Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2, 1-a]isoindol-6(2H)-one, a selective, orally active agonist of the 5-HT 2C receptor

Article abstract of DOI:10.1021/jm0612968

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone- containing, selective 5-HT_2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a] isoindol-6(2H)-one (58), a 5-HT_2C agonist with > 300-fold functional selectivity over 5-HT_2B and > 70-fold functional selectivity over 5-HT_2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT_2C antagonist and caused a reduction in body weight gain in a 4-day rat model.

Full text of DOI:10.1021/jm0612968

J. Med. Chem. 2007, 50, 1365-1379
1365
Discovery of (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-
6(2H)-one, a Selective, Orally Active Agonist of the 5-HT2C Receptor
Dean A. Wacker,* Jeffrey G. Varnes, Sarah E. Malmstrom, Xueying Cao, Chen-Pin Hung, Thao Ung, Ginger Wu, Ge Zhang,
Eva Zuvich, Michael A. Thomas, William J. Keim, Mary Jane Cullen, Kenneth W. Rohrbach, Qinling Qu, Rangaraj Narayanan,
Karen Rossi, Evan Janovitz, Lois Lehman-McKeeman, Mary F. Malley, James Devenny, Mary Ann Pelleymounter,
Keith J. Miller, and Jeffrey A. Robl
Departments of DiscoVery Chemistry, Metabolic Diseases, Lead EValuation, Computer-Assisted Drug Design, DiscoVery Toxicology,
and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400,
Princeton, New Jersey 08543-5400
ReceiVed NoVember 7, 2006
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently
marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-
containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone
core was the identification of the appropriate substitution pattern and functional groups which led to the
discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a
5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over
5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely
reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
Introduction
Obesity is recognized as a major global public health issue.
In the U.S., greater than 66% of the adult population are
considered overweight with a body-mass index (BMI) of >25,
and 32% are classified as obese with a BMI > 30.1 Furthermore,
obesity rates are climbing every year, and, if this trend continues,
Figure 1. Published and proposed 5-HT2C agonists.
obesity will overtake smoking as the leading cause of prevent-
able deaths in the U.S. The issue is not limited to the U.S. or
developed countries, as studies indicate that obesity rates are
rising in every part of the world.2 The increasing prevalence of
obesity is seen across all age groups, and the rate of morbid
obesity is increasing at an even faster rate than obesity.
Obesity negatively affects both the physical and psychological
health of patients. The prevalence of serious, chronic health
problems such as coronary heart disease, hypertension, stroke,
diabetes, arthritis, and some cancers have been correlated to
the severity of obesity.3 For example, it has been estimated that
controlling obesity would reduce the incidence of hypertension
by 48% in Caucasians and 28% in African Americans.4 Also,
evidence from numerous studies indicate that a causal relation-
ship exists between obesity and reduced self-esteem and a lower
quality of life, especially in children.5 Given the widespread
nature of this disease, there is an increasing importance in
finding new treatments for obesity.
Historically, antiobesity pharmacotherapy has focused on
modulation of neurotransmitter receptor activity. The elevation
of monoaminergic neurotransmitter levels by inhibition of
reuptake mechanisms, stimulation of release mechanisms, or
direct activation of the neurotransmitter receptors has provided
several antiobesity drugs such as sibutramine, phentermine, and
dexfenfluramine. However, these drugs have had limited success
because of several undesirable side effects presumably arising
from a lack of receptor selectivity, such as valvular hypertrophy,
pulmonary hypertension, and abuse potential. To overcome these
issues, more recent research has focused on the selective
regulation of the neurotransmitter receptors and, specifically,
serotonin receptors.
Several serotonin receptors have been implicated in the
regulation of appetite, however, a growing body of evidence
implicates 5-HT2C as a primary contributor. In preclinical
models, the nonselective 5-HT2B/2C agonist m-chlorophenylpip-
erazine (mCPP) reduces food intake in rats.6 This effect is
attenuated by the selective 5-HT2C antagonist SB-2420867 and
is absent in 5-HT2C receptor knock-out mice.8 In clinical settings,
mCPP reduces appetite and body weight of both normal and
obese human subjects.9 In light of these results, our efforts have
focused on discovering new structural motifs with potent 5-HT2C
agonist activity. The challenge has been to identify compounds10
that are also selective over the homologous 5-HT2A receptor,
to eliminate the unwanted side-effect of hallucinogenesis, and
5-HT2B receptor, to reduce the possibility of valvular hyper-
trophy.11
A series of tetracyclic indolines, exemplified by 1 (Figure
1), were reported by Bristol-Myers Squibb to be potent and
selective 5-HT2C agonists.12 Selected compounds from the series
exhibited excellent sustained efficacy in in vivo models out to
14 weeks in duration. Unfortunately, the tetracyclic indolines
had unwanted toxicities believed to be associated with the
amphiphilic nature of the molecules, such as parietal cell
necrosis. This toxicity has been observed with multiple 5-HT2C
agonist structural motifs.13 To overcome these issues, we have
focused on retaining the three-dimensional orientation of the
basic amine in relation to the core phenyl ring, while reducing
the size and more evenly distributing the polarity of the
molecule. The pyrazinoisoindolone core structure 2 offered the
* To whom correspondence should be addressed. Phone: 609-818-5381.
Fax: 609-818-3331. E-mail: dean.wacker@bms.com.
10.1021/jm0612968 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/23/2007

1366 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Scheme 1. Synthesis of Pyrazinoisoindolones (Method A)a
Wacker et al.
a Reagents: (a) (1) Oxalyl chloride, 0.1 equiv of DMF, CH2Cl2, (2) 2.2 equiv of diethylamine, CH2Cl2; (b) (1) s-BuLi, TMEDA, THF, -78 °C, 15 min,
then DMF, -78 °C to rt, 1 h; (c) 6 M aq HCl, reflux, 16 h; (d) NaOAc, NaCN, N-Cbz-ethylenediamine hydrochloride, 2:1 EtOH:AcOH; (e) 60 psi H2, 10%
Pd/C, concd HCl, MeOH; (f) (1) Boc2O, CH2Cl2, (2) chiral separation, (3) 12 M HCl; (g) (1) NBS, concd H2SO4, (2) Boc2O, Na2CO3, THF; (h) (1)
R9-B(OH)2, Pd(PPh3)4, K2CO3, DME, H2O, reflux or R9-Sn(n-Bu)3, Pd(PPh3)4, Tol, reflux, (2) 12 M HCl.
Scheme 2. Alternative Synthesis of Pyrazinoisoindolones (Method B)a
a Reagents: (a) NaOAc, NaCN, 2,2-diethoxyethylamine, 2:1 EtOH:AcOH; (b) 1 atm H2, Raney Ni, EtOH; (c) (1) 12 M HCl, (2) NaBH(OAc)3, MeOH,
ClCH2CH2Cl, (3) Boc2O, Na2CO3, EtOAc; (d) 12 M HCl.
potential to accomplish these goals. A puckered shape is retained
at the piperazine ring fusion, while a polar amide is centrally
located in the structure. This paper reports the optimization of
the pyrazinoisoindolone core and identification of (R)-9-ethyl-
1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-
6(2H)-one (58), a potent and selective orally bioavailable 5HT2C
agonist.
with 12 M HCl, afforded final alkyl products 11. Absolute
configuration was determined by X-ray crystallography.15
Alternatively, when the starting benzoic acids had substituents
that were sensitive to hydrogenation conditions with palladium
on carbon, a slightly modified synthetic scheme was used relying
on a Raney nickel-catalyzed reduction (Scheme 2). Isobenzo-
furans 6 were treated with sodium cyanide and 2,2-diethoxy-
ethylamine to provide nitriles 12 in good yield. The cyano group
of 12 was reduced with Raney nickel and hydrogen to yield
intermediates 13. Treatment of 13 with 12 M HCl for 30 min
and then reaction with NaBH(OAc)3 gave the cyclized products
which were protected with di-tert-butyl dicarbonate to facilitate
purification and chiral separation if desired. The final products
9 were obtained by removal of the protecting group with 12 M
HCl.
Chemistry. Two general synthetic routes, based on the work
of Welch,14 were developed for the synthesis of the pyrazi-
noisoindolone core structures (Schemes 1 and 2). The first route
began with readily available benzoic acids 3, which were
converted to the corresponding diethyl amides 4 with oxalyl
chloride and diethylamine in excellent yield. Benzamides 4 were
then deprotonated with sec-butyllithium and TMEDA, and the
resulting anions were quenched with DMF to provide intermedi-
ates 5. Isobenzofurans 6 were formed by refluxing 5 with 6 M
aq HCl overnight. Utilizing the procedures of Welch,14 6 was
reacted with sodium cyanide and N-Cbz-ethylenediamine hy-
drochloride to produce compounds 7. The cyanoisoindolones 7
were cyclized in the presence of palladium on carbon and
hydrogen to yield final products 8. To obtain the chiral products,
compounds 8 were reacted with di-tert-butyl dicarbonate and
the resulting N-Boc carbamates were separated by chiral HPLC.
Deprotection with 12 M HCl afforded the chiral final products
9. Derivatives of the 7-CF3-substituted pyrazinoisoindolone core
were synthesized by reacting 8 with concd H2SO4 and N-
bromosuccinimide to yield intermediate bromide 10. Alkylation
of 10 under Suzuki or Stille conditions, followed by enantio-
meric resolution by chiral HPLC and subsequent deprotection
Compounds with alkyl substitutuents at C1 of the pyrazi-
noisoindolone core were synthesized from isobenzofuran 6a
(Scheme 3). Treatment of 6a with N-Boc-ethylenediamine
hydrochloride and NaBH(OAc)3 yielded isoindolone 14. Inter-
mediate 14 was deprotonated with sec-butyllithium, and the
resulting anion was then quenched with the desired aldehyde.
Alcohols 15 were then oxidized to the corresponding ketones
16 under Dess-Martin conditions. Intermediates 16 were
cyclized to the corresponding enamines with 12 M HCl and
protected with di-tert-butyl dicarbonate and DMAP to yield 17.
This protection was necessary for optimal reduction of the
enamines in the next step. The final products 18 were then
synthesized by reduction of 17 with palladium on carbon and

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1367
Scheme 3. Synthesis of 1-Substituted Pyrazinoisoindolone Corea
a Reagents: (a) NaBH(OAc)3, N-Boc-ethylenediamine hydrochloride, AcOH, ClCH2CH2Cl; (b) (1) s-BuLi, THF, -78 °C, 15 min, (2) RCOH, -78 °C
- 0 °C, 5 min; (c) Dess-Martin periodinane, CH2Cl2; (d) (1) 12 M aq HCl, Et2O, (2) Boc2O, 2 equiv of DMAP; (e) (1) 60 psi H2, 10% Pd/C, MeOH, (2)
chiral separation; (f) 12 M HCl.
Table 1. In Vitro Activity of the Pyrazinoisoindolone Core
5-HT2C
5-HT2B
5-HT2A
5-HT2C
5-HT2B
5-HT2A
chirality
R7
Ki, nMa
Ki, nMa
Ki, nMa
EC50, nMa, b
EC50, nMa, b
EC50, nMa,b
19
20
21
22
23
24
25
26
27
28
29
30
rac
rac
rac
rac
rac
rac
rac
rac
rac
rac
R
H
630 ( 130
19 ( 10
4540 ( 220
249 ( 87
8540 ( 250
110 ( 2
1500 ( 30
24 ( 11
136 ( 46
26 ( 7
>10000
192 ( 6
207 ( 29
498 ( 31
>10000
501 ( 29
>10000
87 ( 32
>10000
825 ( 49
180 ( 26
>10000
>10000
131 ( 17
>10000
87 ( 14
>10000
1780 ( 140
>10000
111 ( 10
>10000
449 ( 69
176 ( 38
>10000
CF3
OMe
OCF3
F
Cl
CN
SMe
OH
OiPr
CF3
CF3
133 ( 62
20 ( 7
192 ( 26
3280 ( 410
67 ( 4
550 ( 300
3690 ( 400
309 ( 79
3930 ( 270
84 ( 6
1030 ( 350
31 ( 20
300 ( 100
40 ( 12
>10000
586 ( 36
>10000
1730 ( 57
37 ( 2
281 ( 35
42 ( 15
514 ( 26
107 ( 28
7 ( 2
216 ( 78
1670 ( 320
250 ( 100
59 ( 5
980 ( 520
115 ( 48
7 ( 1
3740 ( 490
1600 ( 500
74 ( 10
S
1100 ( 330
3430 ( 620
>10000
1840 ( 100
a Ki and EC50 values were calculated from dose-response curves. Positive control was mCPP which gave 5-HT2C Ki ) 17 ( 2 nM, EC50 ) 15 ( 4 nM;
5-HT2B Ki ) 24 ( 1 nM, EC50 ) 287 ( 94 nM; 5-HT2A Ki ) 48 ( 4 nM, EC50 ) 290 ( 110 nM. b Intrinsic activity for all compounds ) 1 as compared
to serotonin at 3 µM unless noted in parentheses.
hydrogen followed by chiral HPLC resolution and deprotection
with 12 M HCl.
large potency increase when compared to the unsubstituted core.
The fluoro group (23) reduced potency, and the cyano func-
tionality (25) provided little potency advantage. Electron-
donating groups also provided mixed results. While the hydroxyl
moiety (27) decreased potency, the methoxy substituent (21)
provided a modest ∼4-fold increase in potency. Large improve-
ments in both binding and function were obtained with the
trifluoromethoxy (22) and methylthiol (26) functionalities when
compared to 19. The greater potency obtained with 22 and 26
is most likely due to the reduced electron-donating ability of
these functional groups when compared to that of a methoxy
group rather than any hydrophobic contribution. This is sup-
ported by compound 28, which is roughly equipotent with 21,
despite the added methyl groups. To evaluate the potential
potency and selectivity differences between enantiomers, all
racemic compounds were separated into their enantiomerically
pure components. As exemplified by the CF3 analogs (29 and
30), the R-enantiomers in all cases proved to be significantly
more potent than the S-enantiomers. The selectivity differences
between the enantiomers could not be meaningfully addressed
due to the low potency of the S-configured compounds. As a
result, all further optimization studies utilized the R-enantiomeric
configuration. This initial exploration of the pyrazinoisoindolone
Results and Discussion
Lead Identification and Optimization. Our initial operating
assumption was that the core structure of an agonist needed to
have some functional preference for 5-HT2C over 5-HT2B and
5-HT2A if we were to achieve our desired selectivity profile.
The goal of our research was to design a 5-HT2C agonist with
a Ki and EC50 of less than 25 nM and greater than 100-fold
functional selectivity over the 5-HT2B and 5-HT2A receptors.
When we tested the unsubstituted, racemic pyrazinoisoindolone
core (19),14 we were very encouraged by the preliminary binding
and functional assay results (Table 1). Although not extremely
potent, compound 19 was >9-fold functionally selective for
5-HT2C over 5-HT2B and >14-fold over 5-HT2A
.
In order to increase the potency and selectivity of the
pyrazinoisoindolone core, our efforts focused on substituting
the 7-position, which, according to our modeling efforts, was
analogous to the lower ring of the tetracyclic indoline core
previously described. Incorporation of the nonpolar electron-
withdrawing CF3 group (20) provided a compound with a ∼30-
fold increase in potency and similar selectivity as compared to
19. However, not all electron-withdrawing groups provided a

1368 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Table 2. In Vitro Activity of Substituted Piperazine Ring Analogs
Wacker et al.
5-HT2C
5-HT2B
5-HT2A
5-HT2C
5-HT2B
5-HT2A
R1
R2
R3
R4
Ki, nMa
Ki, nMa
Ki, nMa
EC50, nMa,b
EC50, nMa,b
EC50, nMa,b
31
32
33
34
35
36
37
38
39
H
H
H
H
H
H
H
S-Me
S-Et
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
R-Me
S-Me
S-i Pr
H
430 ( 200
1450 ( 61
369 ( 236
321 ( 211
74 ( 24
1580 ( 230
3190 ( 390
3010 ( 580
2350 ( 870
116 ( 16
29 ( 13
4120 ( 100
296 ( 68
1580 ( 250
478 ( 87
>10000
417 ( 35
>10000
>10000
>10000
100 ( 19
40 ( 10
14 ( 5
994 ( 8
>10000
>10000
>10000
370 ( 62
91 ( 2
Me, Me
>10000
S-Me
R-Me
H
H
H
>10000
>10000
360 ( 180
82 ( 26
22 ( 14
117 ( 10
38 ( 19
122 ( 25
91 ( 25
18 ( 9
13 ( 3
7 ( 1
10 ( 7
56 ( 10
78 ( 16
126 ( 28
H
H
29 ( 8
24 ( 1
235 ( 32
28 ( 8
22 ( 6
H
335 ( 7
480 ( 94
293 ( 36
a Ki and EC50 values were calculated from dose-response curves. Positive control was mCPP which gave 5-HT2C Ki ) 17 ( 2 nM, EC50 ) 15 ( 4 nM;
5-HT2B Ki ) 24 ( 1 nM, EC50 ) 287 ( 94 nM; 5-HT2A Ki ) 48 ( 4 nM, EC50 ) 290 ( 110 nM. b Intrinsic activity for all compounds ) 1 as compared
to serotonin at 3 µM unless noted in parentheses.
Table 3. In Vitro Activity of Phenyl Ring Analogs
5-HT2C
5-HT2B
5-HT2A
5-HT2C
5-HT2B
5-HT2A
R7
R8
R9
R10
Ki, nMa
Ki, nMa
Ki, nMa
EC50, nMa,b
EC50, nMa,b
EC50, nMa,b
40
41
42
43
44
45
46
47
48
49
50
51
OMe
Cl
Cl
Cl
CF3
Cl
OMe
OMe
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Et
OMe
Et
Cl
Me
Et
OMe
Cl
H
H
H
H
H
5060 ( 780
927 ( 11
425 ( 41
59 ( 42
>10000
>10000
NT
NT
290 ( 51
274 ( 51
>1000
NT
>3000
730 ( 170
547 ( 170
1420 ( 610
4030 ( 680
70 ( 11
4010 ( 740
2420 ( 130
86 ( 1
54 ( 12
46 ( 21
5 ( 1
3280 ( 640
220 ( 120
>3000
H
1084 ( 43
107 ( 5
1473 ( 61
383 ( 37
813 ( 69
43 ( 6
1780 ( 180
589 ( 55
4500 ( 380
4960 ( 510
35 ( 4
20 ( 5
12 ( 1
1.4 ( 0.5
246 ( 84
17 ( 3
86 ( 44
49 ( 13
>1000
Cl
Cl
Et
OMe
OMe
H
57 ( 16
28 ( 3
8 ( 1
>1000
176 ( 15
37 ( 15
86 ( 15
18 ( 3
471 ( 92
75 ( 1
890 ( 140
248 ( 82
872 ( 74
123 ( 22
>1000
2330 ( 780
36 ( 14
>1000
33 ( 7
374 ( 47
>10000
>10000
H
H
209 ( 88
124 ( 1
>10000
>10000
Cl
H
a Ki and EC50 values were calculated from dose-response curves. Positive control was mCPP which gave 5-HT2C Ki ) 17 ( 2 nM, EC50 ) 15 ( 4 nM;
5-HT2B Ki ) 24 ( 1 nM, EC50 ) 287 ( 94 nM; 5-HT2A Ki ) 48 ( 4 nM, EC50 ) 290 ( 110 nM. b Intrinsic activity for all compounds ) 1 as compared
to serotonin at 3 µM unless noted in parentheses.
core provided a very potent compound (29); however, further
efforts were needed to achieve the desired functional selectivity.
To increase the selectivity of compound 29, a variety of
substitution patterns were investigated. The modification of the
piperazine ring by alkylation of the amino group (31) or alpha
to the nitrogen at C3 (32-34) dramatically reduced the binding
and functional potency at all three of the serotonin receptor
subtypes (Table 2). In contrast, substitution of C4 with alkyl
groups (35-37) provided very potent 5-HT2C compounds,
however, functional selectivity versus 5-HT2A and 5-HT2B was
lost. Substitution at C1 with a methyl group (38) also provided
a potent 5-HT2C compound, but again selectivity over 5-HT2A
and 5-HT2B was dramatically reduced. Additionally, any further
increase in steric bulk at C1, as exemplified by compound 39,
decreased both 5-HT2C binding and functional potency.
Similar results were obtained when the substitution pattern
of the aryl ring was investigated (Table 3). Compounds were
either dramatically less potent, as seen with the 7,10-disubsti-
tuted compounds 40-42 and 44, or very potent but with little
to no selectivity over 5-HT2A and 5-HT2B, e.g. 7,8-disubstituted
45-47 and 8,9-disubstituted 49. An exception was compound
43, which was both functionally potent and selective for 5-HT2C
but lacked the desired receptor binding affinity. The most
intriguing results from this work were obtained from 7,9-
disubstituted compounds 50 and 51. Although 50 and 51 were
not extremely potent 5-HT2C agonists, the compounds had
>100-fold functional selectivity for 5-HT2C over 5-HT2A and
5-HT2B. This substitution pattern provided the desired selectivity
profile and suggested additional modification of the substituents
would provide selective 5-HT2C compounds with better potency
to test in our in vivo models.
Due to the desirable combination of potency and selectivity
imparted by the trifluoromethyl group, investigation of the 7,9-
disubstituted pyrazinoisoindolone analogs focused on com-
pounds with this moiety at C7 (Table 4). Diversification of C9
with a wide variety of functional groups was investigated. A
number of these groups, such as halogens (52) and polar
functionalities (53, 54), dramatically decreased binding potency
compared to 29. Methoxy and ethoxy analogs 55 and 56,
respectively, did afford a comparative improvement in both
binding and functional potency at 5-HT2C, but neither compound
met our criteria for 5-HT2C potency. However, a simple methyl
group at C9 provided a very potent 5-HT2C agonist that was
27- and 47-fold functionally selective over 5-HT2A and 5-HT2B,

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1369
Table 4. In Vitro Activity of 7,9-Disubstituted Phenyl Analogs
5-HT2C
5-HT2B
5-HT2A
5-HT2C
5-HT2B
5-HT2A
R9
Ki, nMa
Ki, nMa
Ki, nMa
EC50, nMa,b
EC50, nMa,b
EC50, nMa,b
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Cl
Ac
CH2OH
OMe
OEt
Me
Et
Pr
Bu
900 ( 260
1610 ( 27
460 ( 210
40 ( 4
>10000
>10000
470 ( 290
1040 ( 120
5200 ( 800
3050 ( 890
1400 ( 170
3820 ( 59
560 ( 130
431 ( 41
NT
NT
NT
NT
NT
NT
175 ( 27
NT
NT
NT
289 ( 22
1090 ( 220
1300 ( 460
336 ( 85
153 ( 42
380 ( 130
220 ( 120
190 ( 100
648 ( 270
2099 ( 710
209 ( 84
29 ( 7
11 ( 2
63 ( 10
6 ( 4
16 ( 4
94 ( 4
363 ( 13
72 ( 28
43 ( 21
NT
158 ( 51
9 ( 3
>10000
>10000
282 ( 62
167 ( 41
20 ( 6
48 ( 1
57 ( 13
51 ( 9
4926 ( 498 (0.5)
1170 ( 200 (0.5)
1070 ( 130
627 ( 66
>10000
>10000
>10000
>10000
>10000
>10000
i-Pr
2620 ( 410
829 ( 52
CH2CH
HCC
c-Pr
43 ( 16
332 ( 61
35 ( 3
1610 ( 520
NT
1620 ( 83
NT
513 ( 240
>10000
6560 ( 200
579 ( 94
14 ( 6
54 ( 17
2980 ( 260
1-Me-c-Pr
34 ( 3
2310 ( 89
>10000
a Ki and EC50 values were calculated from dose-response curves. Positive control was mCPP which gave 5-HT2C Ki ) 17 ( 2 nM, EC50 ) 15 ( 4 nM;
5-HT2B Ki ) 24 ( 1 nM, EC50 ) 287 ( 94 nM; 5-HT2A Ki ) 48 ( 4 nM, EC50 ) 290 ( 110 nM. b Intrinsic activity for all compounds ) 1 as compared
to serotonin at 3 µM unless noted in parentheses.
Table 5. Single Dose Plasma Pharmacokinetic Parameters of 58 in
Male Sprague-Dawley Rats
dose iv/po (mg/kg)
4.4/8.8
po Tmax (h)
po Cmax (nM)
po T1/2 (h)
po AUCtot (nM*h)
po F%
0.7 ( 0.3
4050 ( 910
1.6 ( 0.2
11000 ( 1100
77
iv Cl (mL/min/kg)
iv Vss (L/kg)
Caco-2 (nm/s)
protein binding (% bound)
37.4 ( 6.9
4.8 ( 0.6
212
83
respectively. Encouraged by this result, we increased the steric
bulk of the alkyl chain at C9. The structure-activity relationship
was extremely narrow with respect to 5-HT2C potency and
selectivity over 5-HT2B and 5-HT2A. Increasing the size of the
C9 substituent resulted in a decease in 5-HT2C potency; the
propyl 59, butyl 60, and isopropyl 61 compounds no longer
exhibited robust 5-HT2C functional efficacy but in turn had
excellent functional selectivity. In contrast, the ethyl substituent
(58) provided the desired 5-HT2C binding and functional potency
and was >300-fold functionally selective over 5-HT2B and 73-
fold selective over 5-HT2A. Interestingly, 58 was also the first
compound from the series that exhibited partial agonism at both
5-HT2B and 5-HT2A. To further optimize the potency and
selectivity of this molecule, the steric size of the ethyl group
was attenuated by replacement with a vinyl (62) or an acetylene
(63) functionality, but these substitutions only reduced 5-HT2C
potency. Cyclopropyl 64 and 1-methylcyclopropyl 65 were also
investigated and had good 5-HT2C potency and selectivity
profiles. While 58, 64, and 65 were viable candidates for in
vivo experiments, we opted to focus on 58 due to its better
overall potency profile.
Figure 2. 20-h rat operant feeding model with compound 58. Values
indicate percent reduction in consumed pellets from vehicle dosed
animals.
bioavailability. Free fraction in rat and human serum was 17%.
Compound 58 modestly inhibited the cytochrome P-450 3A4
isoform with an IC50 of 8.7 µM, while all other isoforms tested
had IC50s over 40 µM.
In Vivo Pharmacology. The in vivo efficacy of 58 was tested
in an acute food intake model in Sprague-Dawley rats (Figure
2). In this 20 h operant feeding model, 250 g rats were dosed
orally with compound 1 h prior to onset of the dark cycle and
food availability. Compound 58 caused a dose-dependent
reduction in food pellet consumption, with a statistically
significant 32% reduction at 10 mg/kg and 41% at 30 mg/kg.
During the experiment, water consumption and locomotor
activity were within normal ranges and no overt physical or
behavior abnormalities were observed. A reversal experiment
was conducted to confirm that the observed food intake
reduction was mediated by the 5-HT2C receptor (Figure 3). In
the same operant feeding model, 58 was coadminstered with
SB-243213, a selective 5-HT2C antagonist.16 The 5-HT2C
antagonist caused a complete reversal in the food intake in a
dose-dependent manner, indicating that 5-HT2C receptor activa-
tion was the mechanism that mediated food reduction by 58.
The ability of 58 to cause body weight reduction was tested
by subchronic administration to lean Sprague-Dawley rats fed
Pharmacokinetics and Metabolism of 58. A summary of
the pharmacokinetic characteristics of 58 are detailed in Table
5. In Sprague-Dawley rats, 58 had a moderate systemic
clearance with a relatively high volume of distribution and a
brain-to-plasma concentration ratio slightly above 1 when
measured at 2, 4, 8, and 24 h postdose. The absorption
parameters were excellent, with a high Caco-2 value, rapid
absorption in vivo, as seen by the short Tmax, and good oral

1370 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Wacker et al.
the treatment of obesity, the results of which will be disclosed
in the future.
Experimental Section
Chemistry. All nonaqueous reactions were carried out under an
argon or nitrogen atmosphere at room temperature, unless otherwise
noted. All reagents and solvents were purchased from commercial
sources and were used without further purification or distillation,
unless otherwise stated. Analytical thin-layer chromatography (TLC)
was performed on EM Science silica gel 60 F254 (0.25 mm).
Compounds were visualized by UV light and/or stained with either
iodine or cerium molybdate followed by heating. Flash column
chromatography was performed on EM Science silica gel 60
(particle size of 40-63 µm). Radial chromatography was performed
on a Harrison Research Chromatotron. Radial silica gel plates of
1, 2, 4, or 8 mm thickness were obtained from Analtech Research.
Analytical high-pressure liquid chromatography (HPLC) and LC-
MS analyses were conducted using Shimadzu LC-10AS pumps and
a SPD-10AV UV-vis detector set at 220 nm with the MS detection
performed with a Micromass Platform LC spectrometer. NMR (1H
and 13C) spectra were recorded on JEOL 400 MHz spectrometer
and calibrated using an internal reference. Elemental analyses were
performed by Robertson Microlit Laboratories, and the results
obtained are within (0.4% of the theoretical values.
Figure 3. Antagonist reversal in the 20-h rat operant feeding model.
General Procedure A for the Synthesis of Pyrazino[2,1-a]-
isoindol-6(2H)-ones. Preparation of (()-1,3,4,10b-Tetrahydro-
7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochlo-
ric Acid Salt (20). Step A. To a stirring solution of 2-trifluoromethyl-
benzoic acid (3.6 g, 18.9 mmol) in dry CH2Cl2 (150 mL) with DMF
(0.5 mL) was added a 2 M solution of oxalyl chloride in CH2Cl2
(17.5 mL) dropwise over 30 min. The reaction was stirred for 2 h
and then concentrated in Vacuo to a white solid. The solid was
dissolved in CH2Cl2 (150 mL), and diethylamine (3.2 g, 43.8 mmol)
was added. The reaction was stirred for 16 h and then concentrated
in Vacuo to a yellow solid. The solid was purified by radial
chromatography (SiO2, 1:5, EtOAc:hexanes) to yield 4.3 g (93%)
Figure 4. 4-Day rat weight loss model with compound 58. Values
indicate percent reduction in weight gain from vehicle dosed animals.
1
of N,N-diethyl-2-trifluoromethylbenzamide as a colorless oil. H
ad libitum on a choice diet consisting of standard rat chow and
a highly palatable high fat chow (Figure 4). The compound was
administered orally once daily 1 h prior to onset of the dark
cycle for 4 days. Compound 58 reduced the body weight
increase of the rats in a dose-dependent manner with a
statistically significant reduction seen as early as day 2 at the
30 mg/kg dose. The overall reduction in body weight over
control at day 4 at 30 mg/kg was 6%.
The compelling results from the feeding models encouraged
us to evaluate compound 58 for gastric parietal cell necrosis to
determine if this previously observed toxicity had been circum-
vented. Compound 58 was dosed orally to mice at doses up to
300 mg/kg. After 24 h the stomachs were evaluated for lesions
by histopathological analysis, and no effects were observed.
NMR (400 MHz, CDCl3) δ 7.68 (d, J ) 7.9 Hz, 1 H), 7.57 (t, J )
7.5 Hz, 1 H), 7.48 (t, J ) 7.7 Hz, 1 H), 7.32 (d, J ) 7.5 Hz, 1 H),
3.81-3.90 (m, 1 H), 3.21-3.30 (m, 1 H), 3.07 (ddd, J ) 19.0,
14.2, 7.3 Hz, 2 H), 1.22 (t, J ) 7.3 Hz, 3 H), 1.03 (t, J ) 7.0 Hz,
3 H). MS (ESI) 246.2 (M + H).
Step B. To a stirring solution of N,N-diethyl-2-trifluoromethyl-
benzamide (2260 mg, 9.2 mmol) and N,N,N′,N′-tetramethylethyl-
enediamine (1410 mg) in dry THF (20 mL) at -78 °C was added
0.93 M sec-butyllithium in hexanes (10.2 mL) dropwise. The
reaction was stirred for 30 min and then DMF (2.0 mL) was added.
The reaction was stirred for 1 h and then quenched with 1 M HCl
(15 mL). The reaction was extracted with EtOAc (3 × 15 mL).
The organic layers were combined, dried over Na2SO4, and
concentrated in Vacuo to a yellow oil. The oil was purified by radial
chromatography (SiO2, 1:4, EtOAc:hexanes) to yield 2213 mg
(88%) of N,N-diethyl-2-carboxaldehyde-6-trifluoromethylbenzamide
1
as a colorless oil. H NMR (400 MHz, CDCl3) δ 10.06 (s, 1 H),
Conclusion
8.16 (d, J ) 7.9 Hz, 1 H), 7.92 (d, J ) 7.9 Hz, 1 H), 7.66 (t, J )
7.9 Hz, 1 H), 3.85 (dq, J ) 7.0, 6.9 Hz, 1 H), 3.43 (dq, J ) 7.0,
6.9 Hz, 1 H), 3.02-3.13 (m, 2 H), 1.28 (t, J ) 7.0 Hz, 3 H), 1.01
(t, J ) 7.3 Hz, 3 H). MS (ESI) 274.2 (M + H).
Pyrazinoisoindolones were identified as a new class of 5-HT2C
agonists for the treatment of obesity. SAR studies found that
7,9-disubstitution of the aromatic ring presented the best balance
between potency and selectivity, especially over 5-HT2B. After
surveying a wide variety of functional groups at both positions,
58 proved to have the best overall characteristics for advance-
ment. In an acute feeding model, oral dosing of the compound
produced a statistically significant reduction in food intake in a
dose-dependent manner. The effect was reversed with a selective
5-HT2C antagonist, indicating a 5-HT2C mechanism-based reduc-
tion in food intake. In a 4-day model, oral dosing of 58 caused
a robust reduction in body weight gain by young rats, and no
overt physical or behavioral abnormalities were seen in any of
the in vivo models. On the basis of its efficacy and selectivity
profile, compound 58 was selected for further evaluation for
Step C. A stirring solution of N,N-diethyl-2-carboxaldehyde-6-
trifluoromethylbenzamide (1378 mg, 5.3 mmol) in 6 M HCl (70
mL) was heated to 100 °C and stirred for 12 h. The reaction was
cooled to room temperature and extracted with EtOAc (3 × 70
mL). The organic layers were combined, dried over Na2SO4, and
concentrated in Vacuo to a brown oil. The oil was purified by flash
column chromatography (SiO2, 20-50% EtOAc in hexanes) to
provide 3-hydroxy-7-trifluoromethyl-3H-isobenzofuran-1-one as an
1
off-white solid (1365 mg, 99%). H NMR (400 MHz, CDCl3) δ
7.88-7.93 (m, 1 H), 7.84-7.87 (m, 2 H), 6.64 (s, 1 H), 3.97 (s, 1
H). MS (ESI) 201.2 (M - OH).
Step D. The 3-hydroxy-7-trifluoromethyl-3H-isobenzofuran-1-
one (1365 mg, 5.0 mmol) from Step C was added to a stirring

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1371
solution of 1-(benzyloxycarbonylamino)-2-aminoethane hydrochlo-
ride (1156 mg, 5.0 mmol) and sodium acetate (411 mg, 5.0 mmol)
in ethanol (13.5 mL) and acetic acid (6.5 mL), followed by sodium
cyanide (245 mg, 5.0 mmol). The reaction was stirred overnight
and then concentrated in Vacuo to a yellow solid. The solid was
partitioned between water (10 mL) and EtOAc (10 mL). The organic
layer was separated and the aqueous layer was extracted with EtOAc
(3 × 10 mL). The organic layers were combined, dried over Na2-
SO4, and concentrated in Vacuo to a yellow oil. The oil was purified
by radial chromatography (SiO2, 1:3, EtOAc:hexanes) to yield 1331
mg (66%) of (()-2-[2-[(benzyloxycarbonyl)amino]ethyl]-1-carbo-
nitrile-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one as a color-
less oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J ) 7.5 Hz, 1 H),
7.77-7.85 (m, 2 H), 7.16-7.24 (m, 5 H), 5.76 (s, 1 H), 5.09 (s, 1
H), 4.89 (s, 2 H), 4.25 (ddd, J ) 14.6, 10.4, 3.9 Hz, 1 H), 3.70-
3.81 (m, 1 H) 3.47(dt, J ) 14.5, 3.5 Hz, 1 H), 3.33-3.42 (m, 1 H).
MS (ESI) 404.3 (M + H).
Step E. A stirring solution of (()-2-[2-[(benzyloxycarbonyl)-
amino]ethyl]-1-carbonitrile-1,3-dihydro-4-trifluoromethylisoindol-
3(1H)-one (1331 mg, 3.3 mmol) and 10% palladium on carbon
(440 mg) in EtOH (9 mL) and HCl (1 mL) was placed under 80
psi of hydrogen. The reaction was stirred for 96 h. The reaction
was filtered and the filtrate was concentrated in Vacuo to yield a
white solid. The solid was partioned between 1 M aq NaOH (10
mL) and EtOAc (10 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 10 mL). The organic
layers were combined, dried over Na2SO4, and concentrated in
Vacuo to a pale yellow oil. The oil was purified by radial
chromatography (SiO2, 98:2, CH2Cl2:MeOH with NH4OH) to yield
432 mg of the product as a colorless oil. The oil was treated with
1.0 N HCl in ether, dried in Vacuo, and lyophilized from water to
give 20 as a white solid (493 mg, 51%). 1H NMR (400 MHz, CD3-
OD) δ 7.90-7.97 (m, 2 H), 7.85 (t, J ) 7.5 Hz, 1 H), 4.92 (dd, J
) 12.1, 4.2 Hz, 1 H), 4.52-4.60 (m, 1 H), 4.11-4.15 (m, 1H),
3.46-3.57 (m, 2H), 3.01-3.12 (m, 1 H), 2.83 (t, J ) 12.1 Hz, 1
H). MS (ESI) 257.3 (M - Cl). Anal. (C12H11F3N2O‚HCl‚1.3H2O),
C, H, N.
7-Chloro-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-
one Hydrochloric Acid Salt (24). Step A. To (()-1-carbonitrile-
2-(2,2-diethoxyethyl)-1,3-dihydro-4-chloro-isoindol-3(1H)-one (1.0
g, 3.25 mmol) [prepared according to General Procedure A, Steps
A-D, using aminoacetaldehyde diethyl acetal] in ethanol (30 mL)
was added Raney 2400 Nickel (1 mL; slurry in water). The mixture
was degassed and the reaction vessel was fitted with a hydrogen
balloon. After 4 h, the mixture was filtered (with a water wash),
concentrated in Vacuo, and purified by radial chromatography (SiO2,
2% ammonium hydroxide in 4% methanol in dichloromethane) to
give (()-1-(aminomethyl)-2-(2,2-diethoxyethyl)-1,3-dihydro-4-
chloroisoindol-3(1H)-one as a yellow oil (640 mg, 63%). 1H NMR
(400 MHz, CDCl3) 7.47 (t, J ) 7.5 Hz, 1 H), 7.40 (d, J ) 7.9 Hz,
1 H), 7.34 (d, J ) 7.5 Hz, 1 H), 4.81 (t, J ) 5.1 Hz, 1 H), 4.63-
4.68 (m, 1 H), 3.90 (dd, J ) 14.3, 4.6 Hz, 1 H), 3.71-3.81 (m, 2
H), 3.51-3.63 (m, 2 H), 3.31-3.38 (m, 2 H), 3.15-3.21 (m, 1 H),
1.22 (t, J ) 7.0 Hz, 3 H), 1.17 (t, J ) 7.0 Hz, 3 H). MS (ESI)
267.3, 269.2 (M + H).
Step B. To (()-1-(aminomethyl)-2-(2,2-diethoxyethyl)-1,3-di-
hydro-4-chloroisoindol-3(1H)-one (200 mg, 0.65 mmol) was added
concentrated aqueous HCl (5 mL, 12N). The resulting mixture was
stirred for 30 min before being concentrated in Vacuo. The resulting
residue was concentrated from toluene and treated with 1,2-
dichloroethane (5 mL). To this yellow mixture were added sodium
triacetoxyborohydride (270 mg, 1.3 mmol) and methanol (0.5 mL),
and the resulting mixture was stirred for 1 h before being quenched
with aqueous HCl (5 mL, 1N). The mixture was then basified with
sodium carbonate, diluted with EtOAc (6 mL), and treated with
excess di-tert-butyl dicarbonate (400 mg). After 1 h, the reaction
was extracted with EtOAc (×3). The combined organic layers were
dried over sodium sulfate, filtered, and concentrated in Vacuo. The
resulting yellow residue was purified by radial chromatography
(SiO2, 30-50% EtOAc in hexanes) to give (()-N-(tert-butoxycar-
bonyl)-7-chloro-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-
one as a white solid (87 mg, 63%). 1H NMR (400 MHz, CDCl3) δ
7.40-7.48 (m, 2 H), 7.33 (d, J ) 7.0 Hz, 1 H), 4.72 (s, 1 H),
4.34-4.42 (m, 2 H), 4.17 (s, 1 H), 3.07-3.17 (m, 1 H), 2.74 (s, 1
H), 2.32 (s, 1 H), 1.48-1.54 (m, 9 H). MS (ESI) 323.3, 325.3 (M
+ H).
Step C. To (()-N-(tert-butoxycarbonyl)-1,3,4,10b-tetrahydro-
7-chloropyrazino[2,1-a]isoindol-6(2H)-one (15 mg, 0.05 mmol) was
added concentrated HCl (1 mL). After 15 min, the resulting solution
was concentrated in Vacuo, diluted with water, and lyophilized to
give 24 as an off-white solid (12 mg, 100%). 1H NMR (400 MHz,
CD3OD) δ 7.60-7.65 (m, 2 H), 7.51-7.57 (m, 1 H), 4.85-4.88
(m, 1 H), 4.53 (d, J ) 14.5 Hz, 1 H), 4.08 (dd, J ) 12.1, 3.7 Hz,
1 H), 3.46-3.57 (m, 2 H), 3.00-3.10 (m, 1 H), 2.80 (t, J ) 11.9
Hz, 1 H). MS (ESI) 223.2, 225.2 (M - Cl). Anal. (C11H12Cl2N2O‚
1.15HCl‚0.5H2O), C, H, N.
(()-7-Methylthio-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-
6(2H)-one Hydrochloric Acid Salt (26). Prepared according to
General Procedure B with the substitution of 2-(methylthio)benzoic
acid for 2-chlorobenzoic acid in step A. 1H NMR (400 MHz, CD3-
OD) δ 7.59 (t, J ) 7.5 Hz, 1 H), 7.33-7.40 (m, 2 H), 4.81 (dd, J
) 11.9, 3.9 Hz, 1 H), 4.50 (dd, J ) 14.5, 3.9 Hz, 1 H), 4.03 (dd,
J ) 12.1, 3.7 Hz, 1 H), 3.34-3.55 (m, 2 H), 3.41 (d, J ) 3.5 Hz,
1 H), 3.02 (dt, J ) 12.4, 4.2 Hz, 1 H), 2.76 (t, J ) 12.1 Hz, 1 H),
2.50 (s, 3 H). MS (ESI) 235.2 (M - Cl). Anal. (C12H14N2OS‚
1.7HCl‚H2O), C, H, N.
(()-7-Methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-
6(2H)-one Hydrochloric Acid Salt (21). Prepared according to
General Procedure A with substitution of 2-methoxybenzoic acid
for 2-trifluoromethoxybenzoic acid at Step A. 1H NMR (400 MHz,
D2O) δ 7.57 (t, J ) 7.9 Hz, 1 H), 7.11 (d, J ) 7.5 Hz, 1 H), 7.05
(d, J ) 8.4 Hz, 1 H), 4.76-4.79 (m, 1 H), 4.38 (dd, J ) 14.7, 4.2
Hz, 1 H), 4.01 (dd, J ) 12.7, 3.9 Hz, 1 H), 3.85 (s, 3 H), 3.54 (dd,
J ) 12.7, 3.5 Hz, 1 H), 3.40-3.49 (m, 1 H), 3.01 (dt, J ) 12.6,
4.6 Hz, 1 H), 2.74 (t, J ) 12.30 Hz, 1 H). MS (ESI) 219.3 (M -
Cl). Anal. (C12H14N2O2‚HCl‚0.4H2O), C, H, N.
(()-1,3,4,10b-Tetrahydro-7-trifluoromethoxypyrazino[2,1-a]-
isoindol-6(2H)-one (22). Prepared according to General Procedure
A with substitution of 2-trifluoromethoxybenzoic acid for 2-trif-
luoromethylbenzoic acid at Step A. This sample was not treated
1
with 1.0 N HCl or lyophilized from water. H NMR (400 MHz,
CD3OD) δ 7.46 (t, J ) 7.9 Hz, 1 H), 7.26 (d, J ) 7.5 Hz, 1 H),
7.18-7.23 (m, 1 H), 4.33 (dd, J ) 10.8, 4.2 Hz, 1 H), 4.25-4.30
(m, 1 H), 3.53 (dd, J ) 12.1, 4.2 Hz, 1 H), 2.99-3.08 (m, 2 H),
2.47-2.56 (m, 1 H), 2.22 (t, J ) 11.4 Hz, 1 H). MS (ESI) 273 (M
+ H). Anal. (C12H11F3N2O2 · 0.35 CH2Cl2), C, H, N.
(()-7-Fluoro-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-
6(2H)-one Trifluoroacetic Acid Salt (23). Prepared according to
General Procedure A with substitution of 2-fluorobenzoic acid for
2-trifluoromethylbenzoic acid at Step A. Final purification was
accomplished by reverse phase high performance liquid chroma-
(()-7-Nitrile-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-
one Hydrochloric Acid Salt (25). To N-(tert-butoxycarbonyl)-(()-
7-chloro-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-one (25
mg, 0.08 mmol) in a round-bottom flask were added zinc cyanide
(5 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.4
mg, 0.002 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (1.7
mg, 0.003 mmol). To these reagents was added N, N-dimethyl-
acetamide (1 mL), and the resulting mixture was degassed. The
reaction was then subjected to microwave conditions (130 °C, 30
min; 300 W). The reaction was then cooled, and additional zinc
cyanide (0.05 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.002 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (0.003
1
tography (C18, 20-100% CH3CN/H2O w/0.05% TFA). H NMR
(400 MHz, CD3CN) δ 7.63 (dt, J ) 7.9, 4.8 Hz, 1 H) 7.41 (d, J )
7.5 Hz, 1 H) 7.22 (t, J ) 9.0 Hz, 1 H) 4.98 (dd, J ) 11.7, 3.7 Hz,
1 H) 4.34-4.41 (m, 1 H) 3.98 (dd, J ) 12.3, 3.9 Hz, 1 H) 3.45-
3.56 (m, 2 H) 2.87-2.96 (m, 1 H) 2.66 (t, J ) 12.1 Hz, 1 H). MS
(ESI) 207.2 (M - CF3CO2). Anal. (C11H11FN2O‚2.2C2HF3O2‚0.5CH3-
CN), C, H, N.
General Procedure B for the Synthesis of Pyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salts. Preparation of (()-

1372 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Wacker et al.
mmol) were added. The reaction was again subjected to microwave
conditions (160 °C, 60 min; 300 W). The resulting black mixture
was then subjected to microwave conditions for a final time (220
°C, 60 min; 300 W) before being cooled and diluted with
tetrahydrofuran (2 mL) and treated with excess di-tert-butyl
dicarbonate. After 1 h, the reaction was diluted with EtOAc, and
the mixture was washed with saturated aq ammonium hydroxide
and brine. The organic layer was then dried over sodium sulfate,
filtered, and concentrated in Vacuo. The resulting residue was
purified by radial chromatography (SiO2, 30-50% EtOAc in
hexanes) to give a clear residue. To the clear residue was added
concentrated aqueous HCl (1 mL). After 1 min, the solution was
concentrated in Vacuo, diluted with water, and lyophilized to yield
sodium sulfate, filtered, and concentrated in Vacuo. The resulting
residue was purified by radial chromatography (SiO2, 30% EtOAc
in hexanes) to afford a clear residue. To the residue was added
concentrated aqueous HCl (1 mL). After 5 min, the solution was
concentrated in Vacuo, diluted with water, and lyophilized to give
1
28 as a white solid (4 mg, 18%). H NMR (400 MHz, CD3OD) δ
7.55-7.62 (m, 1 H), 7.12-7.18 (m, 2 H), 4.74-4.84 (m, 2 H),
4.51 (dd, J ) 14.5, 3.9 Hz, 1 H), 4.02 (dd, J ) 12.3, 3.9 Hz, 1 H),
3.52 (dd, J ) 12.5, 3.3 Hz, 1 H), 3.38-3.47 (m, 1 H), 3.01 (dt, J
) 12.6, 4.2 Hz, 1 H), 2.69-2.77 (m, 1 H), 1.35-1.41 (m, 6 H).
MS (ESI) 247.3 (M - Cl). Anal. (C14H18N2O2‚HCl‚1.7 H2O), C,
H, N.
General Procedure for the Preparation of Chiral Pyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salts. (R)-1,3,4,10b-
Tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-
one Hydrochloric Acid Salt (29). Step A. To a stirring solution
of (()-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoin-
dol-6(2H)-one (432 mg, 1.1 mmol) in dry CH2Cl2 (10 mL) was
added di-tert-butyl dicarbonate (383 mg, 1.8 mmol). The reaction
was stirred for 4 h and then concentrated in Vacuo to a white solid.
The solid was purified by radial chromatography (SiO2, 1:10,
EtOAc:hexanes). The compound was then separated by chiral HPLC
(Chiracell OD column with 80% heptane with 0.1% diethylamine
and 20% 1:1 MeOH:EtOH with 0.1% diethylamine) to yield 181
mg of N-(tert-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluo-
romethylpyrazino[2,1-a]isoindol-6(2H)-one and 217 mg of the
N-(tert-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one as white solids. R enantio-
mer: Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR
(400 MHz, CDCl3) δ 7.77-7.82 (m, 1 H), 7.64-7.68 (m, 2 H),
4.79 (s, 1 H), 4.46 (dd, J ) 11.0, 4.4 Hz, 1 H), 4.40 (dd, J ) 13.6,
3.5 Hz, 1 H), 4.20 (s, 1 H), 3.11-3.20 (m, 1 H), 2.72-2.84 (m, 1
H), 2.36 (s, 1 H), 1.51 (s, 9 H). MS (ESI) 357.3 (M + H); S
enantiomer: Enantiomeric excess >99:1 based on chiral HPLC.
NMR (400 MHz, CDCl3) δ 7.77-7.82 (m, 1 H), 7.64-7.68 (m, 2
H), 4.79 (s, 1 H), 4.46 (dd, J ) 11.0, 4.4 Hz, 1 H), 4.40 (dd, J )
13.6, 3.5 Hz, 1 H), 4.20 (s, 1 H), 3.11-3.20 (m, 1 H), 2.72-2.84
(m, 1 H), 2.36 (s, 1 H), 1.51 (s, 9 H). MS (ESI) 357.3 (M + H).
Step B. To a stirring solution of N-(tert-butoxycarbonyl)-(R)-
1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-
one (181 mg, 0.51 mmol) in dry ether (5 mL) was added
concentrated HCl (1 mL). The reaction was stirred for 1 h and then
concentrated in Vacuo to a white solid. The solid was dissolved in
1
25 as a white residue (1.0 mg, 18%). H NMR (400 MHz, CD3-
OD) δ 7.98 (t, J ) 7.3 Hz, 2 H), 7.85 (t, J ) 7.7 Hz, 1 H), 4.90-
4.96 (m, 1 H), 4.57 (d, J ) 14.5 Hz, 1 H), 4.13 (dd, J ) 12.3, 3.5
Hz, 1 H), 3.48-3.60 (m, 2 H), 3.03-3.13 (m, 1 H), 2.85 (t, J )
12.1 Hz, 1 H). MS (ESI) 214.3 (M - Cl). Anal. (C12H11N2O2‚
HCl‚0.5H2O), C, H, N.
(()-7-Hydroxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-
6(2H)-one Hydrochloric Acid Salt (27). Step A. To a solution of
(()-7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-
one (1.7 g, 0.008 mmol) prepared according General Procedure A
(substituting 2-methoxybenzoic acid for 2-trifluoromethylbenzoic
acid at Step A) in tetrahydrofuran (20 mL) was added di-tert-butyl
dicarbonate (2.5 g, 0.012 mmol). After 2 h, the solution was
concentrated and purified by flash column chromatography (SiO2,
50-100% EtOAc in hexanes) to give N-(tert-butoxycarbonyl)-(()-
7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-
one as a white solid (2.4 g, quant). 1H NMR (400 MHz, CDCl3) δ
7.47 (app. t, J ) 8.4, 7.5 Hz, 1H), 7.00 (d, J ) 7.5 Hz, 1 H), 6.93
(d, J ) 8.4 Hz, 1 H), 4.63-4.74 (m, 1H), 4.32-4.40 (m, 2 H),
4.11 (s, 1 H), 3.96 (s, 3 H), 3.09 (dt, J ) 12.6, 3.3 Hz, 1 H), 2.65-
2.76 (m, 1 H), 2.31 (s, 1 H), 1.50 (s, 9 H). MS (ESI) 319.3 (M +
H).
Step B. To a solution of N-(tert-butoxycarbonyl)-(()-7-methoxy-
1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-one (100 mg,
0.31 mmol) in dichloromethane (3 mL) at -78 °C was added
dropwise boron tribromide (0.79 mL, 0.79 mmol; 1.0 M in CH2-
Cl2). After 5 min, the reaction was warmed to 0 °C and an additional
0.2 mL of boron tribromide (1.0 M in CH2Cl2) was added. After 2
h, the yellow mixture was cooled to -78 °C and quenched with
water. The reaction was warmed to room temperature and stirred
for 14 h. The mixture was then concentrated in Vacuo and quenched
again with aq HCl (3 M), and the resulting yellow solution was
concentrated in Vacuo to dryness. The residue was diluted with
tetrahydrofuran (10 mL) and saturated aqueous sodium bicarbonate
(1 mL). Di-tert-butyl dicarbonate (69 mg, 0.31 mmol) was added,
and the mixture was stirred for 1 h. The reaction was then diluted
with EtOAc, and the layers were separated. The organic layer was
then dried over sodium sulfate, fitered, and concentrated in Vacuo.
The resulting residue was purified by radial chromatography (SiO2,
20% EtOAc in hexanes) to give an off-white solid. To the solid
was added 12 N aq HCl (1 mL). After 5 min, the solution was
concentrated in Vacuo, diluted with water, and lyophilized to give
1
water and lyophilized to 147 mg of 29 a white solid. H NMR
(400 MHz, CD3OD) δ 7.90-7.97 (m, 2 H), 7.85 (t, J ) 7.5 Hz, 1
H), 4.92 (dd, J ) 12.1, 4.2 Hz, 1 H), 4.52-4.60 (m, 1 H), 4.11-
4.15 (m, 1H), 3.46-3.57 (m, 2H), 3.01-3.12 (m, 1 H), 2.83 (t, J
) 12.1 Hz, 1 H). MS (ESI) 257.3 (M - Cl). [R]D -8.4 (0.238
g/dL, MeOH). Anal. (C12H11F3N2O‚HCl‚1.4 H2O), C, H, N.
(S)-1,3,4,10b-Tetrahydro-7-trifluoromethylpyrazino[2,1-a]i-
soindol-6(2H)-one Hydrochloric Acid Salt (30). Prepared accord-
ing to procedures described for compound 29 with substitution of
N-(tert-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one for N-(tert-butoxycarbonyl)-
(R)-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-
6(2H)-one at Step B. 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J )
7.9 Hz, 1 H), 7.92 (d, J ) 7.5 Hz, 1 H), 7.84 (t, J ) 7.5 Hz, 1 H),
4.96 (dd, J ) 11.7, 3.7 Hz, 1 H), 4.52-4.59 (m, 1 H), 4.15 (dd, J
) 12.1, 3.7 Hz, 1 H), 3.48-3.60 (m, 2 H), 3.02-3.11 (m, 1 H),
2.82 (t, J ) 12.1 Hz, 1 H). MS (ESI) 257.3 (M - Cl). [R]D +8.5
(0.212 g/dL, MeOH). Anal. (C12H11F3N2O‚HCl‚H2O), C, H, N.
(()-2-Methyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one (31). To a stirring solution of (()-
1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-
one (60 mg, 0.23 mmol) in water (1 mL) were added formic acid
(0.22 mL, 5.9 mmol) and formaldehyde (190 mg, 2.3 mmol; 37%
soln in water). The reaction flask was sealed with a rubber septum
(no nitrogen inlet) and warmed to 60 °C. After 24 h, the reaction
was cooled to room temperature and then diluted with saturated
aqueous sodium bicarbonate and extracted with EtOAc (3 × 50
mL), and the combined organic layers were dried over sodium
1
27 as an off-white solid (8 mg, 42%). H NMR (400 MHz, CD3-
OD) δ 7.45-7.51 (m, 1 H), 7.08 (d, J ) 7.5 Hz, 1 H), 6.91 (d, J
) 8.4 Hz, 1 H), 4.80 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.49 (dd, J )
14.3, 4.2 Hz, 1 H), 4.01 (dd, J ) 12.3, 3.9 Hz, 1 H), 3.49-3.54
(m, 1 H), 3.40-3.49 (m, 1 H), 3.03 (dt, J ) 12.4, 4.2 Hz, 1 H),
2.76 (t, J ) 11.9 Hz, 1 H). MS (ESI) 205.2 (M - Cl). Anal.
(C11H12N2O2‚HCl‚1.1H2O), C, H, N.
(()-7-Isopropoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-
6(2H)-one Hydrochloric Acid Salt (28). To a stirring solution of
N,N-dimethylformamide (1.5 mL), N-(tert-butoxycarbonyl)-(()-7-
hydroxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6 (2H)-one (25
mg, 0.083 mmol), and anhydrous potassium carbonate (34 mg, 0.25
mmol) was added 2-iodopropane (0.012 mL, 0.125 mmol). The
mixture was warmed to 80 °C and stirred for 12 h. The reaction
was cooled, diluted with EtOAc, and washed with 50% saturated
aqueous sodium chloride. The organic layer was then dried over

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1373
sulfate, filtered, and concentrated in Vacuo. The resulting residue
was purified by radial chromatography (SiO2, 2% ammonium
hydroxide in 8% methanol in dichloromethane) to afford 31 (33
of (S)-2-amino-1-(benzyloxycarbonylamino)-3-methyl-butane15 hy-
drochloride for 1-(benzyloxycarbonylamino)-2-aminoethane hy-
drochloride. Separation of the diastereomers was carried out at the
1
1
mg, 52%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ
last step during purification. H NMR (400 MHz, DMSO-d6) δ
7.75 (d, J ) 6.2 Hz, 1 H) 7.57-7.65 (m, 2 H), 4.54 (dd, J ) 11.0,
3.9 Hz, 1 H), 4.37 (dd, J ) 13.2, 3.1 Hz, 1 H), 3.36 (dd, J ) 10.8,
4.2 Hz, 1 H), 3.25 (dt, J ) 12.7, 3.9 Hz, 1 H), 2.87 (dd, J ) 11.4,
3.9 Hz, 1 H), 2.38 (s, 3 H), 1.98 (dt, J ) 11.9, 4.2 Hz, 1 H), 1.64
(t, J ) 10.8 Hz, 1 H). MS (ESI) 271.6 (M + H). Anal.
(C13H13F3N2O‚0.7H2O), C, H, N.
8.01 (d, J ) 7.5 Hz, 1 H), 7.89 (d, J ) 7.9 Hz, 1 H), 7.82 (t, J )
7.7 Hz, 1 H), 4.83 (dd, J ) 11.6, 3.7 Hz, 1 H), 4.00 (dd, J ) 11.9,
3.5 Hz, 1 H), 3.59-3.71 (m, 1 H), 3.45 (d, J ) 11.9 Hz, 1 H),
3.15-3.26 (m, 1 H), 2.91 (s, 1 H), 2.75 (s, 1 H), 1.08 (d, J ) 6.6
Hz, 3 H), 0.99 (d, J ) 6.6 Hz, 3 H). MS (ESI) 299 (M - Cl).
Anal. (C15H17F3N2O‚HCl‚1.8H2O), C, H, N.
(()-3,3-Dimethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazi-
no[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (32). Pre-
pared according to General Procedure A with the substitution of
1-amino-2-(benzyloxycarbonylamino)-2-methylpropane hydrochlo-
ride17 for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochlo-
(1S,10bR)-1-Methyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (38).
Step A. To 3-hydroxy-7-(trifluoromethyl)isobenzofuran-1(3H)-one
(5.6 g, 25.7 mmol; General Procedure A, Step C) in 10% acetic
acid in 1,2-dichloroethane (250 mL) were added N-(tert-butoxy-
carbonyl)ethylenediamine (3.7 mL, 23.4 mmol) and sodium tri-
acetoxyborohydride (7.4 g, 35.1 mmol). The resulting mixture was
warmed to 50 °C and maintained at this temperature for 14 h. The
reaction was cooled to 23 °C, diluted with brine, and extracted with
EtOAc (×3). The combined organic layers were dried over sodium
sulfate and filtered, and the filtrate was concentrated in Vacuo. The
resulting residue was purified by flash column chromatography
(SiO2, 0-80% EtOAc in hexanes) to afford 2-[2-[(tert-butoxycar-
bonyl)amino]ethyl]-1,3-dihydro-4-trifluoromethylisoindol-3(1 H)-
1
ride. H NMR (400 MHz, CDCl3) δ 7.77 (d, J ) 6.6 Hz, 1 H),
7.59-7.65 (m, 2 H), 4.34 (dd, J ) 10.8, 4.6 Hz, 1 H), 4.15 (d, J
) 12.7 Hz, 1 H), 3.45 (dd, J ) 12.7, 4.4 Hz, 1 H), 2.85 (d, J )
12.7 Hz, 1 H,) 2.64 (dd, J ) 12.7, 11.0 Hz, 1 H), 1.24 (s, 3 H),
1.06 (s, 3 H). MS (ESI) 285 (M + H). Anal. (C14H15F3N2O2‚HCl‚
0.7 H2O), C, H, N.
(3S,10bR)-3-Methyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (33).
Prepared according to General Procedure A with the substitution
of (S)-1-amino-2-(benzyloxycarbonylamino)propane hydrochloride
for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochloride. Sepa-
ration of the diastereomers was carried out at the last step during
1
one (7.9 g, 89%) as an off-white oily solid. H NMR (400 MHz,
CDCl3) δ 7.75 (d, J ) 7.9 Hz, 1 H), 7.59-7.65 (m, 2 H), 4.81 (s,
1 H), 4.52 (s, 2 H), 3.74 (t, J ) 6.2 Hz, 2 H), 3.45 (q, J ) 5.9 Hz,
2 H), 1.25 (s, 9 H). MS (ESI) 345 (M + H).
1
purification. H NMR (400 MHz, CDCl3) δ 7.74-7.78 (m, 1 H),
7.59-7.64 (m, 2 H), 4.38-4.43 (m, 2 H), 3.63 (dd, J ) 11.9, 4.2
Hz, 1 H), 2.67-2.76 (m, 2 H), 2.38 (app t, J ) 11.7, 10.6 Hz, 1
H), 1.17 (d, J ) 5.9 Hz, 3 H). MS (ESI) 271 (M - Cl). Anal.
(C13H13F3N2O‚HCl‚3.2H2O), C, H, N.
Step B. To 2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-dihydro-
4-trifluoromethylisoindol-3(1H)-one (2.31 g, 6.71 mmol) in tet-
rahydrofuran at -78 °C was added sec-butyllithium (12.3 mL, 14.8
mmol; titrated with diphenylacetic acid, 1.2 M) in cyclohexane/
hexane (92/8) in one portion. After stirring the reaction at -78 °C
for 15 min, acetaldehyde (1.88 mL, 33.6 mmol) was added in one
portion. The brown-green solution was warmed to 0 °C over 5 min
and was then quenched with aq HCl (1 N) and brine. The mixture
was extracted with EtOAc (×3), the combined organic layers were
dried over sodium sulfate and filtered, and the filtrate was
concentrated. The resulting residue was purified by flash column
chromatography (SiO2, 0-50% EtOAc in hexanes) to afford (()-
2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-dihydro-1-(1-hydroxy-
ethyl)-4-trifluoromethylisoindol-3(1H)-one (2.2 g, 84%) as a white
(3R,10bR)-3-Methyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (34).
Prepared according to General Procedure A with the substitution
of (R)-1-amino-2-(benzyloxycarbonylamino)propane hydrochloride
for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochloride. Sepa-
ration of the diastereomers was carried out at the last step during
purification. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J ) 6.6, 1 H),
7.52-7.58 (m, 2 H), 4.34 (dd, J ) 11.0, 4.4, 1 H), 3.28 - 3.37
(m, 2H), 3.23 (dd, J ) 4.4, 13.2 Hz, 1 H), 2.59 (app t, J ) 11.0,
12.2 Hz, 1 H), 1.60 (br s, 2H), 1.04 (d, J ) 6.6 Hz, 3 H). MS
(ESI) 271 (M - Cl). Anal. (C13H13F3N2O‚HCl), C, H, N.
(4R,10bR)-4-Methyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (35).
Prepared according to General Procedure A with the substitution
of (R)-2-amino-1-(benzyloxycarbonylamino)propane hydrochlo-
ride18 for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochlo-
ride. Separation of the diastereomers was carried out at the last
1
foam-like solid. H NMR (400 MHz, CDCl3) δ 7.89 (d, J ) 8.0
Hz, 0.33H), 7.68 (m, 1 H), 7.52-7.61 (m, 1.66 H), 4.93-5.02 (s,
0.65 H), 4.87-4.93 (s, 0.35 H), 4.73 (s, 1 H), 4.48-4.38 (1 H),
3.97-4.80 (m, 1 H), 3.86-3.96 (m, 0.55 H), 3.70-3.85 (m, 2.45
H), 1.98 (s, 3 H), 1.19 (s, 9 H). MS (ESI) 389 (M + H).
Step C. To (()-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-
dihydro-1-(1-hydroxyethyl)-4-trifluoromethylisoindol-3(1H)-one (2.2
g, 5.7 mmol) in dichloromethane at 23 °C was added Dess-Martin
periodinane (3.4 g, 7.9 mmol) in one portion. After 20 min, the
reaction was quenched with methanol (10 mL) and concentrated
in Vacuo. The resulting white mixture was purified by flash column
chromatography (SiO2, 0-50% EtOAc in hexanes) to afford (()-
2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-dihydro-1-(1-oxoethyl)-
4-trifluoromethylisoindol-3(1H)-one (1.9 g, 86%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.78-7.88 (m, 1 H), 7.64-7.73
(m, 2 H), 5.30 (s, 1 H), 4.77 (s, 1 H), 4.17-4.27 (m, 1 H), 3.58 (s,
1 H), 3.17-3.29 (m, 2 H), 1.99 (s, 3 H), 1.22 (s, 9 H). MS (ESI)
387 (M + H).
1
step during purification. H NMR (400 MHz, DMSO-d6) δ 9.88
(s, 1 H), 9.54 (s, 1 H), 8.08 (d, J ) 7.5 Hz, 1 H), 7.91 (d, J ) 7.9
Hz, 1 H), 7.85 (t, J ) 7.7 Hz, 1 H), 4.96 (dd, J ) 11.4, 3.9 Hz, 1
H), 4.62-4.69 (m, 1 H), 3.98-4.05 (m, 1 H), 3.31 (d, J ) 12.7
Hz, 1 H), 3.04-3.13 (m, 1 H), 2.65-2.76 (m, 1 H), 1.41 (d, J )
7.0 Hz, 3 H). MS (ESI) 271 (M - Cl). (C13H13F3N2O‚HCl‚0.7 H2O),
C, H, N.
(4S,10bR)-4-Methyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (36).
Prepared according to General Procedure A with the substitution
of (S)-2-amino-1-(benzyloxycarbonylamino)propane hydrochloride17
for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochloride. Sepa-
ration of the diastereomers was carried out at the last step during
Step D. Concentrated aqueous HCl (5 mL) was added to a
mixture of diethyl ether (20 mL) and (()-2-[2-[(tert-butoxycarbo-
nyl)amino]ethyl]-1,3-dihydro-1-(1-oxoethyl)-4-trifluoromethylisoin-
dol-3(1H)-one (1.9 g, 4.9 mmol). The resulting mixture was stirred
for 5 min and became a yellow solution. The solution was
concentrated in Vacuo to dryness and azeotroped three times with
toluene (5 mL). Finally, the residue was treated with dichlo-
romethane (5 mL) and concentrated in Vacuo to a yellow orange
solid. Di-tert-butyl dicarbonate (4.8 g, 22 mmol) was added to the
residue, and the mixture was warmed to 55 °C. To this mixture
was added 4-(dimethylamino)pyridine (1.2 g, 9.8 mmol). After 5
1
purification. H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J ) 7.5
Hz, 1 H), 7.89 (d, J ) 7.9 Hz, 1 H), 7.82 (t, J ) 7.7 Hz, 1 H,) 4.82
(dd, J ) 11.4, 3.5 Hz, 1 H), 3.98-4.07 (m, 2 H), 3.34 (d, J ) 12.7
Hz, 1 H), 2.83-2.93 (m, 1 H), 2.73-2.83 (m, 1 H), 1.72 (d, J )
6.6 Hz, 3 H). MS (ESI) 271 (M - Cl). (C13H13F3N2O‚1.1HCl‚
H2O), C, H, N.
(4S,10bR)-4-Isopropyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (37).
Prepared according to General Procedure A with the substitution

1374 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Wacker et al.
min, the orange brown solution was directly purified by flash
column chromatography (SiO2, 0-30% EtOAc in hexanes) to afford
N-(tert-butoxycarbonyl)-3,4-dihydro-1-methyl-7-trifluoromethylpyrazi-
dropyrazino[2,1-a]isoindol-6(2H)-one (1.0 g, 2.96 mmol) [prepared
from (a) 2-chloro-5-methylbenzoic acid according to General
Procedure B and (b) the demethylation procedure used for
compound 27 followed by reprotection with di-tert-butyl dicar-
bonate (1.0 equiv)] were added dichloromethane (30 mL), 2,6-
lutidine (1.37 mL, 11.8 mmol), and trifluoromethanesulfonic
anhydride (0.60 mL, 3.55 mmol) at 0 °C. After 40 min, the reaction
was concentrated to a red mixture and purified by flash column
chromatography (SiO2, 0-50% EtOAc in hexanes) to afford N-(tert-
butoxycarbonyl)-(()-7-chloro-1,3,4,10b-tetrahydro-10-trifluo-
romethanesulfonyl-pyrazino[2,1-a]isoindol-6(2H)-one (1.11 g, 80%)
1
no[2,1-a]isoindol-6(2H)-one (1.5 g, 83%) as a yellow solid. H
NMR (400 MHz, CDCl3) δ 7.93 (d, J ) 7.9 Hz, 1 H), 7.71 (d, J
) 7.5 Hz, 1 H), 7.63 (t, J ) 7.7 Hz, 1 H), 3.88 (s, 2 H), 2.53 (s,
2 H), 1.54 (s, 12 H). MS (ESI) 369 (M + H).
Step E. To a solution of N-(tert-butoxycarbonyl)-3,4-dihydro-
1-methyl-7-trifluoromethylpyrazino[2,1-a]isoind ol-6(2H)-one (0.20
g, 0.54 mmol) in methanol (10 mL) was added palladium on carbon
(20 mg, 10 wt %). The resulting mixture was degassed (vacuum
then argon, ×3) and subjected to a hydrogen atmosphere (60 psi)
for 12 h. The mixture was then filtered, and the filtrate was
concentrated in Vacuo. The resulting residue was purified by flash
column chromatography (SiO2, 0-50% EtOAc in hexanes) to afford
N-(tert-butoxycarbonyl)-(()-1-methyl-1,3,4,10b-tetrahydro-7-tri-
fluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (0.19 g, 94%) as
a white solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J ) 7.5 Hz,
1 H), 7.59-7.68 (m, 2 H), 5.03-5.10 (m, 0.66 H), 4.78-4.85 (s,
0.33H), 4.63 (d, J ) 4.4 Hz, 1 H), 4.35 (d, J ) 9.7 Hz, 1 H),
4.10-4.20 (s, 0.33 H), 3.99-4.06 (m, 0.66 H), 2.97-3.21 (m, 2H),
1.51 (s, 12 H). MS (ESI) 371 (M + H).
Step F. The mixture of enantiomers contained in N-(tert-
butoxycarbonyl)-(()-1-methyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one (81 mg, 0.22 mmol) was
separated by chiral HPLC (Chiracell AD column with 90% heptane
containing 0.1% diethylamine and 10% 1:1 MeOH:EtOH containing
0.1% diethylamine). The resulting solids were individually repu-
rified by flash column chromatography (SiO2, 0-50% EtOAc in
hexanes) to yield 35 mg of the (1S,10bR) enantiomer and 36 mg
of the (1R,10bS) enantiomer as white solids. The solids were
individually dissolved in dry ether (1 mL)and the treated with HCl
(1 mL). The reactions were stirred for 5 min and then concentrated
in Vacuo to a white solid. The solids were dissolved in water and
lyophilized to yield 28 mg (quant) of the (1S,10bR) enantiomer
and 28 mg (93%) of the (1R,10bS) enantiomer as white solids.
Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR (400
MHz, D2O) δ 7.88-7.93 (m, 1 H), 7.80-7.84 (m, 2 H), 5.11 (d,
J ) 4.4 Hz, 1 H), 4.52-4.57 (m, 1 H), 4.49 (dd, J)14.9, 4.4 Hz,
1 H), 3.41-3.55 (m, 2 H), 3.33 (dt, J ) 12.9, 4.4 Hz, 1 H), 0.80
(d, J ) 6.6 Hz, 3 H). MS (ESI) 271 (M - Cl). Anal. (C13H13F3N2O‚
HCl‚0.4H2O), C, H, N.
(1S,10bR)-1-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazi-
no[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (39). Pre-
pared according to the procedures described in Example 38 with
substitution of propionaldehyde for acetaldehyde at step B. Enan-
tiomeric excess >99:1 based on chiral HPLC. 1H NMR (400 MHz,
CD3OD) 7.98 (d, J ) 7.5 Hz, 1 H), 7.92 (d, J ) 7.5 Hz, 1 H), 7.85
(t, J ) 7.7 Hz, 1 H), 5.14 (d, J ) 3.9 Hz, 1 H), 4.52 (dd, J ) 14.3,
4.6 Hz, 1 H), 4.32 (ddd, J ) 9.0, 4.8, 4.6 Hz, 1 H), 3.54 (dt, J )
13.4, 4.4 Hz, 1 H), 3.38-3.44 (m, 1 H), 3.26-3.34 (m, 1 H), 1.28-
1.40 (m, 1 H), 0.99-1.10 (m, 1 H), 0.83 (t, J ) 7.7 Hz, 3 H). MS
(ESI) 285 (M - Cl) Anal. (C14H15F3N2O‚HCl‚H2O), C, H, N.
((R)-10-Chloro-7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-
a]isoindol-6(2 H)-one Hydrochloric Acid Salt (40). Prepared
according to General Procedure B with substitution of 5-chloro-
2-methoxybenzoic acid for 2-chlorobenzoic acid. Chiral resolution
and deprotection were carried out according to the General
Procedure for the preparation of chiral pyrazino[2,1-a]isoindol-
6(2H)-one hydrochloric acid salts (Chiracell OJ chiral column and
10% (1:1) methanol/ethanol in heptane containing 0.1% diethy-
lamine. Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR
(400 MHz, D2O) δ 7.58 (d, J ) 8.8 Hz, 1 H), 7.12 (d, J ) 9.2 Hz,
1 H), 4.92 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.44 (dd, J)14.5, 3.9 Hz,
1 H), 4.36 (dd, J)12.3, 3.9 Hz, 1 H), 3.89 (s, 3 H), 3.47-3.58 (m,
2 H) 3.03 (dt, J)12.5, 4.4 Hz, 1 H), 2.82 (t, J)12.1 Hz, 1 H). MS
(ESI) 253, 255 (M - Cl). Anal. (C12H13ClN2O2‚HCl‚0.8H2O), C,
H, N.
1
as a beige solid. H NMR (400 MHz, CDCl3) δ 7.53 (d, J ) 8.8
Hz, 1H), 7.39 (d, J ) 8.8 Hz, 1 H), 4.90 (br s, 1 H), 4.58 (dd, J )
10.8, 4.2 Hz, 1 H), 4.39 (dd, J ) 13.4, 3.3 Hz, 1 H), 4.29 (br s, 1
H), 3.13-3.22 (m, 1 H), 2.65-2.76 (m, 1 H), 2.45 (br s, 1 H),
1.51 (s, 9 H). MS (ESI) 471.2, 473.2 (M - Cl).
Step B. N-(tert-Butoxycarbonyl)-(R)-7-chloro-10-methyl-1,3,4,10b-
tetrahydropyrazino[2,1-a]isoindol-6(2H)-one was prepared accord-
ing to the procedure described for 57 (substituting cesium carbonate
for potassium carbonate and [1,1′-bis(diphenylphosphino)ferrocene]-
dichloropalladium(II) for tetrakis(triphenylphospine)palladium(0))
followed by chiral chromatography (Chiracell OJ column and 15%
(1:1) methanol/ethanol in heptane containing 0.1% diethylamine).
The carbamate was then treated with concentrated aqueous hydrogen
chloride, concentrated in Vacuo, and lyophilized from water to
afford 41 as a white solid. Enantiomeric excess >99:1 based on
1
chiral HPLC. H NMR (400 MHz, D2O) δ 7.33-7.38 (m, 2 H),
4.83 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.50 (dd, J ) 14.3, 4.2 Hz, 1 H),
4.15 (dd, J ) 12.3, 3.95 Hz, 1 H), 3.49-3.59 (m, 2 H), 3.02 (dt,
J ) 12.5, 4.4 Hz, 1 H), 2.75 (t, J)12.1 Hz, 1 H), 2.30 (s, 3 H).
MS (ESI) 237.3, 239.3 (M - Cl). Anal. (C12H13ClN2O‚1.7HCl),
C, H, N.
(R)-7-Chloro-10-ethyl-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (42). Prepared from
N-(tert-butoxycarbonyl)-(()-7-chloro-1,3,4,10b-tetrahydro-10-tri-
fluoromethanesulfonylpyrazino[2,1-a]isoindol-6(2H)-one according
to the procedures described for compounds 58 and 62. Enantiomeric
excess >99:1 based on chiral HPLC. 1H NMR (400 MHz, D2O) δ
7.35-7.41 (m, 2 H), 4.85 (dd, J ) 11.6, 3.7 Hz, 1 H), 4.47 (dd, J
) 14.3, 4.2 Hz, 1 H), 4.09 (dd, J ) 12.3, 3.9 Hz, 1 H), 3.45-3.55
(m, 2 H), 2.99 (dt, J ) 12.5, 4.4 Hz, 1 H),2.75 (t, J ) 12.3 Hz, 1
H), 2.52-2.64 (m, 2 H), 1.15 (t, J ) 7.5 Hz, 3 H). MS (ESI) 251.3,
253.3 (M - Cl). Anal. (C13H15ClN2O‚HCl‚1.3H2O), C, H, N.
(R)-7-Chloro-10-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-
a]isoindol-6(2H)-one Hydrochloric Acid Salt (43). Prepared
according to General Procedure B with substitution of 2-chloro-
5-methoxybenzoic acid for 2-chlorobenzoic acid. Chiral resolution
and deprotection were carried out according to the General
Procedure for the preparation of chiral pyrazino[2,1-a]isoindol-
6(2H)-one hydrochloric acid salts (Chiracell OJ chiral column and
15% (1:1) methanol/ethanol in heptane containing 0.1% diethy-
1
lamine). Enantiomeric excess >99:1 based on chiral HPLC. H
NMR (400 MHz, D2O) δ 7.43 (d, J ) 8.8 Hz, 1 H), 7.14 (d, J )
8.8 Hz, 1 H), 4.80 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.44 (dd, J ) 14.3,
4.2 Hz, 1 H), 4.15 (dd, J ) 12.5, 4.2 Hz, 1 H), 3.84 (s, 3 H),
3.51-3.56 (m, 1 H), 3.42-3.51 (m, 1 H), 3.00 (dt, J ) 12.7, 4.4
Hz, 1 H), 2.72 (t, J ) 12.1 Hz, 1 H). MS (ESI) 253.3, 255.3 (M -
Cl). Anal. (C12H13ClN2O2‚HCl‚1.7H2O), C, H, N.
(R)-10-Chloro-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (44). Prepared
according to General Procedure B and the General Procedure for
the preparation of chiral pyrazino[2,1-a]isoindol-6(2H)-one hydro-
chloric acid salts (Chiracell OJ chiral column and 20% (1:1)
methanol/ethanol in heptane containing 0.1% diethylamine) from
5-chloro-2-trifluoromethylbenzoic acid. Enantiomeric excess >99:1
1
based on chiral HPLC. H NMR (400 MHz, D2O) δ 7.88 (d, J )
8.4 Hz, 1 H), 7.79 (d, J ) 8.34 Hz, 1 H), 5.04 (dd, J ) 11.9, 3.9
Hz, 1 H), 4.53 (dd, J ) 13.2, 3.1 Hz, 1 H), 4.41 (dd, J ) 12.5, 4.2
Hz, 1 H), 2.99-3.07 (m, 1 H) 3.49-3.61 (m, 2 H), 2.83 (t, J )
12.1 Hz, 1 H). MS (ESI) 291.3, 293.3 (M - Cl). Anal. (C12H10-
ClF3N2O‚HCl‚0.7H2O), C, H, N.
(R)-7-Chloro-10-methyl-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (41). Step A. To
N-(tert-butoxycarbonyl)-(()-7-chloro-10-hydroxy-1,3,4,10b-tetrahy-

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1375
(R)-7,8-Dichloro-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-
6(2H)-one Hydrochloric Acid Salt (45). Prepared according to
General Procedure B with substitution of 2,3-dichlorobenzoic acid
for 2-chlorobenzoic acid with chiral resolution and deprotection
carried out according to the General Procedure described for
compound 29. Enantiomeric excess >99:1 based on chiral HPLC.
1H NMR (400 MHz, D2O) δ 7.80 (d, J ) 8.4 Hz, 1 H), 7.51 (d, J
) 8.4 Hz, 1H), 4.88 (dd, J ) 11.9, 3.9 Hz, 1H), 4.51 (dd, J )
14.7, 4.2 Hz, 1H), 4.08 (dd, J ) 12.3, 3.9 Hz, 1H), 3.51-3.61 (m,
1H), 3.51-3.56 (m, 1H), 3.04 (dt, J ) 12.5, 4.4 Hz, 1H), 2.82 (t,
J ) 12.3 Hz, 1H). MS (ESI) 257 (M - Cl). Anal. (C11H10Cl2N2O‚
1.3HCl‚0.5H2O), C, H, N.
2 H), 3.00-3.08 (m, 1 H), 2.78 (t, J ) 12.3 Hz, 1 H). MS (ESI)
253.3, 255.3 (M - Cl). Anal. (C12H13ClN2O2‚HCl), C, H, N.
(R)-9-Ethyl-8-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (49). Prepared ac-
cording to the procedure of compound 47 from N-(tert-butoxycar-
bonyl)-(()-9-chloro-8-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-
a]isoindol-6(2H)-one. Enantiomeric excess >99:1 based on chiral
1
HPLC. H NMR (400 MHz, D2O) δ 7.44 (s, 1 H), 7.30 (s, 1 H),
4.81 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.47 (dd, J ) 13.6, 3.5 Hz, 1 H),
4.07 (dd, J ) 12.3, 3.9 Hz, 1 H), 3.88 (s, 3 H), 3.50-3.61 (m, 2
H), 3.00-3.09 (m, 1 H), 2.64-2.73 (m, 2 H), 1.15 (t, J ) 7.7 Hz,
3 H). MS (ESI) 247.3 (M - Cl). Anal. (C14H18N2O2‚HCl), C, H,
N.
(R)-8-Chloro-7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (46). Prepared ac-
cording to General Procedure B with substitution of 3-chloro-2-
methoxybenzoic acid19 for 2-chlorobenzoic acid with chiral resolution
and deprotection carried out according to the General Procedure
described for compound 29. Enantiomeric excess >99:1 based on
(R)-7-Chloro-9-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (50). Step A. To a
solution of 2-chloro-4-hydroxybenzoic acid hydrate (2.0 g, 12
mmol), iodomethane (2.9 mL, 46 mmol) and N,N-dimethylforma-
mide (50 mL) was added sodium hydride (1.9 g, 46 mmol; 60%
dispersion in mineral oil) in one portion. After the mixture was
vigorously stirred for 16 h, the reaction was quenched with water
and washed with EtOAc. The aqueous layer was then acidified with
aqueous HCl (6 N) to give a white precipitate. The mixture was
filtered and washed with water, and the filter cake was dried in a
vacuum oven to give the desired acid as an off-white solid (1.4 g,
1
chiral HPLC. H NMR (400 MHz, D2O) δ 7.72 (d, J ) 7.9 Hz, 1
H), 7.33 (d, J ) 8.8 Hz, 1 H), 4.86 (dd, J ) 11.9, 3.9 Hz, 1 H),
4.46 (dd, J ) 14.5, 3.9 Hz, 1 H), 4.05 (dd, J ) 12.5, 4.2 Hz, 1 H),
3.95 (s, 3 H), 3.57 (dd, J ) 12.7, 3.5 Hz, 1 H), 3.45-3.53 (m, 1
H), 3.03 (dt, J ) 12.6, 4.6 Hz, 1 H), 2.79 (t, J ) 12.1 Hz, 1 H).
MS (ESI) 253 (M - Cl). Anal. (C12H13ClN2O2‚HCl‚0.90H2O).
1
65%). H NMR (400 MHz, CDCl3) δ 8.02 (d, J ) 8.8 Hz, 1H),
(R)-8-Ethyl-7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (47). Step A. To
N-(tert-butoxycarbonyl)-(()-8-chloro-7-methoxy-1,3,4,10b-tetrahy-
dropyrazino[2,1-a]isoindol-6(2H)-one (0.55 mg, 1.56 mmoL) pre-
pared from 3-chloro-2-methoxybenzoic acid18 using General Pro-
cedure B was added bis(tri-tert-butylphosphine)palladium(0) (32
mg, 0.06 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex
(653 mg, 1.72 mmol), potassium fluoride (633 mg, 11 mmol), and
dioxane (16 mL). The mixture was degassed and warmed to reflux.
After 6 h, an additional portion of catalyst (32 mg) was added.
The reaction was maintained at reflux for another 8 h and was then
cooled to room temperature. The mixture was diluted with saturated
aqueous sodium hydrogen carbonate and brine before being
extracted with EtOAc (×3). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in Vacuo. The
resulting residue was purified by flash column chromatography
(SiO2, 0-50% EtOAc in hexanes) to afford N-(tert-butoxycarbo-
nyl)-(()-8-ethenyl-7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]i-
soindol-6(2H)-one as a yellow solid (475 mg, 88%). 1H NMR (400
MHz, CDCl3) δ 7.68 (d, J ) 7.9 Hz, 1 H), 7.04-7.13 (m, 2 H),
5.76 (d, J ) 18.9 Hz, 1 H), 5.33 (d, J ) 11.0 Hz, 1 H), 4.67 (s, 1
H), 4.29-4.40 (m, 2 H), 4.10 (s, 1 H), 4.04 (s, 3 H), 3.05-3.14
(m, 1 H), 2.72 (s, 1 H), 2.33 (s, 1 H), 1.50 (s, 9 H). MS (ESI)
345.3 (M + H).
Step B. Final product was prepared according to the procedures
of compound 58 substituting N-(tert-butoxycarbonyl)-(()-8-ethenyl-
7-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-
one for N-(tert-butoxycarbonyl)-(R)-9-ethyl-1,3,4,10b-tetrahydro-
7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one to yield 47.
Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR (400
MHz, D2O) δ 7.57 (d, J ) 7.9 Hz, 1 H), 7.30 (d, J ) 7.9 Hz, 1 H),
4.83 (dd, J ) 11.8, 4.4 Hz, 1 H), 4.46 (dd, J ) 14.7, 4.2 Hz, 1 H),
4.05 (dd, J ) 12.3, 3.9 Hz, 1 H), 3.89 (s, 3 H), 3.57 (dd, J ) 12.7,
3.9 Hz, 1 H), 3.45-3.53 (m, 1 H), 3.03 (dt, J ) 12.6, 4.6 Hz, 1
H), 2.65-2.75 (m, 3 H), 1.15 (t, J ) 7.5 Hz, 3 H). MS (ESI) 247
(M - Cl). Anal. (C14H18N2O2‚HCl‚1.1H2O), C, H, N.
6.98 (d, J ) 2.6 Hz, 1H), 6.83 (dd, J ) 8.8, 2.6 Hz, 1H), 3.85 (s,
3H). MS (ESI) 187.1, 189.1 (M + H).
Step B. Final compound was prepared according to General
Procedure B, substituting 2-chloro-4-methoxybenzoic acid for
2-chlorobenzoic acid at Step A with chiral separation according to
General Procedures to yield 50. Enantiomeric excess >99:1 based
1
on chiral HPLC. H NMR (400 MHz, CD3OD) δ 7.18 (s, 1 H),
7.12 (d, J ) 2.20 Hz, 1 H), 4.76 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.52
(dd, J ) 14.7, 4.2 Hz, 1 H), 4.03 (dd, J ) 12.1, 3.7 Hz, 1 H), 3.90
(s, 3 H), 3.51 (dd, J ) 12.5, 3.7 Hz, 1 H), 3.37-3.46 (m, 1 H),
3.02 (dt, J ) 12.5, 4.4 Hz, 1 H), 2.79 (t, J ) 12.1 Hz, 1 H). MS
(ESI) 253.2, 255.2 (M - Cl). Anal. (C12H13ClN2O2‚HCl‚H2O), C,
H, N.
(R)-7-Chloro-9-ethyl-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one HCl (51). Step A. To a stirring solution of
4-bromo-2-chlorobenzoic acid (5.0 g, 21.2 mmol) in dry CH2Cl2
(150 mL) was added a 2 M solution of oxalyl chloride in CH2Cl2
(21.2 mL). Dry DMF (0.1 mL) was added and the reaction was
stirred for 4 h and then concentrated in Vacuo to a white solid. The
solid was dissolved in CH2Cl2 (150 mL), and diethylamine (4.8
mL, 46.6 mmol) was added dropwise over 15 min. The reaction
was washed with brine, dried over sodium sulfate, filtered, and
concentrated in Vacuo. The resulting residue was purified by flash
chromatography (SiO2, 1:5, EtOAc:hexanes) to yield N,N-diethyl-
1
4-bromo-2-chlorobenzamide (6.2 g, 100%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 7.56 (d, J ) 1.8 Hz, 1 H), 7.43 (dd, J
) 8.4, 1.8 Hz, 1 H), 7.14 (d, J ) 7.9 Hz, 1 H), 3.71-3.82 (m, 1
H), 3.30-3.41 (m, 1 H), 3.07-3.18 (m, 2 H), 1.25 (t, J ) 7.0 Hz,
3 H). 1.05 (t, J ) 7.5 Hz, 3 H). MS (ESI) 290 (M + H).
Step B. Tetrakis(triphenylphospine)palladium(0) (30 mg, 0.026
mmol) was added in one portion to a degassed mixture of N,N-
diethyl-4-bromo-2-chlorobenzamide (0.6 g, 2.1 mmol), potassium
carbonate (0.29 g, 2.1 mmol), and 2,4,6-trivinylcyclotriboroxane
pyridine complex (0.78 g, 2.1 mmol) in 1,2-dimethoxyethane (16
mL) and water (5 mL). The mixture was warmed to 100 °C. After
14 h, the reaction was cooled to room temperature, diluted with
brine, and extracted with EtOAc (×3), and the combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in Vacuo. The resulting residue was purified by flash column
chromatography (SiO2, 0-50% ethylacetate/hexanes) to give N,N-
diethyl-2-chloro-4-ethenylbenzamide as a off-white solid (0.47 g,
(R)-9-Chloro-8-methoxy-1,3,4,10b-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one Hydrochloric Acid Salt (48). Prepared ac-
cording to General Procedure B with substitution of 4-chloro-3-
methoxybenzoic acid for 2-chlorobenzoic acid. Chiral resolution
and deprotection were carried out according to the General
Procedure for the preparation of chiral pyrazino[2,1-a]isoindol-
6(2H)-one Hydrochloric acid salts. Enantiomeric excess >99:1
based on chiral HPLC. 1H NMR (400 MHz, D2O) δ 7.70 (s, 1 H),
7.47 (s, 1 H), 4.86 (dd, J ) 11.9, 4.4 Hz, 1 H), 4.44-4.50 (m, 1
H), 4.05 (dd, J ) 12.7, 3.9 Hz, 1 H), 3.96 (s, 3 H), 3.53-3.61 (m,
1
96%). H NMR (400 MHz, CDCl3) δ 7.41 (d, J ) 1.3 Hz, 1 H),
7.31 (dd, J ) 7.9, 1.3 Hz, 1 H), 7.21 (d, J ) 7.9 Hz, 1 H), 6.64
(dd, J ) 17.6, 11.0 Hz, 1 H), 5.78 (d, J ) 17.6 Hz, 1 H), 5.34 (d,
J ) 11.0 Hz, 1 H), 3.73-3.83 (m, 1 H), 3.35 (dd, J ) 13.2, 6.2

1376 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Wacker et al.
Hz, 1 H), 3.15 (dt, J ) 11.4, 7.0 Hz, 2 H), 1.25 (t, J ) 7.3 Hz, 3
H) 1.05 (t, J ) 7.0 Hz, 3 H). MS (ESI) 238 (M + H).
2.73 (s, 3 H). MS (ESI) 299.3 (M - Cl). Anal. (C14H13F3N2O2‚
HCl‚1.3H2O), C, H, N.
Step C. To N,N-diethyl-2-chloro-4-ethenylbenzamide (0.15 g,
0.62mmol) was added ethanol (5 mL), and the resulting solution
was degassed via alternating exposure to vacuum and argon. To
this mixture was added Raney nickel and the black suspension was
subjected a hydrogen atmosphere (1 atm). After 3 h, the reaction
was filtered and concentrated in Vacuo, and the resulting yellow
residue was purified by radial chromatography (SiO2, 0-50%
EtOAc/hexanes) to afford N,N-diethyl-2-chloro-4-ethylbenzamide
(R)-9-Chloro-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (52). Step A.
To a stirring degassed solution of N-(tert-butoxycarbonyl)-(R)-9-
bromo-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoin-
dol-6(2H)-one (464 mg, 1.1 mmol) in dry DMF (5 mL) was added
copper(I) chloride (211 mg, 2.1 mmol). The reaction was heated
to reflux for 4 h and then cooled to room temperature. The reaction
was treated with di-tert-butyl dicarbonate (350 mg, 1.6 mmol). The
reaction was stirred for 1 h and then quenched with 9:1 saturated
NH4Cl:NH4OH. After 15 min, the reaction was extracted with
EtOAc (3 × 10 mL). The organic layers were combined, dried over
Na2SO4, and concentrated in Vacuo to a brown oil. The oil was
purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes)
to yield 140 mg of a colorless oil. To the oil was added concentrated
aqueous HCl (1 mL). After 5 min, the solution was concentrated
in Vacuo, diluted with water, and lyophilized to give 52 as a white
solid (114 mg, 36%). Enantiomeric excess >99:1 based on chiral
1
(0.11 g, 70%) as a clear residue. H NMR (400 MHz, CDCl3) δ
7.20 (d, J ) 1.3 Hz, 1 H), 7.16 (d, J ) 7.9 Hz, 1 H), 7.10 (dd, J)
7.9, 1.3 Hz, 1 H), 3.77 (s, 1 H), 3.36 (s, 1 H), 3.15 (qd, J ) 7.0,
2.2 Hz, 2 H), 2.63 (q, J ) 7.6 Hz, 2 H), 1.20-1.27 (m, 6 H), 1.05
(t, J ) 7.0 Hz, 3 H). MS (ESI) 240 (M - Cl).
Step D. (R)-7-Chloro-9-ethyl-1,3,4,10b-tetrahydropyrazino[2,1-
a]isoindol-6(2H)-one HCl was prepared from N,N-diethyl-2-chloro-
4-ethylbenzamide according to General Procedure B and the General
Procedure for the synthesis of chiral pyrazino[2,1-a]isoindol-6(2H)-
one hydrochloric acid salts. Enantiomeric excess >99:1 based on
1
HPLC. H NMR (400 MHz, D2O) δ 7.95 (s, 1 H), 7.90 (s, 1 H),
1
4.97 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.50 (dd, J ) 14.3, 4.2 Hz, 1 H),
4.10 (dd, J ) 12.5, 4.2 Hz, 1 H), 3.60 (dd, J ) 12.7, 3.5 Hz, 1 H),
3.48-3.57 (m, 1 H), 3.03 (dt, J ) 12.7, 4.4 Hz, 1 H), 2.82 (t, J )
12.3 Hz, 1 H), MS (ESI) 291 (M - Cl). Anal. (C12H10ClF3N2O2‚
HCl‚1.5H2O), C, H, N.
chiral HPLC. H NMR (400 MHz, CD3OD) δ 7.47 (s, 1 H), 7.41
(s, 1 H), 4.83 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.53 (dd, J ) 14.1, 4.4
Hz, 1 H), 4.07 (dd, J ) 12.3, 3.94 Hz, 1 H), 3.47-3.56 (m, 2 H),
3.05 (dt, J ) 12.2, 4.6 Hz, 1 H), 2.74-2.82 (m, 3 H), 1.29 (t, J )
7.5 Hz, 3 H), MS (ESI) 251 (M - Cl). Anal. (C13H15ClN2O‚HCl‚
H2O), C, H, N.
(R)-9-Hydroxymethyl-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (54).
To a stirring solution of N-(tert-butoxycarbonyl)-(R)-9-(cis-1-
propenyl)-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]i-
soindol-6(2H)-one (182 mg, 0.46 mmol) in MeOH (5.0 mL) at -78
°C was bubbled ozone for 5 min until the reaction turned a light
blue color. After 5 min, sodium borohydride (23 mg, 0.6 mmol)
was added. The reaction was stir for 1 h and then warmed to room
temperature. The reaction was concentrated in Vacuo to a white
solid and then dissolved in 1 M aq HCl. After 15 min, the reaction
was diluted with EtOAc, basified with NaHCO3, and treated with
di-tert-butyl dicarbonate (125 mg, 0.58 mmol). After 1 h, the
reaction was extracted with EtOAc (3 × 5 mL). The organic layers
were combined, dried over Na2SO4, and concentrated in Vacuo to
a colorless oil. The oil was purified by flash chromatography (silica
gel, 0-50% EtOAc in hexanes) to give 141 mg of a white solid.
To 14 mg of the white solid was added concentrated aqueous HCl
(1 mL). After 5 min, the solution was concentrated in Vacuo, diluted
with water, and lyophilized to give 54 as a white solid (11 mg).
Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR (400
MHz, D2O) δ 7.90 (s, 1 H), 7.84 (s, 1 H), 4.99 (dd, J ) 11.9, 3.9
Hz, 1 H), 4.79 (s, 2 H), 4.53 (dd, J ) 14.5, 4.4 Hz, 1 H), 4.15 (dd,
J ) 12.3, 3.9 Hz, 1 H), 3.50-3.65 (m, 2 H), 3.06 (dt, J ) 12.3,
4.4 Hz, 1 H,) 2.83 (t, J ) 12.1 Hz, 1 H). MS (ESI) 287 (M - Cl).
(C13H13F3N2O2‚1.25HCl‚0.5H2O), C, H, N.
(R)-9-Methoxy-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (55). Step A.
To a stirring degassed solution of N-(tert-butoxycarbonyl)-(R)-9-
bromo-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoin-
dol-6(2H)-one (435 mg, 1.0 mmol), bis(pinacolato)diboron (279
mg, 1.1 mmol), and potassium acetate (294 mg, 3.0 mmol) in dry
DMF (5.0 mL) was added palladium(II) acetate (6.7 mg, 0.03
mmol). The reaction was heated to 80 °C for 2 h and then cooled
to room temperature. The reaction was quenched with water and
extracted with EtOAc (3 × 5 mL). The organic layers were
combined, dried over Na2SO4, and concentrated in Vacuo to a brown
oil. The oil was dissolved in THF (5 mL) and acetic acid (0.05
mL) and treated with hydrogen peroxide (0.25 mL). The reaction
was stirred for 15 min and then quenched with saturated aqueous
NaHSO3. The reaction was extracted with EtOAc (3 × 5 mL). The
organic layers were combined, dried over Na2SO4, and concentrated
in Vacuo to a brown oil. The oil was purified by flash chromatog-
raphy (SiO2, 0-70% EtOAc in hexanes) to give 347 mg of N-(tert-
butoxycarbonyl)-(R)-9-methoxy-1,3,4,10b-tetrahydro-7-trifluorom-
ethylpyrazino[2,1-a]isoindol-6(2H)-one as a pale yellow solid. 1H
NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1 H), 7.28 (s, 2 H), 7.17
(R)-9-Acetyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (53). Step A.
To a stirring solution of (R)-1,3,4,10b-tetrahydro-7-trifluorometh-
ylpyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt (688 mg,
2.4 mmol) were added concentrated sulfuric acid (2.4 mL) [conc.
sulfuric acid is neat, not aqueous] and N-bromosuccinimide (420
mg, 2.4 mmol). The resulting brown solution was covered with
aluminum foil and stirred in the dark for 24 h. The reaction was
then diluted with ice-water and basified with saturated aqueous
sodium bicarbonate. The resulting mixture was diluted with
tetrahydrofuran (30 mL) and treated with di-tert-butyl dicarbonate
(567 mg, 2.6 mmol). After 4 h, the reaction was extracted with
EtOAc (3 × 50 mL), and the combined organic layers were dried
over sodium sulfate, filtered, and concentrated in Vacuo. The
resulting residue was purified by radial chromatography (SiO2, 25%
EtOAc in hexanes) to afford N-(tert-butoxycarbonyl)-(R)-9-bromo-
1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-
one (878 mg, 85%) as a white foam-like solid. 1H NMR (400 MHz,
CDCl3) δ 7.93 (s, 1 H), 7.80 (s, 1 H), 4.75 (s, 1H), 4.44 (dd, J )
11.0, 4.4 Hz, 1 H), 4.38 (dd, J ) 13.6, 3.1 Hz, 1 H), 4.20 (s, 1 H),
3.10-3.18 (m, 1 H), 2.77 (s, 1 H), 2.37 (s, 1 H), 1.51 (s, 9 H). MS
(ESI) 435.2, 437.2 (M + H).
Step B. To a degassed solution of tetrakis(triphenylphospine)-
palladium(0) (3 mg, 0.002 mmol) in toluene (2 mL) was added
N-(tert-butoxycarbonyl)-(R)-9-bromo-1,3,4,10b-tetrahydro-7-trifluo-
romethylpyrazino[2,1-a]isoindol-6(2H)-one (50 mg, 0.12 mmol).
The resulting solution was degassed by exposure to vacuum and
then an argon atmosphere (×3). To this solution was added tributyl-
(1-ethoxyvinyl)tin (0.041 mL, 0.12 mmol). The resulting solution
was degassed a final time and was then warmed to reflux. The
light yellow solution was maintained at reflux conditions for 14 h
and became gray in color. The reaction was cooled and diluted
with EtOAc, aqueous HCl (1 N), and saturated aqueous sodium
chloride. The layers were separated and the aqueous layer was
extracted with EtOAc. The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in Vacuo. The
resulting residue was purified by radial chromatography (SiO2, 10-
30% EtOAc in hexanes) to give a clear residue. To the residue
was added concentrated aqueous HCl (1 mL). After 5 min, the
solution was concentrated in Vacuo, diluted with water, and
lyophilized to give 53 as a white solid (33 mg, 62%). Enantiomeric
1
excess >99:1 based on chiral HPLC. H NMR (400 MHz, CD3-
OD) δ 8.57 (s, 1 H), 8.41 (s, 1 H), 5.02 (dd, J ) 11.6, 3.7 Hz, 1
H), 4.53-4.63 (m, 1 H), 4.23 (dd, J ) 12.3, 3.9 Hz, 1 H), 3.51-
3.62 (m, 2 H), 3.03-3.13 (m, 1 H), 2.88 (t, J ) 12.1 Hz, 1 H),

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1377
(s, 2 H), 4.56 (s, 1 H), 4.48 (dd, J ) 10.6, 3.9 Hz, 1 H), 4.08 (dd,
J ) 12.7, 3.5 Hz, 1 H), 4.01 (d, J ) 7.0 Hz, 1 H), 3.03 (dt, J )
12.7, 3.9 Hz, 1 H), 2.64-2.76 (m, 1 H), 2.38 (s, 1 H), 1.44 (s, 9
H). MS (ESI) 373 (M + H).
aqueous HCl (1 mL). After 5 min, the solution was concentrated
in Vacuo, diluted with water, and lyophilized to give 58 as a white
solid (17 mg). Enantiomeric excess >99:1 based on chiral HPLC.
1H NMR (500 MHz, CD3OD) δ 7.80 (s, 1 H), 7.75 (s, 1 H), 4.87-
4.90 (m, 1 H), 4.53 (dd, J ) 14.1, 4.4 Hz, 1 H), 4.11 (dd, J )
12.3, 3.9 Hz, 1 H), 3.51-3.56 (m, 1 H), 3.44-3.49 (m, 1 H), 2.99-
3.08 (m, 1 H), 2.87 (q, J ) 7.5 Hz, 2 H), 2.80 (t, J ) 12.1 Hz, 1
H), 1.31 (t, J ) 7.7 Hz, 3 H). 13C (100 MHz, d6-DMSO) δ 162.0
(s, 1H), 148.8 (s, 1H), 144.8 (s, 1H), 126.6 (s, 1H), 126.1 (s, 1H),
126.0 (s, 1H), 125.0 (q, J ) 33.6 Hz, 1H), 122.9 (q, J ) 271.0 Hz,
1H), 53.0 (s, 1H), 45.8 (s, 1H), 41.8 (s, 1H), 35.6 (s, 1H), 28.1 (s,
1H), 15.1 (s, 1H). MS (ESI) 271.3 (M + H). [R]D -23.3 (0.660
g/dL, MeOH). Anal. (C14H15F3N2O‚HCl), C, H, N.
Step B. To a stirring degassed solution of N-(tert-butoxycarbo-
nyl)-(R)-9-methoxy-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one (58 mg, 0.16 mmol), and potassium
carbonate (33 mg, 0.24 mmol) in dry DMF (1.0 mL) was added
methyl iodide (24 mg, 0.17 mmol). The reaction was stirred for 2
h and then quenched with brine. The reaction was extracted with
EtOAc (3 × 5 mL). The organic layers were combined, dried over
Na2SO4, and concentrated in Vacuo to a pale yellow oil. The oil
was purified by flash chromatography (SiO2, 0-50% EtOAc in
hexanes) to give 41 mg of a colorless oil. To the oil was added
concd aq HCl (1 mL). After 5 min, the solution was concentrated
in Vacuo, diluted with water, and lyophilized to give 54 as a white
solid (30 mg, 50%). Enantiomeric excess >99:1 based on chiral
HPLC. 1H NMR (400 MHz, D2O) δ ppm 7.44 (s, 1 H), 7.38 (s, 1
H), 4.93 (d, J ) 11.9 Hz, 1 H), 4.49 (dd, J ) 14.7, 4.2 Hz, 1 H),
4.09 (dd, J ) 12.7, 3.9 Hz, 1 H), 3.92 (s, 3 H), 3.60 (dd, J ) 12.7,
3.5 Hz, 1 H), 3.48-3.56 (m, 2 H), 3.04 (dt, J ) 12.6, 4.2 Hz, 1
H), 2.82 (t, J ) 12.1 Hz, 1 H). MS (ESI) 287 (M - Cl). Anal.
(C13H13F3N2O2‚HCl‚H2O), C, H, N.
(R)-9-Methyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (57). Prepared
according to procedures described for compound 62 with substitu-
tion of trimethylboroxine for 2,4,6-trivinylcyclotriboroxane pyridine
1
complex. Enantiomeric excess >99:1 based on chiral HPLC. H
NMR (400 MHz, CD3OD) 7.76 (s, 1 H), 7.66 (s, 1 H), 4.92 (dd, J
) 11.9, 3.9 Hz, 1 H), 4.51 (dd, J ) 14.7, 4.2 Hz, 1 H), 4.10 (dd,
J ) 12.3, 4.4 Hz, 1 H), 3.60 (dd, J ) 12.7, 3.9 Hz, 1 H), 3.48-
3.57 (m, 1 H), 3.04 (dt, J ) 12.6, 4.2 Hz, 1 H), 2.79 (t, J ) 12.3
Hz, 1 H), 2.48 (s, 3 H). MS (ESI) 271 (M - Cl). Anal.
(C13H13F3N2O‚HCl‚0.7H2O), C, H, N.
(R)-9-Ethoxy-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol -6(2H)-one Hydrochloric Acid Salt (56). Prepared
according to procedures described for compound 55 with substitu-
tion of ethyl iodide for methyl iodide in Step B. Enantiomeric excess
(R)-9-Propyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (59). Prepared
according to the procedures of compound 62 and 58 with the
substitution of cis-1-propenylboronic acid for 2,4,6-trivinylcyclo-
triboroxane pyridine complex. Enantiomeric excess >99:1 based
1
>99:1 based on chiral HPLC. H NMR (400 MHz, D2O) δ 7.43
(s, 1 H), 7.35 (s, 1 H), 4.91 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.49 (dd,
J ) 14.7, 4.2 Hz, 1 H), 4.20 (q, J ) 7.0 Hz, 2 H), 4.08 (dd, J )
12.5, 4.2 Hz, 1 H), 3.59 (dd, J ) 12.7, 3.5 Hz, 1 H), 3.47-3.55
(m, 1 H), 3.03 (dt, J ) 12.6, 4.6 Hz, 1 H), 2.81 (t, J ) 12.3 Hz, 1
H), 1.38 (t, J ) 7.0 Hz, 3 H). MS (ESI) 301 (M - Cl). Anal.
(C14H15F3N2O2‚HCl‚1.2H2O), C, H, N.
1
on chiral HPLC. H NMR (400 MHz, CD3OD) δ 7.79 (s, 1 H),
7.73 (s, 1 H), 4.88-4.92 (m, 1 H), 4.54 (dd, J ) 13.8, 4.2 Hz, 1
H), 4.13 (dd, J ) 12.3, 3.9 Hz, 1 H), 3.46-3.58 (m, 2 H), 3.00-
3.09 (m, 1 H), 2.77-2.85 (m, 3 H), 1.68-1.77 (m, 2 H), 0.98 (t,
J ) 7.5 Hz, 3 H). MS (ESI) 299.3 (M - Cl). Anal. (C15H17F3N2O‚
HCl‚0.4H2O), C, H, N.
(R)-9-Ethenyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindo l-6(2H)-one Hydrochloric Acid Salt (62). Tetrakis-
(triphenylphospine)palladium(0) (305 mg, 0.26 mmol) was added
in one portion to a degassed mixture of N-(tert-butoxycarbonyl)-
(R)-9-bromo-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]-
isoindol-6(2H)-one (4.6 g, 11 mmol), potassium carbonate (1.8 g,
13 mmol), and 2,4,6-trivinylcyclotriboroxane pyridine complex (4.2
g, 11 mmol) in 1,2-dimethoxyethane (80 mL) and water (25 mL).
The mixture was warmed to 100 °C. After 1 h, the reaction was
cooled to room temperature, diluted with brine, and extracted with
EtOAc (×3), and the combined organic layers were dried over
sodium sulfate, filtered, and concentrated in Vacuo. The resulting
residue was purified by flash column chromatography (SiO2,
0-50% ethyl acetate/hexanes) to as a off-white solid (3.53 g, 87%).
To 15 mg of white solid was added concentrated aqueous HCl (1
mL). After 5 min, the solution was concentrated in Vacuo, diluted
with water, and lyophilized to give 62 as a white solid (11 mg).
Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR (400
MHz, CD3OD) δ 8.04 (s, 1 H), 7.94 (s, 1 H), 6.94 (dd, J ) 17.6,
11.0 Hz, 1 H), 6.11 (d, J ) 17.6 Hz, 1 H), 5.56 (d, J ) 11.0 Hz,
1 H), 4.88-4.93 (m, 1 H), 4.55 (dd, J ) 14.3, 4.2 Hz, 1 H,) 4.14
(dd, J ) 12.3, 3.9 Hz, 1 H), 3.52-3.58 (m, 1 H), 3.45-3.50 (m,
1 H), 3.06 (dt, J ) 12.2, 4.2 Hz, 1 H), 2.85 (t, J ) 12.1 Hz, 1 H).
MS (ESI) 283 (M - Cl). Anal. (C14H13F3N2O‚1.3HCl‚2H2O), C,
H, N.
(R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (58). To N-(tert-
butoxycarbonyl)-(R)-9-ethenyl-1,3,4,10b-tetrahydro-7-trifluorom-
ethylpyrazino[2,1-a]isoindol-6(2H)-one (3.53 mg, 9.22) was added
methanol (50 mL), and the resulting solution was degassed via
alternating exposure to vacuum and argon. To this solution was
added 10% palladium on carbon (300 mg, 10 wt %), and the black
suspension was subjected a hydrogen atmosphere (1 atm). After 1
h, the reaction was filtered and concentrated in Vacuo, and the
resulting yellow residue was purified by flash column chromatog-
raphy (SiO2, 0-50% EtOAc/hexanes) to afford a white foam solid
(3.1 g, 87%). To the 21 mg of white solid was added concentrated
(R)-9-Butyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (60). Prepared
according to procedures described in Example 62 with substitution
of n-butylboronic acid for cis-1-propenylboronic acid and 1,1′-bis-
(diphenylphosphino)ferrocene palladium(II) dichloride dichlo-
romethane complex for tetrakis(triphenylphosphine)-palladium(0).
Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR (400
MHz, D2O) δ 7.76 (s, 1 H), 7.67 (s, 1 H), 4.91 (dd, J ) 11.9, 3.9
Hz, 1 H), 4.50 (dd, J ) 14.5, 3.9 Hz, 1 H), 4.09 (dd, J ) 12.5, 4.2
Hz, 1 H), 3.59 (dd, J ) 12.7, 3.9 Hz, 1 H), 3.47-3.56 (m, 1 H),
3.03 (dt, J ) 12.5, 4.4 Hz, 1 H), 2.72-2.82 (m, 3 H), 1.55-1.64
(m, 2 H), 1.25 (dq, J ) 14.9, 7.5 Hz, 2 H), 0.84 (t, J ) 7.0 Hz, 3
H). MS (ESI) 313 (M - Cl). Anal. (C16H19F3N2O‚HCl‚1.1H2O),
C, H, N.
(R)-9-Isopropyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (61). Prepared
according to procedures described for compound 62 and 58 with
substitution of isopropenylboronic acid for 2,4,6-trivinylcyclotri-
boroxane pyridine complex. Enantiomeric excess >99:1 based on
1
chiral HPLC. H NMR (400 MHz, D2O) δ 7.82 (s, 1 H), 7.74 (s,
1 H), 4.93 (dd, J ) 11.9, 3.9 Hz, 1 H), 4.51 (dd, J ) 14.9, 3.9 Hz,
1 H), 4.11 (dd, J ) 12.3, 3.5 Hz, 1 H), 3.62 (d, J ) 2.6 Hz, 1 H),
3.54-3.64 (m, 1 H), 3.47-3.53 (m, 1 H), 3.00-3.13 (m, 1 H),
2.78 (t, J ) 12.1 Hz, 1 H), 1.24 (d, J ) 7.0 Hz, 6 H). MS (ESI)
299 (M - Cl). Anal. (C15H18F3N2O‚1.6HCl‚H2O), C, H, N.
(R)-9-Ethynyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (63). To a
stirring solution of N-(tert-butoxycarbonyl)-(R)-1,3,4,10b-tetrahy-
dro-9-trimethylsilylethynyl-7-trifluoromethylpyrazino[2,1-a]isoin-
dol-6(2H)-one (44 mg, 0.1 mmol) [prepared according to procedures
described for compound 52 with substitution of tributyl(trimeth-
ylsilylethynyl)tin for tributyl(1-ethoxyvinyl)tin] in MeOH (1.0 mL)
was added potassium carbonate (13 mg, 0.1 mmol). The reaction
was stirred for 5 min and then quenched with brine. The reaction
was extracted with EtOAc (2 × 5 mL). The organic layers were
combined, dried over Na2SO4, and concentrated in Vacuo to a pale

1378 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Wacker et al.
yellow oil. The oil was purified by radial chromatography (SiO2,
30% EtOAc in hexanes) to give 27 mg of a pale yellow oil. To the
oil was added concentrated aqueous HCl (1 mL). After 5 min, the
solution was concentrated in Vacuo, diluted with water, and
lyophilized to give 59 as a white solid (21 mg). Enantiomeric excess
>99:1 based on chiral HPLC. 1H NMR (400 MHz, CD3OD) δ 8.05
(s, 1 H), 7.96 (s, 1 H), 4.90 (dd, J ) 11.6, 4.2 Hz, 1 H), 4.55 (dd,
J ) 14.1, 3.9 Hz, 1 H), 4.11 (dd, J ) 12.3, 3.9 Hz, 1 H), 4.00 (s,
1 H), 3.51-3.57 (m, 1 H), 3.44-3.49 (m, 1 H), 3.05 (dt, J ) 12.4,
4.6 Hz, 1 H), 2.85 (t, J)12.1 Hz, 1 H). MS (ESI) 281 (M - Cl).
Anal. (C14H11F3N2O‚HCl‚1.1H2O), C, H, N.
(R)-9-Cyclopropyl-1,3,4,10b-tetrahydro-7-trifluoromethyl-
pyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid Salt (64).
Prepared according to procedures described for compound 62 with
substitution of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane for 2,4,6-trivinylcyclotriboroxane pyridine complex and 1,1′-
bis(diphenylphosphino)ferrocene palladium(II) dichloride dichlo-
romethane complex for tetrakis(triphenylphosphine)palladium(0).
Enantiomeric excess >99:1 based on chiral HPLC. 1H NMR (400
MHz, D2O) δ 7.62 (s, 1 H), 7.52 (s, 1 H), 4.90 (dd, J ) 12.1, 4.2
Hz, 1 H), 4.50 (dd, J ) 14.7, 4.2 Hz, 1 H), 4.08 (dd, J ) 12.3, 4.4
Hz, 1 H), 3.56-3.62 (m, 1 H), 3.47-3.56 (m, 1 H), 3.03 (dt, J )
12.6, 4.6 Hz, 1 H), 2.77 (t, J ) 14.0 Hz, 1H), 2.07-2.13 (m, 1 H),
1.09-1.14 (m, 2 H), 0.81-0.85 (m, 2 H). MS (ESI) 297 (M -
Cl). Anal. (C15H15F3N2O‚HCl‚0.9H2O), C, H, N.
(R)-9-(1-Methylcyclopropyl)-1,3,4,10b-tetrahydro-7-trifluo-
romethylpyrazino[2,1-a]isoindol-6(2H)-one Hydrochloric Acid
Salt (65). To a stirring degassed solution of N-(tert-butoxycarbonyl)-
(R)-9-isopropenyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino-
[2,1-a]isoindol-6(2H)-one (185 mg, 0.47 mmol) and palladium(II)
acetate (1 mg, 0.004 mmol) in CH2Cl2 (1 mL) under Ar was added
a 0.5 M solution of diazomethane in ether (2.6 mL). After 1 h, the
reaction was warmed to room temperature for 16 h. The addition
of diazomethane was repeated twice more. The reaction was filtered
and then concentrated in Vacuo to a pale yellow oil. The oil was
dissolved in acetone (2 mL) and treated with 4-methylmorpholine
N-oxide (55 mg, 0.47 mmole) and osmium tetraoxide in water (1.0
mg in 0.16 mL). The reaction was stirred for 1 h and then quenched
with sat. aq Na2SO3. The reaction was extracted with EtOAc (3 ×
10 mL). The organic layers were combined, dried over MgSO4,
and concentrated in Vacuo to a pale yellow oil. The oil was purified
by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to yield
a colorless oil (83 mg, 43%). To the oil was added concentrated
aqueous HCl (1 mL). After 5 min, the solution was concentrated
in Vacuo, diluted with water, and lyophilized to give 65 as a white
solid (63 mg). Enantiomeric excess >99:1 based on chiral HPLC.
1H NMR (400 MHz, D2O) δ 7.75 (s, 1 H), 7.71 (s, 1 H), 4.89 (dd,
J ) 11.9, 3.9 Hz, 1 H), 4.49 (dd, J ) 14.5, 4.4 Hz, 1 H), 4.08 (dd,
J ) 12.3, 3.9 Hz, 1 H), 3.49-3.60 (m, 2 H), 3.01 (dt, J ) 12.5,
3.9 Hz, 1 H), 2.75 (t, J ) 12.3 Hz, 1 H), 1.40 (s, 3 H), 0.92-0.98
(m, 2 H), 0.87-0.91 (m, 2 H). MS (ESI) 311 (M - Cl). Anal.
(C16H17F3N2O‚HCl‚1.6H2O), C, H, N.
Binding Assays for the 5-HT2A, 5-HT2B, and 5-HT2C Recep-
tors. Radioligand binding studies were conducted to determine the
binding affinities (Ki values) of compounds for the human
recombinant 5-HT2A, 5-HT2B, and 5-HT2C receptors stably expressed
in HEK293E cell line.20 Assays were conducted in disposable
polypropylene 96-well plates (Costar Corp., Cambridge, MA) and
were initiated by the addition of 5-HT2A,5-HT2B, or 5-HT2C
membrane homogenate in tissue buffer (10-30 µg/well) to assay
buffer (50 mM Tris HCl, 0.5 mM EDTA, 10 mM pargyline, 10
mM MgSO4, 0.05% ascorbic acid, pH 7.5) containing [125I]DOI
for the 5-HT2A and 5-HT2C receptors (0.3-0.5 nM, final) or [3H]-
LSD (1-2.0 nM, final) for the 5-HT2B receptor, with or without
competing drug. For a typical competition experiment, a fixed
concentration of radioligand was competed with duplicate concen-
trations of compound (12 concentrations ranging from 10 pM to
10 µM). The reaction mixtures were incubated to equilibrium for
45 min at 37 °C and terminated by rapid filtration (Packard cell
harvester; Perkin-Elmer) over GFF glass-fiber filters that had been
presoaked in 0.3% polyethyleneimine. Filters were washed in ice-
cold 50 mM Tris HCl buffer (pH 7.5) prior to determining
radioactivity content on a Top Count (Packard).
Functional Assays for the 5-HT2A, 5-HT2B, and 5-HT2C
Receptors. HEK293E cells stably expressing the human 5-HT2A
,
5-HT2C, or 5-HT2B receptors were maintained Dulbecco’s modified
Eagle’s media with high glucose (DMEM; Gibco BRL) containing
10% dialyzed fetal bovine serum (FBS) and 500 µg/mL G418
(Gibco BRL). The cells was lifted with 2 mL Cellstripper
(Mediatech/Cellgro) and plated at a density of 20 000 cells/25 µL/
well onto poly-D-lysine-coated 384-well plates (Biocoat; Becton
Dickinson, Bedford, MA) in phenol red free Dulbecco’s modified
Eagle’s media (DMEM; Gibco BRL) containing a high concentra-
tion of glucose without FBS. Following an overnight (∼15-18 h)
incubation at 37 °C, the cell plates were removed from the incubator
and dye loading buffer (25 µL of 1x Hanks BSS without calcium
and magnesium with 25 mM HEPES) containing 5 µM of the
calcium dye reagent Fluo-4 was added to each well. Following the
dye loading of the cells for 1 h at room temperature, the cell plates
were transferred to the FLIPR384 (Molecular Devices, Sunnyvale,
CA). Eleven concentrations of test compounds in 25 µL loading
buffer were added to the cell plate on the FLIPR384 to determine a
concentration-response curve, and the changes in fluorescence units
due to the elevation of intracellular calcium were monitored for a
period of 90 s. The raw data from time sequence recording was
normalized to the percentage response obtained from the positive
control (Serotonin 3 µM) on the same plate and analyzed to fit the
four-parameter logistic equation in order to assess the compound’s
potency (EC50) and efficacy (intrinsic activity) from the 384-FLIPR
agonist assay.
Rat Pharmacokinetic Study. Male Sprague Dawley rats (Charles
River, MA) weighing between 200 and 250 g were used. Animals
were allowed free access to a standard laboratory chow and water.
They were housed in a constant temperature-humidity environment.
Three rats were used in each of the iv and oral (po) arms of the
studies. Doses of 4.4 mg/kg and 8.86 mg/kg were administered
via iv and po routes, respectively. The vehicle consisted of
polyethylene glycol 400:Tween 80:water (15:1:84, v/v). Blood was
sampled from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24
h postdose. Plasma was obtained after centrifugation of the blood
samples. Following protein precipitation using acetonitrile and
subsequent centrifugation, samples were analyzed using LC/MS-
MS.
Rat 20 h Operant Feeding Assay. Compounds were assessed
for their ability to reduce food consumption during a 20 h period,
which began at the onset of the dark cycle. Male Sprague-Dawley
rats, obtained from Charles River Laboratories, were trained in
operant chambers (Coulbourn Instruments, Allentown, Pa) equipped
with a lever, a food hopper, a water bottle with photocells, and an
infrared activity monitor. Rats were trained on a fixed ratio three
(FR3) response paradigm which required three consecutive bar
presses in order to obtain a food pellet (Research Diets purified
food pellet). The number of bar presses and pellets consumed serve
as the measure of food intake by the animal. Rats (n ) 6) were
administered (po) test compound or vehicle (14% PPG, 1% Tween,
85% water, v/v) 60 min prior to the onset of the dark cycle. Treated
animals were then placed in individual operant boxes for 20 h period
(12 h of dark cycle and the first 8 h of the light cycle). Percent
reduction in food intake was calculated as the ratio of total food
intake of drug-treated animals divided to the total food intake of
vehicle-treated counterparts. Simultaneous measurements of water
intake and locomotor activity are also measured during the period
to evaluate potential adverse effects.
Rat 4-Day Body Weight Loss Model. Male Sprague Dawley
(Charles River Breeding Laboratory) rats weighing approximately
240 g were placed in individual plastic cages with AlphaDri
bedding. There were eight rats per treatment group. The room was
maintained at 72 °F and 50% humidity, and a 12/12 light-dark cycle
with lights out at 1600 h. The rats were conditioned for 5 days
prior to the start of the study to have a choice of two diets: (1)
standard chow (Harlan Teklad, 2018) containing 18% protein, 5%
fat, and 73% carbohydrate and (2) a high fat, high sugar diet

5-HT2C Receptor Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1379
4023-4034. (c) Fitzgerald, L. W.; Ennis, M. D. 5-HT2C receptor
modulators: progress in development of new CNS medicines. Annu.
Rep. Med. Chem. 2002, 37, 21-30.
(Research Diets (D2327) containing 20% protein, 40% fat, and 40%
carbohydrate where the carbohydrate is entirely sucrose and the
fat is soybean and coconut oil. Drug treatment was po at 2.0 mL/
kg as a solution in 15% propylene glycol, 1% Tween 80 in water
at 1500 h beginning on day 0, and continuing daily through day 4.
Body weight and consumption of both diets and water were
measured daily. Water was available ad libitum throughout the
study. Body weight data was converted to percent change from
baseline where baseline body weight was measured prior to drug
treatment on day 0 of the study. Differences between dose groups
at specified time points were analyzed using ANOVA followed by
Fisher’s PLSD as the posthoc measure for dose differences.
Gastric Parietal Cell Necrosis Assay. Male CD-1 mice,
obtained from Charles River Laboratories, received a single oral
dose (by gavage) of 0, 30, 100, 200, or 300 mg/kg (n ) 5/group)
of an experimental compound or an internal tetracyclic indoline,
as a positive control. Control animals were dosed with vehicle
(aqueous 1% Tween 80/14% propylene glycol; 5 mL/kg). Mice
were euthanized 24-h after dosing, and a blood sample was collected
to determine plasma concentrations. Stomachs were removed,
cleaned, and fixed in formalin prior to routine processing for
histopathology evaluation following staining with hematoxylin and
eosin (H&E).
(11) (a) Fitzgerald, L. W.; Burn, T. C.; Brown, B. S.; Patterson, J. P.;
Corjay, M. H.; Valentine, P. A.; Sun, J.-H.; Link, J. R.; Abbaszade,
I.; Hollis, J. M.; Largent, B. L.; Hartig, P. R.; Hollis, G. F.; Meunier,
P. C.; Robichaud, A. J.; Robertson, D. W. Possible role of valvular
serotonin 5-HT2B receptors in the cardiopathy associated with
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B.; Baumann, M. H.; Savage, J. E.; Rauser, L.; McBride, A.;
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5-HT2B receptors in the cardiac valvulopathy associated with fen-
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Rosenzweig-Lipson, S.; McGonigle, P.; Levy, R. J.; Liang, B.
Serotonin mechanisms in heart valve disease II: The 5-HT2 receptor
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(12) (a) Robichaud, A. J.; Chen, W.; McClung, C.; McClung, C.; Clark,
D.; Deng, W.; Brondyke-Calvello, E.; Mitchell, I. S.; Lee, T.;
Rajagopalan, P.; Fitzgerald, L. W.; Conklin, D. S.; McElroy, J. F.;
Rohrbach, K. W.; Miller, K. J.; Largent, B. L.; Robertson, D. W.
Synthesis and biological evaluation of novel, selective 5-HT2C
receptor agonists for the treatment of obesity. Abstracts of Papers;
221st American Chemical Society National Meeting, San Diego, CA,
American Chemical Society: Washington, DC, 2001, MEDI-105.
(b) Lee, T.; Robichaud, A. J.; Chen, W.; Lu, Y.; Dowdell, S.; Boyle,
K. E.; Mitchell, I. S.; Fevig, J. M.; Wexler, R. R.; Miller, K. J.;
Largent, B. L.; Rohrbach, K. W.; Devenny, J. J.; McElroy, J. F.
Synthesis and biological evaluation of novel, selective 5-HT2C
receptor agonists for obesity. Abstracts of Papers; 229th American
Chemical Society National Meeting, San Diego, CA; American
Chemical Society: Washington, DC, 2005; MEDI-283.
(13) Richter, H. G. F.; Adams, D. R.; Benardeau, A.; Bickerdike, M. J.;
Bentley, J. M.; Blench, T. J.; Cliffe, I. A.; Dourish, C.; Hebeisen,
P.; Kennett, G. A.; Knight, A. R.; Malcolm, C. S.; Mattei, P.; Misra,
A.; Mizrahi, J.; Monck, N. J. T.; Plancher, J.-M.; Roever, S.; Roffey,
J. R. A.; Taylor, S.; Vickers, S. P. Synthesis and biological evaluation
of novel hexahydro-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazines as potent
and selective 5-HT2C receptor agonists. Bioorg. Med. Chem. Lett.
2006, 16, 1207-1211.
(14) Welch, W. M. Synthesis of the 1,2,3,4-tetrahydropyrazino[2,1-a]-
isoindol-6(2H)-one ring system. J. Org. Chem. 1982, 47, 886-888.
(15) Absolute stereochemistry was determined from the (S)-10-camphor-
sulfamide of compound 30 and correlated to all other compounds
by chiral HPLC retention times. Crystallographic data (excluding
structure factors) for compound 30 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tion number CCDC 632659. Copies of the data can be obtained free
of charge upon application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (Fax: (+44)1223-336-033. E-mail: deposit@
ccdc.cam.ac.uk).
Acknowledgment. The authors thank Cindy Li for assistance
in structural elucidations.
Supporting Information Available: Table of combustion
analysis and X-ray crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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