Novel Agonists of 5HT

2C
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

Mi chael Bos,* Franc oi s Jenck, James R. Marti n, Jean-Luc Moreau, Andrew J. Sl ei ght, Jurgen Wi chmann, and
Ul ri ch Wi dmer
Pharma Division, Preclinical CNS Research, F. Hoffmann-La RocheLtd., CH-4070 Basel, Switzerland
Received J anuary 14, 1997
X
The syntheses of a seri es of substi tuted 2-(i ndol -1-yl )-1-methyl ethyl ami nes and 2-(i ndeno[1,2-
b]pyrrol -1-yl )-1-methyl ethyl ami nes are reported. The bi ndi ng affi ni ti es of the compounds at
5HT
2C
and 5HT
2A
receptors (79% homol ogy i n the transmembrane domai n) were determi ned.
The l i gands di spl ayed sel ecti vi ty for 5HT
2C
receptors rel ati ve to 5HT
2A
receptors. Compounds
were functi onal l y characteri zed both in vitro and in vivo as 5HT
2C
receptor agoni sts. 5f, 5l,
5n, 5o, 5q, 14c, 14f, 14k, and 14mexhi bi ted anti compul si ve acti vi ty i n an ani mal model of
obsessi ve compul si ve di sorder.
Introduction
Sel ecti ve serotoni n reuptake i nhi bi tors (SSRI s) i n-
crease extracellular levels of serotonin (5HT) and thereby
nonsel ecti vel y cause sti mul ati on of al l postsynapti c 5HT
receptor subtypes. SSRI s have become standard therapy
for neuropsychi atri c di sorders such as obsessi ve com-
pul si ve di sorder (OCD), depressi on, and pani c anxi ety.
There i s accumul ati ng evi dence for the i nvol vement of
5HT
2C
receptor-medi ated functi ons i n the therapeuti c
effi cacy of SSRI s.
1,2
The i ncreased 5HTsynapti c content
resul ti ng from the reuptake i nhi bi ti on al so al l ows 5HT
to act on the other 5HT receptor subtypes, possi bl y
expl ai ni ng some of the si de effects associ ated wi th SSRI
treatment. Sel ecti ve 5HT
2C
receptor agoni sts, therefore,
may represent a di rect means to produce the benefi ci al
therapeuti c effects of SSRI s wi thout concomi tant si de
effects.
Our goal was to fi nd 5HT
2C
receptor agoni sts whi ch
(i ) di spl ay at l east 10-fol d sel ecti vi ty versus the 5HT
2A
receptor subtype, for whi ch sequence homol ogy of the
transmembrane regi on i s hi gh, (i i ) show in vivoacti vi ty
after oral admi ni strati on i n functi onal model s of 5HT
2C
receptor acti vati on, and (i i i ) demonstrate therapeuti c
potenti al i n an ani mal model of obsessi ve compul si ve
di sorder.
Gl ennon et al . have shown that N,N-di methyl i so-
tryptami nes, i .e. deri vati ves of N,N-di methyl -2-(i ndol -
1-yl )ethyl ami nes are i sosteri c wi th the correspondi ng
N,N-di methyl tryptami nes wi th respect to serotoni n
receptor affi ni ty.
3
Such compounds are readi l y avai l abl e
vi a N-al kyl ati on. We therefore screened i sotryptami nes
for 5HT
2C
receptor affi ni ty and extended our study to
the methyl ene homol ogues 1,4-di hydroi ndeno[1,2-b]pyr-
rol es.
I n thi s paper we report on the synthesi s and the
pharmacol ogy of i ndol es and 1,4-di hydroi ndeno[1,2-b]-
pyrrol es i n whi ch a 2-ami nopropyl si de chai n i s attached
to the N atom of the heterocycl e. I n anal ogy to phenyl -
al kyl ami nes, the R-methyl group was i ncorporated i n
order to suppress metabol i c si de chai n deami nati on and
to i ncrease the l i pophi l i ci ty of the compounds, al l owi ng
better CNS penetrati on.
4
Wi thi n these seri es of com-
pounds we have i denti fi ed agoni sts to the 5HT
2C
recep-
tor bi ndi ng wi th hi gh affi ni ty and sel ecti vi ty versus the
5HT
2A
receptor. Some of these new l i gands were
eval uated i n rats i n the schedul e-i nduced pol ydi psi a
paradi gm, an ani mal model of obsessi ve compul si ve
di sorder.
5
As a compari son we have i ncl uded 5-fl uoro-
R-tryptami ne (15)
6
and fl uoxeti ne i n our study.
Chemistry
Substi tuted 2-(i ndol -1-yl )-1-methyl ethyl ami nes 5were
prepared accordi ng to Scheme 1. Deprotonati on of
i ndol es 1 fol l owed by al kyl ati on wi th propyl ene oxi de
l ed to the secondary al cohol s 2. S
N
2 reacti on of the
correspondi ng mesyl ates 3 wi th sodi um azi de and
reducti on of the azi des 4wi th ei ther hydrogen or Li Al H
4
produced the ami nes 5 wi th excel l ent yi el ds. The
enanti omeri cal l y pure compounds 5k-qwere prepared
from the (R)- or (S)-epoxi de wi th i nversi on of confi gu-
rati on at the stereogeni c center. The monosubsti tuted
i ndol es are commerci al l y avai l abl e.
The di hal ogenated bui l di ng bl ocks can be prepared
from the correspondi ng di hal ogenated ni trotol uenes as
descri bed i n the patent l i terature.
7
For the synthesi s
of 5-chl oro-6-fl uoroi ndol e 1k we have adopted a protocol
devel oped by Wender and Whi te
8
(Scheme 2). 2-Bromo-
4-chl oro-3-fl uorophenyl ami ne (6)
9
was acyl ated wi th
tri fl uoroaceti c anhydri de to gi ve 7. Upon treatment
wi th methyl l i thi um and tert-butyl l i thi um, a di l i thi um

Dedi cated to Prof. Dr. Di eter Seebach on the occasi on of hi s 60th

bi rthday.
X
Abstract publ i shed i n AdvanceACS Abstracts, Jul y 15, 1997.
Scheme 1
a
a
(a) Propyl ene oxi de, NaH, THF; (b) MsCl , NEt3, CH2Cl 2; (c)
NaN3, DMF; (d) PtO2, H2, EtOH.
2762 J . Med. Chem. 1997, 40, 2762-2769
S0022-2623(97)00030-7 CCC: $14.00 1997 Ameri can Chemi cal Soci ety
reagent was formed whi ch underwent cycl i zati on wi th
chl oroacetal dehyde
10
to the hydroxyami de 8. Dehydra-
ti on fol l owed by hydrol ysi s gave 1k i n ni ne steps and
an overal l yi el d of 15%.
The preparati on of the substi tuted 1,4-di hydroi ndeno-
[1,2-b]pyrrol es i s shown i n Scheme 3. Al kyl ati on of the
i ndan-1-ones 9 was performed by Cl ai sen rearrange-
ment of an in situ formed al l yl vi nyl ether system.
Ozonol ysi s of 10and subsequent cl eavage of the acetal
wi th TFA l ed to the 1,4-di carbonyl compounds 11, whi ch
were then reacted wi th commerci al l y avai l abl e 1-ami no-
2-propanol [(S), (R), (RS)] to yi el d the 1,4-di hydroi ndeno-
[1,2-b]pyrrol es 12. The secondary al cohol s were trans-
formed i nto the ami nes 14vi a the azi des 13as descri bed
for the synthesi s of the i ndol e deri vati ves 5.
Pharmacology
The affi ni ty of the compounds for 5HT
2C
and 5HT
2A
human receptors was assessed usi ng di spl acement of
[
3
H]5HT and [
3
H]DOB, respecti vel y. To assess func-
ti onal effi cacy at 5HT
2C
receptors, the l i gands were
eval uated for sti mul ati on of phosphoi nosi tol turnover
i n the choroi d pl exus of the rat. The compounds were
al so assessed for i nducti on of peni l e erecti on i n rats
whi ch i s a symptom of the serotoni n syndrome refl ecti ng
5HT
2C
receptor acti vati on i n rodents.
11
Fi nal l y, com-
pounds whi ch di spl ayed i nteresti ng in vivoacti vi ty were
further tested i n the schedul e-i nduced pol ydi psi a model
of OCD i n rats for potenti al anti compul si ve effects.
5
Results
The radi ol i gand bi ndi ng experi ments (Tabl e 1) showed
hi gher affi ni ty of the i ndol es 5 and the i ndeno[1,2-b]-
pyrrol es 14for 5HT
2C
bi ndi ng si tes than for the struc-
tural l y (79% homol ogy between the transmembrane
regi ons) very si mi l ar 5HT
2A
receptor. Compounds wi th
hal ogen substi tuents i n posi ti on 4, 5, and 6 of the i ndol e
ri ng possess hi gher affi ni ti es for thi s receptor subtype
as compared to deri vati ves beari ng el ectron-donati ng
substi tuents such as methoxy and methyl groups. The
di hal ogenated i ndol es showed the hi ghest 5HT
2C
recep-
tor affi ni ti es. The (S)-enanti omers di spl ay hi gher af-
Scheme 2
a
k
a
(a) (CF3CO)2O, Na2CO3, di ethyl ether; (b) MeLi , t-BuLi , -100
C, chl oroacetal dehyde, THF; (c) p-TsA, tol uene; (d) NaOH, MeOH.
Scheme 3
a
a
(a) 3-Buten-2-ol , p-TsA, 2,2-di methoxypropane; (b) ozone,
CH2Cl 2-MeOH; (c) TFA, CH2Cl 2; (d) 1-ami no-2-propanol , p-TsA,
tol uene; (e) MsCl , NEt3, CH2Cl 2; (f) NaN3, DMF; (g) PtO2, H2,
EtOH.
Table 1. Substi tuents, Bi ndi ng Affi ni ti es (pKi ) for 5HT2A and
5HT2C Receptors, Effi cacy (pEC50 and I ntri nsi c Acti vi ty) i n
I nduci ng I P3 Formati on in Vitro, and Sel ecti vi ty Rati o
5HT2C:5HT2A for 5, 14, and 15
I P3 formati on
pKi
compd R 5HT2A 5HT2C pEC50
i ntri nsi c
acti vi ty rati o
5a(R,S) 5-OMe not tested 6.1 ( 0.03 5.0 0.3
5b(R,S) 4- OMe not tested 6.9 ( 0.08 4.9 0.3
5c(R,S) 4-Me 7.0 ( 0.01 8.2 ( 0.08 5.6 0.6 16
5d(R,S) 4-F 6.8 ( 0.06 8.1 ( 0.03 5.9 0.7 20
5e(R,S) 5-Me 6.1 ( 0.01 7.2 ( 0.03 5.6 0.9 12.5
5f(R,S) 5-F 6.8 ( 0.02 8.2 ( 0.13 5.8 1 25
5g(R,S) 5-Cl 6.7 ( 0.04 8.1 ( 0.01 5.7 0.9 25
5h(R,S) 5-Br 6.8 ( 0.06 8.4 ( 0.07 5.7 0.8 40
5i(R,S) 6-Me 6.1 ( 0.01 7.8 ( 0.06 5.1 0.9 50
5j(R,S) 6-F 6.6 ( 0.05 8.4 ( 0.12 6.2 1 63
5k(R) 5-F,6-Cl 7.1 ( 0.02 8.0 ( 0.04 5.5 1 8
5l(S) 5-F,6-Cl 7.5 ( 0.04 8.9 ( 0.03 6.7 1 25
5m(R) 5-F,6-F 7.0 ( 0.03 8.4 ( 0.02 6.9 1 25
5n(S) 5-F,6-F 7.0 ( 0.02 9.0 ( 0.04 6.7 1 100
5o(S) 5-Cl ,6-F 7.4 ( 0.02 8.7 ( 0.04 6.4 1 20
5p(R) 4-Cl ,5-F 8.0 ( 0.03 8.9 ( 0.02 6.1 0.9 8
5q(S) 4-Cl ,5-F 7.4 ( 0.03 8.9 ( 0.11 6.5 1 32
14a(RS) 5-OMe 5.5 ( 0.06 7.0 ( 0.01 i nact 32
14b(RS) 6-OMe 6.4 ( 0.02 7.9 ( 0.04 5.7 1 32
14c(RS) 7-OMe 6.9 ( 0.06 9.0 ( 0.23 6.4 1 125
14d(RS) 8-OMe 6.4 ( 0.03 7.9 ( 0.08 5.2 0.7 32
14e(R) 7-OMe 6.9 ( 0.06 8.4 ( 0.04 5.1 0.8 32
14f(S) 7-OMe 6.9 ( 0.01 9.0 ( 0.2 6.6 1 125
14g(S) 7-F 6.7 ( 0.04 8.5 ( 0.05 6.2 1 63
14h(S) 7-Cl 6.7 ( 0.09 8.4 ( 0.02 5.6 0.8 50
14i(S) 7-Br 7.0 ( 0.03 8.4 ( 0.09 5.6 1 25
14j(S) 7-Me 7.2 ( 0.1 8.1 ( 0.08 6.3 1 8
14k(S) 4,4-Me,
7-Me
7.0 ( 0.04 8.5 ( 0.17 6.7 1 32
14l(S) 4,4-Me,
7-F
7.5 (0.01 8.3 ( 0.09 6.7 1 6
14m(S) 4,4-Me,
7-OMe
8.0 ( 0.03 9.4 ( 0.1 7.0 1 25
15(R,S) 7.2 ( 0.02 8.2 ( 0.02 6.8 0.9 10
Table 2. ED50 (mg/kg) for I nduci ng Peni l e Erecti on i n Rats
after sc or po Admi ni strati on for 5, 14, and 15
5a >10 sc 14a >10 sc
5b >10 sc 14b >10 sc
5c 3.2 sc, >30 po 14c 0.6 sc, 11 po
5d >10 sc 14d >10 sc
5e >10 sc 14e 2 sc, >30 po
5f 1 sc, 2.7 po 14f 1.2 sc, 10 po
5g 2.3 sc, >30 po 14g 1.5 sc, >30 po
5h 4 sc, >30 po 14h 2.7 sc, >30 po
5i 3.3 sc, >30 po 14i >10 sc
5j 0.3 sc, >30 po 14j >10 sc
5k 2.1 sc, >30 po 14k 0.9 sc, 10 po
5l 0.5 sc, 5.5 po 14l 2.7 sc, >30 po
5m 2.7 sc, 30 po 14m 0.5 sc, 10 po
5n 0.3 sc, 10 po 15 0.8 sc, 9.9 po
5o 1 sc, 15 po
5p 3.3 sc, i nact po
5q 2.7 sc, >30 po
Novel Agonists of 5HT2C Receptors J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2763
fi ni ty and sel ecti vi ty for the 5HT
2C
receptor as compared
to thei r anti podes. Sel ecti vi ty rati os of 20-100 were
found for the (S)-confi gured i somers (e.g. 5l and 5n).
I n the seri es of the i ndeno[1,2-b]pyrrol es 14, the
opti mal posi ti on for aromati c substi tuti on turned out
to be posi ti on 7. I n contrast to the i ndol es, methoxy-
substi tuted i ndeno[1,2-b]pyrrol es (e.g. 14f and 14m)
show i ncreased affi ni ti es i n compari son to the hal oge-
nated compounds and for the (S)-confi gured i somers
sel ecti vi ty rati os of up to 125 were observed.
For the study i t was of i nterest to compare one of the
potent and sel ecti ve l i gands wi th the structural i somer.
The fl uori nated tryptami ne deri vati ve 15di spl ays si mi -
l ar affi ni ty for the 5HT
2C
receptor as the i somer 5j, but
wi th reduced sel ecti vi ty rel ati ve to the 5HT
2A
receptor.
The effect of the 5HT
2C
receptor l i gands i n sti mul ati ng
phosphoi nosi tol formati on (cf. I P
3
formati on, pEC
50
,
i ntri nsi c acti vi ty, Tabl e 1) was studi ed i n rat choroi d
pl exus. Compounds 5a-d, 14a, and 14d i nduced onl y
a submaxi mal i ncrease whereas the maxi mum re-
sponses of the other deri vati ves 5e-q, 14b, 14c, 14e-
m, and 15were the same as that produced by 5HT(10
-5
M, i ntri nsi c acti vi ty ) 1), suggesti ng that these l i gands
are ful l agoni sts at the 5HT
2C
receptor (cf. 5n, 14m, and
15, Fi gure 1). I n vivo resul ts, i .e. i nducti on of peni l e
erecti ons, are presented i n Tabl e 2 (al though not shown
here, the reference compound fl uoxeti ne was found to
i nduce peni l e erecti on wi th ED
50
) 4.3 mg/kg sc).
SSRI s such as fl uoxeti ne are currentl y i n use for the
treatment of OCD. These drugs, however, exhi bi t a
del ayed onset of acti on and l ess than opti mal therapeu-
ti c effi cacy. Schedul e-i nduced pol ydi psi a i n rats has
been proposed as a model of OCD.
5
I n thi s model , food-
depri ved rats whi ch recei ve i ntermi ttentl y del i vered
food pel l ets on a fi xed-ti me schedul e typi cal l y devel op
a pattern of excessi ve dri nki ng, i .e. pol ydi psi a. Thi s
paradi gm has been pharmacol ogi cal l y val i dated as a
model of OCD. Experi mental compounds are tested i n
thi s model for thei r abi l i ty to attenuate pol ydi psi c
behavi or, i .e. for thei r potenti al anti -OCD effects. The
sel ected 5HT
2C
receptor agoni sts eval uated i n the
schedul e-i nduced pol ydi psi a model al l si gni fi cantl y re-
duced the excessi ve dri nki ng wi th MED val ues (mi ni mal
effecti ve dose; i .e. the l owest dose tested whi ch was
found to stati sti cal l y si gni fi cantl y reduce water i ntake
rel ati ve to vehi cl e treatment) wi thi n the dose range
1-30 mg/kg (i p) wi th doses sel ected at hal f-l ogari thmi c
uni ts (cf. Tabl e 3). The magni tude of the suppressi on
of pol ydi psi a was compared among al l of these com-
pounds for the doses up to 10 mg/kg and was found to
be 75% or more. I n compari son, fl uoxeti ne was much
l ess potent, fi rst achi evi ng a stati sti cal l y si gni fi cant
reducti on i n water i ntake of onl y 11% at 30 mg/kg i p
(wi th no appreci abl e effect at doses up to 10 mg/kg i p).
Conclusions
Compounds were i denti fi ed whi ch exhi bi ted hi gh-
affi ni ty bi ndi ng to human 5HT
2C
receptors wi th sel ec-
ti vi ty versus 5HT
2A
receptors. Such compounds were
characteri zed in vitro and in vivo as 5HT
2C
agoni sts.
Two of these compounds underwent a broad bi ndi ng
eval uati on: 5l and 14k exhi bi ted affi ni ty for several
other 5HT receptor subtypes (1A, 3, 4, 6, 7) whi ch was
at l east 2 l ogari thmi c uni ts l ower than for 5HT
2C
receptors and had I C
50
g 1 m for 26 other receptors
across numerous di fferent neurotransmi tter systems
(unpubl i shed resul ts). I n the i sol ated rat fundus stri p
assay, both 5l and 14k act as agoni sts at the 5HT
2B
receptor (pD
2
) 8.0 and 6.1, respecti vel y; unpubl i shed
resul ts). At present l i ttl e i s known concerni ng the
physi ol ogi cal functi on of 5HT
2B
receptors, due i n part
to the l ack of hi ghl y sel ecti ve l i gands; i nteresti ngl y a
5HT
2C
receptor agoni st whi ch i s structural l y di fferent
from those descri bed i n thi s report and whi ch exhi bi ted
antagoni sti c acti vi ty at the 5HT
2B
receptor was al so
found to reduce schedul e-i nduced pol ydi psi a (unpub-
l i shed resul ts). Therefore the 5HT
2B
receptor i s unl i kel y
to pl ay a major rol e i n the functi onal effects descri bed
here.
These 5HT
2C
receptor agoni sts were found to si gni fi -
cantl y suppress schedul e-i nduced pol ydi psi a i n rats,
even at doses l acki ng any appreci abl e effects on spon-
taneous behavi or. These resul ts suggest that 5HT
2C
receptor agoni sts may be of therapeuti c val ue i n OCD.
I n thi s respect, i t i s i nteresti ng to note that al though
fl uoxeti ne was found to be acti ve i n thi s ani mal model
of OCD, i ts potency was l ow when compared to the dose
range produci ng adverse effects. 5HT
2C
receptor ago-
ni sts may, thus, potenti al l y offer i mproved therapy of
OCD.
Experimental Section
General. Mel ti ng poi nts were determi ned i n capi l l ary
tubes (Buchi 530 apparatus) and are uncorrected. Col umn
chromatography was carri ed out by usi ng si l i ca gel (230-400
Figure1. Effects of 5HT, 5n, 14m, and 15on I P3 formati on
i n the rat choroi d pl exus. Resul ts are expressed as percentage
of the sti mul ati on i n I P3 formati on produced by 10 M 5HT.
Table 3. Acti vi ty i n Schedul e-I nduced Pol ydi psi a Model i n
Rats
compd
mi n
ED
max.
suppressi on
(%) compd
mi n
ED
max.
suppressi on
(%)
5f 3 i p -97 14c 10 i p -79
5l 10 i p -90 14f 1 i p -97
5n 3 i p -73 14k 10 i p -76
5o 3 i p -88 14m 1 i p -75
5q 3 i p -97 fl uoxeti ne 30 i p -11
15 1 i p -96
2764 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 Bos et al.
mesh; Merck) and 0.3-1.0 bar pressure. Spectra were re-
corded wi th the fol l owi ng i nstruments. I R (cm
-1
): Ni col et-
7199-FT-I R.
1
H-NMR ( val ues i n ppm rel ati ve to i nternal
TMS, coupl i ng constants J i n Hertz): Bruker AC-250 (250
MHz). MS: MS9 updated wi th a Fi nni gan MAT data system
SS 200. El ementary anal yses (C, H, N) for novel compounds
were wi thi n 0.4% of the theoreti cal val ues.
5-Methoxyi ndol e, 4-methoxyi ndol e, 4-methyl i ndol e, 5-meth-
yl i ndol e, 5-fl uoroi ndol e, 5-chl oroi ndol e, 5-bromoi ndol e, and
6-methyl i ndol e were purchased from Al dri ch Chemi cal s; 4-
fl uoroi ndol e and 6-fl uoroi ndol e, from Si gma; 5-methoxyi ndan-
1-one and 6-methoxyi ndan-1-one, from Fl uka.
Preparation of (R)-1-(6-Chloro-5-fluoroindol-1-yl)pro-
pan-2-ol (2l) (Standard Procedure A). To a mi xture of
sodi um hydri de (0.09 g, 3.7 mmol ) i n THF (15 mL) was added
6-chl oro-5-fl uoroi ndol e (1k) (0.5 g, 3 mmol ) at 0 C. After 1 h
(R)-propyl ene oxi de (0.42 mL, 6 mmol ) was added, and the
mi xture was sti rred for 48 h at room temperature. The
reacti on was quenched wi th water, and the mi xture was
extracted wi th di ethyl ether and washed wi th bri ne. The
organi c l ayer was dri ed, and the sol vent was removed. The
resi due was subjected to chromatography (tol uene/ethyl ac-
etate, 19:1, as el uent) to yi el d 2l (0.51 g, 74%) as whi te
crystal s: mp 104-105 C; [R]
20
436 ) -60.4
o
(c ) 0.25, CHCl 3);
1
H NMR (CDCl 3) 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/z227 (M
+
), 182 (100). Anal . (C11H11-
Cl FNO) C, H, N.
Preparation of (S)-1-(2-Azidopropyl)-6-chloro-5-fluor-
oindole (4l) (Standard Procedure B). To a sol uti on of 2l
(0.28 g, 1.2 mmol ) i n di chl oromethane (6 mL) and tri ethy-
l ami ne (0.5 mL) was added methanesul fonyl chl ori de (0.2 mL,
2.5 mmol ) at 0 C. After 1 h ether was added and the mi xture
was extracted wi th 1 M sodi um carbonate and washed wi th
bri ne. The organi c l ayer was dri ed, and the sol vent was
removed. The resi due was taken up i n DMF (6 mL), and
sodi um azi de (0.16 g, 2.4 mmol ) was added. The reacti on
mi xture was heated for 7 h at 60 C, poured i nto water, and
extracted wi th ether. The organi c l ayer was dri ed, and the
sol vent was removed. The resi due was puri fi ed by col umn
chromatography (tol uene as el uent) to yi el d 4l as yel l ow oi l
(0.29 g, 93%):
1
H NMR (CDCl 3) 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).
Preparation of (S)-2-(6-Chloro-5-fluoroindol-1-yl)-1-
methylethylamineFumarate(1:1.6) (5l) (Standard Pro-
cedureC). A suspensi on of 0.02 g of PtO2 i n ethanol (5 mL)
was sti rred under hydrogen for 0.5 h. After the addi ti on of a
sol uti on of 4l (0.26 g, 1 mmol ) i n ethanol (5 mL), the mi xture
was sti rred for 2 h, the catal yst was fi l tered off, and the sol vent
was removed. The sal t was prepared i n ether by treatment
wi th fumari c aci d to yi el d 0.25 g (59%) of 5l: mp 169-171 C;
[R]
20
436 ) 31.6 (c ) 0.25, MeOH);
1
H NMR (DMSO-d6) 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); MS (EI ) m/z 226 (M
+
), 183, 44 (100). Anal .
(C11H12FCl N21.6C4H4O4) C, H, N.
Compounds 5a-k and 5m-q were synthesi zed accordi ng
to standard procedures A, B, and C.
(R,S)-2-(5-Methoxyindol-1-yl)-1-methylethylaminefu-
marate(1:1) (5a):62%; mp 175-176 C dec;
1
H NMR (DMSO-
d6) 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 . (C12H16N2OC4H4O4) C, H, N.
(R,S)-2-(4-Methoxyindol-1-yl)-1-methylethylaminefu-
marate (1:0.5) (5b): 59%; mp 185-186 C dec;
1
H NMR
(DMSO-d6) 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
) 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 . (C12H16N2O0.5C4H4O4) C, H, N.
(R,S)-2-(4-Methylindol-1-yl)-1-methylethylaminefuma-
rate (1:1) (5c): 92%; mp 163-164 C dec;
1
H NMR (DMSO-
d6) 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 . (C12H16N2C4H4O4)
C, H, N.
(R,S)-2-(4-Fluoroindol-1-yl)-1-methylethylaminefuma-
rate (1:1) (5d): mp 179-180 C dec;
1
H NMR (DMSO-d6)
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 . (C11H13FN2C4H4O4) C, H, N.
(R,S)-2-(5-Methylindol-1-yl)-1-methylethylaminefuma-
rate (1:1) (5e): 87%; mp 165-167 C dec;
1
H NMR (DMSO-
d6) 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 . (C12H16N2C4H4O4) C,
H, N.
(R,S)-2-(5-Fluoroindol-1-yl)-1-methylethylaminefuma-
rate (1:1) (5f): 95%; mp 169-170 C dec;
1
H NMR (DMSO-
d6) 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 .
(C11H13FN2C4H4O4) C, H, N.
(R,S)-2-(5-Chloroindol-1-yl)-1-methylethylaminefuma-
rate (1:2) (5g): mp 183-185 C dec;
1
H NMR (DMSO-d6)
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 . (C11H13Cl N2
2C4H4O4) C, H, N.
(R,S)-2-(5-Bromoindol-1-yl)-1-methylethylaminefuma-
rate (1:1) (5h): 93%; mp 196-197 C dec;
1
H NMR (DMSO-
d6) 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 .
(C11H13BrN2C4H4O4) C, H, N.
(R,S)-2-(6-Methylindol-1-yl)-1-methylethylaminefuma-
rate (1:1) (5i): 60%; mp 152-153 C dec;
1
H NMR (DMSO-
d6) 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.
(R,S)-2-(6-Fluoroindol-1-yl)-1-methylethylaminefuma-
rate(1:1) (5j): 78%; mp 158-159 C dec;
1
H NMR (DMSO-d6)
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 .
(C11H13FN2C4H4O4) C, H, N.
(R)-2-(6-Chloro-5-fluoroindol-1-yl)-1-methylethyl-
amine fumarate (1:1.5) (5k): 69%; mp 153-154 C dec;
[R]
20
436 ) -28.8 (c) 0.25, MeOH);
1
H NMR (DMSO-d6) 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 . (C11H12FCl N21.5C4H4O4) C, H, N.
Novel Agonists of 5HT2C Receptors J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2765
(R)-2-(5,6-Difluoroindol-1-yl)-1-methylethylamine fu-
marate(1:1) (5m):82%; mp 161-162 C dec; [R]
20
436 ) -34.4
(c ) 0.25, MeOH);
1
H NMR (DMSO-d6) 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 . (C11H12F2N2C4H4O4) C, H, N.
(S)-2-(5,6-Difluoroindol-1-yl)-1-methylethylamine fu-
marate(1:1) (5n):84%; mp 159-160 C dec; [R]
20
436 ) +35.2
(c ) 0.25, MeOH). Anal . (C11H12F2N2C4H4O4) C, H, N.
(S)-2-(5-Chloro-6-fluoroindol-1-yl)-1-methylethyl-
amine fumarate (1:1) (5o): mp 158-160 C dec; [R]
20
D )
+35.2
o
(c ) 0.25, MeOH);
1
H NMR (DMSO-d6) 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 . (C11H12FCl N2C4H4O4) C, H, N.
(R)-2-(4-Chloro-5-fluoroindol-1-yl)-1-methylethyl-
aminefumarate(1:1) (5p):84%; mp 186-187 C dec; [R]
20
436
) -32.4
o
(c ) 0.25, MeOH);
1
H NMR (DMSO-d6) 1.08 (d, J
) 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 . (C11H12FCl N2C4H4O4) C, H, N.
(S)-2-(4-Chloro-5-fluoroindol-1-yl)-1-methylethyl-
aminefumarate(1:1) (5q): 84%; mp 183-184 C dec; [R]
20
436
) +32.4 (c ) 0.25, MeOH). Anal . (C11H12FCl N2C4H4O4) C,
H, N.
N-(2-Bromo-5-chloro-4-fluorophenyl)trifluoroaceta-
mide (7). To a sol uti on of 2-bromo-4-chl oro-3-fl uoropheny-
l ami ne (6) (111 g, 0.5 mol ) i n ether (990 mL) at 0 C were added
sol i d Na2CO3 (78 g) and tri fl uoroaceti c anhydri de (86 mL, 0.9
mol ). After bei ng warmed to room temperature the suspensi on
was sti rred for 2.5 h, di l uted wi th ether, and extracted wi th
water. The organi c l ayer was separated and dri ed (sodi um
sul fate), and the sol vent was removed. The resi due was
recrystal l i zed from n-hexane to yi el d 7as yel l ow crystal s (136
g, 86%): mp 86-88 C;
1
H NMR (CDCl 3) 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 . (C8H3F4Cl BrNO) C, H, N.
(R,S)-1-(Trifluoroacetyl)-6-chloro-5-fluoro-3-hydroxy-
2,3-dihydro-1H-indole (8). A sol uti on of 7(24 g, 75 mmol )
i n THF (750 mL) was cool ed to -100 C. MeLi (75 mmol , 1.6
M i n ether) was added, and 10 mi n l ater t-BuLi (150 mL, 1.7
M i n pentane) was al so added. After 1 h at -100 C a sol uti on
of chl oroacetal dehyde (67.5 mL, 1.7 M i n THF) was added. The
mi xture was sti rred at -78 C for 4 h, and aceti c aci d (13 mL)
was added. After the addi ti on of tri ethyl ami ne (52 mL), the
reacti on mi xture was al l owed to warm to ambi ent temperature
and to sti r for 14 h. Ammoni um chl ori de sol uti on (20%, 150
mL) was added, fol l owed by extracti on wi th ether. The organi c
l ayer was separated and dri ed (sodi um sul fate), and the sol vent
was removed. The resi due was puri fi ed by col umn chroma-
tography (tol uene/ethyl acetate, 19:1) to yi el d 8 (13g, 61%):
mp 97.5-98 C;
1
H NMR (CDCl 3) 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-
Cl NO2) C, H, N.
6-Chloro-5-fluoroindole(1k). A sol uti on of 8(5.5 g, 19.5
mmol ) and p-tol uenesul foni c aci d monohydrate (0.19 g, 0.9
mmol ) i n tol uene (200 mL) was heated at refl ux temperature
for 2 h. The sol vent was removed, and the resi due was
di ssol ved i n methanol (800 mL). After the addi ti on of NaOH
(1 N, 800 mL), the mi xture was refl uxed for 2.5 h. Methanol
was removed, and the crystal s were fi l tered off and dri ed: yi el d
77%; mp 104-105 C;
1
H NMR (CDCl 3) 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).
Preparation of (R,S)-2-(2-Buten-1-yl)-3,3,6-trimethyl-
1-indanone (10i) (Standard Procedure D). A sol uti on of
3,3,6-tri methyl i ndan-1-one (9i)
12-14
(18.9 g, 108 mmol ), 3-buten-
2-ol (22.4 mL, 0.26 mol ), and p-tol uenesul foni c aci d (300 mg)
i n 2,2-di methoxypropane (200 mL) was boi l ed under refl ux for
64 h on a Dean-Stark trap fi l l ed wi th mol ecul ar si eves (0.4
nm, 2 mm pearl shaped). The sol vents were evaporated, and
the resi due was puri fi ed by col umn chromatography on si l i ca
gel (hexane/ethyl acetate, 6:1) to gi ve 10i (12.7 g, 51%) as a
yel l ow oi l :
1
H NMR (CDCl 3) 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 i n the same
way from 4-methoxyi ndan-1-one (9a),
15
5-methoxyi ndan-1-one
(9b), 6-methoxyi ndan-1-one (9c), 7-methoxyi ndan-1-one (9d),
16
6-fl uoroi ndan-1-one (9e),
17
6-chl oroi ndan-1-one (9f),
16
6-bro-
moi ndan-1-one (9g),
17,18
6-methyl i ndan-1-one (9h),
19
6-fl uoro-
3,3-di methyl i ndan-1-one (9j),
12-14,17
and 6-methoxy-3,3-di meth-
yl i ndan-1-one (9k),
12-15
respecti vel y.
Preparation of (R,S)-2-(2-Oxoethyl)-3,3,6-trimethyl-1-
indanone(11i) (StandardProcedureE). An ozone stream
(2.5 g of ozone/h) was conducted for 1 h whi l e sti rri ng through
a sol uti on of 10i (12.7 g, 55.6 mmol ) i n di chl oromethane (200
mL) and methanol (40 mL) cool ed to -70 C. Subsequentl y,
the sol uti on was fl ushed wi th oxygen for 5 mi n and wi th argon
for 10 mi n. After the addi ti on of di methyl sul fi de (6.12 mL,
83.4 mmol ), the mi xture was sti rred at room temperature for
18 h. The reacti on mi xture was evaporated, the resi due was
treated wi th di chl oromethane (150 mL) and after the addi ti on
of water (25 mL) and tri fl uoroaceti c aci d (25 mL), the mi xture
was sti rred at room temperature for 2.5 h. The mi xture was
subsequentl y poured i nto water (150 mL) and neutral i zed
whi l e sti rri ng by addi ti on of hydrogen carbonate. Water (100
mL) was added, the phases were separated, and the aqueous
phase was extracted twi ce wi th di chl oromethane (150 mL each
ti me). The combi ned organi c phases were dri ed (magnesi um
sul fate) and concentrated to gi ve 11i (11.3 g, 94%) as a l i ght
yel l ow oi l :
1
H NMR (CDCl 3) 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.
Preparation of (R)-1-(4,4,7-Trimethyl-1,4-dihydroin-
deno[1,2-b]pyrrol-1-yl)propan-2-ol (12k) (Standard Pro-
cedure F). A sol uti on of 11i (2.16 g, 10 mmol ) and p-tol u-
enesul foni c aci d (80 mg) i n tol uene (90 mL) was heated on a
Dean-Stark trap. A sol uti on of (R)-1-ami no-2-propanol (3.0
g, 40 mmol ) i n tol uene (20 mL) was added dropwi se over a
peri od of 5 mi n. Subsequentl y, the mi xture was boi l ed for an
addi ti onal 45 mi n, duri ng whi ch the sol vent was reduced to a
vol ume of 20 mL. The cool ed reacti on mi xture was puri fi ed
by col umn chromatography (ethyl acetate/hexane, 1:2) to yi el d
12k (1.5 g, 59%) as a brown oi l :
1
H NMR (CDCl 3) 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.
Preparation of (S)-1-(2-Azidopropyl)-4,4,7-trimethyl-
1,4-dihydroindeno[1,2-b]pyrrole(13k) (Standard Proce-
dureG). Methanesul fonyl chl ori de (0.91 mL, 11.7 mmol ) was
added dropwi se whi l e sti rri ng to a sol uti on, cool ed to 0 C, of
12k (1.5 g, 5.87 mmol ) and tri ethyl ami ne (3.27 mL, 23.5 mmol )
i n di chl oromethane (50 mL), and the mi xture was sti rred at
thi s temperature for an addi ti onal 1.5 h. The reacti on mi xture
was subsequentl y di l uted wi th di chl oromethane (150 mL),
washed twi ce wi th saturated sodi um hydrogen carbonate
sol uti on (70 mL each ti me) and once wi th bri ne (70 mL), dri ed
(magnesi um sul fate), and evaporated. The resi due was di s-
sol ved i n DMF (50 mL) and treated wi th sodi um azi de (0.76
g, 11.7 mmol ) and the mi xture was heated to 60 C for 15 h
whi l e sti rri ng. After cool i ng the sol uti on was poured i nto
water (100 mL) and extracted twi ce wi th ethyl acetate (100
mL each ti me). The combi ned organi c phases were washed
once wi th water (100 mL) and once wi th bri ne (100 mL), dri ed
(magnesi um sul fate) and evaporated. The resi due was puri fi ed
by col umn chromatography (hexane/ethyl acetate 4:1) to gi ve
13k (1.13 g, 68%) as a reddi sh oi l :
1
H NMR (CDCl 3) 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
2766 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 Bos et al.
(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.
Preparation of (S)-2-(4,4,7-Trimethyl-1,4-dihydroin-
deno[1,2-b]pyrrol-1-yl)-1-methylethylamineFumarate(1:
1) (14k) (Standard Procedure H). 13k (1.1 g, 3.92 mmol )
di ssol ved i n ethanol (50 mL) was hydrogenated over pl ati num
oxi de (110 mg) for 4 h at room temperature. The catal yst was
subsequentl y fi l tered off and ri nsed wi th ethanol , and the
sol uti on was evaporated. The col orl ess resi due was di ssol ved
i n ether (80 mL), fi l tered, and treated whi l e sti rri ng wi th a
sol uti on of fumari c aci d (455 mg, 3.92 mmol ) i n methanol (15
mL). The mi xture was sti rred at room temperature for 24 h,
and the crystal s were subsequentl y fi l tered off to gi ve 14k (805
mg, 77%) as a whi te sol i d: mp 196 C; [R]
20
D ) +11.2 (c )
0.25, MeOH);
1
H NMR (DMSO-d6) 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 . (C17H22N21C4H4O4) C, H, N.
Compounds 14a-j and 14l,m were synthesi zed accordi ng
to standard procedures D, E, F, G, and H.
(R,S)-2-(5-Methoxy-1,4-dihydroindeno[1,2-b]pyrrol-1-
yl)-1-methylethylamine fumarate (1:0.5) (14a): 83%; mp
194 C;
1
H NMR (DMSO-d6) 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,
2 H); MS (EI ) m/z 242 (M
+
), 199, 44 (100). Anal .
(C15H18N2O0.5C4H4O40.12MeOH) C, H, N.
(R,S)-2-(6-Methoxy-1,4-dihydroindeno[1,2-b]pyrrol-1-
yl)-1-methylethylamine fumarate (1:0.6) (14b): 61%; mp
189 C;
1
H NMR (DMSO-d6) 1.02 (d, J ) 5 Hz, 3 H), 3.33
(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 . (C15H18N2O0.6C4H4O4) C, H,
N.
(R,S)-2-(7-Methoxy-1,4-dihydroindeno[1,2-b]pyrrol-1-
yl)-1-methylethylamine fumarate (1:0.5) (14c): 79%; mp
203 C;
1
H NMR (DMSO-d6) 1.01 (d, J ) 5 Hz, 3 H), 3.33
(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 . (C15H18N2O0.5C4H4O4) C, H,
N.
(R,S)-2-(8-Methoxy-1,4-dihydroindeno[1,2-b]pyrrol-1-
yl)-1-methylethylaminefumarate(1:0.52) (14d):74%; mp
193 C;
1
H NMR (DMSO-d6) 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 .
(C15H18N2O0.52C4H4O4) C, H, N.
(R)-2-(7-Methoxy-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-
1-methylethylamine fumarate (1:0.5) (14e): 68%; mp 207
C; [R]
20
D ) -21.6 (c ) 0.25, MeOH);
1
H NMR (DMSO-d6)
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 .
(C15H18N2O0.5C4H4O4) C, H, N.
(S)-2-(7-Methoxy-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-
1-methylethylamine fumarate (1:0.5) (14f): 77%; mp 206
C; [R]
20
D ) +23.2 (c ) 0.25, MeOH);
1
H NMR (DMSO-d6)
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 .
(C15H18N2O0.5C4H4O4) C, H, N.
(S)-2-(7-Fluoro-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-1-
methylethylamine fumarate (1:0.5) (14g): 54%; mp 194
C; [R]
20
D ) +16.8 (c ) 0.25, MeOH);
1
H NMR (DMSO-d6)
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 . (C14H15FN20.5C4H4O4) C, H, F, N.
(S)-2-(7-Chloro-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-1-
methylethylamine fumarate (1:0.55) (14h): 67%; mp 197
C; [R]
20
D ) +16.0
o
(c ) 0.25, MeOH);
1
H NMR (DMSO-d6)
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
H); MS (EI ) m/z 246 (M
+
), 203, 44 (100). Anal . (C14H15-
Cl N20.55C4H4O4) C, H, Cl , N.
(S)-2-(7-Bromo-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-1-
methylethylaminefumarate(1:0.5) (14i):50%; mp 197 C;
[R]
20
D ) +14.8 (c ) 0.25, MeOH);
1
H NMR (DMSO-d6) 1.01
(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
(EI ) m/z 290,292 (M
+
), 247,249, 44 (100). Anal . (C14H15-
BrN2O0.5C4H4O4) C, H, Br, N.
(S)-2-(7-Methyl-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-1-
methylethylaminefumarate(1:0.5) (14j): 65%; mp 194 C;
[R]
20
D ) +22.8 (c ) 0.25, MeOH);
1
H NMR (DMSO-d6) 1.03
(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 . (C15H18N20.5C4H4O4) C, H, N.
(S)-2-(7-Fluoro-4,4-dimethyl-1,4-dihydroindeno[1,2-b]-
pyrrol-1-yl)-1-methylethylamine fumarate (1:1) (14l):
70%; mp 211 C; [R]
20
D ) +8.8 (c ) 0.25, MeOH);
1
H NMR
(DMSO-d6) 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 . (C16H19FN21C4H4O4) C, H, F, N.
(S)-2-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-
b]pyrrol-1-yl)-1-methylethylaminefumarate(1:1) (14m):
60%; mp 181 C; [R]
20
D ) +10.0 (c ) 0.25, MeOH);
1
H NMR
(DMSO-d6) 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 . (C17H22N2O1C4H4O4) C, H, N.
Cell CultureandMembranePreparation. Membranes
obtai ned from NI H 3T3 cel l l i nes expressi ng ei ther human
5HT2A or human 5HT2C receptors were ki ndl y donated by Dr.
Ni co Stam (N. V. Organon). For each receptor subtype, a
si ngl e batch of membranes were grown usi ng fermentati on
techni ques previ ousl y descri bed.
20
Radioligand Binding Assays. Radi ol i gand bi ndi ng as-
says were as previ ousl y descri bed for the human 5HT2A
receptor wi th mi nor modi fi cati ons for the l abel i ng of human
5HT2C receptors. Bri efl y, on the day of the experi ment,
membranes were thawed and resuspended i n 10 ti mes the
ori gi nal vol ume of assay buffer. Thi s gi ves a concentrati on of
approxi matel y 4 10
5
cel l s per assay tube. Thi s assay buffer
consi sted of Tri s-HCl 50 mM, pargyl i ne 10
-5
M, MgCl 2 5 mM
and ascorbi c aci d 0.1% pH 7.4. Al l compounds were di ssol ved
i n 10% DMSO and di l uted i n assay buffer. Assays were
si mi l ar for each receptor and consi sted of 100 L of membrane
preparati on (dependi ng on the assay), 50 L of radi ol i gand
([
3
H]-5HT1 nM fi nal concentrati on for l abel i ng human 5HT2C
receptor bi ndi ng si tes, and [
3
H]DOB 1 nM fi nal concentrati on
for l abel i ng human 5HT2A receptors). Nonspeci fi c bi ndi ng was
defi ned i n the presence of 10 M 5HTi n the case of the human
5HT2C receptor and 10 M methysergi de i n the case of the
human 5HT2A receptor. Al l i ncubati ons were performed at
room temperature for 1 h and the reacti ons stopped by rapi d
fi l trati on through Whatmann GF/B fi l ters. The fi l ters were
washed wi th 3 2 mL of Tri s-HCl (50 mM, pH 7.4), and the
Novel Agonists of 5HT2C Receptors J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2767
radi oacti vi ty retai ned on the fi l ters was measured by sci nti l -
l ati on spectroscopy i n 2 mL of sci nti l l ati on fl ui d. Al l experi -
ments were performed i n tri pl i cate and repeated at l east three
ti mes.
Saturati on anal yses were performed for each receptor usi ng
at l east ei ght concentrati ons of each radi ol i gand (concentra-
ti ons rangi ng from 0.05 to 10 nM). Di ssoci ati on constants (Kd)
were cal cul ated usi ng the EBDA/LI GAND program.
21,22
Di spl acement curves were constructed for each compound
at each receptor usi ng seven concentrati ons of the di spl aci ng
agents (one data poi nt per l og uni t of concentrati on: 10
-11
-
10
-5
M). Di spl acement curves were anal yzed usi ng EBDA/
LI GAND to cal cul ate pKi val ues.
Radioligands. Radi ol i gands were purchased from New
Engl and Nucl ear. The speci fi c acti vi ti es of [
3
H]5HTand [
3
H]-
DOB were 29.7 and 15.0 Ci /mmol .
TissuePreparation andIncubation for Measurement
of IP3 Production. 5HT2C receptor-medi ated sti mul ati on of
I P3 producti on was measured i n the choroi d pl exus of the rat.
The choroi d pl exus was removed, pl aced i n 200 L of oxygen-
ated Krebs sol uti on, and i ncubated wi th 0.35 nmol of myo-
i nosi tol and 0.35 nmol of [
3
H]myoi nosi tol for 1 h at 37 C.
Duri ng thi s i ncubati on, the tubes were gassed wi th 95%
oxygen/5%CO2 every 20 mi n. A mi xture of Li Cl and pargyl i ne
was then added (fi nal concentrati on: Li Cl ) 10 mM, pargyl i ne
) 10 M) and 10 mi n l ater the test compounds (fi nal i ncuba-
ti on vol ume ) 250 L). Dose-response curves were con-
structed from data obtai ned from three separate measures per
data poi nt. The mi xture was i ncubated for a further 0.5 h at
37 C. The assays were stopped by the addi ti on of 25 L of a
stoppi ng sol uti on (HCl O4 2.64 N + EDTA 40 mM). Assay
tubes were frozen on dry i ce for 15 mi n, thawed, and then kept
on i ce for 1 h. The tubes were then centri fuged for 20 mi n at
24000g. Then, 250 L of the supernatant was removed and
pl aced i n Eppendorf tubes together wi th 25 L of 4 M KOH.
The sampl es were mi xed wel l and kept on i ce for 15 mi n.
These sampl es were then recentri fuged for 15 mi n at 14 000
rpm. We removed 230 L of supernatant and added 30 L of
phyti c aci d. The i sol ati on of I P3 was as descri bed i n a previ ous
report.
23
A concentrati on response curve was constructed for 5HT,
mCPP, and several synthesi zed compounds. Si x concentra-
ti ons were used per test compound wi th the hi ghest concentra-
ti on tested bei ng 0.1 mM. The maxi mal effect produced by
each compound was compared to the sti mul ati on i nduced by
10 M 5HTi n order to cal cul ate the rel ati ve i ntri nsi c acti vi ty.
I n Vi vo Functional Test. I n the test used to eval uate
5HT2C receptor agoni sm in vivo, el i ci tati on of peni l e erecti on
was determi ned i n RORO rats (Bi ol ogi cal Research Labora-
tori es, CH-4414 Ful l i nsdorf, Swi tzerl and). Al l drugs were
di ssol ved or mi crosuspended i n 0.3% v/v Tween-80 i n physi -
ol ogi cal sal i ne. Al l drug sol uti ons were freshl y prepared and
i njected subcutaneousl y (sc) i n a vol ume of 5 mL/kg body
wei ght or admi ni stered oral l y i n a vol ume of 10 mL/kg body
wei ght. Control ani mal s were i njected wi th an equi val ent
vol ume of vehi cl e. When drug sol uti ons were prepared from
a sal t of the compound, the doses refer to the wei ght of the
sal t. Ei ght rats were tested per dose and were i ndi vi dual l y
pl aced i n Pl exi gl as cages (30 25 10 cm) to al l ow counti ng
over a 45 mi n observati on peri od. When a substance was
acti ve i n i nduci ng peni l e erecti ons, hal f maxi mal effecti ve doses
(ED50) were cal cul ated by probi t anal ysi s. I n those i nstances
i n whi ch not al l rats exhi bi ted peni l e erecti on, then the
approxi mate doses produci ng peni l e erecti on i n hal f of the rats
was used.
Schedule-InducedPolydipsiaTask in Rats. Excessi ve
dri nki ng was i nduced i n adul t femal e RORO rats (Bi ol ogi cal
Research Laboratori es, CH-4414 Ful l i nsdorf, Swi tzerl and)
through the use of a fi xed-ti me operant schedul e (FT-1 mi n).
The rats were drug experi enced and were food depri ved
overni ght pri or to each test sessi on. The test apparatus
consi sted of a sound-attenuated chamber surroundi ng a Pl exi -
gl as test box (30 25 30 cm) whi ch was equi pped wi th a
stai nl ess-steel gri d fl oor and a mechani sm to permi t the
automati c del i very of one 45-mg food pel l et (Formul a A/I ; P.
J. Noyes Company, I nc., Lancaster, NH) each mi n i nto a food
cup l ocated wi thi n the apparatus. The test sessi on was 1 h.
The experi mental compounds were gi ven i n 0.3%(w/v) Tween-
80 i n di sti l l ed water i n a vol ume of 2 mL/kg body wei ght.
Treatment was admi ni stered 30 mi n pri or to the start of
testi ng. The same group of 10 rats was used to test vehi cl e
and each of the sel ected doses of a test compound (doses chosen
at hal f-l ogari thmi c uni ts i n the dose range 1-30 mg/kg). Test
days al ternated wi th trai ni ng days on whi ch the sessi on
proceeded i n the same manner as on test days, except no
treatment was gi ven and no data were recorded. A bottl e
contai ni ng tap water attached to the test apparatus was
al ways avai l abl e duri ng test sessi ons wi th i ntake measured
to the nearest 1 g. Eval uati on was done to compare the effect
of each dose to that obtai ned for the vehi cl e condi ti on usi ng a
two-tai l ed Wi l coxon test wi th a p-val ue of e0.05 accepted as
stati sti cal l y si gni fi cant. The l owest dose tested whi ch yi el ded
a stati sti cal l y si gni fi cant di fference to vehi cl e treatment (MED,
mi ni mum effecti ve dose) was determi ned.
Acknowledgment. We woul d l i ke to express our
thanks to Serge Burner, Rol f Canesso, Anni ck Grus-
chwi tz, Benedi kt Hofstetter, and Phi l i pp Oberl i for thei r
ski l l ful techni cal assi stance, Dr. Wol f Arnol d for the
NMR spectra, Wal ter Mei ster for the mass spectra, and
Dr. Stephan Mul l er for the mi croanal yses.
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