Novel agonists of 5HT2C receptors. Synthesis and biological evaluation of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines. Improved therapeutics for obsessive compulsive disorder.

Article abstract of DOI:10.1021/jm970030l

The syntheses of a series of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2- b]pyrrol-1-yl)-1-methylethylamines are reported. The binding affinities of the compounds at 5HT2C and 5HT2A receptors (79% homology in the transmembrane domain)

Full text of DOI:10.1021/jm970030l

2762
J . Med. Chem. 1997, 40, 2762-2769
Novel Agon ists of 5HT2C Recep tor s. Syn th esis a n d Biologica l Eva lu a tion of
Su bstitu ted 2-(In d ol-1-yl)-1-m eth yleth yla m in es a n d
2-(In d en o[1,2-b]p yr r ol-1-yl)-1-m eth yleth yla m in es. Im p r oved Th er a p eu tics for
Obsessive Com p u lsive Disor d er †
Michael Bo¨s,* Franc¸ois J enck, J ames R. Martin, J ean-Luc Moreau, Andrew J . Sleight, J u¨rgen Wichmann, and
Ulrich Widmer
Pharma Division, Preclinical CNS Research, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
Received J anuary 14, 1997X
The syntheses of a series of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-
b]pyrrol-1-yl)-1-methylethylamines are reported. The binding affinities of the compounds at
5HT2C and 5HT2A receptors (79% homology in the transmembrane domain) were determined.
The ligands displayed selectivity for 5HT2C receptors relative to 5HT2A receptors. Compounds
were functionally characterized both in vitro and in vivo as 5HT2C receptor agonists. 5f, 5l,
5n , 5o, 5q, 14c, 14f, 14k , and 14m exhibited anticompulsive activity in an animal model of
obsessive compulsive disorder.
Sch em e 1a
In tr od u ction
Selective serotonin reuptake inhibitors (SSRIs) in-
crease extracellular levels of serotonin (5HT) and thereby
nonselectively cause stimulation of all postsynaptic 5HT
receptor subtypes. SSRIs have become standard therapy
for neuropsychiatric disorders such as obsessive com-
pulsive disorder (OCD), depression, and panic anxiety.
There is accumulating evidence for the involvement of
5HT2C receptor-mediated functions in the therapeutic
efficacy of SSRIs.1,2 The increased 5HT synaptic content
resulting from the reuptake inhibition also allows 5HT
to act on the other 5HT receptor subtypes, possibly
explaining some of the side effects associated with SSRI
treatment. Selective 5HT2C receptor agonists, therefore,
may represent a direct means to produce the beneficial
therapeutic effects of SSRIs without concomitant side
effects.
Our goal was to find 5HT2C receptor agonists which
(i) display at least 10-fold selectivity versus the 5HT2A
receptor subtype, for which sequence homology of the
transmembrane region is high, (ii) show in vivo activity
after oral administration in functional models of 5HT2C
receptor activation, and (iii) demonstrate therapeutic
potential in an animal model of obsessive compulsive
disorder.
Glennon et al. have shown that N,N-dimethyliso-
tryptamines, i.e. derivatives of N,N-dimethyl-2-(indol-
1-yl)ethylamines are isosteric with the corresponding
N,N-dimethyltryptamines with respect to serotonin
receptor affinity.3 Such compounds are readily available
via N-alkylation. We therefore screened isotryptamines
for 5HT2C receptor affinity and extended our study to
the methylene homologues 1,4-dihydroindeno[1,2-b]pyr-
roles.
In this paper we report on the synthesis and the
pharmacology of indoles and 1,4-dihydroindeno[1,2-b]-
pyrroles in which a 2-aminopropyl side chain is attached
to the N atom of the heterocycle. In analogy to phenyl-
alkylamines, the R-methyl group was incorporated in
a
(a) Propylene oxide, NaH, THF; (b) MsCl, NEt3, CH2Cl2; (c)
NaN3, DMF; (d) PtO2, H2, EtOH.
order to suppress metabolic side chain deamination and
to increase the lipophilicity of the compounds, allowing
better CNS penetration.4 Within these series of com-
pounds we have identified agonists to the 5HT2C recep-
tor binding with high affinity and selectivity versus the
5HT2A receptor. Some of these new ligands were
evaluated in rats in the schedule-induced polydipsia
paradigm, an animal model of obsessive compulsive
disorder.5 As a comparison we have included 5-fluoro-
6
R-tryptamine (15) and fluoxetine in our study.
Ch em istr y
Substituted 2-(indol-1-yl)-1-methylethylamines 5 were
prepared according to Scheme 1. Deprotonation of
indoles 1 followed by alkylation with propylene oxide
led to the secondary alcohols 2. SN2 reaction of the
corresponding mesylates 3 with sodium azide and
reduction of the azides 4 with either hydrogen or LiAlH4
produced the amines 5 with excellent yields. The
enantiomerically pure compounds 5k -q were prepared
from the (R)- or (S)-epoxide with inversion of configu-
ration at the stereogenic center. The monosubstituted
indoles are commercially available.
The dihalogenated building blocks can be prepared
from the corresponding dihalogenated nitrotoluenes as
described in the patent literature.7 For the synthesis
of 5-chloro-6-fluoroindole 1k we have adopted a protocol
developed by Wender and White8 (Scheme 2). 2-Bromo-
4-chloro-3-fluorophenylamine (6)9 was acylated with
trifluoroacetic anhydride to give 7. Upon treatment
with methyllithium and tert-butyllithium, a dilithium
† Dedicated to Prof. Dr. Dieter Seebach on the occasion of his 60th
birthday.
X Abstract published in Advance ACS Abstracts, J uly 15, 1997.
S0022-2623(97)00030-7 CCC: $14.00 © 1997 American Chemical Society

Novel Agonists of 5HT2C Receptors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2763
Sch em e 2a
Ta ble 1. Substituents, Binding Affinities (pKi) for 5HT2A and
5HT2C Receptors, Efficacy (pEC50 and Intrinsic Activity) in
Inducing IP3 Formation in Vitro, and Selectivity Ratio
5HT2C:5HT2A for 5, 14, and 15
IP3 formation
pKi
intrinsic
compd
R
5HT2A
5HT2C pEC50 activity ratio
5a (R,S) 5-OMe
5b(R,S) 4- OMe
5c(R,S) 4-Me
5d (R,S) 4-F
5e(R,S) 5-Me
5f(R,S) 5-F
5g(R,S) 5-Cl
5h (R,S) 5-Br
5i(R,S) 6-Me
5j(R,S) 6-F
not tested 6.1 ( 0.03 5.0
not tested 6.9 ( 0.08 4.9
7.0 ( 0.01 8.2 ( 0.08 5.6
6.8 ( 0.06 8.1 ( 0.03 5.9
6.1 ( 0.01 7.2 ( 0.03 5.6
6.8 ( 0.02 8.2 ( 0.13 5.8
6.7 ( 0.04 8.1 ( 0.01 5.7
6.8 ( 0.06 8.4 ( 0.07 5.7
6.1 ( 0.01 7.8 ( 0.06 5.1
6.6 ( 0.05 8.4 ( 0.12 6.2
0.3
0.3
0.6
0.7
0.9
1
0.9
0.8
0.9
1
1
1
1
1
1
0.9
1
16
20
12.5
25
25
40
50
63
8
25
25
100
20
8
32
32
32
125
32
32
125
63
50
25
8
k
a
(a) (CF3CO)2O, Na2CO3, diethyl ether; (b) MeLi, t-BuLi, -100
°C, chloroacetaldehyde, THF; (c) p-TsA, toluene; (d) NaOH, MeOH.
5k (R)
5l(S)
5m (R) 5-F,6-F
5-F,6-Cl 7.1 ( 0.02 8.0 ( 0.04 5.5
5-F,6-Cl 7.5 ( 0.04 8.9 ( 0.03 6.7
Sch em e 3a
7.0 ( 0.03 8.4 ( 0.02 6.9
7.0 ( 0.02 9.0 ( 0.04 6.7
5n (S)
5o(S)
5p (R)
5q(S)
5-F,6-F
5-Cl,6-F 7.4 ( 0.02 8.7 ( 0.04 6.4
4-Cl,5-F 8.0 ( 0.03 8.9 ( 0.02 6.1
4-Cl,5-F 7.4 ( 0.03 8.9 ( 0.11 6.5
14a (RS) 5-OMe
14b(RS) 6-OMe
14c(RS) 7-OMe
14d (RS) 8-OMe
14e(R) 7-OMe
5.5 ( 0.06 7.0 ( 0.01 inact
6.4 ( 0.02 7.9 ( 0.04 5.7
6.9 ( 0.06 9.0 ( 0.23 6.4
6.4 ( 0.03 7.9 ( 0.08 5.2
6.9 ( 0.06 8.4 ( 0.04 5.1
6.9 ( 0.01 9.0 ( 0.2 6.6
6.7 ( 0.04 8.5 ( 0.05 6.2
6.7 ( 0.09 8.4 ( 0.02 5.6
7.0 ( 0.03 8.4 ( 0.09 5.6
7.2 ( 0.1 8.1 ( 0.08 6.3
1
1
0.7
0.8
1
1
0.8
1
1
1
14f(S)
7-OMe
14g(S) 7-F
14h (S) 7-Cl
14i(S)
14j(S)
7-Br
7-Me
14k (S) 4,4-Me, 7.0 ( 0.04 8.5 ( 0.17 6.7
32
7-Me
14l(S)
4,4-Me, 7.5 (0.01 8.3 ( 0.09 6.7
1
6
25
10
7-F
a
(a) 3-Buten-2-ol, p-TsA, 2,2-dimethoxypropane; (b) ozone,
14m (S) 4,4-Me, 8.0 ( 0.03 9.4 ( 0.1 7.0
1
CH2Cl2-MeOH; (c) TFA, CH2Cl2; (d) 1-amino-2-propanol, p-TsA,
toluene; (e) MsCl, NEt3, CH2Cl2; (f) NaN3, DMF; (g) PtO2, H2,
EtOH.
7-OMe
15(R,S)
7.2 ( 0.02 8.2 ( 0.02 6.8
0.9
Ta ble 2. ED50 (mg/kg) for Inducing Penile Erection in Rats
after sc or po Administration for 5, 14, and 15
reagent was formed which underwent cyclization with
chloroacetaldehyde10 to the hydroxyamide 8. Dehydra-
tion followed by hydrolysis gave 1k in nine steps and
an overall yield of 15%.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
>10 sc
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
15
>10 sc
>10 sc
>10 sc
3.2 sc, >30 po
>10 sc
>10 sc
0.6 sc, 11 po
>10 sc
The preparation of the substituted 1,4-dihydroindeno-
[1,2-b]pyrroles is shown in Scheme 3. Alkylation of the
indan-1-ones 9 was performed by Claisen rearrange-
ment of an in situ formed allyl vinyl ether system.
Ozonolysis of 10 and subsequent cleavage of the acetal
with TFA led to the 1,4-dicarbonyl compounds 11, which
were then reacted with commercially available 1-amino-
2-propanol [(S), (R), (RS)] to yield the 1,4-dihydroindeno-
[1,2-b]pyrroles 12. The secondary alcohols were trans-
formed into the amines 14 via the azides 13 as described
for the synthesis of the indole derivatives 5.
2 sc, >30 po
1.2 sc, 10 po
1.5 sc, >30 po
2.7 sc, >30 po
>10 sc
1 sc, 2.7 po
2.3 sc, >30 po
4 sc, >30 po
3.3 sc, >30 po
0.3 sc, >30 po
2.1 sc, >30 po
0.5 sc, 5.5 po
2.7 sc, 30 po
0.3 sc, 10 po
1 sc, 15 po
>10 sc
0.9 sc, 10 po
2.7 sc, >30 po
0.5 sc, 10 po
0.8 sc, 9.9 po
3.3 sc, inact po
2.7 sc, >30 po
P h a r m a cology
Resu lts
The affinity of the compounds for 5HT2C and 5HT2A
human receptors was assessed using displacement of
[3H]5HT and [3H]DOB, respectively. To assess func-
tional efficacy at 5HT2C receptors, the ligands were
evaluated for stimulation of phosphoinositol turnover
in the choroid plexus of the rat. The compounds were
also assessed for induction of penile erection in rats
which is a symptom of the serotonin syndrome reflecting
5HT2C receptor activation in rodents.11 Finally, com-
pounds which displayed interesting in vivo activity were
further tested in the schedule-induced polydipsia model
of OCD in rats for potential anticompulsive effects.5
The radioligand binding experiments (Table 1) showed
higher affinity of the indoles 5 and the indeno[1,2-b]-
pyrroles 14 for 5HT2C binding sites than for the struc-
turally (79% homology between the transmembrane
regions) very similar 5HT2A receptor. Compounds with
halogen substituents in position 4, 5, and 6 of the indole
ring possess higher affinities for this receptor subtype
as compared to derivatives bearing electron-donating
substituents such as methoxy and methyl groups. The
dihalogenated indoles showed the highest 5HT2C recep-
tor affinities. The (S)-enantiomers display higher af-

2764 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17
Bo¨s et al.
Ta ble 3. Activity in Schedule-Induced Polydipsia Model in
Rats
max.
suppression
(%)
max.
suppression
(%)
min
ED
min
ED
compd
compd
14c
14f
14k
14m
5f
5l
5n
5o
5q
15
3 ip
10 ip
3 ip
3 ip
3 ip
1 ip
-97
-90
-73
-88
-97
-96
10 ip
1 ip
10 ip
1 ip
-79
-97
-76
-75
-11
fluoxetine 30 ip
selected 5HT2C receptor agonists evaluated in the
schedule-induced polydipsia model all significantly re-
duced the excessive drinking with MED values (minimal
effective dose; i.e. the lowest dose tested which was
found to statistically significantly reduce water intake
relative to vehicle treatment) within the dose range
1-30 mg/kg (ip) with doses selected at half-logarithmic
units (cf. Table 3). The magnitude of the suppression
of polydipsia was compared among all of these com-
pounds for the doses up to 10 mg/kg and was found to
be 75% or more. In comparison, fluoxetine was much
less potent, first achieving a statistically significant
reduction in water intake of only 11% at 30 mg/kg ip
(with no appreciable effect at doses up to 10 mg/kg ip).
F igu r e 1. Effects of 5HT, 5n , 14m , and 15 on IP3 formation
in the rat choroid plexus. Results are expressed as percentage
of the stimulation in IP3 formation produced by 10 µM 5HT.
finity and selectivity for the 5HT2C receptor as compared
to their antipodes. Selectivity ratios of 20-100 were
found for the (S)-configured isomers (e.g. 5l and 5n ).
In the series of the indeno[1,2-b]pyrroles 14, the
optimal position for aromatic substitution turned out
to be position 7. In contrast to the indoles, methoxy-
substituted indeno[1,2-b]pyrroles (e.g. 14f and 14m )
show increased affinities in comparison to the haloge-
nated compounds and for the (S)-configured isomers
selectivity ratios of up to 125 were observed.
Con clu sion s
Compounds were identified which exhibited high-
affinity binding to human 5HT2C receptors with selec-
tivity versus 5HT2A receptors. Such compounds were
characterized in vitro and in vivo as 5HT2C agonists.
Two of these compounds underwent a broad binding
evaluation: 5l and 14k exhibited affinity for several
other 5HT receptor subtypes (1A, 3, 4, 6, 7) which was
at least 2 logarithmic units lower than for 5HT2C
receptors and had IC50 g 1 µm for 26 other receptors
across numerous different neurotransmitter systems
(unpublished results). In the isolated rat fundus strip
assay, both 5l and 14k act as agonists at the 5HT2B
receptor (pD2 ) 8.0 and 6.1, respectively; unpublished
results). At present little is known concerning the
physiological function of 5HT2B receptors, due in part
to the lack of highly selective ligands; interestingly a
5HT2C receptor agonist which is structurally different
from those described in this report and which exhibited
antagonistic activity at the 5HT2B receptor was also
found to reduce schedule-induced polydipsia (unpub-
lished results). Therefore the 5HT2B receptor is unlikely
to play a major role in the functional effects described
here.
These 5HT2C receptor agonists were found to signifi-
cantly suppress schedule-induced polydipsia in rats,
even at doses lacking any appreciable effects on spon-
taneous behavior. These results suggest that 5HT2C
receptor agonists may be of therapeutic value in OCD.
In this respect, it is interesting to note that although
fluoxetine was found to be active in this animal model
of OCD, its potency was low when compared to the dose
range producing adverse effects. 5HT2C receptor ago-
nists may, thus, potentially offer improved therapy of
OCD.
For the study it was of interest to compare one of the
potent and selective ligands with the structural isomer.
The fluorinated tryptamine derivative 15 displays simi-
lar affinity for the 5HT2C receptor as the isomer 5j, but
with reduced selectivity relative to the 5HT2A receptor.
The effect of the 5HT2C receptor ligands in stimulating
phosphoinositol formation (cf. IP3 formation, pEC50,
intrinsic activity, Table 1) was studied in rat choroid
plexus. Compounds 5a -d , 14a , and 14d induced only
a submaximal increase whereas the maximum re-
sponses of the other derivatives 5e-q, 14b, 14c, 14e-
m , and 15 were the same as that produced by 5HT (10-5
M, intrinsic activity ) 1), suggesting that these ligands
are full agonists at the 5HT2C receptor (cf. 5n , 14m , and
15, Figure 1). In vivo results, i.e. induction of penile
erections, are presented in Table 2 (although not shown
here, the reference compound fluoxetine was found to
induce penile erection with ED50 ) 4.3 mg/kg sc).
SSRIs such as fluoxetine are currently in use for the
treatment of OCD. These drugs, however, exhibit a
delayed onset of action and less than optimal therapeu-
tic efficacy. Schedule-induced polydipsia in rats has
been proposed as a model of OCD.5 In this model, food-
deprived rats which receive intermittently delivered
food pellets on a fixed-time schedule typically develop
a pattern of excessive drinking, i.e. polydipsia. This
paradigm has been pharmacologically validated as a
model of OCD. Experimental compounds are tested in
this model for their ability to attenuate polydipsic
behavior, i.e. for their potential anti-OCD effects. The
Exp er im en ta l Section
Gen er a l. Melting points were determined in capillary
tubes (Bu¨chi 530 apparatus) and are uncorrected. Column
chromatography was carried out by using silica gel (230-400

Novel Agonists of 5HT2C Receptors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2765
mesh; Merck) and 0.3-1.0 bar pressure. Spectra were re-
corded with the following instruments. IR (cm-1): Nicolet-
7199-FT-IR. 1H-NMR (δ values in ppm relative to internal
TMS, coupling constants J in Hertz): Bruker AC-250 (250
MHz). MS: MS9 updated with a Finnigan MAT data system
SS 200. Elementary analyses (C, H, N) for novel compounds
were within 0.4% of the theoretical values.
5-Methoxyindole, 4-methoxyindole, 4-methylindole, 5-meth-
ylindole, 5-fluoroindole, 5-chloroindole, 5-bromoindole, and
6-methylindole were purchased from Aldrich Chemicals; 4-
fluoroindole and 6-fluoroindole, from Sigma; 5-methoxyindan-
1-one and 6-methoxyindan-1-one, from Fluka.
) 15.3, 5 Hz, 1 H), 6.43 (d, J ) 3 Hz, 1 H), 6.44 (s, 1 H), 6.52
(d, J ) 7.5 Hz, 1 H), 7.05 (t, J ) 7.5 Hz, 1 H), 7.13 (d, J ) 7.5
Hz, 1 H), 7.25 (d, J ) 3 Hz, 1 H); MS (EI) m/z 204 (M+), 161,
44 (100). Anal. (C12H16N2O‚0.5C4H4O4) C, H, N.
(R,S)-2-(4-Meth ylin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
1
r a te (1:1) (5c): 92%; mp 163-164 °C dec; H NMR (DMSO-
d6) δ 1.08 (d, J ) 6.5 Hz, 3 H), 2.46 (s, 3 H), 3.52 (m, 1 H),
4.19 (dd, J ) 14.2, 7.5 Hz, 1 H), 4.38 (dd, J ) 14.2, 8.2 Hz, 1
H), 6.49 (s, 3 H), 6.83 (d, J ) 7 Hz, 1 H), 7.04 (dd, J ) 7.5, 7
Hz, 1 H), 7.37 (d, J ) 3.2 Hz, 1 H), 7.37 (d, J ) 7.5 Hz, 1 H);
MS (EI) m/z 188 (M+), 145, 44 (100). Anal. (C12H16N2‚C4H4O4)
C, H, N.
P r ep a r a tion of (R)-1-(6-Ch lor o-5-flu or oin d ol-1-yl)p r o-
p a n -2-ol (2l) (Sta n d a r d P r oced u r e A). To a mixture of
sodium hydride (0.09 g, 3.7 mmol) in THF (15 mL) was added
6-chloro-5-fluoroindole (1k ) (0.5 g, 3 mmol) at 0 °C. After 1 h
(R)-propylene oxide (0.42 mL, 6 mmol) was added, and the
mixture was stirred for 48 h at room temperature. The
reaction was quenched with water, and the mixture was
extracted with diethyl ether and washed with brine. The
organic layer was dried, and the solvent was removed. The
residue was subjected to chromatography (toluene/ethyl ac-
etate, 19:1, as eluent) to yield 2l (0.51 g, 74%) as white
(R,S)-2-(4-F lu or oin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
r a te (1:1) (5d ): mp 179-180 °C dec; H NMR (DMSO-d6) δ
1.09 (d, J ) 7.5 Hz, 3 H), 3.53 (m, 1 H), 4.24 (dd, J ) 15, 7.2
Hz, 1 H), 4.42 (dd, J ) 15, 7.5 Hz, 1 H), 6.49 (s, 2 H), 6.54 (d,
J ) 3 Hz, 1 H), 6.82 (dd, J ) 8, 7.7 Hz, 1 H), 7.13 (m, 1 H),
7.43 (d, J ) 9 Hz, 1 H), 7.46 (d, J ) 3 Hz, 1 H); MS (EI) m/z
192 (M+), 149, 44 (100). Anal. (C11H13FN2‚C4H4O4) C, H, N.
1
(R,S)-2-(5-Meth ylin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
1
r a te (1:1) (5e): 87%; mp 165-167 °C dec; H NMR (DMSO-
d6) δ 1.06 (d, J ) 6.5 Hz, 3 H), 2.36 (s, 3 H), 3.50 (m, 1 H),
4.18 (dd, J ) 14.2, 7.5 Hz, 1 H), 4.38 (dd, J ) 14.2, 5.7 Hz, 1
H), 6.36 (d, J ) 3 Hz, 1 H), 6.49 (s, 3 H), 6.97 (d, J ) 7 Hz, 1
H), 7.33 (dd, J ) 7.5, 7 Hz, 1 H), 7.43 (d, J ) 3.2 Hz, 1 H); MS
(EI) m/z 188 (M+), 145, 44 (100). Anal. (C12H16N2‚C4H4O4) C,
H, N.
crystals: mp 104-105 °C; [R]20 ) -60.4o (c ) 0.25, CHCl3);
436
1H NMR (CDCl3) δ 1.26 (d, J ) 6 Hz, 3 H), 1.61 (d, J ) 5 Hz,
1 H), 3.96 (dd, J ) 12.5 Hz, J ) 8 Hz, 1 H), 4.12 (dd, J ) 12.5
Hz, J ) 3.7 Hz, 1 H), 4.20 (m, 1 H), 6.45 (d, J ) 3.2 Hz, 1 H),
7.17 (d, J ) 3.2 Hz, 1 H), 7.34 (d, J ) 9.5 Hz, 1 H), 7.38 (d, J
) 7.5 Hz, 1 H); MS (EI) m/z 227 (M+), 182 (100). Anal. (C11H11
ClFNO) C, H, N.
-
(R,S)-2-(5-F lu or oin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
1
r a te (1:1) (5f): 95%; mp 169-170 °C dec; H NMR (DMSO-
d6) δ 1.08 (d, J ) 6.5 Hz, 3 H), 3.52 (m, 1 H), 4.22 (dd, J )
14.5, 7.5 Hz, 1 H), 4.39 (dd, J ) 14.5, 6 Hz, 1 H), 6.46 (d, J )
3 Hz, 1 H), 6.49 (s, 2 H), 7.00 (dt, J ) 7.5, 2.5 Hz, 1 H), 7.32
(dd, J ) 10, 2.5 Hz, 1 H), 7.47 (d, J ) 3 Hz, 1 H), 7.58 (dd, J
) 9, 4.5 Hz, 1 H); MS (EI) m/z 192 (M+), 149, 44 (100). Anal.
(C11H13FN2‚C4H4O4) C, H, N.
(R,S)-2-(5-Ch lor oin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
r a te (1:2) (5g): mp 183-185 °C dec; 1H NMR (DMSO-d6) δ
1.11 (d, J ) 6.5 Hz, 3 H), 3.57 (m, 1 H), 4.25 (dd, J ) 14.2, 7.5
Hz, 1 H), 4.42 (dd, J ) 14.2, 6.2 Hz, 1 H), 6.48 (d, J ) 3 Hz, 1
H), 6.54 (s, 2 H), 7.16 (dd, J ) 7.5, 2.5 Hz, 1 H), 7.48 (d, J )
3 Hz, 1 H), 7.61 (d, J ) 7.5 Hz, 1 H), 7.61 (d, J ) 2.5 Hz, 1 H);
MS (EI) m/z 208 (M+), 165, 44 (100). Anal. (C11H13ClN2‚
2C4H4O4) C, H, N.
P r ep a r a tion of (S)-1-(2-Azid op r op yl)-6-ch lor o-5-flu or -
oin d ole (4l) (Sta n d a r d P r oced u r e B). To a solution of 2l
(0.28 g, 1.2 mmol) in dichloromethane (6 mL) and triethy-
lamine (0.5 mL) was added methanesulfonyl chloride (0.2 mL,
2.5 mmol) at 0 °C. After 1 h ether was added and the mixture
was extracted with 1 M sodium carbonate and washed with
brine. The organic layer was dried, and the solvent was
removed. The residue was taken up in DMF (6 mL), and
sodium azide (0.16 g, 2.4 mmol) was added. The reaction
mixture was heated for 7 h at 60 °C, poured into water, and
extracted with ether. The organic layer was dried, and the
solvent was removed. The residue was purified by column
chromatography (toluene as eluent) to yield 4l as yellow oil
(0.29 g, 93%): 1H NMR (CDCl3) δ 1.30 (d, J ) 6.2 Hz, 3 H),
3.90 (m, 1 H), 4.00 (dd, J ) 15, 7 Hz, 1 H), 4.07 (dd, J ) 15, 5
Hz, 1 H), 6.48 (d, J ) 2.5 Hz, 1 H), 7.14 (d, J ) 2.5 Hz, 1 H),
7.34 (d, J ) 5 Hz, 1 H), 7.35 (d, J ) 10 Hz, 1 H); MS (EI) m/z
252 (M+), 182 (100).
(R,S)-2-(5-Br om oin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
1
r a te (1:1) (5h ): 93%; mp 196-197 °C dec; H NMR (DMSO-
d6) δ 1.05 (d, J ) 6.5 Hz, 3 H), 3.49 (m, 1 H), 4.20 (dd, J )
14.5, 7 Hz, 1 H), 4.36 (dd, J ) 14.5, 6.2 Hz, 1 H), 6.46 (d, J )
3.2 Hz, 1 H), 6.49 (s, 2 H), 7.26 (dd, J ) 8.7, 2 Hz, 1 H), 7.45
(d, J ) 3.2 Hz, 1 H), 7.55 (d, J ) 8.7 Hz, 1 H), 7.74 (d, J ) 2
Hz, 1 H); MS (EI) m/z 252, 254 (M+), 211, 209, 44 (100). Anal.
(C11H13BrN2‚C4H4O4) C, H, N.
P r ep a r a tion of (S)-2-(6-Ch lor o-5-flu or oin d ol-1-yl)-1-
m eth yleth yla m in e F u m a r a te (1:1.6) (5l) (Sta n d a r d P r o-
ced u r e C). A suspension of 0.02 g of PtO2 in ethanol (5 mL)
was stirred under hydrogen for 0.5 h. After the addition of a
solution of 4l (0.26 g, 1 mmol) in ethanol (5 mL), the mixture
was stirred for 2 h, the catalyst was filtered off, and the solvent
was removed. The salt was prepared in ether by treatment
(R,S)-2-(6-Meth ylin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
1
r a te (1:1) (5i): 60%; mp 152-153 °C dec; H NMR (DMSO-
d6) δ 1.09 (d, J ) 6.5 Hz, 3 H), 2.41 (s, 3 H), 3.53 (m, 1 H),
4.16 (dd, J ) 14.5, 7.5 Hz, 1 H), 4.36 (dd, J ) 14.5, 5.7 Hz, 1
H), 6.39 (d, J ) 3 Hz, 1 H), 6.50 (s, 2 H), 6.87 (d, J ) 8 Hz, 1
H), 7.29 (d, J ) 3 Hz, 1 H), 7.35 (s, 1 H), 7.42 (d, J ) 8 Hz, 1
H); MS (EI) m/z 188 (M+), 145, 44 (100). Anal. (C12H16N2‚
C4H4O4) C, H, N.
with fumaric acid to yield 0.25 g (59%) of 5l: mp 169-171 °C;
1
[R]20 ) 31.6° (c ) 0.25, MeOH); H NMR (DMSO-d6) δ 1.10
436
(d, J ) 5 Hz, 3 H), 3.51 (m, 1 H), 4.18 (dd, J ) 14.5, 7.2 Hz, 1
H), 4.36 (dd, J ) 14.5, 6.2 Hz, 1 H), 6.48 (d, J ) 2.5 Hz, 1 H),
6.49 (s, 2 H), 7.40 (d, J ) 2.5 Hz, 1 H), 7.35 (s, 1 H), 7.42 (d,
J ) 8 Hz, 1 H); MS (EI) m/z 226 (M+), 183, 44 (100). Anal.
(C11H12FClN2‚1.6C4H4O4) C, H, N.
(R,S)-2-(6-F lu or oin d ol-1-yl)-1-m eth yleth yla m in e fu m a -
r a te (1:1) (5j): 78%; mp 158-159 °C dec; 1H NMR (DMSO-d6)
δ 1.10 (d, J ) 6.5 Hz, 3 H), 3.51 (m, 1 H), 4.18 (dd, J ) 14.5,
7.2 Hz, 1 H), 4.36 (dd, J ) 14.5, 6.2 Hz, 1 H), 6.48 (d, J ) 2.5
Hz, 1 H), 6.49 (s, 2 H), 6.89 (dt, J ) 8.7, 2.2 Hz, 1 H), 7.40 (d,
J ) 2.5 Hz, 1 H), 7.47 (dd, J ) 10.5, 2.2 Hz, 1 H), 7.54 (dd, J
) 8.7, 5.5 Hz, 1 H); MS (EI) m/z 192 (M+), 149, 44 (100). Anal.
(C11H13FN2‚C4H4O4) C, H, N.
(R )-2-(6-C h lor o -5-flu or o in d ol-1-y l)-1-m e t h y le t h y l-
a m in e fu m a r a te (1:1.5) (5k ): 69%; mp 153-154 °C dec;
[R]20436 ) -28.8° (c ) 0.25, MeOH); 1H NMR (DMSO-d6) δ 1.10
(d, J ) 5 Hz, 3 H), 3.51 (m, 1 H), 4.18 (dd, J ) 14.5, 7.2 Hz, 1
H), 4.36 (dd, J ) 14.5, 6.2 Hz, 1 H), 6.48 (d, J ) 2.5 Hz, 1 H),
6.49 (s, 2 H), 7.40 (d, J ) 2.5 Hz, 1 H), 7.35 (s, 1 H), 7.42 (d,
J ) 8 Hz, 1 H). Anal. (C11H12FClN2‚1.5C4H4O4) C, H, N.
Compounds 5a -k and 5m -q were synthesized according
to standard procedures A, B, and C.
(R,S)-2-(5-Meth oxyin d ol-1-yl)-1-m eth yleth yla m in e fu -
m a r a te (1:1) (5a ): 62%; mp 175-176 °C dec; 1H NMR (DMSO-
d6) δ 1.07 (d, J ) 6.5 Hz, 3 H), 3.50 (sept, J ) 6.5 Hz, 1 H),
3.74 (s, 3 H), 4.16 (dd, J ) 15.3, 7.5 Hz, 1 H), 4.36 (dd, J )
15.3, 5.7 Hz, 1 H), 6.37 (d, J ) 3 Hz, 1 H), 6.49 (s, 2 H), 6.78
(dd, J ) 10, 2.5 Hz, 1 H), 7.05 (d, J ) 2.5 Hz, 1 H), 7.33 (d, J
) 3 Hz, 1 H), 7.45 (d, J ) 10 Hz, 1 H); MS (EI) m/z 204 (M+),
161, 44 (100). Anal. (C12H16N2O‚C4H4O4) C, H, N.
(R,S)-2-(4-Meth oxyin d ol-1-yl)-1-m eth yleth yla m in e fu -
m a r a te (1:0.5) (5b): 59%; mp 185-186 °C dec; 1H NMR
(DMSO-d6) δ 1.00 (d, J ) 6.5 Hz, 3 H), 3.36 (sept, J ) 6.5 Hz,
1 H), 3.86 (s, 1 H), 4.07 (dd, J ) 15.3, 7 Hz, 1 H), 4.22 (dd, J

2766 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17
Bo¨s et al.
(R)-2-(5,6-Diflu or oin d ol-1-yl)-1-m eth yleth yla m in e fu -
m a r a te (1:1) (5m ): 82%; mp 161-162 °C dec; [R]20436 ) -34.4°
in 2,2-dimethoxypropane (200 mL) was boiled under reflux for
64 h on a Dean-Stark trap filled with molecular sieves (0.4
nm, 2 mm pearl shaped). The solvents were evaporated, and
the residue was purified by column chromatography on silica
gel (hexane/ethyl acetate, 6:1) to give 10i (12.7 g, 51%) as a
yellow oil: 1H NMR (CDCl3) δ 1.18 (s, 3 H), 1.45 (s, 3 H), 1.69
(d, J ) 2 Hz, 3 H), 2.18 (m, 1 H), 2.39 (s, 3 H), 2.43 (m, 1 H),
2.69 (m, 1 H), 5.58 (m, 2 H), 7.41 (m, 2 H), 7.50 (s, 1 H); MS
(EI) m/z 228 (M+), 213 (M+ - Me), 173 (100), 159, 115, 55.
Compounds 10a -h and 10j-k were prepared in the same
way from 4-methoxyindan-1-one (9a ),15 5-methoxyindan-1-one
(9b), 6-methoxyindan-1-one (9c), 7-methoxyindan-1-one (9d ),16
6-fluoroindan-1-one (9e),17 6-chloroindan-1-one (9f),16 6-bro-
moindan-1-one (9g),17,18 6-methylindan-1-one (9h ),19 6-fluoro-
3,3-dimethylindan-1-one (9j),12-14,17 and 6-methoxy-3,3-dimeth-
ylindan-1-one (9k ),12-15 respectively.
1
(c ) 0.25, MeOH); H NMR (DMSO-d6) δ 1.09 (d, J ) 6.5 Hz,
3 H), 3.49 (m, 1 H), 4.19 (dd, J ) 14.5, 7 Hz, 1 H), 4.33 (dd, J
) 14.5, 6.2 Hz, 1 H), 6.48 (d, J ) 3.2 Hz, 1 H), 6.49 (s, 2 H),
7.47 (d, J ) 3.2 Hz, 1 H), 7.54 (dd, J ) 11.2, 7.5 Hz, 1 H), 7.74
(dd, J ) 11.7, 7 Hz, 1 H); MS (EI) m/z 210 (M+), 167, 166, 44
(100). Anal. (C11H12F2N2‚C4H4O4) C, H, N.
(S)-2-(5,6-Diflu or oin d ol-1-yl)-1-m eth yleth yla m in e fu -
m a r a te (1:1) (5n ): 84%; mp 159-160 °C dec; [R]20436 ) +35.2°
(c ) 0.25, MeOH). Anal. (C11H12F2N2‚C4H4O4) C, H, N.
(S )-2-(5-C h lo r o -6-flu o r o in d o l-1-y l)-1-m e t h y le t h y l-
a m in e fu m a r a te (1:1) (5o): mp 158-160 °C dec; [R]20
)
D
+35.2o (c ) 0.25, MeOH); H NMR (DMSO-d6) δ 1.09 (d, J )
6.7 Hz, 3 H), 3.50 (m, 1 H), 4.20 (dd, J ) 14.5, 7.5 Hz, 1 H),
4.34 (dd, J ) 14.5, 6.5 Hz, 1 H), 6.49 (s, 2 H), 6.49 (d, J ) 3.2
Hz, 1 H), 7.48 (d, J ) 3.2 Hz, 1 H), 7.73 (d, J ) 7.5 Hz, 1 H),
7.74 (d, J ) 10 Hz, 1 H); MS (EI) m/z 226 (M+), 183, 44 (100).
Anal. (C11H12FClN2‚C4H4O4) C, H, N.
1
P r ep a r a tion of (R,S)-2-(2-Oxoeth yl)-3,3,6-tr im eth yl-1-
in d a n on e (11i) (Sta n d a r d P r oced u r e E). An ozone stream
(2.5 g of ozone/h) was conducted for 1 h while stirring through
a solution of 10i (12.7 g, 55.6 mmol) in dichloromethane (200
mL) and methanol (40 mL) cooled to -70 °C. Subsequently,
the solution was flushed with oxygen for 5 min and with argon
for 10 min. After the addition of dimethyl sulfide (6.12 mL,
83.4 mmol), the mixture was stirred at room temperature for
18 h. The reaction mixture was evaporated, the residue was
treated with dichloromethane (150 mL) and after the addition
of water (25 mL) and trifluoroacetic acid (25 mL), the mixture
was stirred at room temperature for 2.5 h. The mixture was
subsequently poured into water (150 mL) and neutralized
while stirring by addition of hydrogen carbonate. Water (100
mL) was added, the phases were separated, and the aqueous
phase was extracted twice with dichloromethane (150 mL each
time). The combined organic phases were dried (magnesium
sulfate) and concentrated to give 11i (11.3 g, 94%) as a light
yellow oil: 1H NMR (CDCl3) δ 1.11 (s, 3 H), 1.51 (s, 3 H), 2.41
(s, 3 H), 2.61 (m, 1 H), 3.04 (m, 2 H), 7.40 (d, J ) 7 Hz, 1 H),
7.46 (d, J ) 7 Hz, 1 H), 7.52 (s, 1 H), 9.99 (s, 1 H); MS (EI) m/z
188 (M+ - CO), 173 (100), 159, 145, 128, 43.
P r ep a r a tion of (R)-1-(4,4,7-Tr im eth yl-1,4-d ih yd r oin -
d en o[1,2-b]p yr r ol-1-yl)p r op a n -2-ol (12k ) (Sta n d a r d P r o-
ced u r e F ). A solution of 11i (2.16 g, 10 mmol) and p-tolu-
enesulfonic acid (80 mg) in toluene (90 mL) was heated on a
Dean-Stark trap. A solution of (R)-1-amino-2-propanol (3.0
g, 40 mmol) in toluene (20 mL) was added dropwise over a
period of 5 min. Subsequently, the mixture was boiled for an
additional 45 min, during which the solvent was reduced to a
volume of 20 mL. The cooled reaction mixture was purified
by column chromatography (ethyl acetate/hexane, 1:2) to yield
12k (1.5 g, 59%) as a brown oil: 1H NMR (CDCl3) δ 1.29 (d, J
) 5 Hz, 3 H), 1.41 (s, 6 H), 2.38 (s, 3 H), 3.99 (m, 1 H), 4.18
(m, 2 H), 6.11 (d, J ) 2 Hz, 1 H), 6.68 (d, J ) 2 Hz, 1 H), 6.90
(d, J ) 7 Hz, 1 H), 7.07 (s, 1 H), 7.21 (d, J ) 7 Hz, 1 H); MS
(EI) m/z 255 (M+), 240 (100), 194.
(R )-2-(4-C h lor o -5-flu or o in d ol-1-y l)-1-m e t h yle t h y l-
a m in e fu m a r a te (1:1) (5p ): 84%; mp 186-187 °C dec; [R]20
436
) -32.4o (c ) 0.25, MeOH); H NMR (DMSO-d6) δ 1.08 (d, J
1
) 6.5 Hz, 3 H), 3.48 (m, 1 H), 4.23 (dd, J ) 14.5, 7 Hz, 1 H),
4.36 (dd, J ) 14.5, 6.5 Hz, 1 H), 6.49 (s, 2 H), 6.54 (d, J ) 3.2
Hz, 1 H), 7.19 (t, J ) 10 Hz, 1H), 7.60 (d, J ) 3.2 Hz, 1 H),
7.42 (d, J ) 8 Hz, 1 H); MS (EI) m/z 226 (M+), 183, 44 (100).
Anal. (C11H12FClN2‚C4H4O4) C, H, N.
(S )-2-(4-C h lo r o -5-flu o r o in d o l-1-y l)-1-m e t h y le t h y l-
a m in e fu m a r a te (1:1) (5q): 84%; mp 183-184 °C dec; [R]20
436
) +32.4° (c ) 0.25, MeOH). Anal. (C11H12FClN2‚C4H4O4) C,
H, N.
N-(2-Br om o-5-ch lor o-4-flu or op h en yl)t r iflu or oa cet a -
m id e (7). To a solution of 2-bromo-4-chloro-3-fluoropheny-
lamine (6) (111 g, 0.5 mol) in ether (990 mL) at 0 °C were added
solid Na2CO3 (78 g) and trifluoroacetic anhydride (86 mL, 0.9
mol). After being warmed to room temperature the suspension
was stirred for 2.5 h, diluted with ether, and extracted with
water. The organic layer was separated and dried (sodium
sulfate), and the solvent was removed. The residue was
recrystallized from n-hexane to yield 7 as yellow crystals (136
g, 86%): mp 86-88 °C; 1H NMR (CDCl3) δ 7.45 (d, J ) 7.6
Hz, 1 H), 8.46 (d, J ) 7 Hz, 1 H); MS (EI) m/z 319, 321 (M+),
240 (100). Anal. (C8H3F4ClBrNO) C, H, N.
(R,S)-1-(Tr iflu or oa cetyl)-6-ch lor o-5-flu or o-3-h yd r oxy-
2,3-d ih yd r o-1H-in d ole (8). A solution of 7 (24 g, 75 mmol)
in THF (750 mL) was cooled to -100 °C. MeLi (75 mmol, 1.6
M in ether) was added, and 10 min later t-BuLi (150 mL, 1.7
M in pentane) was also added. After 1 h at -100 °C a solution
of chloroacetaldehyde (67.5 mL, 1.7 M in THF) was added. The
mixture was stirred at -78 °C for 4 h, and acetic acid (13 mL)
was added. After the addition of triethylamine (52 mL), the
reaction mixture was allowed to warm to ambient temperature
and to stir for 14 h. Ammonium chloride solution (20%, 150
mL) was added, followed by extraction with ether. The organic
layer was separated and dried (sodium sulfate), and the solvent
was removed. The residue was purified by column chroma-
tography (toluene/ethyl acetate, 19:1) to yield 8 (13g, 61%):
P r ep a r a tion of (S)-1-(2-Azid op r op yl)-4,4,7-tr im eth yl-
1,4-d ih yd r oin d en o[1,2-b]p yr r ole (13k ) (Sta n d a r d P r oce-
d u r e G). Methanesulfonyl chloride (0.91 mL, 11.7 mmol) was
added dropwise while stirring to a solution, cooled to 0 °C, of
12k (1.5 g, 5.87 mmol) and triethylamine (3.27 mL, 23.5 mmol)
in dichloromethane (50 mL), and the mixture was stirred at
this temperature for an additional 1.5 h. The reaction mixture
was subsequently diluted with dichloromethane (150 mL),
washed twice with saturated sodium hydrogen carbonate
solution (70 mL each time) and once with brine (70 mL), dried
(magnesium sulfate), and evaporated. The residue was dis-
solved in DMF (50 mL) and treated with sodium azide (0.76
g, 11.7 mmol) and the mixture was heated to 60 °C for 15 h
while stirring. After cooling the solution was poured into
water (100 mL) and extracted twice with ethyl acetate (100
mL each time). The combined organic phases were washed
once with water (100 mL) and once with brine (100 mL), dried
(magnesium sulfate) and evaporated. The residue was purified
by column chromatography (hexane/ethyl acetate 4:1) to give
13k (1.13 g, 68%) as a reddish oil: 1H NMR (CDCl3) δ 1.30 (d,
J ) 5 Hz, 3 H), 1.41 (s, 6 H), 2.39 (s, 3 H), 3.92 (m, 1 H), 4.09
(m, 2 H), 6.12 (d, J ) 2 Hz, 1 H), 6.65 (d, J ) 2 Hz, 1 H), 6.90
1
mp 97.5-98 °C; H NMR (CDCl3) δ 2.36 (d, J ) 7 Hz, 1 H),
5.37 (m, 1 H), 7.26 (d, J ) 7.7 Hz, 1 H), 8.35 (d, J ) 6.25 Hz,
1 H); MS (EI) m/z 283 (M+), 186, 69 (100). Anal. (C10H6F4-
ClNO2) C, H, N.
6-Ch lor o-5-flu or oin d ole (1k ). A solution of 8 (5.5 g, 19.5
mmol) and p-toluenesulfonic acid monohydrate (0.19 g, 0.9
mmol) in toluene (200 mL) was heated at reflux temperature
for 2 h. The solvent was removed, and the residue was
dissolved in methanol (800 mL). After the addition of NaOH
(1 N, 800 mL), the mixture was refluxed for 2.5 h. Methanol
was removed, and the crystals were filtered off and dried: yield
1
77%; mp 104-105 °C; H NMR (CDCl3) δ 6.50 (m, 1 H), 7.24
(m, 1 H), 7.36 (d, J ) 9.5 Hz, 1 H), 7.41 (d, J ) 6 Hz, 1 H); MS
(EI) m/z 169 (M+), 134, 107 (100).
P r ep a r a tion of (R,S)-2-(2-Bu ten -1-yl)-3,3,6-tr im eth yl-
1-in d a n on e (10i) (Sta n d a r d P r oced u r e D). A solution of
3,3,6-trimethylindan-1-one (9i)12-14 (18.9 g, 108 mmol), 3-buten-
2-ol (22.4 mL, 0.26 mol), and p-toluenesulfonic acid (300 mg)

Novel Agonists of 5HT2C Receptors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2767
1
(d, J ) 7 Hz, 1 H), 7.03 (s, 1 H), 7.21 (d, J ) 7 Hz, 1 H); MS
(EI) m/z 280 (M+), 237 (100) , 194, 181, 56.
°C; [R]20 ) +16.8° (c ) 0.25, MeOH); H NMR (DMSO-d6) δ
D
1.02 (d, J ) 5 Hz, 3 H), 3.29 (m, 1 H), 3.40 (s, 3 H), 4.09 (dd,
J ) 10, 7 Hz, 1 H), 4.23 (dd, J ) 10, 4 Hz, 1 H), 6.14 (d, J )
2 Hz, 1 H), 6.45 (s, 1 H), 6.83 (dt, J ) 7, 1 Hz, 1 H), 6.91 (d, J
) 2 Hz, 1 H), 7.40 (m, 2 H); MS (EI) m/z 230 (M+), 187, 44
(100). Anal. (C14H15FN2‚0.5C4H4O4) C, H, F, N.
P r ep a r a tion of (S)-2-(4,4,7-Tr im eth yl-1,4-d ih yd r oin -
d en o[1,2-b]p yr r ol-1-yl)-1-m eth yleth yla m in e Fu m a r a te (1:
1) (14k ) (Sta n d a r d P r oced u r e H). 13k (1.1 g, 3.92 mmol)
dissolved in ethanol (50 mL) was hydrogenated over platinum
oxide (110 mg) for 4 h at room temperature. The catalyst was
subsequently filtered off and rinsed with ethanol, and the
solution was evaporated. The colorless residue was dissolved
in ether (80 mL), filtered, and treated while stirring with a
solution of fumaric acid (455 mg, 3.92 mmol) in methanol (15
mL). The mixture was stirred at room temperature for 24 h,
and the crystals were subsequently filtered off to give 14k (805
(S)-2-(7-Ch lor o-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-yl)-1-
m eth yleth yla m in e fu m a r a te (1:0.55) (14h ): 67%; mp 197
1
°C; [R]20 ) +16.0o (c ) 0.25, MeOH); H NMR (DMSO-d6) δ
D
1.01 (d, J ) 5 Hz, 3 H), 3.30 (m, 1 H), 3.43 (s, 3 H), 4.08 (dd,
J ) 10, 7 Hz, 1 H), 4.27 (dd, J ) 10, 4 Hz, 1 H), 6.15 (d, J )
2 Hz, 1 H), 6.46 (s, 1.1 H), 6.93 (d, J ) 2 Hz, 1 H), 7.07 (dd, J
) 7, 1 Hz, 1 H), 7.41 (d, J ) 7 Hz, 1 H), 7.60 (d, J ) 1 Hz, 1
mg, 77%) as a white solid: mp 196 °C; [R]20 ) +11.2° (c )
H); MS (EI) m/z 246 (M+), 203, 44 (100). Anal. (C14H15
ClN2‚0.55C4H4O4) C, H, Cl, N.
-
D
1
0.25, MeOH); H NMR (DMSO-d6) δ 1.08 (d, J ) 5 Hz, 3 H),
1.32 (s, 6 H), 2.32 (s, 3 H), 3.44 (m, 1 H), 4.14 (dd, J ) 10, 7
Hz, 1 H), 4.41 (dd, J ) 10, 4 Hz, 1 H), 6.06 (d, J ) 2 Hz, 1 H),
6.51 (s, 2 H), 6.79 (d, J ) 2 Hz, 1 H), 6.84 (d, J ) 7 Hz, 1 H),
7.23 (d, J ) 7 Hz, 1 H), 7.33 (s, 1 H); MS (EI) m/z 254 (M+),
211, 196, 44 (100). Anal. (C17H22N2‚1C4H4O4) C, H, N.
Compounds 14a -j and 14l,m were synthesized according
to standard procedures D, E, F, G, and H.
(S)-2-(7-Br om o-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-yl)-1-
m eth yleth yla m in e fu m a r a te (1:0.5) (14i): 50%; mp 197 °C;
[R]20 ) +14.8° (c ) 0.25, MeOH); 1H NMR (DMSO-d6) δ 1.01
D
(d, J ) 5 Hz, 3 H), 3.29 (m, 1 H), 3.41 (s, 3 H), 4.09 (dd, J )
10, 7 Hz, 1 H), 4.26 (dd, J ) 10, 4 Hz, 1 H), 6.15 (d, J ) 2 Hz,
1 H), 6.46 (s, 1 H), 6.93 (d, J ) 2 Hz, 1 H), 7.21 (dd, J ) 7, 1
Hz, 1 H), 7.35 (d, J ) 7 Hz, 1 H), 7.71 (d, J ) 1 Hz, 1 H); MS
(R,S)-2-(5-Meth oxy-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-
yl)-1-m eth yleth yla m in e fu m a r a te (1:0.5) (14a ): 83%; mp
194 °C; 1H NMR (DMSO-d6) δ 1.01 (d, J ) 5 Hz, 3 H), 3.30 (s,
3 H), 3.31 (m, 1 H), 3.83 (s, 3 H), 4.08 (dd, J ) 10, 7 Hz, 1 H),
4.25 (dd, J ) 10, 4 Hz, 1 H), 6.11 (d, J ) 2 Hz, 1 H), 6.45 (s,
1 H), 6.76 (d, J ) 7 Hz, 1 H), 6.85 (d, J ) 2 Hz, 1 H), 7.22 (m,
(EI) m/z 290,292 (M+), 247,249, 44 (100). Anal. (C14H15
BrN2O‚0.5C4H4O4) C, H, Br, N.
-
(S)-2-(7-Meth yl-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-yl)-1-
m eth yleth yla m in e fu m a r a te (1:0.5) (14j): 65%; mp 194 °C;
[R]20 ) +22.8° (c ) 0.25, MeOH); 1H NMR (DMSO-d6) δ 1.03
D
(d, J ) 5 Hz, 3 H), 2.35 (s, 3 H), 3.34 (m, 1 H), 3.36 (s, 3 H),
4.07 (dd, J ) 10, 7 Hz, 1 H), 4.28 (dd, J ) 10, 4 Hz, 1 H), 6.10
(d, J ) 2 Hz, 1 H), 6.46 (s, 1 H), 6.85 (m, 2 H), 7.28 (d, J ) 7
Hz, 1 H), 7.38 (s, 1 H); MS (EI) m/z 226 (M+), 183, 44 (100).
Anal. (C15H18N2‚0.5C4H4O4) C, H, N.
2
H); MS (EI) m/z 242 (M+), 199, 44 (100). Anal.
(C15H18N2O‚0.5C4H4O4‚0.12MeOH) C, H, N.
(R,S)-2-(6-Meth oxy-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-
yl)-1-m eth yleth yla m in e fu m a r a te (1:0.6) (14b): 61%; mp
1
189 °C; H NMR (DMSO-d6) δ 1.02 (d, J ) 5 Hz, 3 H), 3.33
(S)-2-(7-F lu or o-4,4-d im eth yl-1,4-d ih yd r oin d en o[1,2-b]-
(m, 1 H), 3.39 (s, 3 H), 3.75 (s, 3 H), 4.05 (dd, J ) 10, 7 Hz, 1
H), 4.23 (dd, J ) 10, 4 Hz, 1 H), 6.08 (d, J ) 2 Hz, 1 H), 6.46
(s, 1.2 H), 6.77 (d, J ) 2 Hz, 1 H), 6.79 (dd, J ) 7, 2 Hz, 1 H),
7.08 (d, J ) 2 Hz, 1 H), 7.44 (d, J ) 7 Hz, 1 H); MS (EI) m/z
242 (M+), 199, 44 (100). Anal. (C15H18N2O‚0.6C4H4O4) C, H,
N.
p yr r ol-1-yl)-1-m et h ylet h yla m in e fu m a r a t e (1:1) (14l):
1
70%; mp 211 °C; [R]20 ) +8.8° (c ) 0.25, MeOH); H NMR
D
(DMSO-d6) δ 1.05 (d, J ) 5 Hz, 3 H), 1.35 (s, 6 H), 3.41 (m, 1
H), 4.11 (dd, J ) 10, 7 Hz, 1 H), 4.35 (dd, J ) 10, 4 Hz, 1 H),
6.09 (d, J ) 2 Hz, 1 H), 6.49 (s, 2 H), 6.83 (m, 1 H), 6.87 (d, J
) 2 Hz, 1 H), 7.36 (m, 2 H); MS (EI) m/z 258 (M+), 215, 200,
44 (100). Anal. (C16H19FN2‚1C4H4O4) C, H, F, N.
(R,S)-2-(7-Meth oxy-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-
yl)-1-m eth yleth yla m in e fu m a r a te (1:0.5) (14c): 79%; mp
(S)-2-(7-m eth oxy-4,4-d im eth yl-1,4-d ih yd r o-in d en o[1,2-
1
203 °C; H NMR (DMSO-d6) δ 1.01 (d, J ) 5 Hz, 3 H), 3.33
b]p yr r ol-1-yl)-1-m eth yleth yla m in e fu m a r a te (1:1) (14m ):
1
60%; mp 181 °C; [R]20 ) +10.0° (c ) 0.25, MeOH); H NMR
(m, 1 H), 3.34 (s, 3 H), 3.78 (s, 3 H), 4.07 (dd, J ) 10, 7 Hz, 1
H), 4.26 (dd, J ) 10, 4 Hz, 1 H), 6.11 (d, J ) 2 Hz, 1 H), 6.44
(s, 1 H), 6.63 (dd, J ) 7, 2 Hz, 1 H), 6.85 (d, J ) 2 Hz, 1 H),
7.08 (d, J ) 2 Hz, 1 H), 7.29 (d, J ) 7 Hz, 1 H); MS (EI) m/z
242 (M+), 199, 44 (100). Anal. (C15H18N2O‚0.5C4H4O4) C, H,
N.
D
(DMSO-d6) δ 1.05 (d, J ) 5 Hz, 3 H), 1.32 (s, 6 H), 3.41 (m, 1
H), 3.77 (s, 3 H), 4.09 (dd, J ) 10, 7 Hz, 1 H), 4.33 (dd, J ) 10,
4 Hz, 1 H), 6.06 (d, J ) 2 Hz, 1 H), 6.47 (s, 2 H), 6.59 (dd, J )
7, 1.5 Hz, 1 H), 6.80 (d, J ) 2 Hz, 1 H), 7.03 (d, J ) 1.5 Hz, 1
H), 7.24 (d, J ) 7 Hz, 1 H); MS (EI) m/z 270 (M+), 227, 212, 44
(100). Anal. (C17H22N2O‚1C4H4O4) C, H, N.
(R,S)-2-(8-Meth oxy-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-
yl)-1-m eth yleth yla m in e fu m a r a te (1:0.52) (14d ): 74%; mp
Cell Cu ltu r e a n d Mem br a n e P r ep a r a tion . Membranes
obtained from NIH 3T3 cell lines expressing either human
5HT2A or human 5HT2C receptors were kindly donated by Dr.
Nico Stam (N. V. Organon). For each receptor subtype, a
single batch of membranes were grown using fermentation
techniques previously described.20
1
193 °C; H NMR (DMSO-d6) δ 1.01 (d, J ) 5 Hz, 3 H), 3.32
(m, 1 H), 3.41 (s, 3 H), 3.92 (s, 3 H), 4.21 (dd, J ) 10, 7 Hz, 1
H), 4.38 (dd, J ) 10, 4 Hz, 1 H), 6.12 (d, J ) 2 Hz, 1 H), 6.43
(s, 1.04 H), 6.84 (d, J ) 2 Hz, 1 H), 6.96 (m, 1 H), 7.05 (m, 2
H); MS (EI) m/z 242 (M+), 199, 44 (100). Anal.
(C15H18N2O‚0.52C4H4O4) C, H, N.
Ra d ioliga n d Bin d in g Assa ys. Radioligand binding as-
says were as previously described for the human 5HT2A
receptor with minor modifications for the labeling of human
5HT2C receptors. Briefly, on the day of the experiment,
membranes were thawed and resuspended in 10 times the
original volume of assay buffer. This gives a concentration of
approximately 4 × 105 cells per assay tube. This assay buffer
consisted of Tris-HCl 50 mM, pargyline 10-5 M, MgCl2 5 mM
and ascorbic acid 0.1% pH 7.4. All compounds were dissolved
in 10% DMSO and diluted in assay buffer. Assays were
similar for each receptor and consisted of 100 µL of membrane
preparation (depending on the assay), 50 µL of radioligand
([3H]-5HT 1 nM final concentration for labeling human 5HT2C
receptor binding sites, and [3H]DOB 1 nM final concentration
for labeling human 5HT2A receptors). Nonspecific binding was
defined in the presence of 10 µM 5HT in the case of the human
5HT2C receptor and 10 µM methysergide in the case of the
human 5HT2A receptor. All incubations were performed at
room temperature for 1 h and the reactions stopped by rapid
filtration through Whatmann GF/B filters. The filters were
washed with 3 × 2 mL of Tris-HCl (50 mM, pH 7.4), and the
(R)-2-(7-Meth oxy-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-yl)-
1-m eth yleth yla m in e fu m a r a te (1:0.5) (14e): 68%; mp 207
1
°C; [R]20 ) -21.6° (c ) 0.25, MeOH); H NMR (DMSO-d6) δ
D
1.02 (d, J ) 5 Hz, 3 H), 3.32 (m, 1 H), 3.34 (s, 3 H), 3.78 (s, 3
H), 4.07 (dd, J ) 10, 7 Hz, 1 H), 4.26 (dd, J ) 10, 4 Hz, 1 H),
6.10 (d, J ) 2 Hz, 1 H), 6.45 (s, 1 H), 6.61 (dd, J ) 7, 2 Hz, 1
H), 6.86 (d, J ) 2 Hz, 1 H), 7.09 (d, J ) 2 Hz, 1 H), 7.29 (d, J
) 7 Hz, 1 H); MS (EI) m/z 242 (M+), 199, 44 (100). Anal.
(C15H18N2O‚0.5C4H4O4) C, H, N.
(S)-2-(7-Meth oxy-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-yl)-
1-m eth yleth yla m in e fu m a r a te (1:0.5) (14f): 77%; mp 206
1
°C; [R]20 ) +23.2° (c ) 0.25, MeOH); H NMR (DMSO-d6) δ
D
1.01 (d, J ) 5 Hz, 3 H), 3.32 (m, 1 H), 3.34 (s, 3 H), 3.78 (s, 3
H), 4.07 (dd, J ) 10, 7 Hz, 1 H), 4.26 (dd, J ) 10, 4 Hz, 1 H),
6.10 (d, J ) 2 Hz, 1 H), 6.44 (s, 1 H), 6.62 (dd, J ) 7, 2 Hz, 1
H), 6.86 (d, J ) 2 Hz, 1 H), 7.09 (d, J ) 2 Hz, 1 H), 7.29 (d, J
) 7 Hz, 1 H); MS (EI) m/z 242 (M+), 199, 44 (100). Anal.
(C15H18N2O‚0.5C4H4O4) C, H, N.
(S)-2-(7-F lu or o-1,4-d ih yd r oin d en o[1,2-b]p yr r ol-1-yl)-1-
m et h ylet h yla m in e fu m a r a t e (1:0.5) (14g): 54%; mp 194

2768 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17
Bo¨s et al.
radioactivity retained on the filters was measured by scintil-
lation spectroscopy in 2 mL of scintillation fluid. All experi-
ments were performed in triplicate and repeated at least three
times.
cup located within the apparatus. The test session was 1 h.
The experimental compounds were given in 0.3% (w/v) Tween-
80 in distilled water in a volume of 2 mL/kg body weight.
Treatment was administered 30 min prior to the start of
testing. The same group of 10 rats was used to test vehicle
and each of the selected doses of a test compound (doses chosen
at half-logarithmic units in the dose range 1-30 mg/kg). Test
days alternated with training days on which the session
proceeded in the same manner as on test days, except no
treatment was given and no data were recorded. A bottle
containing tap water attached to the test apparatus was
always available during test sessions with intake measured
to the nearest 1 g. Evaluation was done to compare the effect
of each dose to that obtained for the vehicle condition using a
two-tailed Wilcoxon test with a p-value of e0.05 accepted as
statistically significant. The lowest dose tested which yielded
a statistically significant difference to vehicle treatment (MED,
minimum effective dose) was determined.
Saturation analyses were performed for each receptor using
at least eight concentrations of each radioligand (concentra-
tions ranging from 0.05 to 10 nM). Dissociation constants (Kd)
were calculated using the EBDA/LIGAND program.21,22
Displacement curves were constructed for each compound
at each receptor using seven concentrations of the displacing
agents (one data point per log unit of concentration: 10-11
-
10-5 M). Displacement curves were analyzed using EBDA/
LIGAND to calculate pKi values.
Ra d ioliga n d s. Radioligands were purchased from New
England Nuclear. The specific activities of [3H]5HT and [3H]-
DOB were 29.7 and 15.0 Ci/mmol.
Tissu e P r ep a r a tion a n d In cu ba tion for Mea su r em en t
of IP 3 P r od u ction . 5HT2C receptor-mediated stimulation of
IP3 production was measured in the choroid plexus of the rat.
The choroid plexus was removed, placed in 200 µL of oxygen-
ated Krebs solution, and incubated with 0.35 nmol of myo-
inositol and 0.35 nmol of [3H]myoinositol for 1 h at 37 °C.
During this incubation, the tubes were gassed with 95%
oxygen/5% CO2 every 20 min. A mixture of LiCl and pargyline
was then added (final concentration: LiCl ) 10 mM, pargyline
) 10 µM) and 10 min later the test compounds (final incuba-
tion volume ) 250 µL). Dose-response curves were con-
structed from data obtained from three separate measures per
data point. The mixture was incubated for a further 0.5 h at
37 °C. The assays were stopped by the addition of 25 µL of a
stopping solution (HClO4 2.64 N + EDTA 40 mM). Assay
tubes were frozen on dry ice for 15 min, thawed, and then kept
on ice for 1 h. The tubes were then centrifuged for 20 min at
24000g. Then, 250 µL of the supernatant was removed and
placed in Eppendorf tubes together with 25 µL of 4 M KOH.
The samples were mixed well and kept on ice for 15 min.
These samples were then recentrifuged for 15 min at 14 000
rpm. We removed 230 µL of supernatant and added 30 µL of
phytic acid. The isolation of IP3 was as described in a previous
report.23
A concentration response curve was constructed for 5HT,
mCPP, and several synthesized compounds. Six concentra-
tions were used per test compound with the highest concentra-
tion tested being 0.1 mM. The maximal effect produced by
each compound was compared to the stimulation induced by
10 µM 5HT in order to calculate the relative intrinsic activity.
In Vivo F u n ction a l Test. In the test used to evaluate
5HT2C receptor agonism in vivo, elicitation of penile erection
was determined in RORO rats (Biological Research Labora-
tories, CH-4414 Fu¨llinsdorf, Switzerland). All drugs were
dissolved or microsuspended in 0.3% v/v Tween-80 in physi-
ological saline. All drug solutions were freshly prepared and
injected subcutaneously (sc) in a volume of 5 mL/kg body
weight or administered orally in a volume of 10 mL/kg body
weight. Control animals were injected with an equivalent
volume of vehicle. When drug solutions were prepared from
a salt of the compound, the doses refer to the weight of the
salt. Eight rats were tested per dose and were individually
placed in Plexiglas cages (30 × 25 × 10 cm) to allow counting
over a 45 min observation period. When a substance was
active in inducing penile erections, half maximal effective doses
(ED50) were calculated by probit analysis. In those instances
in which not all rats exhibited penile erection, then the
approximate doses producing penile erection in half of the rats
was used.
Ack n ow led gm en t. We would like to express our
thanks to Serge Burner, Rolf Canesso, Annick Grus-
chwitz, Benedikt Hofstetter, and Philipp Oberli for their
skillful technical assistance, Dr. Wolf Arnold for the
NMR spectra, Walter Meister for the mass spectra, and
Dr. Stephan Mu¨ller for the microanalyses.
Refer en ces
(1) Pa¨lvima¨ki, E.-P.; Roth, B. L.; Majasuo, H.; Laakso, A.; Kuop-
pama¨ki, M.; Syva¨lahti, E.; Hietala, J . Interactions of selective
serotonin reuptake inhibitors with the serotonin 5HT2C receptor.
Psychopharmacology 1996, 126, 234-240.
(2) J enck, F.; Moreau, J .-L.; Mutel, V.; Martin, J . R.; Haefely, W.
E. Evidence for a role of 5HT1C receptors in the antiserotonergic
properties of some antidepressant drugs. Eur. J . Pharmacol.
1993, 231, 223-229.
(3) Glennon, A. R.; J acyno, J . M.; Young, R.; McKenney, J . D.;
Nelson, D. Synthesis and evaluation of a novel series of N,N-
dimethylisotryptamines. J . Med. Chem. 1984, 27, 41-45.
(4) Nichols, D. E.; Oberlender, R.; McKenna, D. J . Stereochemical
aspects of hallucinogenesis. In Biochemistry and Physiology of
Substance Abuse, Volume III; Watson, R. R., Ed.; CRC Press:
Boca Raton, 1991; pp 1-39.
(5) Wood, A.; Smith, C.; Szewczak, M.; Dunn, R. W.; Cornfeldt, M.;
Corbett, R. Selective serotonin re-uptake inhibitors decrease
schedule-induced polydipsia in rats:
a model for obsessive
compulsive disorder. Psychopharmacology 1993, 112, 195-198.
(6) Kalir, A.; Szara, S. Synthesis and pharmacological activity of
fluorinated tryptamine derivatives. J . Med. Chem. 1963, 6, 716-
719.
(7) Murakami, Y.; Saito, Y. J apanese Patent 01, 31,760, 1989; Chem.
Abstr. 1989, 111, 115035t.
(8) Wender, P. A.; White, A. W. Methodology for the facile and regio-
controlled synthesis of indoles. Tetrahedron 1983, 39, 3767-
3776.
(9) Ishikura, T.; Gunji, T. J apanese Patent 01,311,056, 1989; Chem.
Abstr. 1990, 112, 216418w.
(10) Weygand/Hilgetag. Preparative Organic Reactions, 4th ed.;
Martini, A., Ed.; Wiley: New York, 1970; p 185.
(11) Berendsen, H. H. G.; J enck, F.; Broekkamp, C. L. E. Involvement
of 5HT1C receptors in drug-induced penile erections in rats.
Psychopharmacology 1990, 101, 57-61.
(12) Hoffman, A. â-Phenylisobutylmethyl ketone and its derivatives.
The synthesis of R- and of â-Phenylvalerianic acid. J . Am. Chem.
Soc. 1929, 51, 2542-2547.
(13) Smith, J . G.; Massicotte, M. P. Synthesis of 1,1-dimethylindane
derivatives having synthetically useful substituents at the 5- and
6-position. Org. Prep. Proced. Int. 1978, 10, 123-131.
(14) Corse, J .; Rohrmann, E. Preparation of some substituted â-phen-
ylisovaleric acids. J . Am. Chem. Soc. 1948, 70, 370-371.
(15) Loudon, J . D.; Razdan, R. K. Rearrangement of chromanones
and dihydrocoumarines by aluminium chloride. J . Chem. Soc.
1954, 4299.
Sch ed u le-In d u ced P olyd ip sia Ta sk in Ra ts. Excessive
drinking was induced in adult female RORO rats (Biological
Research Laboratories, CH-4414 Fu¨llinsdorf, Switzerland)
through the use of a fixed-time operant schedule (FT-1 min).
The rats were drug experienced and were food deprived
overnight prior to each test session. The test apparatus
consisted of a sound-attenuated chamber surrounding a Plexi-
glas test box (30 × 25 × 30 cm) which was equipped with a
stainless-steel grid floor and a mechanism to permit the
automatic delivery of one 45-mg food pellet (Formula A/I; P.
J . Noyes Company, Inc., Lancaster, NH) each min into a food
(16) Barco, A.; Benetti, S.; Pollini, G. P. Concerning the synthesis of
4-methoxyindan-1-one. Org. Prep. Proced. Int. 1976, 8, 7-11.
(17) Olivier, M.; Marechal, E. Etude de monomeres halogenes et de
leur polimerisation cationique. I. Synthese de divers fluoro-
indenes. Bull. Soc. Chim. Fr. 1973, 11, 3092-3095. Olivier, M.;
Marechal, E. Etude de monomeres halogenes et de leur polimer-
isation cationique. II. Synthese de divers chloroindenes. Bull.
Soc. Chim. Fr. 1973, 11, 3096-3099.
(18) Hannig, E.; Heyde, R.; Matschiner, H. Zur Kenntnis einiger
2-aminomethylierter kernsubstituierter Indanone-(1). Pharma-
zie 1973, 28, 217-220.

Novel Agonists of 5HT2C Receptors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2769
(19) Budhram, R. S.; Palaniswami, V. A.; Eisenbraun, E. J . Steric
effects in the synthesis of 1,7-Dialkylindanes. J . Org. Chem.
1986, 51, 1402-1406.
(20) Sleight, A. J .; Stam N. J .; Mutel, V.; Vanderheyden, P. M. L.
Radiolabelling of the human 5HT2A receptor with an agonist, a
partial agonist and an antagonist: Effects on apparent agonist
affinities. Biochem. Pharmacol. 1996, 51, 71-76.
(22) Munson, P.; Rodbard, D. LIGAND: A versatile computerized
approach for the characterization of ligand-binding system. Anal.
Biochem. 1980, 107, 220-239.
(23) Bourson, A.; Wanner, D.; Wyler, R.; Petit, N.; Zwingelstein, C.;
Rudler, A.; Sleight, A. J . Pharmacological evaluation of the
discriminative stimulus of mCPP. Pharmacol. Biochem. Behav.
1995, 53, 107-114.
(21) McPherson, G. A. 1985, Biosoft, Cambridge.
J M970030L