5-Substituted 3,4-dihydro-3-amino-2H-1-benzopyran derivatives: Synthesis and interaction with serotoninergic receptors

Article abstract of DOI:10.1211/0022357011776388

A new series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives (1 and 2) bearing various substituents on the 5-position was successfully prepared via palladium-mediated cross-coupling reactions. Some of the new compounds showed high affinity for 5-HT

Full text of DOI:10.1211/0022357011776388

Journal of
Pharmacy and Pharmacology
JPP 2001, 53: 959–968
# 2001 The Authors
Received December 19, 2000
Accepted April 4, 2001
ISSN 0022-3573
5-Substituted 3,4-dihydro-3-amino-2H-1-benzopyran
derivatives: synthesis and interaction with
serotoninergic receptors
R. Rezaie, B. Joseph, J. B. Bremner, P. Delagrange, C. Kopp, R. Misslin,
B. Pfeiffer, P. Renard and G. Guillaumet
Abstract
A new series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives (1 and 2) bearing various
substituents on the 5-position was successfully prepared via palladium-mediated cross-coupling
reactions. Some of the new compounds showed high affinity for 5-HT1A and 5-HT7 receptors.
The best affinity for the 5-HT1A and 5-HT7 receptors was obtained for 2b (Ki l 0.3 nM for 5-HT1A
and 3.1 nM for 5-HT7). The anxiolytic activity of compound 2b was evaluated.
Institut de Chimie Organique et
Analytique, UMR-CNRS 6005,
Universite d’Orleans, BP 6759,
45067 Orleans Cedex 2, France
Introduction
The dysfunction in serotoninergic systems of the brain has been found to be a most
probable cause of illnesses such as anxiety and depression (Barrett & Vanover 1993;
Blier & de Montigny 1994; Hamon 1994). Physiological actions of serotonin
(5-HT) are transduced through receptors located on both pre- and postsynaptic
neuronal membranes. Presently, seven receptors divided into different subtypes
have been classified (5-HT1A-F, 5-HT2A-C, 5-HT3, 5-HT4, 5-HT5A-B, 5-HT6 and
5-HT7) (Gerhardt & van Heerikhuizen 1997). The 5-HT7 receptors, positively
coupled to adenylate cyclase, were recently discovered by molecular cloning (Bard
et al 1993; Lovenberg et al 1993). Many psychotherapeutic drugs of diverse classes
appear to have high affinity for 5-HT7 receptors. Thus, high 5-HT7-receptor affinity
is observed for 5-HT, 5-carboxyamidotryptamine (5-CT), 5-methoxytryptamine
(5-MeOT) and methiothepin, moderate affinity for 8-hydroxy-di-n-propylamino-
tetralin (8-OH-DPAT), clozapine and ritanserin, and low affinity for pindolol,
sumatriptan and buspirone (Roth et al 1994). Recently, three selective 5-HT7
antagonists SB-258719, SB-269970 and DR-4004 have been reported (Figure 1).
The compound SB-258719 has been described as the first 5-HT7 receptor antagonist
with 100-fold selectivity over other 5-HT, α1b-adrenergic and D2,D3 dopaminergic
receptors (Forbes et al 1998). Compared with SB-258719, the compound SB-
269970 shows a high affinity for 5-HT7 (pKi l 8.9) with an improved selectivity
over 13 other receptors (Lovell et al 2000). The compound DR-4004 acts as a potent
5-HT7 antagonist (pKi l 8.7) with selectivity over 5-HT2 receptors (Kikuchi et al
1999).
R. Rezaie, B. Joseph,
G. Guillaumet
Department of Chemistry,
University of Wollongong,
Northfields Avenue,
Wollongong, NSW 2522,
Australia
J. B. Bremner
IRI Servier, 6, Place des Pleiades,
92415 Courbevoie Cedex, France
P. Delagrange
Laboratoire de
Psychophysiologie, associe au
CNRS, Universite Louis Pasteur,
7 rue de l’Universite, 67000
Strasbourg, France
C. Kopp, R. Misslin
ADIR, 1, rue Carle Hebert, 92415
Courbevoie Cedex, France
B. Pfeiffer, P. Renard
Correspondence: G. Guillaumet,
Institut de Chimie Organique et
Analytique, UMR-CNRS 6005,
Universite d’Orleans, BP 6759,
45067 Orleans Cedex 2, France.
The biological function of 5-HT7 receptors is poorly understood. Nevertheless,
receptor localisation studies, combined with some preliminary pharmacological
results, suggest that 5-HT7 receptors could be involved in the pathophysiology of
959

960
R. Rezaie et al
Figure 1 Structures of 5-HT7 receptor antagonists (Forbes et al 1998; Kikuchi et al 1999; Lovell et al 2000).
(Rezaie et al 1998a). On this basis, we planned the
further design of potent and selective 5-HT7 ligands, in
particular by varying systematically the nature of the
substituent at the 5-position of the 2H-1-benzopyran
ring to cover further hydrophobic, aromatic ring and H-
bond acceptor capacities.
This paper reports the synthesis and the preliminary
pharmacological evaluation of a series of 3,4-dihydro-3-
amino-2H-1-benzopyran derivatives of formulae 1
(Rezaie et al 1998b) and 2 (Figure 4) bearing N-substitu-
ents already known for their high affinities for 5-HT1A
(Podona et al 1994). The substituents on the 5-position
were introduced via well-documented palladium-medi-
Figure 2 Structures of derivatives I (Besson et al 1993; Podona et al
1994; Comoy et al 1996).
sleep disorders, depression and schizophrenia (Eglen et ated cross-coupling reactions (Carrera & Sheppard
al 1997). Therefore, the discovery of agonists and an- 1994; Stille 1986). This chemical strategy has been
tagonists of 5-HT7 receptors may have clinical utility. reported previously for the preparation of 8-substituted
A range of N-disubstituted (5-methoxy-3,4-dihydro- 2-(dipropylamino)tetralin (Liu et al 1993).
2H-1-benzopyran-3-yl)amino derivatives (I; Figure 2),
prepared in our laboratory, exhibited high affinity for 5-
HT1A receptors (Besson et al 1993; Podona et al 1994;
Materials and Methods
Comoy et al 1996). Moreover, screening of derivatives I
against the cloned human 5-HT7 receptor showed, for
Chemistry
some of them such as 5-methoxy-3,4-dihydro-3-di-n- Melting points were determined using a Buchi SMP-20
propylamino-2H-1-benzopyran (5-MeO-DPAC) and melting point apparatus and are uncorrected. The IR
S20244 (Figure 3), significant affinity for this receptor spectra were recorded on a Perkin Elmer FTIR paragon
Figure 3 Structures of 5-MeO-DPAC and S20244.

961
Synthesis of 5-HT1 and 5-HT7 receptor antagonists
Figure 4 Structures of 5-substituted 3,4-dihydro-3-amino-2H-1-benzopyran derivatives 1 and 2.
1000 spectrophotometer. Proton and carbon NMR were NH), 6.05 (br s, 1H, OH), 6.43 (t, J l 8.3, 2H, HAr), 6.97
recorded at 300mK in CDCl3 or DMSO-d6 on a Bruker (t, J l 8.3, 1H, HAr); 13C-NMR (CDCl3): δ 26.0 (CH2),
Avance DPX 250 spectrometer (250.13 MHz for H 28.4 (3 CH3), 43.0 (CH), 68.0 (CH2), 80.0 (C), 107.4 (2
1
and 62.90 MHz for 13C). Coupling constants are in Hz CH), 108.9 (CH), 127.4 (CH), 155.0 (2 C), 155.6 (CꢀO);
+
and chemical shifts are expressed in parts per million MS: m\z 266 (Mj1) ; Calculated for C14H19NO4 : C,
and are referenced to tetramethylsilane. MS spectra 63.38; H, 7.22; C, 5.28; found: C, 63.56; H, 7.07, N,
were recorded on a Perkin-Elmer SCIEX API 300 5.33.
instrument using ionspray methodology. Analytical
TLC was run on pre-coated silica-gel plates (Merck 5-(Trifluoromethylsulfonyloxy)-3,4-dihydro-3-(tert-
60F254) and spots visualised with UV light. Flash chro- butoxycarbonylamino)-2H-1-benzopyran (5)
matography was carried out on column using silica gel To a stirred solution of compound 4 (2.2 g, 8.3 mmol) in
60 Merck (40–63 µm) as the stationary phase. Organic dichloromethane (50 mL) under argon at k30mC was
solvents were purified as necessary as described by added pyridine (1.4 mL, 17.3 mmol) followed by tri-
Armarego & Perrin (1996) or purchased from Sigma- fluoromethanesulfonic anhydride (1.8 mL, 10.7 mmol).
Aldrich or Acros. All reactions requiring anhydrous The solution was stirred at k20mC for 2 h and then
conditions were conducted in flame-dried apparatus.
allowed to reach room temperature. The organic sol-
ution was then washed with saturated aqueous sodium
bicarbonate solution (30 mL) and water (20 mL), dried
over magnesium sulphate and evaporated in-vacuo. The
5-Hydroxy-3,4-dihydro-3-(tert-butoxycarbonylamino)-
2H-1-benzopyran (4)
A solution of compound 3 (2.1 g, 12 mmol) in hydro- residue was purified by flash chromatography (petro-
bromic acid 48% in water (13 mL) and glacial acetic leum ether–ethyl acetate, 94:6) to give 5 as crystals
acid (20 mL) was heated at 138mC for 6 h. The solution (3.0 g,93%yield);mp82–84mC(ethylacetate–petroleum
1
was evaporated to give quantitatively the demethylated ether); IR (KBr): ν 3374, 1682 cm ; 1H-NMR
−
hydrobromide salt as crystals. To a suspension of the (CDCl3): δ 1.43 (s, 9H, C(CH3)3), 2.84 (dd, J l 4.1, 18.4,
latter compound (1.9 g, 7.7 mmol) in tetrahydrofuran 1H, CH2Ar), 3.07 (dd, J l 5.3, 18.4, 1H, CH2Ar), 4.13–
(20 mL) were added aqueous 1  sodium hydroxide 4.26 (m, 3H, CHN, CH2O), 4.85 (br d, J l 7.6, 1H,
solution (18 mL) and di-tert-butyldicarbonate (2.1 g, NH), 6.89 (d, J l 8.5, 2H, HAr), 7.19 (t, J l 8.5, 1H,
9.6 mmol). The solution was stirred overnight. The two HAr); 13C-NMR (CDCl3): δ 26.5 (CH2), 28.3 (3 CH3),
phases were separated and the aqueous phase was 42.3 (CH), 68.3 (CH2), 80.1 (C), 113.6 (CH), 113.9 (CH),
acidified with aqueous 1  hydrochloric acid solution 117.0 (C), 118.6 (q, J l 320.2 Hz, CF3), 128.1 (CH),
and then extracted with dichloromethane (3i20 mL). 148.6 (C), 155.0 (C), 155.4 (CꢀO); MS m\z 398
+
The combined organic phases were dried over mag- (Mj1) ; Calculated for C15H18F3NO6S : C, 45.34; H,
nesium sulphate and evaporated in-vacuo. The crude 4.57; C, 3.52; found: C, 44.99; H, 4.38; N, 3.65.
residue was purified by flash chromatography (petro-
leum ether–ethyl acetate, 8:2) to give 4 as crystals (2.0 g, 5-Ethyl-3,4-dihydro-3-(tert-butoxycarbonylamino)-2H-
98% yield); mp 158–160mC (ethyl acetate–petroleum 1-benzopyran (6a)
1
ether); IR (KBr): ν 3374, 1682 cm ; 1H-NMR To a mixture of 5 (2.5 g, 6.3 mmol), lithium chloride
−
(CDCl3): δ 1.45 (s, 9H, C(CH3)3), 2.69 (br d, J l 16.3, (667 mg, 15.7 mmol) and bis(triphenylphosphine)pal-
1H, CH2Ar), 2.89 (dd, J l 5.6, 16.3, 1H, CH2Ar), 4.02– ladium chloride (221 mg, 0.31 mmol) in dry N,N-
4.20 (m, 3H, CHN, CH2O), 4.97 (br d, J l 7.6, 1H, dimethylformamide (30 mL) under argon was added tri-

962
R. Rezaie et al
butyl(vinyl)tin (2.2 mL, 7.6 mmol). The stirred solution (CH2), 43.2 (CH), 68.0 (CH2), 79.7 (C), 119.8 (CH),
was heated at 90mC for 5 h. The solvent was then 121.0 (CH), 122.8 (CH), 127.1 (CH), 138.5 (C), 154.7
+
removed in-vacuo and the remaining residue was puri- (C), 155.1(CꢀO), 200.9(CꢀO);MS:m\z292(Mj1) ;
fied by flash chromatography (petroleum ether–ethyl Calculated for C16H21NO4 : C, 65.96; H, 7.27; C, 4.81;
acetate 9:1) to give the vinyl derivative (1.31 g, 75% found: C, 66.23; H, 7.33; N, 4.96.
yield) used in the next step without further character-
isation. A mixture of vinyl compound (532 mg, 5-Phenyl-3,4-dihydro-3-(tert-butoxycarbonylamino)-
1.9 mmol) and palladium on charcoal 10% (50 mg) in 2H-1-benzopyran (6c)
ethanol (20 mL) was shaken in a Parr apparatus under To a stirred solution of 5 (1.5 g, 3.8 mmol) in toluene
50 psig of hydrogen at room temperature for 6 h. The (30 mL) under argon was added freshly prepared tetra-
catalyst was filtered through celite and the solvent was kis(triphenylphosphine)palladium (219 mg, 0.2 mmol).
removed in-vacuo. The crude residue was purified by The mixture was allowed to stir for 30 min at room
flash chromatography (petroleum ether–ethyl acetate, temperature. Phenylboronic acid (695 mg, 5.7 mmol) in
9:1) to give 6a as crystals (365 mg, 65 % overall yield); ethanol (15 mL) was then added, followed immediately
mp 98–99mC (ethyl acetate–petroleum ether); IR (KBr): by saturated aqueous sodium bicarbonate solution
1
1
−
ν 3439, 1705 cm ; H-NMR (CDCl3): δ 1.19 (t, J l (15 mL). The heterogeneous solution was thereafter
7.5, 3H, CH3), 1.44 (s, 9H, C(CH3)3), 2.54 (q, J l 7.5, refluxed for 5 h. Brine solution was then added, the two
2H, CH2), 2.72 (br d, J l 16.6, 1H, CH2Ar), 2.96 (dd, layers were separated and the aqueous phase was
J l 5.6, 16.6, 1H, CH2Ar), 3.66–3.73 (m, 1H, CHN), extracted with dichloromethane (3i30 mL). The
4.08–4.22 (m, 2H, CH2O), 4.96 (br d, J l 7.0, 1H, NH), combined organic extracts were dried over magnesium
6.72 (d, J l 7.9, 1H, HAr), 6.80 (d, J l 7.9, 1H, HAr), sulphate and evaporated in-vacuo. The crude residue
7.09 (t, J l 7.9, 1H, HAr); 13C-NMR (CDCl3): δ 14.1 was purified by flash chromatography (petroleum ether–
(CH3), 25.3 (CH2), 28.4 (3 CH3), 28.5 (CH2), 43.4 (CH), ethyl acetate, 95:5 then 80:20) to afford 6c as crystals
67.9 (CH2), 79.6 (C), 114.5 (CH), 117.7 (C), 120.7 (CH), (990 mg, 80% yield); mp 116–118mC (ethyl acetate–
1
1
−
127.3 (CH), 144.2 (C), 154.0 (C), 155.3 (CꢀO); MS: petroleum ether); IR (KBr): ν 3439, 1706 cm ; H-
+
m\z 278 (Mj1) ; Calculated for C16H23NO3 : C, 69.29; NMR (CDCl3): δ 1.40 (s, 9H, C(CH3)3), 2.54 (dd, J l
H, 8.36; C, 5.05; found: C, 68.95; H, 8.54; N, 4.93.
4.3, 16.7, 1H, CH2Ar), 2.96 (br d, J l 16.7, 1H, CH2Ar),
4.11–4.18 (m, 3H, CH2O, CHN), 4.77 (br s, 1H, NH),
6.84–6.89 (m, 2H, HAr), 7.19 (t, J l 7.8, 1H, HAr),
7.26–7.44 (m, 5H, HAr); 13C-NMR (CDCl3): δ 28.3 (3
5-Acetyl-3,4-dihydro-3-(tert-butoxycarbonylamino)-
2H-1-benzopyran (6b)
To a mixture of 5 (1.3 g, 3.3 mmol), lithium chloride CH3), 30.4 (CH2), 43.3 (CH), 68.1 (CH2), 79.7 (C), 115.9
(350 mg, 8.3 mmol) and bis(triphenylphosphine)pal- (CH), 117.2 (C), 122.6 (CH), 127.2 (CH), 127.3 (CH),
ladium chloride (116 mg, 0.16 mmol) in dry N,N- 128.3 (2 CH), 129.0 (2 CH), 140.5 (C), 143.7 (C), 154.0
+
dimethylformamide (20 mL) under argon was added (C), 155.1 (CꢀO); MS: m\z 326 (Mj1) ; Calculated
tributyl(1-ethoxyvinyl)tin (1.34 mL, 4.0 mmol). The for C20H23NO3 : C, 73.82; H, 7.12; C, 4.30; found: C,
stirred solution was heated at 90mC for 3.5 h. The solvent 74.11; H, 7.02; N, 4.47.
was then removed in-vacuo and the crude residue was
purified by flash chromatography (petroleum ether– General method for the preparation of 5-substituted-
ethyl acetate, 9:1 then 75:25) to give a pale yellow oil. 3,4-dihydro-3-amino-2H-1-benzopyrans (7a–c)
The oil was then treated with aqueous 1  hydrochloric To a stirred solution of 6 (4.62 mmol) in dichloro-
acid solution at room temperature for 1 h. Solid pot- methane (5 mL) was added trifluoroacetic acid (4 mL);
assium carbonate was added to adjust the pH to 9. The stirring continued for 1 h. The solvent was evaporated
basic solution was extracted with ethyl acetate (2i and the crude residue was extracted with dichloro-
15 mL). The organic phase was dried over magnesium methane (2i20 mL). The organic extract was washed
sulphate and evaporated in-vacuo to give 6b as an oil with saturated aqueous sodium bicarbonate solution
1
−
(758 mg, 79% yield); IR (film): ν 3441, 1702, 1688 cm ; (2i10 mL). The combined aqueous layers were ex-
1H-NMR (CDCl3): δ 1.43 (s, 9H, C(CH3)3), 2.56 (s, 3H, tracted with dichloromethane (30 mL). The combined
CH3), 2.96 (dd, J l 5.1, 17.6, 1H, CH2Ar), 3.31 (dd, J l organic extracts were dried over magnesium sulphate
5.6, 17.6, 1H, CH2Ar), 4.01–4.16 (m, 3H, CH2O, CHN), and evaporated to give 7 as an oil.
4.75 (br s, 1H, NH), 7.01 (dd, J l 1.2, 7.7, 1H, HAr), 7.20
(t, J l 7.7, 1H, HAr), 7.36 (dd, J l 1.2, 7.7, 1H, HAr); 5-Ethyl-3,4-dihydro-3-amino-2H-1-benzopyran (7a). Oil
1
1
13C-NMR (CDCl3): δ 28.3 (3 CH3), 29.5 (CH3), 30.6 (90% yield); IR (film): ν 3426, 3361 cm ; H-NMR
−

963
Synthesis of 5-HT1 and 5-HT7 receptor antagonists
(CDCl3): δ 1.21 (t, J l 7.6, 3H, CH3), 1.40 (br s, 2H, addition of water, the product was extracted with di-
NH2), 2.47 (dd, J l 8.0, 16.3, 1H, CH2Ar), 2.57 (q, J l chloromethane (30 mL). The organic layer was washed
7.6, 2H, CH2), 3.01 (dd, J l 4.7, 16.3, 1H, CH2Ar), with water (2i10 mL), dried over magnesium sulphate,
3.33–3.39 (m, 1H, CHN), 3.76 (ddd, J l 0.7, 7.4, 10.4, then evaporated in-vacuo. The crude oil was purified by
1H, CH2O), 4.12 (ddd, J l 1.6, 3.0, 10.4, 1H, CH2O), column chromatography (ethyl acetate–MeOH, 95:5
6.71 (d, J l 8.1, 1H, HAr), 6.79 (d, J l 8.1, 1H, HAr), for 8a and 8b; petroleum ether–ethyl acetate, 94:6 then
7.07 (t, J l 8.1, 1H, HAr); 13C-NMR (CDCl3): δ 14.2 ethyl acetate for 8c) to give 8.
(CH3), 25.4 (CH2), 32.0 (CH2), 44.4 (CH), 71.0 (CH2),
114.3 (CH), 118.5 (C), 120.3 (CH), 127.1 (CH), 143.8
8-[N-(5-Ethyl-3,4-dihydro-2H-1-benzopyran-3-yl)-
aminobutyl]-8-azaspiro[4.5]decane-7,9-dione (8a). Oil
+
(C), 154.0 (C); MS: m\z 178 (Mj1) ; Calculated for
C11H15NO: C, 74.54; H, 8.53; C, 7.90; found: C, 74.33;
H, 8.50; N, 8.05.
1
1
−
(70% yield); IR (film): ν 3376, 1724, 1667 cm ; H-
NMR (CDCl3): δ 1.20 (t, J l 7.3, 3H, CH3), 1.46–1.74
(m, 13H, NH, CH2), 2.48–2.61 (m, 6H, CH2CH3,
5-Acetyl-3,4-dihydro-3-amino-2H-1-benzopyran(7b).Oil CH2CO), 2.65–2.80 (m, 3H, CH2Ar, CH2N), 2.94 (dd,
1
1
−
(97% yield); IR (film): ν 3426, 1681 cm ; H-NMR J l 5.2, 15.6, 1H, CH2Ar), 3.07–3.17 (m, 1H, CHN),
(CDCl3): δ 1.46 (br s, 2H, NH2), 2.56 (s, 3H, CH3), 2.82 3.73–3.85 (m, 3H, CH2NCO, CH2O), 4.15–4.22 (m, 1H,
(dd, J l 8.8, 18.6, 1H, CH2Ar), 3.25–3.34 (m, 2H, CH2O), 6.69 (d, J l 7.8, 1H, HAr), 6.77 (d, J l 7.8, 1H,
CH2Ar, CHN), 3.79–3.86 (m, 1H, CH2O), 4.11–4.17 (m, HAr), 7.05 (t, J l 7.8, 1H, HAr);13C-NMR (CDCl3): δ
1H, CH2O), 7.00 (dd, J l 1.3, 8.1, 1H, HAr), 7.18 (t, J l 14.1 (CH3), 24.2 (2 CH2), 25.4 (CH2), 25.7 (CH2), 27.8
8.1, 1H, HAr), 7.34 (dd, J l 1.3, 8.1, 1H, HAr); 13C-NMR (CH2), 29.5 (CH2), 37.6 (2 CH2), 39.3 (CH2), 39.5 (C),
(CDCl3): δ 29.6 (CH3), 33.8 (CH2), 43.8 (CH), 70.8 44.9 (2 CH2), 46.7 (CH2), 50.4 (CH2), 68.4 (CH2), 114.2
(CH2), 120.6 (CH, C), 122.5 (CH), 126.8 (CH), 138.4 (CH), 118.7 (C), 120.2 (CH), 126.9 (CH), 143.7 (C),
+
+
(C), 154.7 (C), 201.2 (CꢀO); MS: m\z 192 (Mj1) ; 154.4 (C), 172.2 (2 CꢀO); MS: m\z 399 (Mj1) ;
Calculated for C11H13NO2 : C, 69.09; H, 6.85; C, 7.32; Calculated for C24H34N2O3 : C, 72.33; H, 8.60; C, 7.03 ;
found: C, 68.78; H, 6.97; N, 7.15.
found: C, 72.54; H, 8.52; N, 6.88.
5-Phenyl-3,4-dihydro-3-amino-2H-1-benzopyran (7c). 8-[N-(5-Acetyl-3,4-dihydro-2H-1-benzopyran-3-yl)-
1
Oil (99% yield); IR (film): ν 3367, 3289 cm ; H- aminobutyl]-8-azaspiro[4.5]decane-7,9-dione (8b).
1
−
NMR (CDCl3): δ 1.43 (br s, 2H, NH2), 2.44 (dd, J l 6.0, Solid (60% yield); mp 82mC (ethyl acetate–petroleum
1
1
−
16.5, 1H, CH2Ar), 2.86 (br d, J l 16.5, 1H, CH2Ar), ether); IR (KBr): ν 3376, 1724, 1669 cm ; H-NMR
3.23–3.35 (m, 1H, CHN), 3.82 (dd, J l 7.2, 10.1, 1H, (CDCl3): δ 1.46–1.74 (m, 13H, NH, CH2), 2.56 (s, 3H,
CH2O), 4.16 (br d, J l 10.1, 1H, CH2O), 6.81–6.86 (m, COCH3), 2.57 (s, 4H, CH2CO), 2.72 (t, J l 7.0, 2H,
2H, HAr), 7.16 (t, J l 7.8, 1H, HAr), 7.26–7.43 (m, 5H, CH2N), 2.82 (dd, J l 7.3, 17.3, 1H, CH2Ar), 3.00–3.10
HAr); 13C-NMR (CDCl3): δ 30.9 (CH2), 44.1 (CH), 71.2 (m, 1H, CHN), 3.27 (dd, J l 4.8, 17.3, 1H, CH2Ar), 3.76
(CH2), 115.6 (CH), 118.0 (C), 122.2 (CH), 125.9 (C), (t, J l 7.3, 2H, CH2NCO), 3.88 (dd, J l 7.3, 10.6, 1H,
127.1 (CH), 128.1 (2 CH), 129.1 (2 CH), 140.8 (C), 143.5 CH2O), 4.20 (br d, J l 10.6, 1H, CH2O), 6.98 (d, J l
+
(C), 154.0 (C); MS: m\z 226 (Mj1) ; Calculated for 7.8, 1H, HAr), 7.18 (t, J l 7.8, 1H, HAr), 7.34 (d, J l 7.8,
C15H15NO: C, 79.97; H, 6.71; C, 6.22; found: C, 80.24; 1H, HAr). 13C-NMR (CDCl3): δ 24.2 (2 CH2), 25.7
H, 6.88; N, 6.09.
(CH2), 27.7 (CH2), 29.7 (CH2), 31.2 (CH2), 37.6 (2 CH2),
39.3 (CH2), 39.5 (C), 44.9 (2 CH2), 46.8 (CH2), 49.9
(CH), 68.6 (CH2), 120.7 (CH), 120.9 (C), 122.4 (CH),
126.8 (CH), 138.5 (C), 155.1 (C), 172.3 (2 CꢀO), 201.3
General method for the preparation of 8-[N-(5-
substituted-3,4-dihydro-2H-1-benzopyran-3-
yl)aminobutyl]-8-azaspiro[4.5]decane-7,9-diones
(8a–c)
+
(CꢀO); MS: m\z 413 (Mj1) ; Calculated for
C24H32N2O4 : C, 69.88; H, 7.82; C, 6.79; found: C,
69.67; H, 8.01; N, 6.85.
To a stirred solution of 7 (6.8 mmol) in dry aceto-
nitrile (30 mL) under argon was added a solution of
8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione 8-[N-(5-Phenyl-3,4-dihydro-2H-1-benzopyran-3-yl)-
(10 mmol) in dry acetonitrile (10 mL) and then pot- aminobutyl]-8-azaspiro[4.5]decane-7,9-dione (8c). Oil
1
1
−
assium carbonate (20 mmol) and a catalytic amount of (57% yield); IR (film): ν 3376, 1723, 1673 cm ; H-
sodium iodide. The mixture was stirred at 90mC over- NMR (CDCl3): δ 1.40–1.71 (m, 13H, NH, CH2), 2.47–
night, and the solvent was removed in-vacuo. After 2.67 (m, 7H, CH2CO, CH2N, CH2Ar), 2.77 (dd, J l 6.3,

964
R. Rezaie et al
17.2, 1H, CH2Ar), 2.99–3.02 (m, 1H, CHN), 3.64–3.89 CH3), 1.37–1.72 (m, 14 H, CH2), 2.43–2.57 (m, 11H,
(m, 3H, CH2NCO, CH2O), 4.20–4.27 (m, 1H, CH2O), CH2CO, CH2N, CH3), 2.99–3.10 (m, 3H, CH2Ar, CHN),
6.80–6.85 (m, 2H, HAr), 7.14 (t, J l 7.6, 1H, HAr), 3.72–3.85 (m, 3H, CH2NCO, CH2O), 4.21–4.27 (m, 1H,
7.27–7.46 (m, 5H, HAr);13C-NMR (CDCl3): δ 24.1 (2 CH2O), 6.93 (dd, J l 1.2, 7.9, 1H, HAr), 7.14 (t, J l 7.9,
CH2), 25.7 (CH2), 27.7 (CH2), 31.4 (CH2), 37.5 (2 CH2), 1H, HAr), 7.28 (dd, J l 1.2, 7.9, 1H, HAr);13C-NMR
39.2 (CH2), 39.5 (C), 44.9 (2 CH2), 46.8 (CH2), 50.4 (CDCl3): δ 11.7 (CH3), 21.8 (CH2), 24.1 (2 CH2), 25.7
(CH), 68.7 (CH2), 115.6 (CH), 118.3 (C), 122.1 (CH), (CH2), 26.1 (CH2), 26.8 (CH2), 29.7 (CH2), 37.5 (2 CH2),
127.0 (2 CH), 128.1 (2 CH), 129.0 (2 CH), 140.8 (C), 39.3 (CH2), 39.4 (C), 44.8 (2 CH2), 50.3 (CH2), 52.5
143.3 (C), 154.4 (C), 172.2 (2 CꢀO); MS: m\z 447 (CH), 53.0 (CH2), 67.7 (CH2), 120.4 (CH), 121.9 (C),
+
(Mj1) ; Calculated for C28H34N2O3 : C, 75.31; H, 7.67; 122.0 (CH), 126.5 (CH), 138.6 (C), 155.2 (C), 172.1 (2
+
C, 6.27; found: C, 75.60; H, 7.82; N, 6.11.
CꢀO), 201.3 (CꢀO); MS: m\z 455 (Mj1) ; Calcu-
lated for C27H38N2O4 : C, 71.34; H, 8.43; C, 6.16; found:
C, 71.15; H, 8.27; N, 6.23.
General method for the preparation of 8-[4-N-propyl-
N-(5-substituted-3,4-dihydro-2H-1-benzopyran-3-
yl)aminobutyl]-8-azaspiro[4.5]decane-7,9-diones
(2a–c)
8-[4-N-Propyl-N-(5-phenyl-3,4-dihydro-2H-1-benzo-
pyran-3-yl)aminobutyl]-8-azaspiro[4.5]decane-7,9-di-
1
−
one (2c). Oil (53% yield); IR (film): ν 1724, 1671 cm ;
To a stirred solution of 8 (2.7 mmol) in dry acetonitrile
(25 mL) under argon were added potassium carbonate
(2.7 mmol) and then iodopropane (5.1 mmol). The mix-
ture was stirred at 90mC for 20 h. The reaction was
diluted with water, then acetonitrile was evaporated and
the mixture was extracted with dichloromethane
(40 mL). The organic layer was washed with water
(2i15 mL), dried over magnesium sulphate and evapo-
rated in-vacuo. The crude residue was purified by
columnchromatography(petroleumether–ethylacetate,
1:1 then ethyl acetate) to afford 2 as an oil.
1H-NMR (CDCl3): δ 0.80 (t, J l 7.3, 3H, CH3),
1.26–1.73 (m, 14H, CH2), 2.37–2.75 (m, 10H, CH2N,
CH2CO, CH2Ar), 2.99–3.10 (m, 1H, CHN), 3.72 (t, J l
7.2, 2H, CH2NCO), 3.85 (t, J l 10.2, 1H, CH2O),
4.23–4.30 (m, 1H, CH2O), 6.79–6.87 (m, 2H, HAr), 7.14
(t, J l 7.8, 1H, HAr), 7.30–7.45 (m, 5H, HAr);13C-NMR
(CDCl3): δ 11.7 (CH3), 21.8 (CH2), 24.2 (2 CH2), 25.7
(CH2), 26.1 (CH2), 27.3 (CH2), 37.5 (2 CH2), 39.3 (CH2),
39.5 (C), 44.9 (2 CH2), 50.2 (CH2), 52.6 (CH), 53.5
(CH2), 67.7 (CH2), 115.6 (CH), 119.6 (C), 122.0 (CH),
126.9 (CH), 127.0 (CH), 128.1 (2 CH), 129.0 (2 CH),
141.0 (C), 143.4 (C), 154.5 (C), 172.2 (2 CꢀO); MS:
8-[4-N-Propyl-N-(5-ethyl-3,4-dihydro-2H-1-benzo-
pyran-3-yl)aminobutyl]-8-azaspiro[4.5] decane-7,9-di-
one (2a). Oil (49% yield); IR (film): ν 1725,
+
m\z 489 (Mj1) ; Calculated for C31H40N2O3 : C, 76.19;
H, 8.25; C, 5.73; found: C, 76.47; H, 8.33; N, 5.87.
1
1
−
1673 cm ; H-NMR (CDCl3) δ 0.91 (t, J l 7.4, 3H,
CH3), 1.25 (t, J l 7.6, 3H, CH3), 1.44–1.75 (m, 14H,
CH2), 2.51–2.71 (m, 11H, CH2CO, CH2N, CH2Ar,
CH3CH2), 2.90 (dd, J l 5.2, 15.6 Hz, 1H, CH2Ar), 3.10–
3.22 (m, 1H, CHN), 3.63–3.73 (m, 3H, CH2NCO,
CH2O), 4.27–4.31 (m, 1H, CH2O), 6.70 (d, J l 8.1, 1H,
HAr), 6.79 (d, J l 8.1, 1H, HAr), 7.07 (t, J l 8.1, 1H,
HAr);13C-NMR (CDCl3): δ 11.8 (CH3), 14.1 (CH3), 22.0
(CH2), 24.2 (2 CH2), 25.3 (CH2), 25.5 (CH2), 25.8 (CH2),
26.3 (CH2), 37.6 (2 CH2), 39.4 (CH2), 39.5 (C), 44.9 (2
CH2), 50.3 (CH), 52.6 (CH2), 53.5 (CH2), 67.2 (CH2),
114.2 (CH), 119.9 (C), 120.0 (CH), 126.8 (CH), 143.7
Pharmacology
5-HT A receptor binding
5-HT1A receptor binding was determined on bovine
"
frontal cortex and hippocampus membranes. Mem-
branes were incubated at 23mC for 40 min with 0.5 n
[3H]-8-OH-DPAT in 50 m Tris-HCl buffer, pH 7.4,
supplemented with 4 m CaCl2 and 10 µ pargyline.
Non-specific binding was determined in the presence of
10 µ buspirone. Competition experiments were ana-
lysed using the iterative non-linear least-square fitting
with GRAPHPAD software. Results were expressed as
Kips.e.m. and Ki were determined using the method of
Cheng & Prusoff (1973).
+
(C), 154.5 (C), 172.2 (2 CꢀO); MS: m\z 441 (Mj1) ;
Calculated for C27H40N2O3 : C, 73.60; H, 9.15; C, 6.36;
found: C, 73.56; H, 9.06; N, 6.49.
5-HT receptor binding
(
8-[4-N-Propyl-N-(5-acetyl-3,4-dihydro-2H-1-benzo- 5-HT7 receptor binding was determined on the human
pyran-3-yl)aminobutyl]-8-azaspiro[4.5]decane-7,9- recombinant receptor. Membranes were incubated at
dione (2b). Oil (44% yield); IR (film): ν 1724, 27mC for 90 min with 3.7 n [3H]-LSD (-lysergic acid
1
1
−
1671 cm ; H-NMR (CDCl3): δ 0.85 (t, J l 7.3, 3H, diethylamide) in 50 m Tris-HCl buffer, pH 7.4, sup-

965
Synthesis of 5-HT1 and 5-HT7 receptor antagonists
plemented with 4 m MgCl2. Non-specific binding was overall yield. The triflate 5 was then obtained in 93%
determined in the presence of 10 µ of methiothepin. yield by reaction of the hydroxy compound 4 with triflic
Competition experiments were analysed using the itera- anhydride in methylene chloride in the presence of
tive non-linear least-square fitting with GRAPHPAD pyridine.
software. Results were expressed as Kips.e.m. and Ki Coupling of 5 with tributyl(vinyl)tin in the presence
were determined using the method of Cheng & Prusoff of bis(triphenylphosphine)palladium (II) chloride, fol-
(1973).
lowed by hydrogenation, afforded the ethyl compound
6a in 65% yield. The palladium coupling reaction of 5
with tributyl(1-ethoxyvinyl)tin afforded, after a sub-
sequent hydrolysis, the desired acetyl product 6b in
79% yield. Finally, a Suzuki coupling reaction of 5 and
phenylboronic acid in the presence of freshly prepared
tetrakis(triphenylphosphine)palladium (0) in ethanol
and saturated aqueous sodium bicarbonate solution
gave the phenyl compound 6c in 80% yield (Figure 6 ).
Using the same methodologies, the compounds 1a–c
were prepared from 5-[(trifluoromethyl)sulfonyl]oxy-
3,4-dihydro-3-di-n-propylamino-2H-1-benzopyran in
good yields (Rezaie et al 1998b); the compound 1b has
already been described in the literature (Larsson et al
1991).
Light–dark test
The anxiolytic-like activity of the compound was tested
using an unconditioned conflict test, the light–dark test
behaviorally validated for detecting anxiolytic agents in
mice. In brief, the apparatus consisted of two poly(vinyl
chloride) boxes covered by plexiglass. One of these boxes
was darkened, and the other was lightened by a lamp.
Swiss mice (n l 15) were placed in the lit box to start the
test session. The amount of time spent by mice in the lit
box (TLB) and the number of transitions through the
tunnel were recorded over a 5-min period, after the first
entry in the dark box. A mouse with all four paws in the
new box was considered as having changed boxes.
The products 6a–c were deprotected in high yields
(90–99%, Figure 7) using trifluoroacetic acid in dry
dichloromethane. N-Alkylation of 7 was then carried
out using 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-
dione in the presence of potassium carbonate and so-
dium iodide in acetonitrile to afford compounds 8a–c in
moderate-to-good yields. Final N-alkylation of 8 was
performed with iodopropane to give 2 in 44–53% yields.
1
−
Compound 2b was tested at 0.25, 0.5 and 1 mg kg
intraperitoneally. The lack of sedative or excitatory
effects of the compounds at the tested doses was pre-
viously measured in a free exploratory test. The stat-
istical significance of differences between control and
treated groups was ascertained by a combined analysis
of variance and a Bonferroni’s posteriori t-test.
Results and Discussion
Pharmacology
Chemistry
Six 5-substituted 3,4-dihydro-3-amino-2H-1-benzopy-
The 3,4-dihydro-3-amino-2H-l-benzopyran derivatives, ran derivatives (1, 2) were designed, prepared and first
2, were all prepared from the precursor triflate, 5. This evaluated for their affinity for both 5-HT1A and 5-HT7
key intermediate in turn was elaborated in excellent receptors. Binding values of compounds 1a–c, 2a–c, 5-
yield from 5-methoxy-3,4-dihydro-3-amino-2H-1-ben- MeO-DPAC, S20244, 5-CT and buspirone are reported
zopyran 3 (Figure 5). Demethylation of 3 followed by in Table 1.
Boc-protection of the primary amine afforded 4 in 98%
Whatever the substituent at the 5-position of the
Figure 5 Synthesis of 5-(trifluoromethylsulfonyloxy)-3,4-dihydro-3-(tert-butoxycarbonylamino)-2H-1-benzopyran 5. Reagents and cond-
itions: i, HBr 48% in CH3COOH, then i  NaOH, Boc2O; ii, Tf2O, pyridine, CH2Cl2.

966
R. Rezaie et al
Figure 6 Synthesis of 5-substituted derivatives 6. Reagents and conditions: i, CH2lCHSnBu3, Pd(PPh3)2Cl2, DMF, 90mC, then H2, Pd\C
10%, EtOH, rt, 50 psig; ii, CH2lC(OEt)SnBu3, Pd(PPh3)2Cl2, DMF, 90mC, then 1 HCl, H2O; iii, PhB(OH)2, Pd(PPh3)4, NaHCO3, toluene–
EtOH reflux.
Figure 7 Synthesis of final compounds 2. Reagents and conditions: I, TFA, CH2Cl2 ; ii, 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione,
K2CO3, NaI, acetonitrile, 90mC; iii, CH3CH2CH2I, K2CO3, DMF, 90mC.
benzopyranic system, all the compounds bearing an ment of the acetyl with ethyl, phenyl or methoxy sub-
N-(4-(8-azaspiro[4.5]decane-7,9-dione)butyl moiety on stituents resulted in a clear decrease in affinity for the 5-
the basic nitrogen (2a–c and S20244) had better affinities HT1A receptor (by a factor of about 10) and the 5-HT7
for both 5-HT1A and 5-HT7 receptors than their N- receptor (2- to 7-fold). These results suggest perhaps a
propyl substituted counterparts (1a–c and 5-MeO- hydrogen donor site at each receptor binding site inter-
DPAC).
acts with the carbonyl group oxygen. Unfortunately,
Concerning the substitution of the benzopyran, the none of these evaluated compounds showed any sel-
best affinities for 5-HT1A and 5-HT7 receptors in both ectivity for 5-HT7 over 5-HT1A receptors. Selectivity
series were obtained with a 5-acetyl substituent (2b: Ki over other serotoninergic receptor subtypes or different
l 0.3 n for 5-HT1A and 3.1 n for 5-HT7). Replace- receptor types has not been investigated as yet.

967
Synthesis of 5-HT1 and 5-HT7 receptor antagonists
Table 1 In-vitro binding values of benzopyran derivatives 1 and 2.
Compound
Ag
Ki (n)
5-HT7
5-HT1A
1aa
1ba
1cb
2ac
2bc
2cc
CH2CH3
COCH3
Ph
31p7
0.50p0.07
62p4
2.0p0.4
0.30p0.03
7.8p0.5
6.9p0.8
1.3p0.3
6.9p1.0
7.0p1.0e
157p27
32p6
104p12
12p4
3.1p0.7
13p2
50p7
CH2CH3
COCH3
Ph
5-MeO-DPAC
S20244
5-CT
5.5p0.7
0.93p0.20d
398f
Figure 9 Number of transitions, made by mice, through the tunnel
after intraperitoneal administration of 2b (oxalate form). Values are
meanps.e.m., n l 15. *P ! 0.05, treated group vs control group
(combined analysis of variance and a Bonferroni’s posteriori t-test).
Buspirone
Values are meansps.e.m. Ki was calculated from salt (1a–b, 2a–c) and
base (1c) forms. All compounds tested were racemic forms and used,
respectively, as the hydrochloridea, free baseb or oxalatec forms. dBard
et al 1993. eEl Ahmad et al 1991. fRuat et al 1993. gSee Figure 4.
Conclusion
The chemical modulations performed within this series
led to the generation of very potent ligands for both 5-
HT1A and 5-HT7 receptors. Compound 2b, which ex-
hibits nano and sub-nanomolar affinities (Ki l 0.3 n
for 5-HT1A and 3.1 n for 5-HT7), was also found to be
anxiolytic in mice at a very low dose in the light–dark
test. According to the preliminary results, compound 2b
could be a promising candidate for future development.
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