the normalized response ratio [F F/M]/[F F/M]=1
and the indexed activity of the various treatments are
Scheme 3.
Scheme 4.

108
I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
Table 1. Pharmacological evaluation on ovine pars tuberalis mem-
branes of compounds 1
can notice that ethanamide 1b and pentanamide 1g have
comparable anities which are 2.5- to 3.5-fold lower
than those of propanamides (1ca, 1c, 1ha) and butana-
mides (1d, 1f).
Binding
Activity
Agonist index
F/D‹SD
Ovine pars tuberalis
Log Ki‹SD (n=3)
Antagonist
index F/M/D
‹SD (n=3)
A methanamide side chain (1a) and to a lesser extent
ethanamide (1b), is precluding a simultaneous favor-
able interaction between the N-acyl group and the het-
eroatoms of the molecule, and the main amino acid
residues of the transmembrane domains, thus playing a
role in establishment of a binding interaction as shown
on ovine melatonin receptor by Conway et al.,36
Navajas et al.,37 and Sugden et al.38 This is the same
case with too much ¯exibility of pentanamide side
chain 1g.
(n=3)
Melatonin
9.52‹0.10
3.70‹0.34
6.62‹0.07
7.11‹0.01
7.46‹0.03
7.12‹0.01
7.02‹0.07
7.14‹0.04
6.66‹0.04
7.20‹0.09
7.48‹0.35
5.60‹0.03
6.45‹0.05
6.05‹0.04
4.68‹0.01
<4.0
1
1a
1b
1ca
1cb
1d
1e
0.13‹0.08
0.45‹0.14
0.85‹0.21
0.71‹0.01
0.28‹0.13
0.43‹0.12
0.31‹0.19
0.13‹0.1
0.39‹0.11
0.66‹0.29
0.29‹0.17
0.42‹0.09
0.29‹0.17
0.17‹0.18
ND
1.01‹0.08
0.86‹0.07
0.94‹0.25
0.76‹0.02
0.66‹0.08
0.88‹0.24
0.82‹0.19
0.61‹0.11
0.81‹0.05
0.97‹0.33
0.98‹0.16
1.00‹0.08
0.93‹0.03
0.94‹0.13
ND
1f
1g
1ha
1hb
1i
1j
1k
1l
Moreover, 1g is the only compound of this series which
displays an antagonist activity. The NH group of the
amidic function can not take place with such a long side
chain in order to provide a hydrogen bond for full
functional activation of the receptor response. All the
other compounds have at least a partial agonist activity
and the best activation of the receptor occurs with
compound 1ca, which is a full agonist.
1m
Table 2. Pharmacological evaluaton on chicken brain membranes of
compounds 1cb and 1hb
Log Ki Chicken brain‹SD (n=3)
The results obtained for compound 1d, have helped to
determine which of the two oxygen atoms plays a
predominant role in the anity. Indeed the Ki value of
1d (Ki=7.6Â10 8 M) and the Ki value published for
the N-acetyl 3-(3-methoxyphenyl)-propanamine29
(Ki=6.3Â10 8 M) are of the same rank of order,
whereas there is a large di€erence with the value of
Ki for the N-acetyl-3-(2-methoxyphenyl)propanamine
(Ki=1.1Â10 6 M).
Melatonin
1cb
1hb
10.0‹0.16
8.62‹0.36
8.15‹0.14
calculated as the ratio [F treatment]/[F F/M], where
treatments are: basal response melatonin alone, drug
alone, forskolin/drug (F/D, agonist index) or forskolin/
melatonin/drug (F/M/D, antagonist index) at ®nal
concentrations indicated above. The criteria used to
categorize the biological properties of the compounds
are as follows:
Therefore, one of the interactions that occur between
the heterocyclic compounds and the receptor, concerns
preferentially the oxygen atom in meta position of the
side chain rather than the oxygen, or sulfur atom, in the
ortho position. It was already the case with tricyclic
compounds published by Leclerc et al.,26 where it was
shown that the electronic interaction between oxygen
and receptor was optimal when the lone pairs of elec-
trons were appropriately oriented.
Agonist index
(F/D)
F/D>0.8
0.4<F/D<0.8
0.4<F/D<0.8
Antagonist index
(F/M/D)
F/M/D>0.8
F/M/D>0.8
0.2<F/M/D<0.8
Full agonist
Weak agonist
Partial agonist/
antagonist
F/D<0.4
F/D<0.4
F/M/D<0.2
F/M/D>0.8
Antagonist
No activity
Globally, the di€erent heterocyclic skeletons do not lead
to important variations of the binding anities, from a
structural family to another (on the one hand, 2,3-
dihydro-1,4-benzodioxin 1ca, 2,3-dihydro-1,4-benzo-
xathiin 1e, 1,4-benzodioxin 1ha, and on the other hand,
2,3-dihydro-1,4-benzodioxin 1d, 2,3-dihydro-1,4-benz-
oxathiin 1f), as long as the presence of the oxygen atom
in meta position of the side chain is respected.
The results are summarized in Table 1.
The binding results obtained in the 2,3-dihydro-1,4-
benzodioxinic, 2,3-dihydro-1,4-benzoxathiinic, and 1,4-
benzodioxinic series are in good agreement with those
of Garratt et al.29 Indeed in the (alkoxyphenyl)alkyl
amide series, when the alkoxy position is ®xed, espe-
cially in meta position of the side chain, there is a
signi®cant increase in anity if this chain becomes
longer. This is the case for the series in this study, with
compounds containing oxygen atoms at ®xed positions.
(e.g. 1a Ki=2.0Â10 4 M, 1d Ki=7.6Â10 8 M).
However, inside an homogeneous heterocyclic family,
di€erences appear when the nature of the N-acyl group
is modi®ed. Indeed among the best compounds such as
1ca and 1ha (Ki=7.7Â10 8 M and 6.3Â10 8 M, respec-
tively), the replacement of the acetyl group by a buta-
noyl group leads to an improvement of the anity (1cb
Ki=3.5Â10 8 M, 1hb Ki=3.3Â10 8 M). This result is
not surprising, according to former publications in
other melatoninergic series.15,16,21,23,29
If we compare compounds 1b, 1ca, 1d, 1e, 1f, 1g, 1ha,
which possess variable alkyl acetamide side chains, we

I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
109
Another type of bioisosteric pharmacomodulations
Experimental Protocols
concerns the intercalation of an oxygen atom between
the aromatic cycle and the alkyl side chain, in 2,3-di-
hydro-1,4-benzodioxin, chroman, thiochroman series,
which leads to a signi®cant loss of anity (1j
Ki=3.5Â10 7 M compared to 1d Ki=7.6Â10 8 M).
In that case, it is obvious that the oxygen atom
plays an unfavorable role since there is a loss of anity
(ꢀ4.5-fold).
Chemistry
Melting points were determined on a Ko¯er hot-stage
and are uncorrected. Proton NMR were recorded on a
Bruker 300 spectrometer. The coupling constants are
recorded in hertz (Hz) and the chemical shifts are
reported in parts per million (d, ppm) down®eld from
tetramethylsilane (TMS), which was used as an internal
standard. Infrared spectra were obtained with Perkin±
Elmer spectrophotometers 297 and Paragon 1000 PC
version 2. Mass spectra were recorded on a R 10-10 C
Nermag (70 eV) apparatus. Organic solvents were pur-
i®ed when necessary according to literature methods39
or purchased from Aldrich Chimie. All solutions were
dried over anhydrous magnesium sulfate and evapo-
rated on a Buchi rotatory evaporator. Analytical thin-
layer chromatography (TLC) was carried out on
precoated plates (silica gel, 60 F254), and spots were
visualized with UV light or an alcohol solution of am-
monium cerium (IV) nitrate. Column chromatography
was performed with Kieselgel 60 (70±230 mesh) silica
gel (Merck) for gravity columns and Kieselgel 60 (230±
400 mesh) silica gel (Merck) for ¯ash columns. When
analyses are indicated by symbols of the elements, ana-
lytical results obtained for those elements were ‹0.4%
of the theoretical values. All anhydrous reactions were
performed in over-dried glassware under an atmo-
sphere of argon. The column chromatography solvents
employed were distilled and solvent mixtures were
reported as volume to volume ratios.
These results correlate with previous results, although
not provided on the same membrane preparation, where
the incidence of a such oxygen atom is similar, and
where the same structural analogy exists between
these described compounds and our compounds.
Indeed, on one hand the sequence N-acetyl-2-(3-alkoxy-
phenyloxy)ethanamine can be identi®ed both in 1j
(Ki=3.5Â10 7 M) and in the N-acetyl-3-amino-5-meth-
oxychroman23 which also displays a poor binding a-
nity (Ki=8.4Â10 6 M). On the other hand, the sequence
N-acetyl-3-(3-alkoxyphenyl)propanamine is contained
both in 1d (Ki=7.6Â10 8 M) and in the 2-acetamido-8-
methoxytetralin (Ki=4.6Â10 8 M).22
In that series with alkoxy acetamidic side chain, the
particularly very poor binding obtained for compounds
1l and 1m can be explained by the absence of oxygen
atom in meta position. However, 1i displays a better
anity which con®rms the respective roles of the het-
eroatoms contained in these heterocyclic structures.
The two best compounds in this study are 1cb and
1hb. Their binding anities have been evaluated on
chicken brain membranes (Table 2) in order to be com-
pared with the values obtained on ovine pars tuberalis
membranes (Table 1). Chicken binding experiments
provide similar binding anity values to ovine binding
experiments and con®rm the possible comparison
between the ovine binding model and the chicken
binding model. The anities of these compounds are
in the nanomolar range (1cb Ki=2.4Â10 9 M, 1hb
Ki=7.0Â10 9 M) and are quite similar to those of the
N-butanoyl-3-(3-methoxyphenyl) propanamine descri-
bed by Garratt et al.,29 (Ki=5.5Â10 9 M) on chicken
brain too.
The compound 2a was prepared from 2-methylresorcinol
by heating in acetone in the presence of 1,2-dibromo-
ethane and potassium carbonate followed by treatment
of the obtained compound with N-bromosuccinimide in
the presence of 2,20-azobisisobutyronitrile in carbon
tetrachloride at re¯ux (global yield: 67%).
The compounds 2i±2m were obtained by treatment of
appropriate phenols with 1,n-dibromoalkanes in the
presence of potassium carbonate in acetone at re¯ux
(yields: 40±74%).
The compound 2e was synthesized by heating of N-[2-
(3,4-dihydro-2H-1-benzothiopyran-8-yloxy)]-bromo-
ethane 2m in anhydrous acetonitrile at re¯ux for 48 h
(yield: 80%).
These results con®rm the interaction of the N-acyl
group and heteroatom for conformational restricted
compounds 1cb and 1hb, previously described for
methoxyphenylalkylamides compounds.29 In these two
families of compounds, the interacting groups are
retained in the appropriate relative position and provide
to the compounds signi®cant binding anities for the
melatonin receptor.
General procedure for the synthesis of the amines 3a, 3e,
3i±3m
The appropriate bromo derivatives 2 (6 mmol) and
potassium phthalimide 1.67 g, (9.03 mmol) were stirred
in the presence of catalytic amount of potassium iodide
(700mg, 0.42mmol) in N,N-dimethylformamide (10 mL)
at re¯ux for 3 h under inert atmosphere. After cooling at
room temperature, the insoluble salts were eliminated
by ®ltration and the mixture was diluted with water.
The solid precipitate was ®ltered, washed with water
and dried in a vacuum dessicator over phosphorous
pentoxide to give the desired phthalimido compounds
which were used without further puri®cation.
Conclusion
In conclusion, these results show the interest of the new
2,3-dihydro-1,4-benzodioxin or 1,4-benzodioxin deriva-
tives as non-indolic melatoninergic agents. This study
con®rms the hypothesis that compounds with con-
formational restriction are melatoninergic ligands.

110
I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
To a solution of compounds obtained above (6 mmol) in
ethanol (20 mL) was added, at re¯ux, hydrazine hydrate
(0.58 mL, 12 mmol). After re¯uxing for 5 h and cooling
of the reaction mixture, the volatiles were evaporated
under reduced pressure to give a dark brown oil which
is dissolved in a cold solution of methylene chloride in
order to precipitate the phthalylhydrazine. This one was
®ltered o€ and the solvent was evaporated under
reduced pressure to provide the pure amino derivatives
3a, 3e and 3i±3m.
General procedure for the synthesis of the cyano
derivatives 5b and 5f
To a stirred mixture of bromo derivatives 2c (200 mg,
0.87 mmol) or 2e (200 mg, 0.73 mmol) in anhydrous
N,N-dimethylformamide (5 mL) was added potassium
cyanide (1.1 equiv) under inert atmosphere. The reac-
tion mixture was stirred at room temperature for 12 h,
then potassium cyanide (1.1 equiv) was added again.
After this addition, the reaction mixture was allowed to
stir at room temperature for supplementary 12 h. The
solvent was removed at reduced pressure and the resi-
due was taken up with dichloromethane and water. The
aqueous phase was extracted with dichloromethane and
the collected organic layers were washed with water and
then dried (MgSO4).
N-[(2,3-Dihydro-1,4-benzodioxin-5-yl]-methanamine 3a.
Yellow oil; yield: 62%. IR (neat) n 3370±3280, 1205,
1
1070 cm 1. H NMR (CDCl3) d 1.80 (br s, 2H, NH2),
3.73 (s, 2H, CH2N), 4.18±4.24 (m, 4H, H2 and H3), 6.72
(s, 3H, Harom).
N-[3-(2,3-Dihydro-1,4-benzoxathiin-5-yl)]-propanamine
3e. Yellow oil; yield: 60%; IR (neat) n 3370±3290,
1258, 1084 cm
J=7.4, CH2), 1.96 (br s, 2H, NH2), 2.61 (t, 2H, J=7.4,
ArCH2), 2.76 (t, 2H, J=7.4, CH2N), 3.11 (t, 2H, J=4.7,
H3), 4.36 (t, 2H, J=7.4, H2), 6.68±6.76 (m, 2H, H6 and
H8), 6.68±7.82 (m, 1H, H7).
After evaporation of the solvent under reduced pres-
sure, the crude product was puri®ed by column chro-
matography (eluent: petroleum ether:AcOEt, 9:1 for 5b
and petroleum ether:AcOEt, 7:3 for 5f).
1
.
1H NMR (CDCl3) d 1.74 (q, 2H,
5-Cyanomethyl-2,3-dihydro-1,4-benzodioxin 5b. White
solid; mp 46±47 ꢁC; yield: 71%, IR (KBr) n 2365,
1052 cm 1; 1H NMR (CDCl3) d 3.60 (s, 2H, CH2), 4.21±
4.27 (m, 4H, H2 and H3), 6.78±6.86 (m, 3H, H6, H7 and
H8), anal C10H9NO2 (C,H,N).
N-[2-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)]ethanamine
3i. Orange solid; mp 64±65 ꢁC; yield: 75%; IR (KBr) n
1
3560±3360, 1207, 1038 cm 1; H NMR (CDCl3) d 1.65
(br s, 2H, NH2), 3.04 (t, 2H, J=5.2, CH2N), 3.97 (t, 2H,
J=5.2, OCH2), 4.17±4.25 (m, 4H, H2 and H3), 6.42±
6.48 (m, 2H, H6 and H8), 6.67 (t, 1H, J=8.3, H7).
5-(3-Cyano propyl)-2,3-dihydro-1,4-benzoxathiin 5f.
1
Colorless oil; yield: 97%; IR (neat) n 2234, 1054 cm
;
1H NMR (CDCl3) d 1.99 (q, 2H, J=7.2, CH2), 2.36 (t,
2H, J=7.2, CH2), 2.74 (t, 2H, J=7.2, CH2), 3.13 (t, 2H,
J=4.6, H3), 4.37 (t, 2H, J=4.6, H2), 6.71 6.76 (m, 2H,
H6 and H8), 6.95 (t, 1H, J=7.9, H7), anal C12H13NOS
(C,H,N).
N-[3-(2,3-Dihydro-1,4-benzodioxin-5-yloxy]-propanamine
3j. White solid; mp 133±134 ꢁC, yield: 69%; IR (KBr)
1
3560±3400, 1209, 1111 cm 1; H NMR (CDCl3) d 1.55
(br s, 2H, NH2), 1.90 (q, 2H, J=6.4, CH2), 2.85 (t, 2H,
J=6.4, CH2N), 4.03 (t, 2H, J=6.4, OCH2), 4.17±4.23
(m, 4H, H2 and H3), 6.41±6.45 (m, 2H, H6 and H8), 6.66
(t, 1H, J=8.2, H7).
5-(3-Cyanopropyl)-2,3-dihydro-1,4-benzodioxin 5d.
A
mixture of tosylate 4 (2 g, 5.74 mmol) and potassium
cyanide (448 mg, 6.89 mmol) in N,N-dimethylforma-
mide (20 mL) was stirred for 5 h 30 min at 100 ꢁC
under inert atmosphere. After cooling, the solvent was
removed at reduced pressure and the mixture was taken
up with dichloromethane and water. The aqueous phase
was extracted three times with dichloromethane and the
organic extract was washed with water, then dried
(MgSO4), and concentrated under vacuum. The crude
product was puri®ed by column chromatography (elu-
ent: petroleum ether:AcOEt, 7:3) to obtain the desired
N-[4-2(2,3-Dihydro-1,4-benzodioxin-5-yloxy]-butanamine
3k. Yellow oil; yield: 85%; IR (neat) n 3370±3300, 1215,
1
1044 cm 1; H NMR (CDCl3) d 1.55 (br s, 2H, NH2),
1,59 (q, 2H, J=6.6, CH2), 1.85 (q, 2H, J=6.6, CH2),
2.74 (t, 2H, J=6.6, CH2N), 4.00 (t, 2H, J=6.6, OCH2),
4.21±4.29 (m, 4H, H2 and H3), 6.44±6.50 (m, 2H, H6
and H8), 6.71 (t, 1H, J=8.3, H7).
N-[2-(3,4-Dihydro-2H-1-benzopyran-8-yloxy)]-ethanamine
3l. Yellow oil; yield: 46%; IR (neat) n 3410±3320,
compound 5d as a yellowish oil; yield: 77%; IR (neat) n
2250, 1092 cm
J=7.4, CH2), 2.30 (t, 2H, J=7.4, CH2), 2.71 (t, 2H,
J=7.4, CH2), 4.20±4.26 (m, 4H, H2 and H3), 6.65±6.75
(m, 3H, Harom), anal C12H13NO2 (C,H,N).
1
;
1H NMR (CDCl3) d 1.95 (q, 2H,
1
1206 cm 1; H NMR (CDCl3) d 1.62 (br s, 2H, NH2),
1.95 (q, 2H, J=6.0, H3), 2.75 (t, 2H, J=6.0, H4), 3.04
(t, 2H, J=5.4, CH2N), 4.18±4.27 (m, 4H, H2 and
OCH2), 6.70±6.77 (m, 3H, Harom).
General procedure for the synthesis of the amines 3b, 3d
and 3f
N-[2-(3,4-Dihydro-2H-1-benzothiopyran-8-yloxy)]-ethan-
amine 3m. White solid; mp 44±45 ꢁC; yield: 64%; IR
1
(neat) 3390±3300, 1210 cm
;
1H NMR (CDCl3) d
To a stirred suspension of lithium aluminum hydride
(173 mg, 4.5 mmol) in anhydrous ether (10 mL) under an
Ar atmosphere and at 0 ꢁC was added dropwise a
solution of cyano compounds 4b, 4d or 4f (2.3 mmol)
in ether (5 mL). After the addition, the reaction mix-
ture was heated at re¯ux for 4 h. After cooling, water
1.93 (br s, 2H, NH2), 2.06 (q, 2H, J=6.6, H3), 2.79
(t, 2H, J=6.6, H2 or H4), 2.97 (t, 2H, J=6.6, H2 or
H4), 3.06 (t, 2H, J=5.9, CH2N), 4.08 (t, 2H, J=5.9,
OCH2), 6.74 (t, 2H, J=8.1, H5 and H7), 6.90 (t, 1H,
J=8.1, H6).

I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
111
(0.17 mL), 15% NaOH solution (0.17 mL) and water
(0.52 mL) were successively added. The mixture was ®l-
tered, and the ®ltrate was dried over MgSO4. The sol-
vent was evaporated in vacuo to a€ord the pure amines
3b, 3d and 3f.
Z isomer), 7.33 (d, 1H, J=17.0, ArCH E isomer), anal
C11H7NO2 (C,H,N).
General procedure for the synthesis of the amino
compounds 3c and 3h
N-[2-(2,3-Dihydro-1,4-benzodioxin-5-yl]ethanamine 3b.
Yellowish oil; yield: 100%; IR (neat) n 3600±3140,
To a solution of the propenenitriles 8c or 8h (5 mmol) in
anhydrous diethyl ether (40 mL) was added portionwise
lithium aluminum hydride (20 mmol) at room tempera-
ture under inert atmosphere and the mixture was stirred
at re¯ux for 5 h. After cooling at room temperature,
water was added dropwise to destroy the excess hydride,
the mixture was ®ltered on Celite and the ®ltrate was
concentrated in vacuo to give the pure amines 3c or 3h.
1
1283, 1118 cm 1; H NMR (CDCl3) d 1.52 (br s, 2H,
NH2), 2.64±2.68 (m, 2H, CH2), 2.84±2.88 (m, 2H, CH2),
4.16±4.20 (m, 4H, H2 and H3), 6.62±6.70 (m, 3H,
Harom).
N-[4-(2,3-Dihydro-1,4-benzodioxin-5-yl]-butanamine 3d.
Colorless oil; yield: 97%; IR (neat) n 3620±3160; 1290,
1
1085 cm 1; H NMR (CDCl3) d 1.30 (br s, 2H, NH2),
3-(2,3-Dihydro-1,4-benzodioxin-5-yl)-propanamine 3c.
Yellowish oil; yield 63%; IR (neat) n 3390±3150, 1282,
1.58±1.70 (m, 4H, CH2), 2.61 (t, 2H, J=7.4, ArCH2),
2.71 (m, 2H, CH2N), 4.18±4.23 (m, 4H, H2 and H3),
6.66±6.74 (m, 3H, Harom).
1
1087 cm 1; H NMR (CDCl3) d 1.25 (br s, 2H, NH2),
1.79 (q, 2H, J=7.8, CH2), 2.62 (t, 2H, J=7.8, CH2),
2.72 (t, 2H, J=7.8, CH2), 4.22±4.29 (m, 4H, H2 and
H3), 6.68±6.79 (m, 3H, Harom).
N-[4-(2,3-Dihydro-1,4-benzoxathiin-5-yl]-butanamine 3f.
Yellowish oil; yield: 88%; IR (neat) n 3680±3140, 1302,
1
1075 cm 1; H NMR (CDCl3) d 1.25 (br s, 2H, NH2),
3-(1,4-Benzodioxin-5-yl)-propanamine 3h. Yellow oil;
yield 96%; IR (neat) n 3390±3250, 1255 cm 1; 1H NMR
(CDCl3) d 1.65±1.75 (m, 4H, CH2 and NH2), 2.54 (t, 2H,
J=7.5, CH2), 2.78 (t, 2H, J=7.0, CH2), 5.92 (d, 1H,
J=3.5, H2 or H3), 5.97 (d, 1H, J=3.5, H2 or H3), 6.52
(dd, 1H, J=7.5, 2.0, Harom), 6.71±6.88 (m, 2H, Harom).
1.47±1.70 (m, 4H, CH2), 2.58 (t, 2H, J=7.4, ArCH2),
2.73 (t, 2H, J=6.6, CH2N), 3.13 (t, 2H, J=4.4, H3),
4.38 (t, 2H, J=4.4, H2), 6.67±6.75 (m, 2H, H6 and H8),
6.92 (t, 2H, J=8.1, H7).
General procedure for the synthesis of propenenitrile
derivatives 8c and 8h
5-(4-Cyanobut-3-ene)-2,3-dihydro-1,4-benzoxathiin 8g.
Compound 8g was prepared starting from the aldehyde
9 (500 mg, 2.4 mmol) according to the general procedure
described above and puri®ed by column chromato-
graphy (eluent: petroleum ether:AcOEt, 7:3) to a€ord
To a stirred suspension of sodium hydride (1.15 equiv,
60% dispersion in mineral oil) in tetrahydrofuran
(20 mL), at 0 ꢁC, was added diethyl cyanomethylpho-
sphonate (1.1 equiv) under inert atmosphere. After stir-
ring for 10 min at 0 ꢁC, the reaction mixture was cooled
at 78 ꢁC, then was dropwise added a solution of the
aldehyde 6 (984 mg, 6 mmol) or 7 (988 mg, 6.1 mmol) in
THF (20 mL). Stirring was maintained at 78 ꢁC for
90 min. The reaction mixture was warmed at room
temperature and quenched with saturated sodium
hydrogenocarbonate solution. The mixture was extrac-
ted with ethyl acetate. The organic layer was washed
with water, dried (MgSO4), ®ltered and concentrated to
leave a residue which was chromatographed on silica gel
(eluent: petroleum:AcOEt, 7:3) to furnish the cyano
derivatives 8c and 8h.
the pure compound 8g (E isomer) as yellowish oil; yield:
1
81%; IR (neat) n 2208, 1305, 1076 cm
;
1H NMR
(CDCl3) d 2.55 (td, 2H, J=6.0, 2.0, CH2), 2.75 (t, 2H,
J=6.0, ArCH2), 3.13 (t, 2H, J=5.0, H3), 4.38 (t, 2H,
J=5.0, H2), 5.35 (td, 1H, J=17.0, 2.0, CHˆC), 6.69±
6.80 (m, 3H, CHCN, H6 and H8), 6.95 (t, 1H, J=7.7,
H7), anal C13H13NOS (C,H,N).
5-(4-Cyanobutyl)-2,3-dihydro-1,4-benzoxathiin 5g. The
unsaturated nitrile 8g (400 mg, 1.71 mmol) was dissolved
in anhydrous ethanol (20 mL), (10% in mass). Pd-C
catalyst was added, and the reaction mixture was treated
in a Parr hydrogenation ¯ask for 12h at room tempera-
ture under a hydrogen pressure of 50 psi. After ®ltering
o€ of the catalyst, the volatiles were removed under
reduced pressure. The crude product was puri®ed by
column chromatography (eluent: petroleum ether:
AcOEt, 7:3) to a€ord 5g in 95% yield as a colorless oil;
3-(2,3-Dihydro-1,4-benzodioxin-5-yl)-2-propenenitrile 8c.
White solid; the mixture of two isomers Z and E was
obtained (Z/E:3/1), yield 91%; IR (KBr) n 2208, 1300,
1
1102 cm 1; H NMR (CDCl3) d 4.37±4.28 (m, 4H, H2
1
and H3), 5.55 (d, 1H, J=12.0, CHCN Z isomer), 6.05
(d, 1H, J=16.0, CHCN E isomer), 6.85±6.95 (m, 3H,
Harom), 7.45 (d, 1H, J=12.0, ArCH Z isomer), 7.55 (d,
1H, J=16.0, ArCH E isomer), anal C11H9NO2 (C,H,N).
IR (neat) n 2244, 1302, 1078 cm 1; H NMR (CDCl3) d
1.99 (t, 4H, J=7.3, CH2), 2.35 (t, 2H, J=7.3, CH2CN),
2.68 (t, 2H, J=7.3, ArCH2), 3.08 (t, 2H, J=4.4, H3),
4.32 (t, 2H, J=4.4, H2), 6.60±6.80 (m, 2H, H6 and H8),
6.95 (t, 1H, J=7.9, H7), anal C13H15NOS (C,H,N).
3-(1,4-Benzodioxin-5-yl)-2-propenenitrile 8h. White solid;
the mixture of two isomers Z and E was obtained
General procedure for the synthesis of the acetamides 1a,
1b, 1ca, 1d±1f, 1ha, 1i±1m
1
(Z/E:1/1), yield 96%; IR (KBr) n 2210, 1250 cm 1; H
NMR (CDCl3) d 5.50 (d, 1H, J=12.0, CHCN Z iso-
mer), 5.93±6.02 (m, 3H, OCH and CHCN E isomer),
6.70±6.99 (m, 3H, Harom), 7.14 (d, 1H, J=12.0, ArCH
To a stirred solution of amines 3 (3 mmol) in anhydrous
pyridine (5mL) under an Ar atmosphere and at 0 ꢁC was

112
I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
added dropwise acetic anhydride (0.34 mL, 3.6 mmol).
After the addition, the reaction mixture was stirred at
room temperature for 2 h. After evaporation of the sol-
vent under reduced pressure, the residue was dissolved
in dichloromethane. The combined organic extracts
were washed with water and dried over MgSO4, and the
solvent was evaporated in vacuo. The crude product
was puri®ed by ¯ash chromatography (eluent:
CHCl3:AcOEt, 70:30) to yield 1a, 1b, 1ca, 1d±1f, 1ha,
1i±1m.
2H, CH2), 2.02 (s, 3H, CH3), 2.54 (t, 2H, J=7.2,
ArCH2), 3.31 (t, 2H, J=7.2, CH2N), 5.93 (d, 1H,
J=3.5, OCH), 5.96 (d, 1H, J=3.5, OCH), 6.53 (dd, 1H,
J=2.0, 8.0, H6 or H8), 6.72 (dd, 1H, J=2.0, 8.0, H6 or
H8), 6.79 (t, 1H, J=8.0, H7), MS (CI with NH3) m/z 234
(M+1), anal C13H15NO3 (C,H,N).
N-[2-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)ethyl]-acetamide
1i. Yield 90%. White solid; mp 93±94 ꢁC; IR (KBr) n
1
3274, 1640, 1112 cm 1; H NMR (CDCl3+D2O) d 1.95
(s, 3H, CH3), 3.66 (t, 2H, J=5.0, CH2N), 4.08 (t, 2H,
J=5.0, OCH2), 4.26±4.32 (m, 4H, H2 and H3), 6.50 (d,
1H, J=8.3, H6 or H8), 6.57 (d, 1H, J=8.3, H6 or H8),
6.76 (t, 1H, J=8.3, H7), MS (CI with NH3) m/z 238
(M+1), anal C12H15NO4 (C,H,N).
N-[2,3-Dihydro-1,4-benzodioxin-5-yl)methyl]-acetamide
1a. Yield 85%. White solid; mp 117±118 ꢁC; IR (KBr)
1
n 3300, 1638, 1099 cm 1; H NMR (CDCl3+D2O) d
1.92 (s, 3H, CH2), 4.18±4.25 (m, 4H, H2 and H3), 4.34
(s, 2H, CH2N), 6.70±6.85 (m, 3H, Harom), MS (CI with
NH3) m/z 208 (M+1), anal C11H13NO3 (C,H,N).
N-[3-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)propyl]-ace-
tamide 1j. Yield 89%. White solid; mp 95±96 ꢁC; IR
1
N-[2-(2,3-Dihydro-1,4-benzodioxin-5-yl)ethyl]-acetamide
1b. Yield 91%. White solid; mp 56±57 ꢁC; IR (KBr) n
(KBr) n 3268, 1641, 1111 cm
;
1H NMR (CDCl3+
D2O) d 1.92±1.97 (m, 5H, CH2 and CH3), 3.42 (t, 2H,
J=5.9, CH2N), 4.06 (t, 2H, J=5.9, CH2O), 4.22±4.24
(m, 4H, H2 and H3), 6.40±6.50 (m, 2H, H6 and H8), 6.70
(t, 1H, J=8.1, H7), MS (CI with NH3) m/z 252 (M+1),
anal C13H17NO4 (C,H,N).
1
3340, 1629, 1068 cm 1; H NMR (CDCl3+D2O) d 1.92
(s, 3H, CH3), 2.77 (t, 2H, J=6.6, ArCH2), 3.45 (t, 2H,
J=6.6, NCH2), 4.20±4.26 (m, 4H, H2 and H3), 6.65±
6.75 (m, 3H, Harom), MS (CI with NH3) m/z 222
(M+1), anal C12H15NO3 (C,H,N).
N-[4-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)butyl]-ace-
tamide 1k. Yield 85%. White solid; mp 90±91 ꢁC; IR
N-[3-(2.3-Dihydro-1,4-benzodioxin-5-yl)propyl]-acetamide
1ca. Yield 77%. Yellowish oil; IR (neat) n 3291, 1672,
1109 cm
J=7.4, CH2), 1.88 (s, 3H, CH3), 2.53 (t, 2H, J=7.4,
ArCH2), 3.17 (t, 2H, J=7.4, CH2N), 4.13±4.23 (m, 4H,
H2 and H3), 6.59±6.68 (m, 3H, Harom), MS (CI with
NH3) m/z 236 (M+1), anal C13H17NO3 (C,H,N).
1
(KBr) n 3276, 1635, 1114 cm
;
1H NMR (CDCl3+
1
;
1H NMR (CDCl3+D2O) d 1.71 (q, 2H,
D2O) d 1.69 (q, 2H, J=6.6, CH2), 1.85 (q, 2H, J=6.6,
CH2), 1.93 (s, 3H, CH3), 3.29 (t, 2H, J=6.6, CH2N),
4.00 (t, 2H, J=6.6, OCH2), 4.23±4.28 (m, 4H, H2 and
H3), 6.40±6.50 (m, 2H, H6 and H8), 6.73 (t, 1H, J=8.1,
H7), MS (CI with NH3) m/z 266 (M+1), anal
C14H19NO4 (C,H,N).
N-[4-(2,3-Dihydro-1,4-benzodioxin-5-yl)butyl]-acetamide
1d. Yield 82%. Yellow gum; IR (neat) n 3308, 1672,
N-[2-(3,4-Dihydro-2H-1-benzopyran-8-yloxy)ethyl]-ace-
tamide 1l. Yield 84%. White solid; mp 110±111 ꢁC; IR
1
1076 cm
;
1H NMR (CDCl3+D2O) d 1.49±1.66 (m,
1
4H, CH2), 1.95 (s, 3H, CH3), 2.58 (t, 2H, J=7.3,
ArCH2), 3.25 (t, 2H, J=6.9, CH2N), 4.22±4.26 (m, 4H,
H2 and H3), 6.65±6.75 (m, 3H, Harom), MS (CI with
NH3) m/z 250 (M+1), anal C14H19NO3 (C,H,N).
(KBr) n 3338, 1636, 1094 cm
;
1H NMR (CDCl3+
D2O) d 2.00±2.07 (m, 5H, H3 and CH3), 2.80 (t, 2H,
J=5.8, H4), 3.64 (t, 2H, J=4.8, CH2N), 4.07 (t, 2H,
J=4.8, OCH2), 4.26 (t, 2H, J=5.8, H2), 6.72±6.80 (m,
3H, Harom), MS (CI with NH3) m/z 236 (M+1), anal
C13H17NO3 (C,H,N).
N-[3-(2,3-Dihydro-1,4-benzoxathiin-5-yl)propyl]-acetamide
1e. Yield 86%. Yellow gum; IR (neat) n 3308, 1656,
1
1075 cm
;
1H NMR (CDCl3+D2O) d 1.77 (q, 2H,
N-[2-3,4-Dihydro-2H-1-benzothiopyran-8-yloxy)ethyl]-
acetamide 1m. Yield 95% White solid; mp 116±117 ꢁC;
J=7.3, CH2), 1.96 (s, 3H, CH3), 2.58 (t, 2H, J=7.3,
ArCH2), 3.13 (t, 2H, J=4.7, H3), 3.27 (t, 2H, J=7.3,
CH2N), 4.38 (t, 2H, J=4.7, H2), 6.68±6.74 (m, 2H, H6
and H8), 6.92 (t, 1H, J=7.8, H7), MS (CI with NH3) m/z
252 (M+1), anal C13H17NO2S (C,H,N).
1
IR (KBr)
n
3234, 1636, 1084 cm
;
1H NMR
(CDCl3+D2O) d 2.00 (s, 3H, CH3), 2.10 (q, 2H, J=6.0,
H3), 2.83 (t, 2H, J=6.0, H2 or H4), 3.02 (t, 2H, J=6.0,
H2 or H4), 3.65 (t, 2H, J=5.0, CH2N), 4.08 (t, 2H,
J=5.0, OCH2), 6.66 (d, 1H, J=7.9, H5 or H7), 6.71 (d,
1H, J=7.9, H5 or H7), 6.95 (t, 1H, J=7.9, H6), MS (CI
with NH3) m/z 252 (M+1), anal C13H17NO2S (C,H,N).
N-[4-(2,3-Dihydro-1,4-benzoxathiin-5-yl)butyl]-acetamide
1f. Yield 90%. Yellow gum; IR (neat) n 3300, 1646,
1075 cm
1
;
1H NMR (CDCl3+D2O) d 1.56±1.70 (m,
4H, CH2), 1.96 (s, 3H, CH3), 2.59 (t, 2H, J=7.3,
ArCH2), 3.13 (t, 2H, J=4.7, H3), 3.28 (t, 2H, J=6.9,
CH2N), 4.38 (t, 2H, J=4.7, H2), 6.65±6.74 (m, 2H, H6
and H8), 6.93 (t, 1H, J=7.8, H7), MS (CI with NH3) m/z
266 (M+1), anal C14H19NO2S (C,H,N).
N-[4-(2,3-Dihydro-1,4-benzoxathiin-5-yl)pentyl]-acetamide
1g. To a suspension of Raney nickel (48 mg) in acetic
anhydride (10 mL) were added the nitrile 5g (400 mg,
1.71 mmol) and sodium acetate (211 mg, 2.57 mmol).
The mixture was treated in a Parr hydrogenation ¯ask
for 12 h at 50 ꢁC under a hydrogen pressure of 40 psi.
After cooling, the salts were ®ltered and then the solvent
was removed under reduced pressure. The residue was
diluted with ethyl acetate and the organic layer was
N-[3-(1,4-Benzodioxin-5-yl)propyl]-acetamide 1ha. Yield
79%. Yellowish oil; IR (neat) n 3420±3240, 1670,
1225 cm
1
;
1H NMR (CDCl3+D2O) d 1.76±1.84 (m,

I. Charton et al. / Bioorg. Med. Chem. 8 (2000) 105±114
113
washed with saturated sodium hydrogenocarbonate
solution. After drying over magnesium sulfate and
removal of the solvent in vacuo, the resulting oil was
submitted to column chromatography (eluent:
CHCl3:AcOEt, 70:30) to a€ord the compound 1g in
47% yield as a white solid; mp 92±93 ꢁC; IR (KBr) n
incubated with 50 pM 2-[125I]-iodomelatonin and
11 concentrations of competing ligand for 2 h at
37 ꢁC. Melatonin was tested as reference. Indivi-
dual compounds were assayed in triplicate and the
values expressed in LogKi‹SD.
. Chickens (Gallus domesticus), 12 days old, were
sacri®ced at 1 pm. The brains were quickly
removed, prepared at 4 ꢁC and stored at 80 ꢁC.
Membranes were prepared according to the
method described by Yuan and Pang.42 Mem-
branes aliquots were incubated at 25 ꢁC for 60 min
with 50 pM 2-[125I]-iodomelatonin and ligands
were evaluated at 10 concentrations in triplicate.
Melatonin was tested in the same conditions as
reference. Results are expressed in Log Ki‹SD.
1
3268, 1634, 1298, 1075 cm 1; H NMR (CDCl3+D2O)
d 1.33±1.71 (m, 6H, CH2), 1.96 (s, 3H, CH3), 2.53±2.59
(m, 2H, ArCH2), 3.13 (t, 2H, J=4.4, H3), 3.21±3.28 (m,
2H, CH2N), 4.38 (t, 2H, J=4.4, H2), 6.68±6.75 (m, 2H,
H6 and H8), 6.93 (t, 1H, J=7.9, H7), SM (CI with NH3)
m/z 280 (M+1), anal C15H21NO2S (C,H,N).
General procedure for the synthesis of the butyramides
1cb and 1hb
To a well-stirred solution of the amine 3c or 3h
(5.23 mmol) in dichloromethane (20 mL) were succes-
sively added, at 0 ꢁC, butyryl chloride (0.78 g, 7.32mmol)
then triethylamine (1.58 g, 15.7 mmol). After 30 min of
stirring under inert atmosphere at 0 ꢁC and after addi-
tion of HCl 1 N to pH 1, the phases were separated and
the aqueous layer was extracted with dichloromethane.
Subsequently, the organic layers were combined and
dried over MgSO4. After evaporation under reduced
pressure, the residue was chromatographed on silica gel
(eluent: petroleum ether:AcOEt, 8:2 for 1cb and petro-
leum ether:AcOEt, 1:1 for 1hb).
Non speci®c binding was de®ned with 1 mM melatonin.
Cyclic AMP studies. The compounds (10 mM) were tes-
ted alone and were compared to melatonin (1 nM) for
their inhibition of forskolin (10 mM) stimulated cAMP
production. These experiments were carried out in tri-
plicate. The compounds were tested for their antagonist
activity at 10 mM with melatonin 1 nM. In this case an
antagonist will prevent the cAMP inhibition induced by
melatonin.
Acknowledgements
N-[3-(2,3-Dihydro-1,4-benzodioxin-5-yl)propyl]-n-butyr-
amide 1cb. Yield 56%. Colorless oil; IR (neat) n 3295,
1644, 1283, 1101 cm 1; 1H NMR (CDCl3) d 0.94 (t, 3H,
J=7.4, CH3), 1.64 (sext., 2H, J=7.4, CH2), 1.79 (q, 2H,
J=7.2, CH2), 2.12 (q, 2H, J=7.2, COCH2), 2.62 (t, 2H,
J=7.2, ArCH2), 3.27 (q, 2H, J=7.2, CH2N), 4.21±4.29
(m, 4H, H2 and H3), 5.56 (br s, 1H, NH), 6.67±6.79 (m,
3H, Harom). MS (CI with NH3) m/z 264 (M+1), anal
C15H21NO3 (C,H,N).
The authors thank Mrs. M. M. Le Floch and M. Obert
for typing the manuscript.
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