N,N-disubstituted aminomethyl benzofuran derivatives: Synthesis and preliminary binding evaluation

Article abstract of DOI:10.1016/S0968-0896(98)00239-9

A series of new N-substituted 2,3-dihydro-2-aminomethyl-2H-1-benzofuran derivatives was prepared and evaluated for affinity at 5-HT(1A), 5-HT(2A), 5-HT(2C), 5-HT₃, D₂, and D₃ receptors. Compound 9, 8-[4-[N-propyl-N-(7-hydroxy-2,3-dihydro-2H-1-benzofuran-2-yl)methyl]aminobutyl]-8-azaspiro[4,5]decane-7,9-dione, bound at 5-HT(1A) sites with nanomolar affinity (IC₅₀=1.5nM) and high selectivity over 5-HT(2A), 5-HT(2C), 5-HT₃, D₂, and D₃ receptors. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00239-9

Bioorganic & Medicinal Chemistry 7 (1999) 335±341
N,N-Disubstituted Aminomethyl Benzofuran Derivatives:
Synthesis and Preliminary Binding Evaluation
a
b
b
c
Sophie Boye
Â
, Bruno Pfei€er, Pierre Renard, Marie-Claire Rettori,
a
a,
Ge
Â
rald Guillaumet and Marie-Claude Viaud *
aInstitut de Chimie Organique et Analytique, associe au CNRS, Universite d'OrleÂans, B.P. 6759, 45067 OrleÂans Cedex 2, France
bA.D.I.R., 1, rue Carle HeÂbert, 92415 Courbevoie Cedex, France
cI.R.I. Servier, 6, place des PleÂiades, 92415 Courbevoie Cedex, France
Received 23 June 1998; accepted 5 October 1998
AbstractÐA series of new N-substituted 2,3-dihydro-2-aminomethyl-2H-1-benzofuran derivatives was prepared and evaluated for
anity at 5-HT1A, 5-HT2A, 5-HT2C, 5-HT
benzofuran-2-yl)methyl]aminobutyl]-8-azaspiro[4,5]decane-7,9-dione, bound at 5-HT1A sites with nanomolar anity (IC50
.5 nM) and high selectivity over 5-HT2A, 5-HT2C, 5-HT , D , and D receptors. # 1999 Elsevier Science Ltd. All rights reserved.
3 2 3
, D , and D receptors. Compound 9, 8-[4-[N-propyl-N-(7-hydroxy-2,3-dihydro-2H-1-
=
1
3
2
3
Introduction
One of those (+)-8-[4-[N-propyl-N-(5-methoxy-3,4-
dihydro-2H-1-benzopyran-3-yl)amino]butyl]-8-azaspiro-
[4,5]decane-7,9-dione (S 20499, Alnespirone) is today
under clinical development.14
Serotonin (5-hydroxytryptamine, 5-HT) is an important
neurotransmitter that mediates a wide variety of phy-
siological responses in both the peripheral and central
1
±3
nervous systems. The receptors that are activated by
-HT have been divided into at least seven classes (5-
HT1±7) and each class has been further subdivided into
5
4±6
di€erent subtypes (A, B,. . .). Of the serotonin receptor
subtypes, the 5-HT1A receptor subtype is the best studied
and it is generally accepted that it is involved in psychia-
In continuation of our previous works, we report, in
this paper, the preparation and receptor binding pro®le
of a series of compounds A which possess the amino-
methyl benzofuran structure.
7,8
9,10
tric disorders such as depression and anxiety.
early discovery of 8-hydroxy-2-(N,N-di-n-propylami-
The
1
1
no)tetralin
(8-OH-DPAT) a highly selective and
potent 5-HT1A agonist, enabled the search for new
selective compounds for the 5-HT1A subtype. This
search has led to the discovery of several serotoninergic
6
ligands of di€erent chemical classes (indoles, aminote-
tralines, arylpiperazines, and benzodioxans). Buspirone,
an arylpiperazine derivative, was the ®rst agent to be
approved for chemical use as an antianxiety agent.1
2,13
Chemistry
Our interest in the development of such therapeutic
agents that display high anity for 5-HT1A receptor sites
has recently led us to synthesize several derivatives1
of 3,4-dihydro-3-amino-2H-1-benzopyran I, 3,4-dihy-
dro-3-amino-methyl-2H-1-benzopyran II and (2,3-dihy-
dro-1,4-dioxino[2,3-b]pyridinyl)-methanamine III.
The benzopyrans 5b and 5c were prepared from the
corresponding nitro derivatives 1 and 2 by known pro-
cedure18 (Scheme 1). The unsaturated nitro compounds
1 or 2 reacted with sodium borohydride in the presence
of silica gel in a mixture of chloroform and 2-propanol
to give the saturated derivatives 3 and 4.19 These products
were easily converted into the amines 5b and 5c by means
of a modi®ed procedure using hydrazine in the presence
of Raney nickel.20 The N,N-dipropyl compounds 6a±d
were synthesized in good yields by treatment of amines
4±17
Key words: 2,3-Dihydro-2-aminomethyl-2H-1-benzofurans; ring con-
traction; serotoninergic and dopaminergic receptor binding.
*Corresponding author. Tel.: +33 2 38 49 45 80; fax: +33 2 38 41 70 78;
e-mail. Marie-Claude.Viaud@univ-orleans.fr
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(98)00239-9

3
36
S. Boye et al. / Bioorg. Med. Chem. 7 (1999) 335±341
Scheme 1.
5a±d with propyl iodide in N,N-dimethylformamide in
the presence of potassium carbonate.
ment of this compound by boron tribromide according
1
4
to the procedure described for the synthesis of 7 furnish
compound 9 in 35% yield. Regardless of the conditions
used, a relatively large amount of the demethylated
benzopyran product was always obtained.
The treatment of benzopyrans 6a±d by boron tri-
bromide in methylene chloride under re¯ux provide an
2
1
unexpected rearrangement. This methodology fur-
nishes the demethylated benzofurans 7a±d in 67±96 %
yields. Starting from 6a and 6c, the reaction of the
demethylation is also observed and so the corresponding
hydroxybenzopyrans 10a and 10c are obtained with 22
and 13% yields, respectively. The preparation of the
compound 9 is described in Scheme 2. The treatment
of 8-(4-bromobutyl)-8-azaspiro[4,5]decane-7,9-dione,
Pharmacology
The compounds were evaluated for in vitro 5-HT1A
5
,
-HT2A, 5-HT , 5-HT , D , and D receptor anity by
2C
3
2
3
radioligand binding assays. All the compounds were
used in the form of oxalate salts and were water-soluble.
1
4
obtained by known procedure, with 8-methoxy-3,4-
dihydro-3-amino-2H-1-benzopyran 5d18 in N,N-dime-
thylformamide in the presence of triethylamine and
potassium iodide provided the corresponding N-mono-
substituted amino derivative. This compound was sub-
sequently treated with 1-iodopropane to give the desired
benzopyran 8 in satisfactorily overall yield. The treat-
Results and Discussion
None of the synthesized compounds shows any anity
for the 5-HT2A, 5-HT , 5-HT , D , and D receptors,
with the exception of compound 9 which exhibits
2C
3
2
3
moderate anity for the 5-HT2A and D2 receptors.

S. Boye et al. / Bioorg. Med. Chem. 7 (1999) 335±341
337
Among these, only compound 10a shows a high anity
IC =4 nM) for the 5-HT receptors. The results are
(
50
1A
in agreement with those obtained with aminomethyl
benzofuran series since the relative position of the
hydroxyl group toward the amino moiety is the same
for the compounds 10a, 7d, and 9. Compounds 10b and
1
respectively (10b, IC =1.2 nM; 10d, IC =7 nM) in
0d exhibit high anity for D2 and D3 receptors,
50
50
opposition to derivatives 7 which are devoid of any
anity for the receptors precited.
Conclusion
In conclusion, we have synthesized and evaluated a new
family of potential 5-HT1A ligands having a 2-amino-
methyl benzofuran skeleton. Compound 9 exhibits
excellent nanomolar anity for the 5-HT1A receptor
with a high selectivity (>100) toward the 5-HT2A
5-HT , 5-HT , and D receptors. According to these
,
Scheme 2.
2C
3
2
in vitro results, compound 9 could be a promising can-
didate for future development.
However, all these compounds present moderate to high
anity for the 5-HT1A receptors.
Experimental
Chemistry
The study of the data reported in Table 1 shows that: (1)
Among the N,N-dipropylated derivatives 7, compound
7
d, which is substituted by a hydroxyl group in 7-posi-
tion, exhibits a good anity for the 5-HT1A receptors
IC =10 nM) with a good selectivity toward the 5-
È
Melting points were determined on a Ko¯er hot-stage
apparatus 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-
(
5
0
HT2A, 5-HT , 5-HT (IC >10,000 nM), D , and D
3
2C
3
50
2
receptors (IC >1,000 nM). (2) Replacement of one
0
5
propyl moiety of compound 7d by an imidobutyl group
results in a selective high anity 5-HT1A ligand (com-
pound 9 IC =1.5 nM). Nevertheless, this compound
®eld from tetramethylsilane (TMS), which was used as
an internal standard. Infrared spectra were obtained
with Perkin±Elmer spectrophotometer 297. Mass spec-
tra were recorded on a R 10-10 C Nermag (70 eV)
apparatus. Organic solvents were puri®ed when neces-
sary by the methods described by D. D. Perrin, W. L. F.
Armarego and D. R. Perrin (Puri®cation of Laboratory
5
0
exhibits moderate but signi®cant anity for D receptors
2
(
IC =190 nM).
50
The 2-aminomethylbenzofuran derivatives were also
compared with their 3-aminobenzopyran ``parents'' 10.
Table 1 In vitro binding values of compounds 7a±d and 9a
IC50‹SE (nM)
5-HT2C
Compound
5-HT1A
5-HT2A
5-HT
3
D
2
D
3
7
7
7
7
9
a
b
c
270‹52
1600‹200
93‹9
10‹3
1.5‹0.3
>10 000
>10 000
>10 000
>10 000
890‹47
>10 000
b
>10 000
>10 000
>10 000
>10 000
>10 000
>1 000
>1 000
>1 000
>1 000
190‹29
>1 000
>1 000
>1 000
>1 000
ND
ND
b
d
>10 000
7 000‹500
b
ND
aAll compounds tested were racemic forms and used as oxalate.
b
ND: Not determined.

3
38
S. Boye et al. / Bioorg. Med. Chem. 7 (1999) 335±341
Chemicals; Pergamon: Oxford, 1986) or purchased from
Aldrich Chimie. All solutions were dried over anhy-
drous magnesium sulfate and evaporated on a Buchi
rotatory evaporator. Analytical thin-layer chromato-
graphy (TLC) was carried out on precoated plates
6-Methoxy-3-amino-3,4-dihydro-2H-1-benzopyran 5b.
Under inert atmosphere, benzopyran 3 (2.0 g, 9.6 mmol)
was dissolved in ethanol (150 mL) by heating to 80 C,
ꢀ
ꢀ
and then the solution was cooled to 45 C. Wet Raney
nickel (1.90 g) was introduced, and 5.50 mL of 98%
hydrazine hydrate was added portionwise for 1 h with
(
silica gel, 60 F254), and spots were visualised with UV
ꢀ
light or an alcohol solution of ammonium 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
vigorous stirring. The mixture was stirred at 45 C for
an additional 30 min, at which time the reaction was
complete, monitored by TLC. After cooling, the reac-
tion mixture was ®ltered on Celite and the remaining
catalyst washed with ethanol. The solvent was evapo-
rated to dryness, and the crude was puri®ed by ¯ash
chromatography (eluent: dichloromethane then dichlor-
omethane/methanol, 9/1) to a€ord 1.62 g (95%) of 5b as
(
Merck) for ¯ash columns. When analyses are indicated
by symbols of the elements, analytical results obtained
for those elements were ‹0.4% of the theoretical
values. All anhydrous reactions were performed in
oven-dried glassware under an atmosphere of argon.
The column chromatography solvents employed were
distilled and solvent mixtures were reported as volume
to volume ratios.
�
1
a yellow oil: IR (neat) n 3570±3100, 1190±1230 cm
;
H NMR (CDCl ), 1.43 (br s, 2H, NH ), 2.55 (dd, 1H,
1
3
2
J=6.8, 16.3 Hz, H ), 3.04 (dd, 1H, J=5.3, 16.3 Hz, H ),
4
4
3.29±3.37 (m, 1H, H ), 3.74 (s, 3H, OCH ), 3.78 (dd,
3
3
1
H, J=6.9, 10.6 Hz, H ), 4.06±4.12 (m, 1H, H ), 6.58 (d,
2 2
The compounds 1 and 2 were prepared by published
2
1H, J=3.0 Hz, H ), 6.68 (dd, 1H, J=3.0, 8.9 Hz, H ),
5 7
6.76 (d, 1H, J=8.9 Hz, H ). Anal. (C H NO ) C,H,N.
8 10 13 2
2
procedure. The compounds 5a and 5d have been
1
8
described in literature. The hydroxy derivatives 10
were obtained, in very good yields, by treatment of the
compounds 6 with 48% hydrobromic acid at re¯ux or
boron tribromide at low temperature.1
7-Methoxy-3-amino-3,4-dihydro-2H-1-benzopyran 5c.
This compound was obtained from 4 (2.71 g, 12.9 mmol)
according to the method used for 5b. The crude residue
was puri®ed by column chromatography (eluent:
dichloromethane/methanol, 9/1) to give 2.1 g (90%) of
4,23±25
6
- Methoxy-3-nitro-3,4-dihydro-2H-1- benzopyran 3.
�
1 1
Under inert atmosphere, 7-methoxy-3-nitro-2H-1-ben-
zopyran 1 (6.3 g, 30.4 mmol) was dissolved in a mixture
of chloroform (195 mL) and 2-propanol (65 mL). While
maintaining vigorous stirring, silica gel (70±230 mesh,
ASTM, 15.4 g) was then poured into the ¯ask and
powdered sodium borohydride (2.90 g, 76.0 mmol) was
added portionwise over a period of 15 min. The mixture
was stirred for an additional 15 min, and the reaction
was stopped by dropwise addition of acetic acid
5c as an oil: IR (neat) v 3400±3180, 1270, 1032 cm ; H
NMR (CDCl ) d 1.66 (br s, 2H, NH ), 2.46 (dd, 1H,
3
2
J=7.0, 15.8 Hz, H ), 2.94 (dd, 1H, J=4.8, 15.8 Hz, H ),
3.25±3.37 (m, 1H, H ), 3.71 (s, 3H, OCH ), 3.76 (dd,
4
4
3
3
1H, J=7.0, 10.7 Hz, H ), 4.03±4.13 (m, 1H, H ), 6.34 (d,
2
2
1H, J=2.2 Hz, H ), 6.42 (dd, 1H, J=2.2, 8.8 Hz, H ),
8
6
6.89 (d, 1H, J=8.8 Hz, H ). Anal. (C H NO ) C,H,N.
5
10 13
2
Methoxy-3,4-dihydro-3-(di-n-propylamino)-2H-1-benzo-
pyrans 6. General procedure. A mixture of amines 5, 1-
iodopropane (3 equiv) and potassium carbonate (3
equiv) in DMF (10 mL) was warmed with stirring at
(
4.8 mL). The reaction mixture was stirred for an addi-
tional 15 min. The insoluble material was ®ltered by
suction and washed with dichloromethane, and then the
solvent was removed in vacuo. The crude was puri®ed
by ¯ash chromatography using petroleum ether/
dichloromethane, 1/1 as eluent to give 5.87 g (92%) of 3
ꢀ
60 C for 6 h, under inert atmosphere. The reaction
mixture was isolated to room temperature, and the sol-
vent was removed under reduced pressure. After aqu-
eous hydrolysis, the product was extracted with ethyl
ꢀ
as a pale-yellow solid: mp 92 C; IR (KBr) n 1560, 1210±
�
1 1
1
1
3
230 cm ; H NMR (CDCl ) d 3.29 (dd, 1H, J=6.1,
acetate and the organic layer was dried (MgSO ), and
4
3
7.4 Hz, H ), 3.53 (dd, 1H, J=5.5, 17.4 Hz, H ), 3.76 (s,
H, OCH ), 4.37 (dd, 1H, J=2.9, 11.5 Hz, H ), 4.59
evaporated to dryness. Puri®cation by column chroma-
tography (eluent: petroleum ether/ethyl acetate, 9/1)
gave the pure compounds 6.
4
4
3
2
(
dd, 1H, J=5.8, 11.5 Hz, H ), 4.88±4.96 (m, 1H, H ),
2 3
6.64 (d, 1H, J=3.0 Hz, H ), 6.72 (dd, 1H, J=3.0, 8.8 Hz,
H ), 6.79 (d, 1H, J=8.8 Hz, H ). Anal. (C H NO )
C,H,N.
5
5-Methoxy-3,4-dihydro-3-(di-n-propylamino)-2H-1-benzo-
pyran 6a.14 By starting from 5a (1.0 g, 5.58 mmol), this
compound (1.21 g) was prepared in DMF (10 mL)
according to the general procedure (82% yield).
7
8
10 11
4
7-Methoxy-3-nitro-3,4-dihydro-2H-1-benzopyran 4. This
compound was synthesized from 2 (3.13 g, 30.4 mmol)
according to the method used for 3. The crude product
was chromatographed on a silica gel column using
dichloromethane as eluent to give 2.9 g (92%) of 4 as a
6-Methoxy-3,4-dihydro-3-(di-n-propylamino)-2H-1-benzo-
pyran 6b. The title compound (1.40 g) was prepared in
83 % yield from 5b (1.14 g, 6.38 mmol) in DMF (10 mL)
according to the general procedure; colorless oil; IR
ꢀ
pale-yellow solid: mp 72±73 C; IR (KBr) n 1561, 1282,
�
1
1
� 1
1
1
1
3
161 cm ; H NMR (CDCl ) d 3.26 (dd, 1H, J=5.9,
(neat) n 1213 cm
6H, J=7.3 Hz, CH ), 1.34±1.47 (m, 4H, CH ), 2.38±
;
H NMR (CDCl ) d 0.83 (t,
3
3
6.3 Hz, H ), 3.47 (dd, 1H, J= 5.5, 16.3 Hz, H ), 3.75 (s,
H, OCH ), 4.36±4.44 (m, 1H, H ), 4.60 (dd, 1H,
4
4
3
2
2.54 (m, 4H, NCH ), 2.77 (d, 2H, J=9.6 Hz, H ), 3.06±
2 4
3
2
J=5.9, 11.8 Hz, H ), 4.86±4.94 (m, 1H, H ), 6.41 (d, 1H,
3
3.17 (m, 1H, H ), 3.69 (s, 3H, OCH ), 3.72 (t, 1H,
3 3
2
J=2.2, H ), 6.54 (dd, 1H, J=2.2, 8.8 Hz, H ), 7.01 (d,
8
J=10.3 Hz, H ), 4.20 (ddd, 1H, J=15.4, 10.3 Hz, H ),
2 2
6
1
H, J=8.8 Hz, H ). Anal. (C H NO ) C,H,N.
10 11
6.56 (d, 1H, J=2.9 Hz, H ), 6.61 (dd, 1H, J=2.9,
5
5
4

S. Boye et al. / Bioorg. Med. Chem. 7 (1999) 335±341
339
8.8 Hz, H ), 6.68 (d, 1H, J=8.8 Hz, H ). Anal. (C H
NO ) C, H, N.
in 96% yield from 6b (132 mg) according to the general
procedure (Method B); yellow oil; IR (neat) n 3660±
7
8
16 23
2
�
1 1
3
6H, J=7.3 Hz, CH ), 1.38±1.54 (m, 4H, CH ), 2.47 (t,
095, 1199 cm ; H NMR (CDCl +D O) d 0.86 (t,
3
2
7
-Methoxy-3,4-dihydro-3-(di-n-propylamino)-2H-1-benzo-
pyran 6c. This compound (2.30 g) was synthesized from
c (2.1 g, 11.8 mmol) in DMF (20 mL) according to
the general procedure (74% yield); colorless oil; IR
3 2
4H, J=7.3 Hz, NCH ), 2.59 (dd, 1H, J=5.9, 13.6 Hz,
2
5
NCH ), 2.78 (dd, 1H, J=6.6, 13.6 Hz, NCH ), 2.93 (dd,
2
2
1H, J=7.3, 15.4 Hz, H ), 3.19 (dd, 1H, J=8.8, 15.4 Hz,
3
�
1 1
(
neat) v 1288±1157 cm ; H NMR (CDCl ) d 0.83 (t,
H ), 4.78±4.90 (m, 1H, H ), 6.53 (dd, 1H, J=2.2,
3
3
2
6
2
3
H, J=7.3 Hz, CH ), 1.33±1.49 (m, 2H, CH ), 2.38±
.53 (m, 2H, NCH ), 2.72 (d, 2H, J=8.1 Hz, H ), 3.03±
8.3 Hz, H ), 6.60 (d, 1H, J=8.3 Hz, H ), 6.67 (d, 1H,
6 7
3
2
J=2.2 Hz, H ); MS (IC/NH ) m/z 250 (M+1). Anal.
4
2
4
3
.15 (m, 1H, H ), 3.70 (s, 3H, OCH ), 3.74 (t, 1H,
3
(C H NO ) C,H,N.
15 23 2
3
J=10.3 Hz, H ), 4.22 (dd, 1H, J=3.7, 10.3 Hz, H ), 6.32
2
2
(
H ), 6.90 (d, 1H, J=8.1 Hz, H ). Anal. (C H NO )
C,H,N.
d, 1H, J=2.2 Hz, H ), 6.40 (dd, 1H, J=2.2, 8.1 Hz,
6-Hydroxy-2,3-dihydro-2-(di-n-propylaminomethyl)-2H-
1-benzofuran 7c. This compound (82.5 mg) was synthe-
sized in 66% yield from 6c (132 mg) according to
the general procedure (Method B). In this case, 16 mg
(13%) of benzopyran 10c was also obtained; yellow
8
6
5
16 25
2
8
-Methoxy-3,4-dihydro-3-(di-n-propylamino)-2H-1-benzo-
pyran 6d. The title compound (2.30 g) was obtained in
8% yield from 5d (2.0 g, 11.16 mmol) in DMF (20 mL)
according to the general procedure; colorless oil; IR
�
1
1
oil; IR (neat) n 3575±3150, 1142 cm
;
H NMR
7
(CDCl +D O) d 0.87 (t, 6H, J=7.3 Hz, CH ), 1.40±
3
2
3
1.55 (m, 4H, CH ), 2.48 (t, 4H, J=7.3 Hz, NCH ),
2.59 (dd, 1H, J=5.5, 13.4 Hz, CH N), 2.79 (dd, 1H,
2
2
�
1 1
(
neat) n 1213, 1263 cm ; H NMR (CDCl ) d 0.83 (t,
3
2
6
2
3
3
H, J=7.3 Hz, CH ), 1.35±1.47 (m, 4H, CH ), 2.44±
.50 (m, 4H, NCH ), 2.80 (d, 2H, J=9.1 Hz, H ), 3.09±
J=6.6, 13.4 Hz, CH N), 2.85 (dd, 1H, J=7.0, 15.3 Hz,
2
3
2
H ), 3.16 (dd, 1H, J=8.8, 15.3 Hz, H ), 4.83±4.94 (m,
3
2
4
3
.19 (m, 1H, H ), 3.80 (t, 1H, J=9.8 Hz, H ), 3.81 (s,
3
1H, H ), 6.24±6.32 (m, 2H, H and H ), 6.95 (d, 1H,
2 5 7
2
H, OCH ), 4.38 (dd, 1H, J=3.0, 9.8 Hz, H ), 6.62±6.78
3
J=8.1 Hz, H ); MS (IC/NH ) m/z 250 (M+1). Anal.
4
2
3
(
m, 3H, H , H , H ). Anal. (C H NO ) C, H, N.
5
(C H NO ) C, H,N.
15 23
6
7
16 25
2
2
Hydroxy-2,3-dihydro-2-(di-n-propylaminomethyl)-2H-1-
benzofurans 7. General procedure. Method A. To a stir-
red solution of benzopyrans 6 (0.5 mmol) in dichloro-
methane (5 ml) was added dropwise boron tribromide
7-Hydroxy-2,3-dihydro-2-(di-n-propylaminomethyl)-2H-
1-benzofuran 7d. The title compound (96 mg) was pre-
pared in 77% yield from 6d (132 mg) according to the
general procedure (Method A); yellow oil; IR (neat) n
�
1 1
(
0.05 ml, 0.55 mmol) in dichloromethane (2 mL) at room
3670±3120 cm ; H NMR (CDCl +D O) d 0.87 (t, 6H,
3
2
temperature under inert atmosphere. The reaction mix-
ture was heated with stirring at re¯ux for 2 h, then was
cooled to room temperature. The mixture was neu-
tralized with saturated aqueous solution of sodium
hydrogenocarbonate, and the product was extracted
with dichloromethane. The combined organic phases
J=7.3 Hz, CH ), 1.40±1.54 (m, 4H, CH ), 2.50 (t, 4H,
J=7.3 Hz, NCH ), 2.60 (dd, 1H, J=5.1, 13.2 Hz,
3 2
2
CH N), 2.82 (dd, 1H, J=7.3, 13.2 Hz, CH N), 2.98 (dd,
2
2
1H, J=7.3, 15.4 Hz, H ), 3.28 (dd, 1H, J=8.8, 15.4 Hz,
3
H ), 4.87±5.00 (m, 1H, H ), 6.72 (s, 3H, H , H , and
3
2
4
5
H ); MS (IC/NH ) m/z 250 (M+1). Anal. (C H NO )
6
3
15 23
2
were dried (MgSO ), ®ltered, and concentrated. The
4
C,H,N.
resulting crude product was puri®ed by chromato-
graphy on a silica gel column (eluent: dichloromethane,
then dichloromethane/methanol, 9/1). Method B. The
benzopyran derivatives 6 were treated by boron tri-
bromide (2.1 equiv) for 24 h according to the Method A
described above.
8-[4-[N-Propyl-N-(8-methoxy-3,4-dihydro-2H-1-benzo-
pyran-3-yl)amino]butyl]-8-azaspiro[4,5]decane-7,9-dione 8.
A mixture of aminobenzopyran 5d (1.20 g, 6.70 mmol),
1
4
8 - (4 - bromobutyl) - 8 - azaspiro[4,5]decane - 7,9 - dione
(2.04 g, 6.70 mmol), triethylamine (2.8 mL, 20.2 mmol),
and potassium iodide (333 mg, 2.01 mmol) in 30 mL of
ꢀ
4
1
-Hydroxy-2,3-dihydro-2(di-n-propylaminomethyl)-2H-
-benzofuran 7a. The title compound (84 mg) was pre-
DMF was warmed with stirring at 60 C for 24 h under
inert atmosphere. The reaction mixture was cooled to
room temperature, and the solvent was removed under
reduced pressure. After aqueous hydrolysis, the product
was extracted from the resulting crude with ethyl acetate.
pared in 67% yield from 6a (132 mg) according to the
general procedure (Method B). In this case, 27.5 mg
(
22%) of benzopyran 10a was also obtained; yellow oil;
1 1
�
IR (neat) n 3660±3000, 1220 cm ; H NMR (CDCl ) d
0
The solvent was dried (MgSO ) and evaporated to dry-
4
3
.88 (t, 6H, J=7.3 Hz, CH ), 1.41±1.55 (m, 4H, CH ),
ness under reduced pressure. The crude material was
chromatographed on silica gel using ethyl acetate as elu-
ent to give 1.75 g (65%) of pure desired compound as a
3
2
2.52 (t, 4H, J=7.3 Hz, NCH2 CH ), 2.65 (dd, 1H,
J=5.6, 13.5 Hz, NCH ), 2.84 (dd, 1H, J=6.8, 15.3 Hz,
2
2
�
1 1
NCH ), 2.90 (dd, 1H, J=7.2, 15.3 Hz, H ), 3.21 (dd,
2
yellow oil; IR (neat) n 3320, 1723, 1663 cm ; H NMR
(CDCl +D O) d 1.42±1.74 (m, 12H, CH ), 2.58 (s, 4H,
3
1H, J=9.1, 15.3 Hz, H ), 4.33 (br s, 1H, OH), 4.87±4.98
3
3
2
2
(
H ), 6.95 (t, 1H, J=8.0 Hz, H ); MS (IC/NH ) m/z 250
m, 1H, H ), 6.29 and 6.36 (2d, 2H, J=8.0 Hz, H and
COCH ), 2.65 (dd, 1H, J=7.3, 15.9 Hz, H ), 2.70±2.81
(m, 2H, NCH ), 3.01 (dd, 1H, J=5.2, 15.9 Hz, H ), 3.07±
2 4
2
5
2
4
7
6
3
(
M+1). Anal. (C H NO ) C,H,N.
1
3.16 (m, 1H, H ), 3.77 (t, 2H, J=7.1 Hz, CONCH ), 3.86
3 2
5
22
2
(
(ddd, 1H, J=2.1, 10.6 Hz, H ), 6.68 and 6.71 (2d, 2H,
s, 3H, OCH ), 3.96 (dd, 1H, J=7.1, 10.6 Hz, H ), 4.27
3 2
5
1
-Hydroxy-2,3-dihydro-2(di-n-propylaminomethyl)-2H-
-benzofuran 7b. This compound (120 mg) was prepared
2
J=7.6 Hz, H and H ), 6.81 (t, 1H, J=7.6 Hz, H ).
7
5
6

3
40
S. Boye et al. / Bioorg. Med. Chem. 7 (1999) 335±341
A mixture of the compound described above (656 mg,
.64 mol), 1-iodopropane (0.30 mL, 2.46 mmol), and
potassium carbonate (680 mg, 4.91 mmol) was heated
The concentration of the radioligands used in competi-
tion studies were approximately equal to the KD of the
binding system. The anity of the ligands tested to
these receptors was expressed as IC50 (concentration
inhibiting 50% of the speci®c binding) and calculated
using LUNDON 2 software. The results obtained are
reported in Table 1.
1
ꢀ
with stirring at 60 C in DMF (8 mL) for 30 h under
inert atmosphere. The reaction mixture was cooled to
room temperature, and the solvent was removed under
reduced pressure to yield a yellow oil. The crude was
diluted by the addition of water, and the product was
extracted with ethyl acetate. The combined organic frac-
Acknowledgements
tions were dried (MgSO ) and evaporated to dryness
4
The authors thank Mrs M. M. Le Floch and M. Obert
for typing the manuscript.
under reduced pressure. The resulting crude material was
puri®ed by silica gel column chromatography (eluent:
petroleum ether/ethyl acetate, 6/4) to give 640 mg (88%)
�
1 1
of 8 as yellow oil: IR (neat) v 1725, 1673 cm ; H NMR
(
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�
1 1
3
0
2
2
690±3105, 1724, 1679 cm ; H NMR (CDCl +D O) d
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.87 (t, 3H, J=7.4 Hz, CH ), 1.37±1.76 (m, 14H, CH ),
.40±2.64 (m, 5H, CH and CHN), 2.58 (s, 4H, COCH ),
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3
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2
2
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6
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(
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26
3
27
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3
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2
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3
3
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2
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3
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