Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity

Article abstract of DOI:10.1021/jm011125x

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarb

Full text of DOI:10.1021/jm011125x

J . Med. Chem. 2002, 45, 3509-3523
3509
Discover y a n d Op tim iza tion of a Ser ies of Ca r ba zole Ur ea s a s NP Y5 An ta gon ists
for th e Tr ea tm en t of Obesity
Michael H. Block,†,* Scott Boyer,‡ Wayne Brailsford,† David R. Brittain,† Debra Carroll,§ Steve Chapman,†
David S. Clarke,† Craig S. Donald,† Kevin M. Foote,† Linda Godfrey,† Anthony Ladner,| Peter R. Marsham,†
David J . Masters,§ Christine D. Mee,| Michael R. O’Donovan,| J . Elizabeth Pease,† Adrian G. Pickup,†
J ohn W. Rayner,† Andrew Roberts,† Paul Schofield,† Abid Suleman,† and Andrew V. Turnbull§
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom, and Medicinal Chemistry,
Cardiovascular Research, Drug Metabolism and Pharmacokinetics, Bioscience, Cardiovascular Research, and
Genetic Toxicology, Safety Assessment, AstraZeneca, Molndal, Sweden
Received December 17, 2001
The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective
appetite suppressants for the treatment of obesity has prompted vigorous research to identify
suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a )
that are potent and selective Y5 antagonists, representing interesting starting points but
suffering from poor bioavailability and concerns about potential toxicity as a consequence of
the embedded aminocarbazole fragment. It proved relatively easy to improve the drug
metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a )
but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have
the potential to be drugs, we believed that both the compound itself and the component aniline
must be free of mutagenic activity. Parallel structure-activity relationship studies looking at
the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl
substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines
that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known
as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a
diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including
central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo
but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting
that the Y5 receptor alone has no significant role in feeding in these models.
In tr od u ction
including the most profound ability to acutely stimulate
feeding of any peptide discovered thus far. For many
years, there has been a debate over which receptor is
primarily responsible for this effect, with evidence
pointing to a role for both the Y1 and the Y5 subtypes.3,4
However, a more fundamental question about the
importance of the NPY system was prompted by the
observations that the NPY peptide and Y1 receptor and
Y5 receptor knockout mice are perfectly viable and do
not display any profound (body weight-related) pheno-
type.5 One view has been that feeding stimulated by
NPY only has any real significance in situations of
starvation. If hunger is one of the reasons that people
fail to adhere to diets, then it is possible that an agent
that reduces the sense of “starvation” would prove
valuable, and we,6a-c along with many others,6d-u,7 have
hoped that a selective Y5 antagonist may provide a
useful drug for treating obesity.
Obesity represents one of the most significant medical
problems facing society today. In the U.S.A., approxi-
mately half of the population is now considered at least
overweight and both the prevalence and the severity of
obesity continue to increase. While the situation in
many other countries may be less extreme, the trends
are the same, and the worldwide incidence of related
diseases such as type II diabetes is escalating rapidly.1
Behavioral modification is rarely successful in the
long term; therefore, there is a very real need for
improved medicines for those most seriously afflicted.
At the most basic level, it is necessary to reduce energy
intake or increase energy expenditure, and suppression
of appetite by promoting satiety is one way to achieve
this goal. In recent years, there has been a growing
understanding of the biological pathways that control
appetite, and a number of specific targets for interven-
tion have been identified.2 Among the most studied
systems, neuropeptide Y (NPY) has been featured
highly.2,3 It is one of the most abundant peptides present
in the mammalian brain and has many activities
Among the published Y5 antagonists are a series of
thioether amides reported by Bayer, of which 1 (see
Chart 1) is a representative example (see Table 1).6p We
discovered first that the thioether linkage is not es-
sential for Y5 binding, with the carbon analogue 2
having equivalent activity and second that incorporation
of a carbazole anilide, as in 3a (Chart 2), gave a
remarkable increase in potency. This compound repre-
sented an interesting starting point but suffered from
poor oral bioavailability and real concerns about poten-
* To whom correspondence should be addressed. Tel: 001-781-839-
4859. Fax: 001-781-839-4540. E-mail: Michael.Block@Astrazeneca.com.
† Medicinal Chemistry, Cardiovascular Research.
‡ Drug Metabolism and Pharmacokinetics.
§ Bioscience, Cardiovascular Research.
| Genetic Toxicology, Safety Assessment.
10.1021/jm011125x CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/02/2002

3510 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
Ch a r t 1
Ch a r t 2
Resu lts a n d Discu ssion
Ch em ica l Syn th esis. Compound 1 was prepared as
described in the patent literature.6p The pyridyl propi-
onate derivatives 2 and 3a , the ring-substituted ana-
logues 3b,c,d ,g-i, and the isomeric carbazole deriva-
tives 9-11) were prepared by condensation of the
corresponding aniline with pyridyl propionic acid. The
urea derivatives 4a ,i were prepared by conversion of
3-amino-N-ethylcarbazole to the intermediate p-nitro-
phenyl carbamate followed by reaction with morpholine.
The substituted analogues 4d -i,n -s) were prepared by
reaction of the corresponding aminocarbazole with mor-
pholinocarbamoyl chloride. The urea derivatives 4j,k
were prepared by rearrangement of the ring-substituted
carbazole 3-carboxylic acids to the corresponding iso-
cyanates followed by condensation with morpholine.
The N-methyl derivative 5 was synthesized from 3a
by reaction with NaH and methyl iodide. The reversed
amide 6 was prepared from N-ethyl-carbazole-3-carbox-
aldehyde (13) by oxidation to the acid 14 and condensa-
tion with 2-(4-pyridyl)ethylamine, as illustrated in
Scheme 1. The acid 14 was also converted to the
corresponding primary amide, reduced with LiAlH4 to
give the amine 15, and coupled with pyridyl acetic acid
to give 7.
The synthesis of 8 was achieved by Fischer indole
condensation of the commercially available ketone 16
with phenyl hydrazine and N-alkylation to give 17,
followed by ring oxidation to 18 and hydrolysis and
amide coupling, as illustrated in Scheme 2.
The N-9 (R1)-substituted anilines 12d -i were pre-
pared by derivatization of 3-nitrocarbazole followed by
reduction of the nitro group. The 6-substituted and
8-substituted analogues (as in 12j,k ) were constructed
as illustrated in Scheme 3. The appropriately substi-
tuted phenyl hydrazine was condensed with the com-
mercially available ketone 19 to give 20 with unam-
biguous regiochemistry. Oxidation of the ring and
alkylation on nitrogen lead to carbazole ester 21, which
Ta ble 1. Human NPY5 Binding Affinity for Benzophenone and
Carbazole Derivatives
hY5 binding
IC50 (nM)
hY5 binding
IC50 (nM)
b
b
compda
compda
1
2
3a
4a
5
350
300
2
7
8
9
3400
2250
440
7
10
800
>10 000
2200
700
11c
6
a
Samples gave correct CHN analyses within (0.4 unless
b
otherwise noted. IC50 data are the mean of a minimum of two
results. CGP-716834a was used as a standard in all assays; IC50
) 0.9 nM (95% confidence for any individual result ( 2.6-fold).
c The sample gave the correct accurate mass, but no 13C NMR
spectrum was recorded.
tial toxicity as a consequence of the N-ethyl aminocar-
bazole fragment, which is a known animal carcinogen.8
In this paper, the work that has been undertaken to
address both of these concerns will be described. As a
consequence of these studies, we have identified highly
potent and selective Y5 antagonists with an improved
safety profile and excellent drug metabolism and phar-
macokinetic (DMPK) profile including central nervous
system (CNS) penetration.
Most of the evidence in support of the Y5 hypothesis
has been generated in rodents,2,3,5a but recently, there
have been reports suggesting that Y5 antagonists have
little or no effect in rodent feeding models.9 The ability
to interpret observations of this type is critically de-
pendent on the quality of the compounds used in the
studies and a good understanding of their properties.
The compounds resulting from the work discussed here
have allowed definitive in vivo experiments to be
performed, and the outcome of these studies will also
be summarized.10

Ureas as Antagonists for the Treatment of Obesity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3511
Sch em e 1a
Sch em e 3a
a
Reagents: (a) KMnO4, acetone-water, 87%. (b) EDAC, DMAP,
a
Reagents: (a) 4-F-PhNHNH2, EtOH, 97% or 2-Me-PhNHNH2,
CH2Cl2, 30%. (c) EtOCOCl, Et3N, THF. (d) NH4OH, 79%. (e)
LiAlH4, THF, 17%. (f) 4-Pyridyl acetic acid, iPrNEt2, HATU, DMF,
31%.
EtOH, 70%. (b) DDQ, xylene, 76% (R2 ) 6-F), 68% (R2 ) 8-Me).
(c) NaH, 2-Br-Pr, 45% (R2 ) 6-F) or Cs2CO3, 2-Br-Pr, 29% (R2 )
8-Me). (d) LiOH, THF. (e) (PhO)2PON3, Et3N, toluene. (f) TMS-
ethyl-alcohol. (g) TBAF, THF, 38% (R2 ) 6-F, 4 steps), 50% (R2 )
8-Me, 4 steps).
Sch em e 2a
Sch em e 4a
a
Reagents: (a) PhNHNH2, HCl, Et2O, 87%. (b) NaH, EtI, DMF,
97%. (c) 10% Pd/C, 200 °C. (d) NaOH, 37% from 17. (e) 4-Amino-
methyl-pyridine, EDAC, DMAP, 80%.
a
Reagents: (a) HCl, Et2O, 22% (R3 ) Cl, R4 ) H). (b) HNO3,
H2SO4, 80% (R3 ) Cl, R4 ) H), 51% (R3 ) R4 ) Me). (c) NaH,
2-Br-Pr, 58% (R3 ) Cl, R4 ) H), 74% (R3 ) Me R4 ) H), 20% (R3
) R4 ) Me). (d) DDQ, dioxane, 57% (R3 ) Cl, R4 ) H), 63% (R3
) Me R4 ) H), 69% (R3 ) R4 ) Me). (e) H2, Pd, EtOH, 50% (R3
) Cl, R3′ ) H), 83% (R3 ) Me R4 ) H), 92% (R3 ) R4 ) Me).
was converted to the desired anilines via hydrolysis to
the corresponding acid followed by Curtius rearrange-
ment to the isocyanate, capture as the trimethylsilane
(TMS) ethyl carbamate, and hydrolysis with fluoride.11
The 2-substituted derivatives (as in 12l,m ) were
accessed by coupling of the meta-substituted aniline
with R-chlorocyclohexanone to give predominantly the
6-substituted indole 22 (equivalent to the 2-carbazole,
R3 ) Me or Cl, R4 ) H), as illustrated in Scheme 4.12
Nitration on the aromatic ring gave 23 (R3 ) Me or Cl,
R4 ) H), which was converted by a sequence of ring
oxidation, alkylation, and nitro reduction to the desired
anilines. The dimethyl derivative 12s (R3 ) R4 ) Me)
was prepared in a similar manner.
zylamine derivative (24) as illustrated in Scheme 6.
Replacement of the bromo group by benzophenone
hydrazine in a Pd-mediated Buchwald reaction14 gave
hydrazone 25, which under acidic conditions was con-
verted directly to the indole 26, which was in turn
converted by alkylation, oxidation, and hydrogenolysis
of the benzyl groups to 12n .
The predominance of 2-substituted carbazoles pro-
duced by the Fischer indole route illustrated in Scheme
4 makes access to the 4-substituted carbazoles prob-
lematic. It was discovered that reaction of N-isopropyl-
The 1,4-substituted derivative 12r was synthesized
from 5-bromo-indole by condensation with hexane-2,5-
dione to form 1,4-dimethyl-6-bromocarbazole,13 followed
by alkylation, nitration on the 3-position, and reduction
of the nitro and bromine functionality, as illustrated in
Scheme 5.
i
3-nitrocarbazole with alkyl Grignard (Me, Pr),15 fol-
lowed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) gave the 4-substituted products
(27, R4 ) Me, iPr) exclusively and in high yield as shown
in Scheme 7. These compounds were converted by
reduction of the nitro group to the target aniline (12o,p ).
The 4-ethoxy derivative 12q was prepared in low yield
The 2,4 difluoro aniline 12n was synthesized from
4-bromo-2,6-difluoro-aniline and protected as its diben-

3512 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
Sch em e 5a
tains similar moderate potency to the previously re-
ported sulfur-linked compound 1.6p Incorporation of the
3-substituted carbazole as in 3a gave a 100-fold increase
in affinity for the Y5 receptor. Compound 3a binds with
high affinity to the human and rat receptors (hY5 IC50
) 2 nM, rY5 IC50 ) 7 nM)17 and has also been shown to
be a functional antagonist of NPY activity in cellular
calcium flux6u (IC50 ) 2 nM) and reporter gene10 (IC50
) 11 nM) assays, and it demonstrates high selectivity
against related receptors (Y1, Y2, Y4 > 10 µM). As such,
3a represented an interesting starting point for medici-
nal chemistry but suffered from two major drawbacks,
namely, poor pharmacokinetic (PK) properties and
concerns about potential toxicity as a consequence of the
embedded aminocarbazole fragment.
Improving the DMPK properties of these aminocar-
bazole derivatives proved relatively straightforward as
a wide range of amide and urea side chains were
compatible with good Y5 binding (results not shown).
Compound 3a has a short half-life in rats (T1/2 ) 15 min)
and low oral bioavailability (∼1%) primarily as a
consequence of poor solubility (∼1 µM) and poor meta-
bolic stability. In contrast, the morpholine urea 4a has
slightly improved solubility (∼3 µM) and greatly en-
hanced metabolic stability resulting in an improved
half-life in rats (T1/2 ) 3 h) and excellent oral bioavail-
ability (F ∼ 100%). Brain levels of 4a were 25-fold the
unbound drug concentration in plasma (500 and 21 nM,
respectively, 90 min after a 2 mg/kg oral dose, see Table
2) indicating that there is little barrier to penetration
into the CNS for this compound. Furthermore, cerebro-
spinal fluid (CSF) concentrations were equivalent to
those of free drug in plasma (see Table 2), supporting
this conclusion. As such, 4a was recognized as a valu-
able pharmacological tool but never considered to be
suitable as a potential drug because of genotoxicity
concerns.
a
Reagents: (a) Hexane-2,5-dione,13 35%. (b) KN(SiMe3)2, 2-I-
Pr, DMF, 27%. (c) HNO3, acetic acid, 37%. (d) H2, Pd, EtOAc, 28%.
Sch em e 6a
a
Reagents: (a) (Ph)2CNNH2, Pd(OAc)2, S-BINAP, toluene, 94%.
Initial studies to evaluate the importance of the
anilide NH and to eliminate the carbazole aniline
fragment focused on alkylation, reversal of the amide
linkage, incorporation of an extra methylene group, or
replacement of the amide nitrogen. Unfortunately,
compounds such as 5-8 showed relatively poor Y5
binding activity (hY5 IC50 ) 700-2200 nM). In analogy
with R and â naphthylamine (see, for example, ref 22),
it might be hoped that 1- and 4-aminocarbazole might
have much reduced genotoxic potential. However, the
1, 2, and 4 isomeric derivatives (9-11) all had greatly
reduced affinity for the Y5 receptor. With the exception
of genotoxicity concerns, compounds such as 4a do have
an otherwise interesting profile and this prompted us
to consider whether there were other ways of addressing
the concerns about the carbazole aniline fragment and,
specifically in the work outlined here, whether substitu-
tion on the carbazole ring would reduce the toxicity of
any potential aniline fragments.
(b) Cyclohexanone, pTSA, 83%. (c) NaH, 2-Br-Pr, 78%. (d) DDQ,
dioxane, 63%. (e) NH4+HCO3-, MeOH-H2O, Pd/C, 88%.
Sch em e 7a
a
Reagents: (a) R4MgCl. (b) DDQ, 46% (R4 ) iPr), 79% (R4 )
Me). (c) H2/Pd, EtOH, 99% (R4 ) iPr), 90% (R4 ) Me). (d) Zn,
EtOH, 11% (R4 ) OEt).
by reaction of N-isopropyl-3-nitrocarbazole with Zn
ethoxide to give the substituted aniline 12q directly.16
Id en tifica tion of a “P h a r m a cologica l Tool” a n d
Attem p ts to Rem ove th e An ilin e F r a gm en t. The
binding affinities at the human Y5 receptor were
determined in a filter binding assay using [125I] porcine
peptide YY (PYY), and the results for the two benzo-
phenone derivatives 1 and 2, along with the N-ethyl
carbazole derivatives (3a , 4a , and 5-11) are illustrated
in Table 1. The pyridyl propionate derivative (2) main-
Effects of Rin g Su bstitu tion on th e Mu ta gen ic
Activity of Ca r ba zole An ilin es a n d th e Y5 Activity
of Acyla ted Der iva tives. Carbazoles as a chemical
class have been relatively well-studied for carcinogenic-
ity and mutagenicity because they are commonly de-
tected environmental pollutants resulting from coal
burning and are a major component of cigarette smoke.
Carbazole itself, although hepatocarcinogenic in rats

Ureas as Antagonists for the Treatment of Obesity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3513
Ta ble 2. Concentrations of 4a ,o in Rat Plasma and the CNS Following Oral Dosing
concn (nM)
time of
rat plasma
protein binding:
fraction free (FF) (%)
estimated free
plasma concn
[plasma] × FF (nM)
dose
(mg/kg)
analysis
(min)
whole
brain
plasma
CSF
4a
4o
2
10.5
90
60
740
35 000
500
nd
17
153
2.8
0.9
21
315
Ta ble 3. Mutagenicity (Ames Activity) of
9-Ethyl-3-aminocarbazole for S. typhimurium TA98 and TA100
in the Presence of Rat Liver S9 Mix
significantly less mutagenic than the corresponding
N-ethyl and N-methyl carbazoles.18c The structural
factors influencing the mutagenic activity of aromatic
amines have been investigated using several chemical
series. Shape, lipophilicity, and the reactivity of the
ultimate electrophilic (nitrenium) species have all been
shown to be important factors. Among the literature
reports are several examining the effect of alkyl sub-
stitution next to the amino moiety in an attempt to block
its metabolic activation.21 In some series, e.g., benzidine
(4,4′-diaminobiphenyl), ortho-methyl substitution re-
duces mutagenic activity while in others, e.g., amino-
biphenyl and amino-naphthalene, it has little effect and
in some cases can actually increase it.22 The loss of
mutagenic activity observed in some series by ortho-
alkyl substitution may be a structurally specific, rather
than a general, phenomenon. In the carbazole series
work by Andre´ and co-workers,23 it was shown that
addition of a 1,4-dimethyl moiety considerably decreases
the Ames activity of 9-methyl-3-aminocarbazole. En-
couraged by these limited data suggesting appropriate
ring substitution can reduce Ames activity in the
carbazole series, we set out to determine in parallel the
influence of ring substitution on the Ames activity of
substituted carbazole anilines (12) and on the Y5
activity of the acylated derivatives (3 and 4), recognizing
that any substituent would need to be beneficial in both
contexts.
revertant colonies per plate
concn (µg/plate)
TA98
TA100
control
3.3
35
623
120
192
358
466
483
10
33
100
1416
1227
897
and mice, is not genotoxic, but a variety of relatively
simple substituted carbazoles display in vitro genotox-
icity with apparently differing modes of action.18a-d In
particular, amino-substituted carbazoles have been
shown to contribute to the mutagenicity of some tobacco
components and behave as reactive frame shift mu-
tagens acting mainly through the formation of esterified
(acetylated) hydroxylamines in a similar way to other
planar aromatic amines.19a,b Alkyl substituents, includ-
ing 9-methyl and 9-ethyl carbazole, have been shown
to be mutagenic in salmonella with the 9-hydroxy
metabolites as the probable proximate mutagens.18c,d
Although 3-amino-9-ethylcarbazole, an industrial aro-
matic amine dye intermediate, has been shown to be
carcinogenic in the livers of male and female rats and
mice,8 there appear to be no published reports of testing
for mutagenicity in vitro. 3-Amino-9-ethyl-carbazole was
evaluated in a standard Ames test using five strains of
Salmonella typhimurium.20 As expected, the results
(illustrated in Table 3) show that it is mutagenic for both
TA98 and TA100, in the presence of S9, indicating that
its activity resembles that of both 3-aminocarbazole and
9-ethylcarbazole. The very high degree of mutagenicity
observed illustrates the sensitivity of this assay for
detecting mutagenic compounds of this type.
The primary metabolic product of 4a (in vitro rat S9)
results from N-dealkylation and there is no evidence for
formation of 3-amino-9-ethylcarbazole under these con-
ditions. Under accelerated hydrolysis conditions, 4a is
again very stable with an extrapolated half-life of 50
years at pH 7 and 37 °C. However, at extremes of pH,
some 3-amino-9-ethylcarbazole is generated, and al-
though plasma stability appears to be very good, the
possibility of some enzymic hydrolysis in vivo cannot
be discounted. It is considered impossible to establish
“no effect” levels for genotoxins; consequently, we real-
ized that regardless of how sensitive the levels of
detection it would be impossible to prove that there was
“no” carbazole aniline generated in vivo. Therefore, for
any potential drugs derived from acylated carbazole
anilines, we believed that it would be essential to
demonstrate that both the parent compound and the
component aniline were Ames negative.
The mutagenic activity of the anilines (12) was
evaluated in the Ames test against strains TA98 and
TA100, in both the presence and the absence of a
metabolic activation system based on the postmito-
chondrial supernatant of livers from rats pretreated
with Aroclor 1254 (S9).20 The results for strain TA98 +
S9 (the most sensitive conditions) are illustrated in
Table 4 and are presented as the maximum increase in
mutation frequency observed relative to background
across the dose range (6-2000 µg/plate). In parallel, the
Y5 binding activity of the pyridyl propionate (3) or
morpholine urea (4) derivatives was evaluated, and
again, the results are presented in Table 4.
A wide range of substitution at the N-9 position (R1)
appears to be tolerated in terms of the Y5 activity of
the derivatives. For the alkyl substituents (3a -d ), there
is a clear trend in potency with i-propyl (3d ) being the
most potent, with reduction from ethyl (3a ) to methyl
(3b) and through to the unsubstituted derivative (3c).
The potency of the i-propyl is also reflected in the ureas
(4a ,d ) but does not extend to the neopentyl (4e) or
tetrahydrofuran (THF) (4f) side chains. Electron-
withdrawing groups on N-9 also seem compatible with
good potency (3g-i and 4h ,i). However, in the majority
of cases, the component anilines resulting from N-9
substitution (12f,h ,i) were at least as mutagenic as
N-ethylaminocarbazole (12a ) and in some cases more
so. However, although still positive in the Ames test,
incorporation of the i-propyl group gave a significant
There is precedent for modulating mutagenicity both
within the alkyl carbazole series and for amino-
substituted carbazoles and a variety of other aromatic
anilines. N-Isopropyl-carbazole has been shown to be

3514 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
Ta ble 4. Effect of Ring Substitution on the Mutagenic (Ames) Activity of the Carbazole Aniline (12) and the Human NPY5 Binding
Affinity of the Carbazole Amide (3) or Urea (4)
Ames activity in
TA 98 + S9 for aniline 12
substitution
R2
Y5 binding activitya
(max fold increase
R1
R3
R4
anilineb
in mutation frequency)
amideb
(nM)
ureab
(nM)
11
Et
Me
H
12a
12b
12c
12d
12e
12f
12g
12h
12id
12j
43
3a
2
33
230
1
4a
3b
3cc
3d
iPr
3
5
66
4d
4e
4f
2
78
40
neopentyl
THF
COMe
SO2Me
SO2NMe2
iPr
c
3g
3h
3i
3
1
8
35
39
15
6
3
43
2
4h
4i
4j
15
350
3
6-F
8-Me
iPr
12k
12l
4k
2
iPr
2-Me
2-Cl
2-F
iPr
12m
12n c
12o
12p
12qc
12r c
12s
iPr
4-F
4n
4o
4p
4q
4r
12
3
770
270
710
390
iPr
4-Me
4-iPr
4-OEt
4-Me
4-Me
no increase
no increase
no increase
no increase
no increase
iPr
iPr
iPr
1-Me
2-Me
iPr
4s
a
IC50 data are the mean of a minimum of two results. CGP-716834a was used as a standard in all assays; IC50 ) 0.9 nM (95% confidence
b
for any individual result ( 2.6-fold). Except where noted, all samples gave correct CHN analyses within (0.4 or correct accurate mass
in conjunction with 13C NMR. c Compounds gave correct accurate masses, but no 13C NMR spectra were recorded. No accurate mass or
d
13C NMR were recorded for this compound.
Ta ble 5. Properties of NPY5RA-972 (4o)
reduction in the mutagenicity of the aniline (12d ) and
hY5 binding IC50 ) 3 nM
hY5 functional antagonism
hY5 functional antagonism
rY5 binding IC50 ) 9 nM
(Ca flux) IC50 ) 6 nM
(Bgal reporter assay)
IC50 ) 37 nM
∼70% inhibition of 5HT2b and
adenosine transport at 10 µM
Y1, Y2, Y4, plus 80 other
receptors > 10 µM
3.5
as already discussed the acylated derivatives (3d and
4d ) were also significantly more potent in terms of
binding to Y5. Consequently, the i-propyl group was
selected as the N-9 substituent of choice and we
continued to investigate a range of further substituents
in conjunction with the N-9 i-propyl group.
selectivity
Addition of small groups at C-6 and C-8 was well-
tolerated in terms of the Y5 activity of the urea (4j,k )
but showed no benefit in terms of eliminating Ames
activity of the anilines (12j,k ). Similarly, a methyl group
incorporated at C-2 had little effect on the Ames activity
of the aniline (12l) but was tolerated in terms of the Y5
activity of related amides (results not shown). The
2-chloro group caused an increase in Ames activity
(12m ). The 2,4-difluoro substitution gave potent Y5
antagonists (as in 4n ) and helped to reduce the Ames
activity of the parent aniline (12n ). However, it was
other 4-substituents that had the most dramatic effects,
completely eliminating the Ames activity of the parent
anilines (12o-s). In many cases, this was accompanied
by a significant reduction in the Y5 binding of the
corresponding urea (4p -s). However, in the case of
4-methyl substitution, excellent Y5 binding affinity was
maintained for the urea (4o) while at the same time
completely eliminating the mutagenic activity of the
parent aniline (12o).
LogD7.4
protein binding (rat)
solubility (24 h, pH 7.4)
PK parameters (rat,
DMA:PEG:H2O
1:1:1 solution)
0.9% free
9 µM
iv (10 µmol/kg)
T1/2 ) 3.7 h, Vss ) 0.41 L/kg,
CL ) 0.08 L/h/kg
T1/2 ) 6.4 h, Cmax ) 35 µM,
Tmax ) 1 h, F ) 76%
po (30 µmol/kg)
that it had a very exciting profile (illustrated in Table
5);10 4o was not only bound very potently to the Y5
receptor (rat and human) and was a functional antago-
nist (human) but also had excellent selectivity with
respect to other NPY receptors and to a large and
diverse selection of unrelated receptors, enzymes, and
transporters. The only other activity observed was a
degree of binding to the 5HT2b receptor and partial
inhibition of adenosine transport, both determined at
10 µM.26 Compound 4o has a low level of metabolism
in vitro (Rat S9) and displays an excellent PK profile
in rats including low clearance, good oral bioavailability,
and an iv half-life of 3.7 h. Robust levels of 4o are seen
in the CSF (153 nM at 1 h after 10.5 mg/kg oral dose,
see Table 2), and as with 4a , these correspond fairly
closely to estimated free plasma levels, again suggesting
that in this case there is little barrier to penetration to
the CNS. On the basis of these results, it was antici-
pated that when dosed at 10 mg/kg orally that free
levels of 4o in the brain would exceed the Y5 binding
IC50 (rat) by at least 15-fold.
(It should also be noted that in evaluation of the
unsubstituted urea 4d there was evidence both in vitro24
and in vivo of cytochrome P450 1a1 (CyP 1a1) induction.
These results were consistent with aromatic hydro-
carbon (Ah) receptor activation, which is known to cause
a multitude of detrimental effects.25 In contrast, the
4-methyl derivative 4o showed no CyP1a1 induction in
vitro at doses up to 12 µM or in vivo following dosing of
2 × 10 mg/kg for 10 days.)
In Vivo P r op er ties of NP Y5RA-972 (4o). Further
evaluation of 4o (also known as NPY5RA-972) showed

Ureas as Antagonists for the Treatment of Obesity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3515
There is also evidence for CyP1A1 induction for some products
(4d ), consistent with Ah receptor activation. Appropriate
precautions should be taken in handling the compounds.
Biologica l Meth od s. All equipment, which was to come
in contact with NPY or PYY, was presiliconized with Sigma-
Cote (Sigma Aldrich, catalog no. SL 2).
In Vitr o Y5 Mem br a n e Bin d in g Assa ys. Hi5 insect cells
(48 h) infected (baculo virus-infected) with either rat or human
NPY-5 receptor were used for preparation of NPY-5 mem-
branes. Human NPY-1, NPY-2, and NPY-4 membranes were
prepared from SK-N-MC, KAN-TS, and stable NPY Y4 ex-
pressing Chinese hamster ovary (CHO) cells, respectively.
Membranes were prepared by sonication (3 × 15 s) in ice-cold
hypotonic buffer (12.5 mM Tris, 1.25 mM ethylenediamine-
tetraacetic acid (EDTA), 2.5% sucrose, pH 7.4) containing
complete protease inhibitor tablets (one per 100 mL) (Roche
Molecular Biochemicals, East Sussex, U.K.). The lysate was
layered onto a 41% sucrose cushion and centrifuged at
100 000g for 1 h. The membrane layer was harvested and
stored (in 50 mM Tris, 5 mM EDTA, 10% sucrose, pH 7.4) at
-80 °C until use.
Binding assays were performed in presiliconized round-
bottomed, polypropylene, 96 well plates (Corning Costar,
Bucks, U.K.). Compounds were dissolved in dimethyl sulfoxide
(DMSO) and diluted (20-fold) in binding buffer (50 mM N-(2-
hydroxyethyl)piperazine-N′-ethanesulfonic acid (HEPES), 2.5
mM CaCl2, 1 mM MgCl2, 0.5% bovine serum albumin (BSA),
pH 7.4). Each incubate had 0.01 µCi of [125I]PYY (Amersham
Pharmacia Biotech, Berks, U.K.) added to 10-80 µL of
membranes (sufficient to give a specific binding of 1500 cpm)
and 10 µL of compound solution. After 2 h of incubation at
room temperature, incubates were filtered onto Canberra
Packard GF/C 96 well filter plates (Packard Instruments,
Berks, U.K.) pretreated with 0.5% polyethyleneimine using a
Brandel harvester. The plates were washed twice with wash
buffer (binding buffer + 0.5 M NaCl). The filter plates were
dried overnight and counted on a Canberra Packard Top Count
(Packard Instruments) after addition of 20 µL of Microscint
40 (Packard Instruments) to each well.
F igu r e 1. Effect of NPY-5 selective antagonist NPY5RA-972
(4o) on food intake induced by NPY and the NPY-5 selective
agonist, [cPP1-7, NPY19-23, Ala31, Aib32, Gln34]hPP. Vehicle or
NPY5RA-972 (4o, 3 mg/kg) was dosed by oral gavage (po) 1 h
before administration of maximal doses of either [cPP1-7
,
NPY19-23, Ala31, Aib32, Gln34]hPP (0.6 nmol), or NPY (2.0 nmol)
into the third cerebroventricle (icv) of male rats during the
light cycle. Control animals received vehicle (HPMC/Tween,
po) followed 1 h later by icv vehicle (sterile water) (n ) 5-6);
***, P < 0.001 vs NPY-5 selective agonist; ns, not significant
vs NPY (one way analysis of variance, followed by Bonferroni
multiple comparisons test).
Injection of the selective Y5 agonist [cPP1-7, NPY19-23
,
Ala31, Aib32, Gln34]hPP27 directly into the third ventricle
of the brain of AP Wistar rats produces a robust and
reproducible stimulation of feeding. This effect is com-
pletely blocked by 4o when dosed orally at 3 mg/kg 1 h
prior to stimulation, thus proving that this compound
is also an extremely potent Y5 antagonist in vivo (Figure
1). However, the same compound (also at 3 mg/kg) is
unable to block the feeding induced by icv injection of
NPY.28 Compound 4o has little or no effect on free
feeding or fasting-induced feeding in AP Wistar rats
even when dosed at 30 mg/kg po.
Am es Test.20 The S. typhimurium strains TA98 and TA100
were obtained from Professor B. N. Ames (University of
California); the cultures were handled, and the tests performed
as described by Maron and Ames (1983). Briefly, plate
incorporation assays were done in both the presence and the
absence of an exogenous metabolic activation system (S9 mix)
comprising the postmitochondrial fraction (S9) from the livers
of Aroclor 1254-treated Sprague-Dawley rats, supplemented
with cofactors for reduced nicotinamide adenine dinucleotide
phosphate (NADPH) generation.
Con clu sion
Ch em istr y Meth od s. All procedures were carried out at
room temperature unless otherwise stated. All commercially
available reagents and solvents were used without further
purification unless otherwise stated. Organic solvent extracts
were dried over anhydrous Na2SO4 or MgSO4. 1H and 13C
nuclear magnetic resonance (NMR) were recorded on Bruker
DPX-300, DPX-400, or Varian Gemini 2000 instruments using
CDCl3 or Me2SO-d6 with Me4Si as internal reference.
Chemical shifts are in δ (ppm). Mass spectra were recorded
on Micromass Platform positive and negative electrospray
spectrometers. For thin-layer chromatography (TLC) analysis,
Merck precoated TLC plates (silica gel 60 F254, d ) 0.25 mm)
were used. Flash chromatography was performed on silica
(Merck Keiselgel: Art.9385) unless otherwise stated.
A series of carbazole amides and ureas have been
identified as highly potent and selective Y5 antagonists
with the demonstrated potential for good DMPK prop-
erties. Parallel structure-activity studies looking at the
effects of ring substitution have proved that it is possible
by incorporation of a 4-methyl substituent to produce
carbazole ureas with potent Y5 activity, comprised of
carbazole anilines that in themselves are devoid of
activity in the Ames test. NPY5RA-972 (4o) is extremely
selective and has an excellent DMPK profile including
CNS penetration and consequently is a highly potent
Y5 antagonist in vivo. However, NPY5RA-972 (4o) does
not block NPY-induced feeding nor does it reduce free
feeding or fasting-induced feeding in rats, which sug-
gests that the Y5 receptor alone has no significant role
in feeding in these models.
1-[N-(4-Ben zoylp h en yl)]-2-(m er ca p to-p yr id in -4yl)a cet-
a m id e (1).6p 1H NMR (Me2SO-d6): δ 4.1 (s, 2H), 7.32 (d, J )
7 Hz, 2H), 7.52 (t, J ) 7 Hz, 2H), 7.6-7.8 (m, 7H,), 8.36 (d, J
) 7 Hz, 2H), 10.70 (s, 1H). MS (ES+): 349 (MH+). Anal. for
C
20H16N2O2S‚0.5H2O.
N-(4-Ben zoylp h en yl)-3-p yr id in -4-ylp r op a n a m id e (2).
p-Aminobenzophenone (404 mg, 2.05 mmol), 3-(4-pyridyl)-
propionic acid (309 mg, 2.05 mmol), (dimethylamino)propyl-
3-ethylcarbodiimide (EDAC, 422 mg, 2.2 mmol), and (dimeth-
ylamino)pyridine (DMAP) (269 mg, 2.2 mmol) were stirred in
CH2Cl2 (10 mL) at room temperature under an atmosphere of
Exp er im en ta l Section
Ca u tion ! 3-Amino-N-ethyl-carbazole is a known animal
carcinogen and several of the carbazole amines discussed in
this paper have been shown to be mutagenic in the Ames test.

3516 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
argon for 2 h and then heated at reflux for a further 4 h. The
reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and
washed with water (20 mL) and partitioned. The organic layer
was dried, filtered, and concentrated under vacuum to a yellow
oil, which was chromatographed on silica using 20-75%
EtOAc/i-hexane as eluent. The resulting solid was recrystral-
lised from MeOH:EtOAc:i-hexane to give 2 as a white solid
(289 mg, 43%). 1H NMR (Me2SO-d6): δ 2.80 (t, J ) 7 Hz, 2H),
3.00 (t, J ) 7 Hz, 2H), 7.30 (d, J ) 7 Hz, 2H), 7.66 (m, 9H),
8.46 (d, J ) 7 Hz, 2H), 10.34 (br s, 1H). MS (ES+): 331 (MH+).
Anal. for C21H18N2O2.
N -(9-E t h yl-9-H -ca r b a zol-3yl)-3-p yr id in -4-ylp r op a n -
a m id e (3a ). Compound 3a was prepared in a similar manner
as 2 but using 3-amino-9-ethylcarbazole and dimethyl form-
amide (DMF) as solvent. The resulting solid was recrystallized
from EtOAc (100 mL) to give a white solid. Yield, 42%. 1H
NMR (Me2SO-d6): δ 1.30 (t, J ) 7 Hz, 3H) 2.70 (t, J ) 7 Hz,
2H), 2.98 (t, J ) 7 Hz, 2H), 4.40 (q, J ) 7 Hz, 2H), 7.18 (t, J
) 7 Hz, 1H), 7.30 (d, J ) 7 Hz, 2H), 7.44 (t, J ) 7 Hz, 1H),
7.50 (m, 3H), 8.04 (d, J ) 7 Hz, 1H), 8.38 (s, 1H), 8.47 (d, J )
7 Hz, 2H), 9.96 (s, 1H). MS (ES+): 344 (MH+). Anal. for
2H), 7.40 (t, J ) 8 Hz, 1H), 7.53 (m, 2H), 7.98 (d, J ) 9 Hz,
1H), 8.05 (d, J ) 8 Hz, 1H), 8.10 (d, J ) 8 Hz, 1H) 8.44 (m,
3H), 10.16 (s, 1H). 13C NMR (Me2SO-d6): δ 29.84, 36.26, 38.19,
110.39, 114.30, 114.45, 119.54, 120.22, 123.34, 123.75, 124.50,
124.63, 127.43, 134.31, 134.97, 138.78, 149.44, 150.04, 169.91.
MS (ES+): 423 (MH+). HRMS for C22H22N4O3S.
N -(9-E t h yl-9H -ca r b a zol-3-yl)m or p h olin e -4-ca r b ox-
a m id e (4a ). A solution of 3-amino-9-ethylcarbazole (25.0 g,
0.12mol) in EtOAc (300 mL) was added dropwise over 30 min
to a mixture of p-nitrophenyl chloroformate (24.0 g, 0.12mol)
and K2CO3 (16.6 g, 0.12mol) in EtOAc (200 mL). The mixture
was stirred for 18 h and poured into water (500 mL), and the
organic layer was separated, was washed with water (500 mL)
and brine (250 mL), and dried. The solution was evaporated
under vacuum to leave a brown solid. The crude product was
stirred in MeOH (500 mL) and then filtered. The filtered solid
was washed with Et2O (2 × 250 mL) and dried in air to give
3-(4-nitrophenoxycarbonylamino)-9-ethylcarbazole as a pale
yellow solid (36.0 g, 80%). 1H NMR (Me2SO-d6): δ 1.30 (t, J )
8 Hz, 3H), 4.40 (q, J ) 8 Hz, 2H), 7.15 (t, J ) 8 Hz, 1H), 7.45
(t, J ) 8 Hz, 1H), 7.55 (m, 5H), 8.1 (d, J ) 8 Hz, 1H), 8.3 (m,
3H), 10.4 (br s, 1H).
C
22H21N3O.
N-(9-Met h yl-9-H -ca r b a zol-3yl)-3-p yr id in -4-ylp r op a n -
To a solution of 3-(4-nitrophenoxycarbonylamino)-9-ethyl-
carbazole (250 mg, 0.67 mmol) and DMAP (4 mg, 0.03 mmol)
in EtOAc (10 mL) was added morpholine (0.067 mL, 0.73
mmol). The mixture was stirred for 18 h at room temperature
a m id e (3b). Compound 3b was prepared in a similar manner
1
as described for 3a in 58% yield. H NMR (Me2SO-d6): δ 2.70
(m, 2H), 2.98 (m, 2H), 3.83 (s, 3H), 7.19 (t, J ) 7 Hz, 1H), 7.33
(d, J ) 6 Hz, 2H), 7.46 (t, J ) 7 Hz, 1H), 7.48-7.58 (m, 3H),
8.06 (d, J ) 7.5 Hz, 1H), 8.39 (s, 1H), 8.48 (d, J ) 6 Hz, 2H),
9.88 (s, 1H). 13C NMR (Me2SO-d6): δ 28.76, 29.89, 36.17,
108.66, 108.90, 111.02, 118.32, 118.84, 119.75, 121.52, 121.74,
123.57, 125.49, 130.98, 137.14, 140.94, 149.25, 150.00, 169.27.
MS (ES+): 330 (MH+). HRMS for C21H19N3O.
1
and then filtered to give 4a (145 mg, 67%). H NMR (Me2SO-
d6): δ 1.28 (t, J ) 7 Hz, 3H), 3.44 (m, 4H), 3.62 (m, 4H), 4.38
(qu, J ) 7 Hz, 2H), 7.14 (t, J ) 7 Hz, 1H), 7.4 (t, J ) 7 Hz,
1H), 7.47 (s, 2H), 7.53 (d, J ) 7.5 Hz, 1H), 8.02 (d, J ) 7.5 Hz,
1H), 8.15 (s, 1H), 8.50 (s, 1H). MS (ES+): 324 (MH+). Anal.
for C19H21N3O2.
N-(9-H-Ca r ba zol-3yl)-3-p yr id in -4-ylp r op a n a m id e (3c).
Compound 3c was prepared in a similar manner as described
for 3a and purified by chromatography on silica using EtOAc
N-(9-Isop r op yl-9H-ca r ba zol-3-yl)m or p h olin e-4-ca r box-
a m id e (4d ). Under an inert atmosphere, Et3N (0.43 mL, 3.06
mmol) was added to a solution of 3-amino-9-isopropylcarbazole
(12d ) (624 mg, 2.78 mmol) in CH2Cl2 (10 mL) cooled in an ice
bath. Morpholine carbamoyl chloride (0.36 mL, 3.06 mmol) was
added dropwise, and then, the mixture was stirred for 72 h.
The mixture was diluted with CH2Cl2, washed with aqueous
K2CO3 solution, dried, filtered, and then concentrated. Chro-
matography on silica gel (eluent gradient of CH2Cl2 to EtOAc)
1
as eluent, to give 3c in 9% yield. H NMR (Me2SO-d6): δ 2.65
(t, J ) 7 Hz, 2H), 2.95 (t, J ) 7 Hz, 2H), 7.11 (t, J ) 7 Hz,
1H), 7.28 (d, J ) 6 Hz, 2H), 7.35 (m, 2H), 7.45 (m, 2H), 7.99
(d, J ) 7 Hz, 1H), 8.32 (s, 1H), 8.46 (d, J ) 6 Hz, 2H), 9.89 (s,
1H), 11.05 (s, 1H). MS (ES+): 316 (MH+). HRMS for C20H17N3O.
N-(9-Isopr opyl-9-H-ca r ba zol-3yl)-3-p yr id in -4-ylpr opa n -
a m id e (3d ). Compound 3d was prepared in a similar manner
1
gave 4d as an off white solid. Yield, 854 mg (91%). H NMR
1
(Me2SO-d6): δ 1.60 (d, J ) 7 Hz, 6H), 3.45 (t, J ) 5 Hz, 4H),
3.64 (t, J ) 5 Hz, 4H), 5.05 (m, 1H,), 7.13 (dd, J ) 8, 8 Hz,
1H), 7.38 (dd, J ) 8, 8 Hz 1H), 7.43 (dd, J ) 8, 2 Hz 1H), 7.58
(d, J ) 8 Hz, 1H), 7.64 (d, J ) 8 Hz, 1H), 8.02 (d, J ) 8 Hz,
1H), 8.16 (d, J ) 2 Hz, 1H), 8.54 (br s, 1H). MS (ES+): 338
(MH+). Anal. for C20H23N3O2.
as described for 3a in 67% yield. H NMR (Me2SO-d6): δ 1.60
(d, J ) 7 Hz, 6H), 2.69 (t, J ) 8 Hz, 2H), 2.96 (t, J ) 8 Hz,
2H), 5.05 (sept, J ) 7 Hz, 1H), 7.13 (t, J ) 7 Hz, 1H), 7.28 (d,
J ) 6 Hz, 2H), 7.39 (t, J ) 8 Hz, 1H), 7.48 (d, J ) 9 Hz, 1H),
7.63 (t, J ) 9 Hz, 2H), 8.03 (d, J ) 8 Hz, 1H), 8.36 (s, 1H),
8.45 (d, J ) 6 Hz, 2H), 9.92 (s, 1H). 13C NMR (Me2SO-d6): δ
20.426, 30.014, 36.300, 45.989, 110.326, 110.962, 118.262,
118.674, 119.976, 122.250, 123.763, 125.484, 130.885, 135.481,
139.438, 149.393, 150.221, 169.426. MS (ES+): 358 (MH+).
HRMS for C23H23N3O.
N-(9-Neopen tyl-9H-car bazol-3-yl)m or ph olin e-4-car box-
a m id e (4e). Compound 4e was prepared in a similar manner
1
as described for 4d in 20% yield. H NMR (Me2SO-d6): δ 1.00
(s, 9H), 3.44 (t, J ) 5 Hz, 4H), 3.62 (t, J ) 5 Hz, 4H), 4.13 (s,
2H), 7.12 (t, J ) 8 Hz, 1H), 7.33-7.46 (m, 2H), 7.50 (d, J ) 9
Hz, 1H), 7.57, (d, J ) 8 Hz, 1H), 8.00 (d, J ) 8 Hz, 1H), 8.13
(d, J ) 2 Hz, 1H), 8.49 (s, 1H). MS (ES+): 366 (MH+). Anal.
for C22H27N3O2.
N-(9-Acet yl-9-H -ca r b a zol-3yl)-3-p yr id in -4-ylp r op a n -
a m id e (3g). Compound 3g was prepared in a similar manner
1
as described for 3a in 14% yield. H NMR (Me2SO-d6): δ 2.72
(m, 2H), 2.87 (s, 3H), 2.96 (m, 2H), 7.31 (d, J ) 6 Hz, 2H),
7.40 (t, J ) 8 Hz, 1H), 7.53 (m, 2H), 8.06 (d, J ) 8 Hz, 1H),
8.18 (d, J ) 8 Hz, 1H), 8.24 (d, J ) 8 Hz, 1H), 8.44 (m, 3H),
10.18 (s, 1H). 13C NMR (Me2SO-d6): δ 27.31, 29.86, 36.27,
110.01, 116.27, 116.43, 119.18, 119.81, 123.54, 123.84, 125.47,
125.68, 127.47, 133.99, 135.17, 138.42, 149.21, 150.40, 169.89,
170.11. MS (ES+): 358 (MH+). HRMS for C22H19N3O2.
N-(9-Tetr a h yd r ofu r a n -3-yl-9H-ca r ba zol-3-yl)m or p h o-
lin e-4-ca r boxa m id e (4f). Compound 4f was prepared in a
similar manner as described for 4d in 30% yield. 1H NMR
(Me2SO-d6): δ 2.20 (m, 1H), 2.40 (m, 1H), 3.45 (m, 4H), 3.65
(m, 4H), 3.75 (m, 1H), 4.00 (m, 1H), 4.15 (dd, 1H), 4.30 (m,
1H), 5.60 (m, 1H), 7.15 (dd, J ) 1,7 Hz, 1H), 7.40 (dd, J ) 2,
9 Hz, 1H), 7.40 (dd, J ) 1, 7 Hz, 1H), 7.60 (d, J ) 9 Hz, 1H),
7.65 (dd, J ) 1, 9 Hz 1H), 8.00 (d, J ) 7 Hz, 1H), 8.15 (d, J )
2 Hz, 1H) 8.5 (s, 1H). MS (ES+): 366 (MH+). HRMS for
N-[9-(Meth ylsu lfon yl)-9-H-ca r ba zol-3yl]-3-p yr id in -4-yl-
p r op a n a m id e (3h ). Compound 3h was prepared in a similar
manner as described for 3a in 28% yield. 1H NMR (Me2SO-
d6): δ 2.72 (m, 2H), 2.94 (m, 2H), 3.24 (s, 3H), 7.30 (d, J ) 6
Hz, 2H), 7.43 (t, J ) 8 Hz, 1H), 7.55 (m, 2H), 7.93 (d, J ) 8
Hz, 1H), 8.02 (d, J ) 8 Hz, 1H), 8.10 (d, J ) 8 Hz, 1H), 8.45
(m, 3H), 10.19 (s, 1H). MS (ES+): 393 (MH+). Anal. for
C
21H23N3O3.
N-(9-Met h ylsu lfon yl-9H -ca r b a zol-3-yl)m or p h olin e-4-
ca r boxa m id e (4h ). Compound 4h was prepared in a similar
manner as described for 4d in 55% yield. 1H NMR (Me2SO-
d6): δ 3.21 (s, 3H), 3.42 (t, J ) 5 Hz, 4H), 3.61 (t, J ) 5 Hz,
4H), 7.44 (t, J ) 8 Hz, 1H), 7.53 (t, J ) 8 Hz, 1H), 7.54 (d, J
) 9 Hz, 1H), 7.90 (d, J ) 9 Hz, 1H), 8.01 (d, J ) 8 Hz, 1H),
8.07 (d, J ) 8 Hz, 1H), 8.27 (s, 1H), 8.73 (s, 1H). MS (ES+):
374 (MH+). Anal. for C18H19N3O4S.
C
21H19N3O3S.
N-{9-[(Dim et h yla m in o)su lfon yl]-9-H -ca r b a zol-3yl}-3-
p yr id in -4-ylp r op a n a m id e (3i). Compound 3i was prepared
in a similar manner as described for 3a in 47% yield. 1H NMR
(Me2SO-d6): δ 2.74 (m, 8H), 2.96 (t, J ) 8 Hz, 2H), 7.28 (m,

Ureas as Antagonists for the Treatment of Obesity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3517
N-{9-[(Dim eth yla m in o)su lfon yl]-9H-ca r ba zol-3-yl)m or -
p h olin e-4-ca r boxa m id e (4i). Compound 4i was prepared in
a similar manner as described for 4a in 21% overall yield. H
1H), 6.18 (br s, 1H), 7.20 (ddd, J ) 8, 8, 1 Hz, 1H), 7.37 (d, J
) 8 Hz, 1H), 7.40 (d, J ) 8 Hz, 1H), 7.43 (ddd, J ) 8, 8, 1 Hz,
1H), 7.55 (d, J ) 8 Hz, 1H), 8.25 (d, J ) 8 Hz, 1H). MS (ES+):
380 (MH+). 13C NMR (Me2SO-d6): δ 20.25, 21.02, 29.18, 44.25,
45.71, 66.13, 107.79, 110.27, 118.24, 120.13, 121.93, 122.72,
124.50, 128.05, 129.30, 138.0, 139.35, 140.65, 157.32. HRMS
for C23H29N3O2.
N-(4-Eth oxy-9-isop r op yl-9H-ca r ba zol-3-yl)m or p h olin e-
4-ca r boxa m id e (4q). Compound 4q was prepared in a similar
manner as described for 4d in 58% yield. 1H NMR (Me2SO-
d6): δ 1.55 (t, J ) 7 Hz, 3H), 1.71 (d, J ) 7 Hz, 6H), 3.57 (t, J
) 5 Hz, 4H), 3.80 (t, J ) 5 Hz, 4H), 4.21 (q, J ) 7 Hz, 2H),
4.97 (m, 1H), 7.02 (br s, 1H), 7.22 (ddd, J ) 8, 8, 1 Hz, 1H),
7.29 (d, J ) 8 Hz, 1H), 7.44 (ddd, J ) 8, 8, 1 Hz, 1H), 7.52 (d,
J ) 8 Hz, 1H), 8.06 (d, J ) 8 Hz, 1H), 8.19 (d, J ) 8 Hz, 1H).
MS (ES+): 382 (MH+). Anal. for C22H27N3O3.
N-(9-Isop r op yl-1,4-d im eth yl-9H-ca r ba zol-3-yl)m or p h o-
lin e-4-ca r boxa m id e (4r ). Compound 4r was prepared in a
similar manner as described for 4d in 94% yield. 1H NMR
(Me2SO-d6): δ 1.70 (d, J ) 7 Hz, 6H), 2.59 (s, 3H), 2.78 (s,
3H), 3.50 (m, 4H), 3.69 (m, 4H), 5.57 (m, J ) 7 Hz, 1H), 7.08
(s, 1H), 7.56 (dd J ) 9, 2 Hz, 1H), 7.82 (d, J ) 9 Hz, 1H), 8.25
(s, 1H), 8.31 (d, J ) 2 Hz, 1H). MS (ES+): 367 (MH+). Anal.
for C22H27N3O2.
N-(9-Isop r op yl-2,4-d im eth yl-9H-ca r ba zol-3-yl)m or p h o-
lin e-4-ca r boxa m id e (4s). Compound 4s was prepared in a
similar manner as described for 4d in 80% yield. 1H NMR
(CDCl3): δ 1.69 (d J ) 7 Hz, 6H), 2.44 (s, 3H), 2.76 (s, 3H),
3.50 (m, 4H), 3.75 (m, 4H), 4.97 (sept, J ) 7 Hz, 1H), 5.90 (s,
1H), 7.20 (t, J ) 8 Hz, 1H), 7.25 (s, 1H), 7.40 (t, J ) 8 Hz, 1H),
7.52 (d, J ) 8 Hz, 1H), 8.18 (d, J ) 8 Hz, 1H). MS (ES+): 366
(MH+). Anal. for C22H27N3O2.
1
NMR (Me2SO-d6): δ 1.04 (s, 1H), 1.05 (s, 1H), 3.48 (m, 4H),
3.64 (m, 4H), 7.41 (t, J ) 7.5 Hz, 1H), 7.53 (t, J ) 8 Hz, 1H,),
7.57 (dd, J ) 2, 9 Hz, 1H), 7.95 (d, J ) 9 Hz, 1H), 8.05 (d, J )
8 Hz, 1H), 8.08 (d, J ) 7.5 Hz, 1H), 8.29 (d, J ) 2 Hz, 1H),
8.73 (s, 1H). 13C NMR (Me2SO-d6): δ 38.20, 44.14, 65.97,
111.20, 114.035, 114.30, 120.10, 120.53, 123.17, 124.57, 124.71,
127.20, 133.81, 136.25, 138.76, 155.38. MS (ES+): 403 (MH+).
HRMS for C19H22N4O4S.
N-(6-F lu or o-9-isop r op yl-9H-ca r ba zol-3-yl)m or p h olin e-
4-ca r boxa m id e (4j) (Sch em e 3). Et3N (139 µL, 1 mmol) was
added to a stirred suspension of 6-fluoro-9-isopropyl-9 H
carbazol-3-yl carboxylic acid (see prep of 12j) (271 mg, 1 mmol)
and diphenylphosphoryl azide (275 mg, 1.1 mmol) in dry
toluene (15 mL) under argon. The resultant solution was
stirred for 1 h and then heated to reflux for 1 h. The heat
source was removed, and morpholine (200 µL, 3 mmol) was
added, and the resultant solution was stirred overnight at
ambient temperature. The mixture was filtered, and the
filtrate was diluted with EtOAc (30 mL) and washed with
water (10 mL), 1 M HCl (10 mL), 0.2 M NaOH (10 mL), water
(10 mL), and saturated brine (10 mL), dried, and evaporated
to dryness under reduced pressure. The resultant gum was
purified using a Bond Elute column (20 g) eluting with 0.5%
1
MeOH/CH2Cl2 to give 4j (259 mg) as a white solid. H NMR
(Me2SO-d6): δ 1.6 (d, J ) 6.8 Hz, 6H), 3.5 (t, J ) 4.9 Hz, 4H),
3.65 (t, J ) 4.9 Hz, 4H), 5.0 (sept, J ) 6.8 Hz, 1H), 7.2 (dt, J
) 9.0, 9.0, 2.6 Hz, 1H), 7.4 (dd, J ) 2.2, 8.8 Hz, 1H), 7.6 (d, J
) 8.8 Hz, 1H), 7.7 (dd, J ) 3, 9.1 Hz, 1H), 7.85 (dd, J ) 2.8,
9.1 Hz, 1H), 8.2 (d, J ) 2.2 Hz, 1H), 8.5 (s, 1H). MS (ES+):
356 (MH+). 13C NMR (Me2SO-d6): δ 20.88, 44.554, 46.60, 66.43,
105.87 (d, J ) 116 Hz), 110.65, 111.59 (d, J ) 43 Hz), 113.21
(d, J ) 107 Hz), 113.32, 121.66, 122.20, 123.24 (d, J ) 46.5
Hz, 132.15, 136.33, 136.66, 156.24, 156.50 (d, J ) 1160 Hz).
HRMS for C20H22N3O2F.
N-(9-Isop r op yl-8-m eth yl-9H-ca r ba zol-3-yl)m or p h olin e-
4-ca r boxa m id e (4k ). Compound 4k was prepared from
8-methyl-9-isopropyl-9H-carbazol-3-yl carboxylic acid (see prep
of 12k ) in a similar manner as described for 4j in 31% yield.
1H NMR (CDCl3): δ 1.7 (d, J ) 7 Hz, 6H), 2.8 (s, 3H), 3.5 (t,
J ) 5 Hz, 4H), 3.8 (t, J ) 5 Hz, 4H), 5.5 (sept, J ) 7 Hz, 1H),
6.4 (s, 1H), 7.0 (m, 1H), 7.2 (d, J ) 7.1 Hz, 1H), 7.3 (dd, J )
2.0, 8.9 Hz, 1H), 7.6 (d, J ) 8.9 Hz, 1H), 7.8 (d, J ) 7.6 Hz,
1H), 8.0 (d, J ) 2.0 Hz, 1H). 13C NMR (Me2SO-d6): δ 21.30,
21.52, 44.58, 47.52, 66.43, 112.36, 112.60, 118.09, 118.96,
120.27, 120.35, 123.345, 123.93, 129.724, 132.36, 135.284,
139.752, 156.215. HRMS for C21H25N3O2.
N-(2,4-Diflu or o-9-isop r op yl-9H-ca r ba zol-3-yl)m or p h o-
lin e-4-ca r boxa m id e (4n ). Compound 4n was prepared in a
similar manner as described for 4d in 83% yield. 1H NMR
(Me2SO-d6): δ 1.67 (d, J ) 7 Hz, 6H), 3.54 (t, J ) 5 Hz, 4H),
3.76 (t, J ) 5 Hz, 4H), 4.87 (sept, J ) 7 Hz, 1H,), 5.92 (br s,
1H), 7.06 (dd, J ) 10, 1 Hz, 1H), 7.21 (d, J ) 8 Hz, 1H), 7.43
(ddd, J ) 8, 7, 1 Hz, 1H), 7.49 (d, J ) 8 Hz, 1H), 8.14 (d, J )
7 Hz, 1H). 13C NMR (Me2SO-d6): δ 20.13, 44.20, 46.65, 65.91,
93.55 (d), 106.81, 107.19 (m), 110.80, 119.59, 119.69, 121.65,
125.51, 137.63 (m), 139.02, 153.50 (d), 155.98, 157.34 (d). MS
(ES+): 374 (MH)+. HRMS for C20H21F2N3O2.
N-(9-E t h yl-9H -ca r b a zol-3-yl)-N-m et h yl-3-p yr id in -4-yl
P r op a n a m id e (5). Sodium hydride (60% dispersion in oil) (65
mg, 1.5 mmol) was added to a solution of 3a (500 mg, 1.5 mmol)
in THF (10 mL) at 0 °C under an argon atmosphere. After it
was heated to 50 °C for 2 h, the mixture was allowed to cool
to room temperature whereupon MeI (0.1 mL, 1.5 mmol) was
added dropwise. After it was heated to 50 °C for 2 h, the
mixture was allowed to cool to room temperature. Water (30
mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 50 mL). The organics were concentrated and then
purified by flash column chromatography to give 5 as a brown
1
solid. Yield, 225 mg (43%). H NMR (Me2SO-d6): δ 1.30 (t, J
) 7 Hz, 3H), 2.35 (t, J ) 7 Hz, 2H), 2.78 (t, J ) 7 Hz, 2H),
3.25 (s, 3H), 4.42 (q, J ) 7 Hz, 2H), 7.05 (d, J ) 6 Hz, 2H),
7.19 (t, J ) 8 Hz, 1H), 7.28 (d, J ) 8 Hz, 1H), 7.45 (t, J ) 8
Hz, 1H), 7.64-7.56 (m, 2H), 7.88 (s, 1H), 8.11 (d, J ) 8 Hz,
1H), 8.32 (d, J ) 6 Hz, 2H). MS (ES+): 358 (MH+). Anal. for
C
23H23N3O.
9-Eth yl-N-(2-p yr id in -4-yleth yl)-9H-ca r ba zole-3-ca r box-
a m id e (6) (Sch em e 1). To a solution of 9-ethyl-3-formyl-
carbazole (13) (8.3 g, 37.2 mmol) in acetone (25 mL) was added
KMnO4 (12.1 g, 76.6 mmol) in water (50 mL), and the mixture
was heated at reflux for 18 h, filtered through Celite, and
acidified with HCl to give 9-ethyl-3-carboxycarbazole (14) as
1
a white solid. Yield, 7.7 g (87%). H NMR (Me2SO-d6): δ 1.33
(t, J ) 7 Hz, 3H), 4.47 (q, J ) 7 Hz, 2H), 7.25 (t, J ) 7 Hz,
1H), 7.50 (t, J ) 7 Hz, 1H), 7.68 (m, 2H), 8.06 (d, J ) 7 Hz,
1H), 8.26 (d, J ) 7 Hz, 1H), 8.78 (s, 1H), 12.53 (s, 1H). MS
(ES+): 240 (MH+).
N-(9-Isop r op yl-4-m eth yl-9H-ca r ba zol-3-yl)m or p h olin e-
4-ca r boxa m id e (4o). Compound 4o was prepared in a similar
manner as described for 4d in 71% yield. 1H NMR (Me2SO-
d6): δ 1.71 (d, J ) 7 Hz, 6H), 2.77 (s, 3H), 3.49 (t, J ) 5 Hz,
4H), 3.73 (t, J ) 5 Hz, 4H), 5.00 (m, 1H), 6.20 (br s, 1H), 7.24
(ddd, J ) 8, 8, 1 Hz, 1H), 7.35 (d, J ) 8 Hz, 1H), 7.38 (d, J )
8 Hz, 1H), 7.46 (ddd, J ) 8, 8, 1 Hz, 1H), 7.57 (d, J ) 8 Hz,
1H), 8.25 (d, J ) 8 Hz, 1H). MS (ES+): 352 (MH+). Anal. for
Compound 14 was coupled with 2-(4-pyridyl)ethylamine in
a similar manner as described for 2, and the product was
purified by chromatography on silica using 5-10% MeOH/
EtOAc as eluent to give 6 as gum, which solidified on standing
(30% yield). 1H NMR (Me2SO-d6): δ 1.32 (t, J ) 7 Hz, 3H)
2.90 (t, J ) 7 Hz, 2H), 3.58 (dt, J ) 7 Hz, 2H), 4.45 (q, J ) 7
Hz, 2H), 7.25 (m, 3H), 7.50 (t, J ) 8 Hz, 1H), 7.65 (d, J ) 8
Hz, 2H), 7.95 (d, J ) 8 Hz, 1H), 8.15 (d, J ) 8 Hz, 1H), 8.45
(d, J ) 7 Hz, 2H), 8.55 (t, J ) 7 Hz, 1H), 8.65 (s, 1H). MS
(ES+): 344 (MH+). Anal. for C22H21N3O.
C
21H25N3O2.
N-(4,9-Diisop r op yl-9H-ca r ba zol-3-yl)m or p h olin e-4-ca r -
boxa m id e (4p ). Compound 4p was prepared in a similar
manner as described for 4d in 82% yield. 1H NMR (Me2SO-
d6): δ 1.58 (d, J ) 7 Hz, 6H), 1.72 (d, J ) 7 Hz, 6H), 3.53 (t,
J ) 5 Hz, 4H), 3.78 (t, J ) 5 Hz, 4H), 4.34 (br m, 1H), 5.03 (m,
N-[(9-Eth yl-9H-ca r ba zol-3-yl)m eth yl]-2-p yr id in e-4-yl-
a ceta m id e (7) (Sch em e 1). To a solution of 14 (7.347 g, 30.7
mmol) and Et3N (4.32 mL, 31 mmol) in dry THF (100 mL) was

3518 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
added ethyl chloroformate (2.96 mL, 31 mmol) slowly at 0 °C
under an argon atmosphere and allowed to warm to room
temperature. Two hours later, NH4OH (30 mL) was added
slowly. After 3 h, the reaction mixture was concentrated, water
(100 mL) was added, and the mixture was extracted with
EtOAc (2 × 100 mL). The organic layer was dried and
concentrated to give 9-ethyl-3-carbamoylcarbazole as a yellow
δ 1.31 (m, 6H), 1.70 (m, 1H), 2.12 (m, 1H), 2.46 (m, 4H), 2.79
(m, 2H), 2.96 (m, 1H), 4.08 (q, J ) 7 Hz, 2H), 4.20 (q, J ) 7
Hz, 2H), 7.07 (t, J ) 7 Hz, 1H), 7.16 (t, J ) 7 Hz, 1H), 7.28 (d,
J ) 8 Hz, 1H), 7.46 (d, J ) 8 Hz, 1H). MS (ES+): 286 (MH+).
Compound 17 (4.436 g, 15.56 mmol) was stirred with 10%
palladium on carbon (1.24 g) at 200 °C for a total of 6.5 h with
argon blown over the reaction mixture. The mixture was
allowed to cool and was then diluted with CH2Cl2 (200 mL)
before the catalyst was filtered off. The catalyst was washed
with CH2Cl2 (2 × 100 mL), and the combined organics were
concentrated to give 18 as a brown oil (4.61 g). 1H NMR
(CDCl3): δ 1.28 (t, J ) 7 Hz, 3H), 1.43 (t, J ) 7 Hz, 3H), 3.80
(s, 2H), 4.19 (q, J ) 7 Hz, 2H), 4.36 (q, J ) 7 Hz, 2H), 7.22 (t,
J ) 7 Hz, 1H), 7.41 (m, 4H), 8.02 (s, 1H), 8.09 (d, 1H). MS
(ES+): 282 (MH+).
1
solid. Yield, 5.76 g (79%). H NMR (Me2SO-d6): δ 1.31 (t, J )
7 Hz, 3H), 4.47 (q, J ) 7 Hz, 2H), 6.38 (br s, 1H), 7.22 (t, J )
7 Hz, 1H), 7.46 (t, J ) 7 Hz, 1H), 7.62 (m, 2H), 8.01 (d, J ) 7
Hz, 1H), 8.17 (d, J ) 7 Hz, 1H), 8.72 (s, 1H). MS (ES+): 239
(MH+).
To a solution of 9-ethyl-3-carbamoylcarbazole (5.5 g, 23.1
mmol) in dry THF (100 mL) was added LiAlH4 (1 M solution
in THF; 25 mL, 25 mmol) slowly at 0 °C under an argon
atmosphere. After complete addition, the mixture was heated
at reflux for 72 h. After it was cooled to 0 °C, water (100 mL)
and then 15% w/v NaOH solution (100 mL) were added to the
orange mixture before stirring for 1 h. The mixture was filtered
under vacuum, and the filtrate was concentrated. Water (100
mL) was added followed by extraction with CH2Cl2 (2 × 100
mL). The organic layer was dried and concentrated to give a
yellow oil. Chromatography (eluent gradient of CH2Cl2 to 5%
NH4OH, 15% MeOH, CH2Cl2) gave 9-ethyl-3-aminomethyl-
carbazole (15) as a brown oil, which solidified on standing.
Yield, 902 mg (17%). 1H NMR (CDCl3): δ 1.42 (t, J ) 7 Hz,
3H), 4.02 (s, 2H), 4.34 (q, J ) 7 Hz, 2H), 7.23 (t, J ) 7 Hz,
1H), 7.45 (m, 4H), 8.01 (s, 1H), 8.06 (d, J ) 7 Hz, 1H). MS
(ES+): 208 (M+ - NH3).
An amount of 2 M NaOH (40 mL) was added to a solution
of 18 (approximately 15.56 mmol) in EtOH (80 mL) and stirred
at room temperature for 37 min. The reaction mixture was
acidified with 2 M HCl and allowed to stand, and the resulting
precipitate was filtered off and washed with water (2 × 50
mL). The product was partitioned between saturated K2CO3
solution (2 × 100 mL) and EtOAc (100 mL), and the combined
aqueous layer was washed with EtOAc (100 mL) and then
acidified with 2 M HCl solution. Extraction with EtOAc (2 ×
100 mL) and concentration of the organic layer yielded
(9-ethyl-9H-carbazol-3-yl)acetic acid as an off-white solid (1.45
1
g, 37%). H NMR (Me2SO-d6): δ 1.29 (t, J ) 7 Hz, 3H), 3.70
(s, 2H), 4.41 (q, J ) 7 Hz, 2H), 7.16 (t, J ) 8 Hz, 1H), 7.37 (d,
J ) 8 Hz 1H), 7.43 (t, J ) 7 Hz, 1H), 7.52 (d, J ) 8 Hz 1H),
7.56 (d, J ) 8 Hz 1H), 8.00 (s, 1H), 8.10 (d, J ) 8 Hz, 1H),
12.19 (br s, 1H). MS (ES+): 254 (MH+).
4-Pyridyl acetic acid (145 mg, 0.836 mmol) was suspended
in DMF (2 mL) to which was added diisopropylethylamine
(0.265 mL, 1.52 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-
tetramethyluronium hexafluorophosphate (HATU, 323 mg,
0.85 mmol). This was stirred for 10 min, and 15 (170 mg, 0.76
mmol) was added. The reaction mixture was stirred at room
temperature for 1 h and then concentrated in vacuo. The
residue was dissolved in CH2Cl2 (50 mL) and washed with
water (3 × 100 mL). The organic layer was dried and
concentrated to yield a gum. This was placed under a high
vacuum for 12 h, which resulted in a foam. The solid was
stirred in 1 N HCl (20 mL) for 3 h and then extracted with
EtOAc (3 × 50 mL). The EtOAc was dried and concentrated
(9-Ethyl-9H-carbazol-3-yl)acetic acid was coupled with 4-
(aminomethyl)pyridine using the conditions equivalent to those
described previously for 2 to yield 8 as a white solid (80%
1
yield). H NMR (Me2SO-d6): δ 1.29 (t, J ) 7 Hz, 3H), 3.66 (s,
2H), 4.29 (d, J ) 6 Hz, 2H), 4.40 (q, J ) 7 Hz, 2H), 7.17 (t, J
) 7 Hz, 1H), 7.20 (d, J ) 6 Hz, 2H), 7.41(t, J ) 7 Hz, 1H),
7.43 (d, J ) 7 Hz, 1H), 7.52 (d, J ) 8 Hz, 1H), 7.55 (d, J ) 8
Hz, 1H), 8.01 (s, 1H), 8.08 (d, J ) 8 Hz, 1H), 8.44 (d, J ) 6 Hz,
2H), 8.57 (t, J ) 6 Hz, 1H). MS (ES+): 344 (MH+). Anal. for
C
22H21N3O.
N -(9-E t h yl-9-H -ca r b a zol-1yl)-3-p yr id in -4-ylp r op a n -
1
under vacuum to yield 7 (80 mg, 31%). H NMR (Me2SO-d6):
a m id e (9). 1-Amino-N-ethyl carbazole was prepared from
1-Nitro-carbazole29 and condensed with pyridyl propionic acid
in a similar manner as described for 3a to give 9 in 47% overall
δ 1.28 (t, J ) 7 Hz, 3H), 3.55 (s, 2H), 4.35-4.48 (m, 4H), 7.17
(t, J ) 7 Hz, 1H), 7.25-7.38 (m, 3H), 7.42 (t, J ) 7 Hz, 1H),
7.5-7.6 (m, 2H), 7.95 (s, 1H), 8.05 (d, J ) 7 Hz, 1H), 8.47 (d,
2H), 8.58-8.68 (m, 1H). MS (ES+): 344 (MH+). Anal. for
1
yield. H NMR (Me2SO-d6): δ 1.09 (t, J ) 7 Hz, 3H) 2.79 (t, J
) 7 Hz, 2H), 2.97 (t, J ) 7 Hz, 2H), 4.36 (q, J ) 7 Hz, 2H),
7.03-7.22 (m, 3H), 7.34 (d, J ) 7 Hz, 2H), 7.44 (t, J ) 8 Hz,
1H), 7.55 (d, J ) 8 Hz, 1H), 8.05 (d, J ) 8 Hz, 1H), 8.13 (d, J
) 8 Hz, 1H), 8.50 (d, J ) 7 Hz, 2H), 9.90 (s, 1H). MS (ES+):
344 (MH+). Anal. for C22H21N3O‚0.15C2H10O.
C
22H21N3O.
2-(9-E t h yl-9H -ca r b a zol-3-yl)-N-(p yr id in -4-ylm et h yl)-
a ceta m id e (8) (Sch em e 2). An amount of 2 M HCl in Et2O
(16.3 mL, 32.6 mmol) was added to a stirred solution of
phenylhydrazine (3.52 g, 32.6 mmol) in EtOH (100 mL). The
milky suspension was heated to 40 °C, and ethyl(4-oxocyclo-
hexyl)acetate (6 g, 32.6 mmol) was added before heating at
reflux for 2 h. The reaction solvent was removed under
vacuum, and the residue was partitioned between EtOAc (200
mL) and water (2 × 200 mL). The aqueous layer was extracted
with EtOAc (200 mL), and the combined organic layers was
dried and concentrated to yield ethyl-1,2,3,4-tetrahydro-1H-
carbazol-3-yl acetate as a slightly orange solid (7.3 g, 87%).
1H NMR (CDCl3): δ 1.29 (t, J ) 7 Hz, 3H), 1.65 (m, 2H), 2.43
(m, 4H), 2.78 (m, 2H), 2.92 (m, 1H), 4.15 (q, J ) 7 Hz, 2H),
7.10 (m, 2H), 7.26 (d, J ) 7 Hz, 1H), 7.43 (d, J ) 7 Hz, 1H),
7.71 (br s, 1H). MS (ES+): 258 (MH+).
N -(9-E t h yl-9-H -ca r b a zol-2yl)-3-p yr id in -4-ylp r op a n -
a m id e (10). 2-Nitro-carbazole (3.0 g, 14.1 mmol) was added
as a solid in portions to a slurry of NaH (60%, 623 mg, 15.5
mmol) in DMF (70 mL) under argon and cooled in an ice bath.
Once effervescence had completed, EtI (1.25 mL, 15.5 mmol)
was added dropwise and the mixture allowed to warm to room
temperature and stirred overnight. The mixture was then
partitioned between EtOAc and water, and the organic layer
was washed with water and brine and then dried. Filtration
and evaporation gave N-ethyl-1-nitrocarbazole as a yellow solid
(4.21 g) contaminated with DMF. 1H NMR (Me2SO-d6): δ 1.48
(t, J ) 7 Hz, 3H), 4.42 (d, J ) 7 Hz, 2H), 7.30 (t, J ) 8 Hz,
1H), 7.48 (d, J ) 8 Hz, 1H), 7.60 (t, J ) 8 Hz, 1H), 8.13 (s,
2H), 8.16 (d, J ) 8 Hz, 1H), 8.34 (s, 1H). MS (ES+): 241 (MH+).
This material (2.0 g) was dissolved in EtOH (20 mL) and
EtOAc (10 mL) and was stirred under an atmosphere of H2
along with 10% Pd/C (200 mg) as catalyst. After 3 h, the
mixture was filtered through Celite, washed with EtOAc, and
concentrated. The residue was dissolved in CH2Cl2, dried, and
filtered. HCl in Et2O was added to the resulting solution, and
the 2-amino-N-ethyl-carbazole was precipitated as the HCl salt
NaH (60% dispersion in mineral oil, 752 mg, 18.8 mmol)
was added portion wise to a solution of ethyl-1,2,3,4-tetra-
hydro-1H-carbazol-3-yl acetate (4.40 g, 17.1 mmol) in dry DMF
(50 mL) under an inert atmosphere. EtI (1.5 mL, 18.8 mmol)
was added dropwise before heating to 65 °C for 1.5 h. The
reaction solvent was removed under vacuum, and the residue
was partitioned between EtOAc (200 mL) and water (2 × 200
mL). The aqueous layers were further extracted with EtOAc,
and the combined organic layer was dried and concentrated
1
(1.64 g, 99% over two steps). H NMR (Me2SO-d6): δ 1.30 (t,
1
to yield 17 as an orange gum (4.74 g, 97%). H NMR (CDCl3):
J ) 7 Hz, 3H), 4.40 (d, J ) 7 Hz, 2H), 7.21 (m, 2H), 7.48 (t, J

Ureas as Antagonists for the Treatment of Obesity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3519
) 8 Hz, 1H), 7.59 (s, 1H), 7.63(d, J ) 8 Hz, 2H), 8.18 (d, J )
8 Hz, 1H), 8.25 (d, J ) 8 Hz, 1H), 10.5 (br s, 3H). MS (ES+):
211 (MH+).
(t, J ) 8 Hz, 1H), 7.23 (d, J ) 2 Hz, 1H), 7.25-7.33, (m, 2H),
7.46 (d, J ) 8 Hz, 1H), 7.89 (d, J ) 8 Hz, 1H). Anal. for
C15H20N2.
9-Tetr ah ydr ofu r an -3-yl-9H-car bazole-3-am in e (12f). This
procedure was the same as for 12d using 3-methanesulfoxy-
tetrahydrofuran and cesium carbonate as base, to give 3-nitro-
9-(3-tetrahydrofuryl)carbazole in 58% yield. 1H NMR (Me2SO-
d6): δ 2.20 (m, 1H), 2.55 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H),
4.25 (m, 1H), 4.35 (m, 1H), 5.80 (m, 1H), 7.30 (dd, J ) 1, 7 Hz,
1H), 7.55 (dd, J ) 1, 7 Hz, 1H), 7.85 (dd, J ) 1, 9 Hz, 1H),
7.90 (d, J ) 9 Hz, 1H), 8.30 (dd, J ) 2, 9 Hz, 1H), 8.40 (d, J )
7 Hz, 1H), 9.15 (d, J ) 2 Hz, 1H).
2-Amino-N-ethyl-carbazole was condensed with pyridyl pro-
pionic acid in a similar manner as described for 3a to give 10
in 94% yield. 1H NMR (Me2SO-d6): δ 1.40 (t, J ) 7 Hz, 3H)
2.71 (t, J ) 7 Hz, 2H), 3.08 (t, J ) 7 Hz, 2H), 4.31 (q, J ) 7
Hz, 2H), 6.87 (dd, J ) 1, 8 Hz, 1H) 7.18 (m, 3H), 7.32 (s, 1H),
7.37 (d, J ) 7 Hz, 1H), 7.42 (t, J ) 7 Hz, 1H), 7.85 (d, J ) 8
Hz, 1H), 8.0 (d, J ) 7 Hz, 1H), 8.05 (s, 1H), 8.48 (d, J ) 7 Hz,
2H). MS (ES+): 344 (MH +). Anal. for C22H21N3O.
N -(9-E t h yl-9-H -ca r b a zol-4yl)-3-p yr id in -4-ylp r op a n -
a m id e (11). A mixture of 9-ethyl-1,2,3,4-tetrahydrocarbazol-
4-one30 (2.13 g, 10 mmol), hydroxylamine hydrochloride (1.04
g, 15 mmol), sodium acetate (1.23 g, 15 mmol) in 22 mL of
ethanol, and 15 mL of water was heated under reflux for 20
h. After the EtOH was evaporated, the resulting precipitate
was filtered, washed with water (3 × 15 mL), and dried to
give 2.26 g (99%) of 9-ethyl-1,2,3,4-tetrahydrocarbazol-4-one-
oxime as white crystals. 1H NMR (CDCl3): δ 1.35 (t, J ) 7
Hz, 3H), 2.1 (quin, J ) 6 Hz, 2H), 2.8 (t, J ) 6.5 Hz, 2H), 2.9
(t, J ) 6.5 Hz, 2H), 4.1(q, J ) 7 Hz, 2H), 7.1-7.3 (m, 3H), 7.4
(br s, 1H), 8.0 (m, 1H). MS (ES+): 229 (MH+).
Hydrogenation gave 12f. 1H NMR (Me2SO-d6): δ 2.20 (m,
1H), 2.40 (m, 1H), 3.75 (m, 1H), 3.95 (m, 1H), 4.15 (m, 1H),
4.25 (m, 1H), 4.70 (s, 2H), 5.50 (m, 1H), 6.80 (dd, J ) 2, 9 Hz,
1H), 7.05 (dd, J ) 1, 7 Hz, 1H), 7.25 (d, J ) 2 Hz, 1H), 7.35
(dd, J ) 1, 7 Hz, 1H), 7.40 (d, J ) 9 Hz, 1H), 7.60 (dd, J ) 1,
9 Hz, 1H), 7.90 (d, J ) 7 Hz). MS (ES+): 253 (MH+). Anal. for
C
16H16N2O.
9-Acetyl-9H-ca r ba zole-3-a m in e (12g). This procedure
was the same as for 12d using acetyl chloride and NaH as
base, in 68% overall yield. 1H NMR (Me2SO-d6): δ 2.80 (s, 3H),
5.14 (br s, 2H), 6.81 (dd, J ) 8, 2 Hz, 1H), 7.24 (d, J ) 2 Hz,
1H), 7.35 (dd, J ) 8, 8 Hz, 1H), 7.44 (dd, J ) 8, 8 Hz, 1H),
7.93 (d, J ) 8 Hz, 1H), 7.95 (d, J ) 8 Hz, 1H), 8.2 (d, J ) 8 Hz,
1H). MS (ES+): 225 (MH+). Anal. for C14H12NO.
A mixture of 9-ethyl-1,2,3,4-tetrahydrocarbazol-4-one-oxime
(1.0 g, 4.8 mmol) and 5% Pd/C (600 mg) in diethylene glycol
diethyl ether was heated at reflux for 2 h under argon. The
mixture was cooled to room temperature, the catalyst was
removed by filtration and washed with EtOAc, and the filtrate
was treated with 1 N HCl. The resultant precipitate was
filtered and washed with EtOAc and then treated with 1 N
HCl (20 mL) and extracted with EtOAc (3 × 30 mL). The
combined organics were washed with saturated brine, dried,
and evaporated. The residue was purified by chromatography
on silica eluting with toluene to give 4-amino-9-ethyl-carbazole
9-Meth ylsu lfon yl-9H-ca r ba zole-3-a m in e (12h ). This pro-
cedure was the same as for 12d using methane sulfonyl
1
chloride and NaH as base, 78% yield. H NMR (Me2SO-d6): δ
3.07 (s, 3H), 5.16 (s, 2H), 6.80 (dd, J ) 2, 9 Hz, 1H), 7.22 (d,
J ) 2 Hz, 1H), 7.37 (dt, J ) 7, 8 Hz, 1H,), 7.47 (dt, J ) 7, 8
Hz, 1H), 7.67 (d, J ) 9 Hz, 1H), 7.96 (dd, J ) 7, 8 Hz, 2H). MS
(ES+): 261 (MH+). Anal. for C13H12N2O2S.
9-(Dim eth ylam in o)su lfon yl-9H-car bazole-3-am in e (12i).
This procedure was the same as for 12d using dimethylamino
sulfonyl chloride and NaH as base, 44% yield. 1H NMR
(Me2SO-d6): δ 2.70 (s, 6H), 5.10 (s, 2H), 6.80 (dd, J ) 2, 9 Hz,
1H), 7.21 (d, J ) 2 Hz, 1H), 7.33 (t, J ) 8 Hz, 1H), 7.45 (t, J
) 8 Hz, 1H), 7.70 (d, J ) 9 Hz, 1H), 7.95 (d, J ) 8 Hz). MS
(ES+): 290 (MH+).
1
(593 mg, 59%). H NMR (Me2SO-d6): δ 1.3 (t, J ) 7 Hz, 3H),
4.5 (q, J ) 7 Hz, 2H), 7.19 (d, J ) 7.5 Hz, 1H), 7.23 (t, J ) 7.5
Hz, 1H), 7.4-7.5 (m, 3H), 7.6 (d, J ) 8 Hz, 1H), 8.2 (d, J ) 8
Hz 1H). MS (ES+): 211 (MH+).
4-Amino-9-ethyl-carbazole was condensed with pyridyl pro-
pionate in a similar manner as described for 3a except that
HATU was used as a coupling agent to give 11 in 16% yield.
1H NMR (CDCl3): 1.34 (t, J ) 7.5 Hz, 3H), 2.89 (t, J ) 7 Hz,
2H), 3.08 (t, J ) 7 Hz, 2H), 4.41 (q, J ) 7.5 Hz, 2H), 7.13 (t, J
) 7.5 Hz, 1H), 7.16 (dd, J ) 1,7 Hz, 1H), 7.36-7.47 (m, 5H),
(d, J ) 7.5 Hz, 1H), 7.95 (d, J ) 7.5 Hz, 1H), 8.52 (d, J ) 7.5
Hz, 2H). MS (ES+): 344 (MH +). HRMS for C22H21N3O.
9-Isop r op yl-9H-ca r ba zole-3-a m in e (12d ). Under inert
atmosphere at ambient temperature, 3-nitro-9H-carbazole
(1.03 g, 4.86 mmol)29 was added portion wise as a solid to a
suspension of NaH (60% in oil) (292 mg, 7.29 mmol) in DMF
(40 mL) followed by 2-bromo-propane (0.69 mL, 7.29 mmol)
and then heated to 60 °C for 18 h. After it was cooled to room
temperature, the mixture was diluted with CH2Cl2, washed
with water, dried, and concentrated. Chromatography on silica
gel (eluent gradient of i-hexane to CH2Cl2) gave 9-isopropyl-
3-nitrocarbazole as a yellow solid. Yield, 0.98 g (79%). 1H NMR
(Me2SO-d6): δ 1.64 (d, J ) 7 Hz, 6H), 5.20 (sept, J ) 7 Hz,
1H), 7.31 (dd, J ) 8, 7 Hz, 1H), 7.54 (ddd, J ) 7, 7, 1 Hz, 1H),
7.82 (d, J ) 8 Hz, 1H), 7.87 (d, J ) 9 Hz, 1H), 8.27 (dd, J ) 9,
2 Hz, 1H), 8.40 (d, J ) 8 Hz, 1H), 9.15 (d J ) 2 Hz, 1H).
9-Isopropyl-3-nitrocarbazole (950 mg, 3.73 mmol) was dis-
solved in EtOAc (50 mL) and hydrogenated under an atmo-
sphere of H2 using 10% Pd/C as catalyst (100 mg). After 2 h,
the slurry was filtered through Celite, washed with CH2Cl2,
and concentrated to give 12d as a pale brown foam. Yield, 834
mg (99%). 1H NMR (Me2SO-d6): δ 1.59 (d, J ) 7 Hz, 6H), 4.77
(br s, 2H), 4.96 (m, 1H), 6.83 (dd, J ) 9, 2 Hz, 1H), 7.07 (dd,
J ) 8, 7 Hz, 1H), 7.30 (d, J ) 2 Hz, 1H), 7.33 (ddd, J ) 7, 7,
1 Hz, 1H), 7.40 (d, J ) 9 Hz, 1H), 7.55 (d, J ) 8 Hz, 1H), 7.95
(d, J ) 8 Hz, 1H). Anal. for C15H16N2:HCl:0.5H2O.
6-Fluoro-9-isopropyl-9H-carbazole-3-amine (12j)(Scheme
3). A stirred mixture of 4-fluorophenylhydrazine hydrochloride
(4.4 g, 27 mmol) and ethyl-4-oxocyclohexanecarboxylate (19)
(4.6 g, 27 mmol) in EtOH (100 mL) was heated under reflux
overnight. The solution was cooled in an ice bath, and the
resultant white crystals were filtered off and washed with ice
cold EtOH to give 20 (R2 ) 6-F). Yield, 6.3 g (79%). NMR
(CDCl3): δ 1.3 (t, J ) 7 Hz, 3H), 1.9-2.1 (m, 1H), 2.3 (m, 1H),
2.7-2.9 (m, 4H), 3.0 (m, 1H), 4.2 (q, J ) 7 Hz, 2H), 6.8 (ddd,
J ) 2, 8.5, 9.5 Hz, 1H), 7.1(dd, J ) 2, 9.5 Hz, 1H), 7.2 (dd, J
) 4, 8.5 Hz, 1H), 7.7 (s, 1H). MS (ES+): 262 (MH+).
Compound 20 (R2 ) 6-F) (3.13 g, 12 mmol) in xylene was
treated with DDQ (6.45 g, 26 mmol), and the mixture was
heated under reflux for 4 h, cooled to ambient temperature,
and filtered through Celite, and the filtrate was loaded on to
a Bond Elute column (20 g) and eluted with 5% EtOAc/toluene.
The eluent was concentrated and then recrystallized from
EtOAc/i-hexane to give 6-fluoro-3-ethoxycarbonylcarbazole;
yield, 2.35 g (76%). NMR (CDCl3): δ 1.5 (t, J ) 7 Hz, 3H), 4.4
(q, J ) 7 Hz, 2H), 7.2 (ddd, J ) 2, 8.5, 9 Hz, 1H), 7.3 (dd, J )
4, 8.5 Hz, 1H), 7.4 (d, J ) 8.5, 1H), 7.8 (dd, J ) 2, 8.5 Hz, 1H),
8.2 (dd, J ) 1.5, 8.5 Hz 1H), 8.3 (s, 1H), 8.8 (d, J ) 1.5 Hz,
1H). MS (ES+): 258 (MH+).
6-Fluoro-3-ethoxycarbonylcarbazole was alkylated with 2-
bromo-propane as described for 12d to give 21 (R2 ) 6-F) in
45% overall yield. NMR (CDCl3): δ 1.4 (t, J ) 7 Hz, 3H), 1.7
(d J ) 7 Hz, 6H), 4.5 (q, J ) 7 Hz, 2H), 5.0 (sept, J ) 7 Hz,
1H), 7.2 (ddd, J ) 2.5, 8.5, 9 Hz,1H), 7.4 (dd, J ) 4, 8.5 Hz,
1H), 7.5 (d, J ) 8.5 Hz, 1H), 7.8 (dd, J ) 2.5, 8.5 Hz, 1H), 8.2
(dd, J ) 1.5, 8.5 Hz, 1H), 8.8 (d, J ) 1.5 Hz, 1H). MS (ES+):
300 (MH+).
9-Neop en tyl-9H-ca r ba zole-3-a m in e (12e). This proce-
dure was the same as for 12d using neopentyl iodide and NaH
Compound 21 (R2 ) 6-F) (1.46 g) was dissolved in THF:
MeOH (3:1, 40 mL), 1 M LiOH (19 mL) was added, and the
solution was heated at 60 °C for 1 h. After it was cooled, the
1
as base, in 20% overall yield. H NMR (Me2SO-d6): δ 1.00 (s,
9H), 4.03 (s, 2H), 4.68 (s, 2H), 6.78 (dd, J ) 2, 8 Hz, 1H), 7.03

3520 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
organic solvents were removed under vacuum, the resultant
aqueous solution was acidified to pH 1 with concentrated HCl,
and the resultant precipitate was filtered and dried to give
6-fluoro-9-isopropyl-9H-carbazol-3-yl carboxylic acid (1.3 g).
NMR (CDCl3): δ 1.6 (d, J ) 7 Hz, 6H), 5.1 (sept, J ) 7 Hz
1H), 7.3 (dt, J ) 2.5, 8.5 Hz, 1H), 7.7 (m, 2H), 8.0 (dd, J ) 1.5,
8.5 Hz, 1H), 8.2 (dd, J ) 2.5, 9 Hz, 1H), 8.8 (d, J ) 1.5 Hz,
1H). MS (ES+): 272 (MH+).
mixture was concentrated, diluted with water, and extracted
into EtOAc. The organic layers were separated and washed
with water and brine and dried. Chromatography (eluent 25%
EtOAc/i-hexane) yielded 1,2,3,4-tetrahydro-9-isopropyl-7-methyl-
6-nitrocarbazole as a yellow solid (1.53 g, 74%). 1H NMR
(Me2SO-d6): δ 1.50 (d, J ) 7 Hz, 6H), 1.77 (m, 2H), 1.87 (m,
2H), 2.64 (m, 5H), 2.75 (m, 2H), 4.68 (m, J ) 7 Hz, 1H), 7.52
(s, 1H), 8.13 (s, 1H).
Et3N (139 µL, 1 mmol) was added to a stirred suspension of
6-fluoro-9-isopropyl-9H-carbazol-3-yl carboxylic acid (271 mg,
1 mmol) and diphenylphosphoryl azide (216 µL, 1 mmol) in
dry toluene (15 mL) under argon. The resultant solution was
stirred at ambient temperature for 1 h and then heated to
reflux for 1 h. After the solution was allowed to cool to 80 °C,
trimethylsilyl ethanol (285 µL, 2 mmol) was added and the
heating was continued at 80 °C for 6 h. The mixture was
diluted with EtOAc (30 mL) and washed with water (10 mL),
0.5 N NaOH (10 mL), water (10 mL), and saturated brine (10
mL), and then dried, evaporated, and purified by chromatog-
raphy on silica using a 5 g Bond Elute cartridge and eluting
with CH2Cl2 to give N-carboxytrimethylsilylethyl(6-fluoro-9-
isopropyl-9H-carbazol-3-yl)-4-amine (295 mg), which was dis-
solved in 1 M TBAF in THF and heated at 50 °C for 30 min.
The solution was allowed to cool, and the solvent was removed
at reduced pressure. The residue was dissolved in EtOAc (5
mL), water (5 mL) was added, and the layers were mixed by
rapid stirring for 15 min. The organic layer was washed with
saturated ammonium chloride and dried, evaporated, and
purified by chromatography on silica using a 5 g Bond Elute
cartridge and eluting with 1:1 CH2Cl2/toluene to give a sticky
oil, which was dissolved in EtOAc and treated with a solution
of HCl in EtOAc to give 106 mg of off-white solid 12j as the
HCl salt. 1H NMR (Me2SO-d6): δ 1.6 (d, J ) 7 Hz, 6H), 5.1
(sept, J ) 7 Hz, 1H), 7.3 (ddd, J ) 3, 9, 9 Hz, 1H), 7.4 (dd, J
) 2, 9 Hz, 1H), 7.7 (dd, J ) 4, 9 Hz, 1H), 7.8 (d, J ) 9 Hz, 1H),
8.05 (dd, J ) 3, 9 Hz, 1H), 8.1 (d, J ) 2 Hz, 1H). MS (ES+):
243 (MH+). Anal. for C15H16FClN2.
To a stirred solution of 1,2,3,4-tetrahydro-9-isopropyl-7-
methyl-6-nitrocarbazole (1.53 g, 5.62 mmol) in 1,4-dioxane at
room temperature was added DDQ (2.56 g, 11.24 mmol)
portion wise. The reaction mixture was stirred at 100 °C for
20 h before it was concentrated. Chromatography (eluent 10%
EtOAc/i-hexane) yielded 2-methyl-9-isopropyl-3-nitrocarbazole
1
as a yellow solid (947 mg, 63%). H NMR (Me2SO-d6): δ 1.63
(d, J ) 7 Hz, 6H), 2.76 (s, 3H), 5.17 (sept, J ) 7 Hz, 1H), 7.26
(t, J ) 7 Hz, 1H), 7.50 (t, J ) 7 Hz, 1H), 7.73 (s, 1H), 7.77 (d,
J ) 7 Hz, 1H), 8.29 (d, J ) 7 Hz, 1H), 8.96 (s, 1H).
2-Methyl-9-isopropyl-3-nitrocarbazole (947 mg, 3.5 mmol)
was dissolved in EtOAc (20 mL) and hydrogenated under an
atmosphere of H2 using 10% Pd/C as catalyst (180 mg). After
12 h, the slurry was filtered through Celite, washed with
EtOAc, and concentrated under vacuum to give 12l as a brown
oil, which solidified on standing (700 mg, 83%). 1H NMR
(Me2SO-d6): δ 1.57 (d, J ) 7 Hz, 6H), 2.26 (s, 3H), 4.45 (br s,
2H), 4.93 (sept, J ) 7 Hz, 1H), 7.03 (t, J ) 7 Hz, 1H), 7.26 (t,
J ) 7 Hz, 1H), 7.30 (2 x s, 2H), 7.49 (d, J ) 7 Hz, 1H), 7.86 (d,
J ) 7 Hz, 1H). MS (ES+): 239 (MH+). Anal. for C16H18N2.
9-Isop r op yl-2-ch lor o-9H -ca r b a zole-3-a m in e
(12m )
(Sch em e 4). 3-Chloroaniline (18.5 mL, 175.2 mmol) and
2-chlorocyclohexanone (10 mL, 87.6 mmol) were stirred in
EtOH at reflux for 3 h. After it was cooled, the reaction mixture
was concentrated and the residue was stirred in Et2O (150
mL). An amount of 2 M HCl in Et2O (43.8 mL) was added to
the mixture and stirred for 2 h before filtering and washing
with Et2O (2 × 50 mL). The filtrate was concentrated, and
the residue was purified by chromatography (eluent, CH2Cl2).
The solid obtained was recrystallized from EtOAc/i-hexane to
yield 22 (R3 ) Cl, R4 ) H) as a light brown solid (3.9 g, 22%).
1H NMR (Me2SO-d6): δ 1.78 (m, 4H), 2.58 (m, 2H), 2.67 (m,
2H), 6.89 (d, J ) 8 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J ) 8 Hz,
1H), 10.76 (br s, 1H).
9-Isop r op yl-8-m et h yl-9H -ca r b a zole-3-a m in e
(12k )
(Sch em e 3). Compound 12k was prepared using 2-methyl-
phenylhydrazine in the first step and methods analogous to
those described for 12j in 56% overall yield from the corre-
1
sponding acid. H NMR (CDCl3): δ 1.6 (d, J ) 7 Hz, 6H), 2.7
(s, 3H), 5.4 (sept, J ) 7 Hz, 1H), 6.8 (dd, J ) 2, 8.5 Hz, 1H),
7.0 (t, J ) 7.5 Hz, 1H), 7.1 (d, J ) 7 Hz, 1H), 7.4 (d, J ) 2 Hz,
1H), 7.45 (d, J ) 8.5 Hz, 1H), 7.8 (d, J ) 7.5 Hz, 1H). MS
(ES+): 239 (MH+). Anal. for C16H18N2.
Compound 22 (R3 ) Cl, R4 ) H) (3.42 g, 16.64 mmol) was
stirred in concentrated H2SO4 (50 mL) at 0 °C for 30 min.
Potassium nitrate (1.68 g, 16.64 mmol) was added slowly
before the reaction mixture was stirred at 0 °C for 3 h. The
mixture was poured onto ice/water, and the resulting yellow
precipitate was filtered and washed with dilute ammonia
solution (20%) and then water. The solid was dried at 40 °C
under vacuum overnight and then purified by chromatography
(eluent, CH2Cl2) to give 23 (R3 ) Cl, R4 ) H) as a yellow solid
The intermediates were obtained as follows:
8-Methyl-3-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole (20,
1
R2 ) 8-Me) in 70% overall yield. H NMR (CDCl3): δ 1.3 (t, J
) 7 Hz, 3H), 1.9-2.1 (m, 1H), 2.3 (m, 1H), 2.5 (s, 3H), 2.7-2.9
(m, 4H), 3.0 (m, 1H), 4.2 (q, J ) 7 Hz, 2H), 6.9 (d, J ) 7 Hz,
1H), 7.0 (t, J ) 7 Hz, 1H), 7.3 (d J ) 7.5 Hz, 1H), 7.7 (s, 1H).
8-Methyl-3-ethoxycarbonylcarbazole in 68% overall yield.
NMR (CDCl3): δ 1.5 (t, J ) 7 Hz, 3H), 2.6 (s, 3H), 4.4 (q, J )
7 Hz, 2H), 7.2 (m, 2H), 7.4 (d, J ) 8.5 Hz, 1H), 8.0 (d, J ) 7.5
Hz, 1H), 8.2 (d, J ) 8.5 Hz, 1H), 8.3 (s, 1H), 8.8 (s, 1H). MS
(ES+): 254 (MH+).
1
(3.33 g, 80%). H NMR (Me2SO-d6): δ 1.78 (m, 4H), 2.60 (m,
2H), 2.70 (m, 2H), 7.46 (s, 1H), 8.11 (s, 1H), 11.44 (br s, 1H).
1,2,3,4-Tetrahydro-7-chloro-9-isopropyl-6-nitrocarbazole was
prepared in a similar manner as described for 1,2,3,4-tetra-
hydro-9-isopropyl-7-methyl-6-nitrocarbazole. A yellow solid
was obtained (58%). 1H NMR (Me2SO-d6): δ 1.75 (m, 2H), 1.85
(m, 2H), 2.64 (m, 2H), 2.78 (m, 2H), 7.80 (s, 1H), 8.14 (s, 1H).
MS (ES+): 293 (MH+).
8-Methyl-9-isopropyl-3-ethoxycarbonylcarbazole (21, R2 )
8-Me) (using Cs2CO3 as base) in 29% overall yield. NMR
(CDCl3): δ 1.4 (t, J ) 7.1 Hz, 3H), 1.7 (d, J ) 7.1 Hz, 6H), 2.8
(s, 3H), 4.4 (q, J ) 7 Hz, 2H), 5.6 (sept, J ) 7 Hz, 1H), 7.2 (m,
2H), 7.6 (d, J ) 9 Hz, 1H), 8.0 (dd, J ) 7.5, 1 Hz, 1H), 8.1 (dd,
J ) 9, 2 Hz, 1H), 8.8 (d, J ) 1 Hz, 1H). MS (ES+): 296 (MH+).
8-Methyl-9-isopropyl-9H-carbazol-3-yl carboxylic acid in 84%
overall yield. MS (ES+): 268 (MH+).
2-Chloro-9-isopropyl-3-nitrocarbazole was prepared in a
manner similar to 2-methyl-9-isopropyl-3-nitrocarbazole. A
1
yellow solid was isolated (57%). H NMR (Me2SO-d6): δ 1.64
(d, J ) 7 Hz, 6H), 5.21 (sept, J ) 7 Hz, 1H), 7.32 (t, J ) 8 Hz,
1H), 7.54 (t, J ) 8 Hz, 1H), 7.84 (d, J ) 8 Hz, 1H), 8.05 (s,
1H), 8.35 (d, J ) 8 Hz, 1H), 9.05 (s, 1H).
9-Isop r op yl-2-m et h yl-9H -ca r b a zole-3-a m in e
(12l)
2-Chloro-9-isopropyl-3-nitrocarbazole (635 mg, 2.2 mmol)
was stirred in EtOH/water (35 mL/25 mL) at reflux. Sodium
hydrosulfite (2.57 g, 14.76 mmol) was added in one portion,
and the reaction mixture was stirred at reflux for 2 h. After it
was cooled, the EtOH was removed under vacuum and the
remaining aqueous mixture was extracted with EtOAc (2 ×
100 mL) and washed with water (100 mL) and brine (100 mL).
The organic layer was dried and concentrated. Chromatogra-
phy (eluent, CH2Cl2) yielded 12m as a brown solid (286 mg,
(Sch em e 4). NaH (60% in oil, 454 mg, 11.34 mmol) was added
slowly to a solution of 23 (R3 ) Me, R4 ) H)12 (1.74 g) in dry
DMF at 0 °C under an argon atmosphere. Once effervescence
had ceased, 2-bromo-propane (1.06 mL, 11.34 mmol) was added
and the reaction mixture was heated at 60 °C for 20 h before
cooling. Further NaH (60% in oil, 1.21 g, 30.24 mmol) was
added followed by 2-bromo-propane (2.84 mL, 30.24 mmol),
and the mixture was heated at 60 °C for 4 h. The reaction

Ureas as Antagonists for the Treatment of Obesity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3521
1
50%). H NMR (Me2SO-d6): δ 1.56 (d, J ) 7 Hz, 6H), 4.88 (br
1H NMR (CDCl3): δ 1.65 (d, J ) 7 Hz, 6H), 4.82 (m, 1H), 7.01
(dd, J ) 12, 1 Hz, 1H), 7.19 (ddd, J ) 8, 8, 1 Hz, 1H), 7.39
(ddd, J ) 8, 8, 1 Hz, 1H), 7.45 (d, J ) 8 Hz, 1H), 8.15 (d, J )
8 Hz, 1H). MS (ES+): 261 (MH+). HRMS for C15H14F2N2.
s, 2H), 4.95 (sept, J ) 7 Hz, 1H), 7.08 (t, J ) 7 Hz, 1H), 7.34
(t, J ) 7 Hz, 1H), 7.50 (s, 1H), 7.56 (d, J ) 7 Hz, 1H), 7.57 (s,
1H), 7.93 (d, J ) 7 Hz, 1H). MS (ES+): 259 (MH+). Anal. for
C15H15ClN2.
9-Isop r op yl-4-m et h yl-9H -ca r b a zole-3-a m in e
(12o)
2,4-Diflu or o-9-isop r op yl-9H-ca r ba zole-3-a m in e (12n )
(Sch em e 6). Benzyl bromide (3.72 mL, 31.3 mM) was added
to a suspension of 4-bromo-2,6-difluoroaniline (2.17 g, 10.4
mM) and K2CO3 (5.77 g, 41.7 mM) in DMF (10 mL) and heated
to 100 °C for 18 h. After it was cooled to room temperature,
the mixture was diluted with CH2Cl2, washed with water,
dried, and concentrated. Chromatography on silica gel (eluent
gradient of i-hexane to CH2Cl2:i-hexane (1:19)) gives 24 as a
colorless, clear oil. Yield, 3.50 g (87%). 1H NMR (CDCl3): δ
7.40-7.15 (10H, m), 7.00-6.85 (2H, m), 4.22 (4H, s). MS
(ES+): 388/390 (1:1) (MH+).
(Sch em e 7). A solution of 9-isopropyl-3-nitrocarbazole (1.13
g, 4.46 mmol) in dry THF (50 mL) was cooled to -15 °C under
an argon atmosphere. MeMgCl (3 M solution in THF, 2.23 mL,
6.7 mmol) was added dropwise, and the resultant solution was
stirred for a further hour at -15 °C. DDQ (1.71 g, 7.54 mmol)
was added keeping the temperature below -10 °C and then
allowed to warm to room temperature and left for 48 h
(believed to be unnecessary). The reaction mixture was diluted
with CH2Cl2 (50 mL) and washed with water (30 mL), and the
organic layer was dried. Solvent was removed, and chroma-
tography (eluent, 10-30% CH2Cl2/i-hexane) yielded 27 (R4 )
1
Me) as a yellow solid (940 mg, 79%). H NMR (Me2SO-d6): δ
Benzophenone hydrazone (1.31 g, 6.63 mM), Pd(OAc)2 (15
mg, 0.06 mM), and (S)-BINAP (62 mg, 0.1 mM) were sus-
pended in toluene (11 mL) and heated to 100 °C for 3 min
under an inert atmosphere. After it was cooled to room
temperature, a solution of 24 (2.58 g, 6.63 mM) in toluene (2
mL) was added followed by NaOtBu (893 mg, 9.29 mM) and
the mixture was heated to 100 °C for 3 h. After it was cooled,
the mixture was filtered through Celite, and the filter cake
was rinsed with Et2O. Concentration and then chromatogra-
phy on silica gel (eluent gradient of i-hexane to CH2Cl2) gave
1.64 (d, J ) 7 Hz, 6H), 3.01 (s, 3H), 5.20 (sept, J ) 7 Hz, 1H),
7.32 (t, J ) 8 Hz, 1H), 7.54 (t, J ) 8 Hz, 1H), 7.74 (d, J ) 9
Hz, 1H), 7.85 (d, J ) 8 Hz, 1H), 8.02 (d, J ) 9 Hz, 1H), 8.32
(d, J ) 8 Hz, 1H). MS (ES+): 269 (MH+).
Compound 27 (R4 ) Me) (828 mg, 3.09 mmol) was hydro-
genated in a similar manner as described in the preparation
of 12d and chromatographed on silica gel (eluent, 50% EtOAc/
i-hexane) to give 12o as a colorless solid (661 mg, 90%). 1H
NMR (Me2SO-d6): δ 1.55 (d, J ) 7 Hz, 6H), 2.56 (s, 3H), 4.50
(br s, 2H), 4.97 (sept, J ) 7 Hz, 1H), 6.87 (d, J ) 9 Hz, 1H),
7.06 (t, J ) 8 Hz, 1H), 7.28 (m, 2H), 7.53 (d, J ) 8 Hz, 1H),
8.15 (d, J ) 8 Hz, 1H). MS (ES+): 239 (MH+). Anal. for
1
25 as a solid. Yield, 3.13 g (94%). H NMR (CDCl3): δ 7.60-
7.45 (5H, m), 7.35-7.15 (16H, m), 6.55-6.45 (2H, m), 4.16 (4H,
s). MS (ES+): 504 (MH+).
C
16H18N2‚HCl.
Compound 25 (3.05 g, 6.06 mM), cyclohexanone (0.95 mL,
9.09 mM), and p-toluenesulfonic acid (3.45 g, 18.19 mM) in
EtOH (31 mL) were heated to reflux for 18 h. After it was
cooled, the mixture was diluted with CH2Cl2, washed with
K2CO3 solution, dried, and concentrated. Chromatography on
silica gel (eluent gradient of Hexane to CH2Cl2:i-hexane (1:1))
gave 26 as a solid. Yield, 2.03 g (83%). 1H NMR (CDCl3): δ
7.50 (1H, s), 7.45-7.15 (10H, m), 6.63 (1H, d), 4.22 (4H, s),
2.80 (2H, m), 2.59 (2H, m), 1.84 (4H, m). MS (ES+): 403 (MH+).
4,9-Diisop r op yl-9H-ca r ba zole-3-a m in e (12p ) (Sch em e
7). Isopropylmagnesium chloride (2 M solution in THF) (2.23
mL, 4.46 mmol) was added to 9-isopropyl-3-nitrocarbazole (1.13
g, 4.45 mmol) in THF (20 mL) at -15 °C. After 1 h, DDQ (2.22
g, 9.79 mmol) was added and then allowed to warm to ambient
temperature for 18 h. The mixture was diluted with CH2Cl2,
washed with K2CO3 solution, dried, and concentrated. Chro-
matography on silica gel (eluent gradient of i-hexane to
i
CH2Cl2) gave 27 (R4 ) Pr) as a yellow solid. Yield, 0.56 g
Compound 26 (1.97 g, 4.90 mmol) was added to NaH (60%
dispersion in oil) (392 mg, 9.80 mmol) in DMF (5 mL) followed
by 2-bromo-propane (0.92 mL, 9.80 mmol) and heated to 60
°C for 18 h. After it was cooled, NaH (60% dispersion in oil)
(392 mg, 9.80 mmol) was added followed by 2-bromo-propane
(0.92 mL, 9.80 mmol) and again heated to 60 °C for 18 h. After
this was cooled, the mixture was diluted with CH 2Cl2, washed
with K2CO3 solution, dried, and concentrated. Chromatography
on silica gel (eluent gradient of i-hexane to EtOAc:i-hexane
(1:9)) gave 9-(prop-2-yl)-7-dibenzylamino-6,8-difluoro-1,2,3,4-
1
(46%). H NMR (CDCl3): δ 1.66 (d, 6H), 1.76 (d, 6H), 4.25 (m,
1H), 5.07 (m, 1H), 7.34 (dd, J ) 8 Hz, 1H), 7.42 (d, J ) 9 Hz,
1H), 7.52 (dd, J ) 8 Hz, 1H), 7.65 (d, J ) 8 Hz, 1H), 7.77 (d,
J ) 9 Hz, 1H), 8.29 (d, J ) 8 Hz, 1H). MS (ES+): 297 (MH+).
i
Compound 27 (R4 ) Pr) (0.55 g, 1.86 mmol) in EtOH (20
mL) was hydrogenated over 10% Pd/C (100 mg) at ambient
temperature under atmospheric pressure of hydrogen. The
catalyst was filtered off through Celite, and the filtrate was
concentrated. Chromatography on silica gel (eluent gradient
of i-hexane to CH2Cl2) gave 12p as a pale brown foam. Yield,
0.55 g. 1H NMR (CDCl3): δ 1.63 (d, 6H), 1.71 (d, 6H), 4.43 (m,
1H), 4.98 (m, 1H), 6.90 (d, J ) 8 Hz, 1H), 7.16 (ddd, J ) 8, 8,
1 Hz, 1H), 7.26 (d, J ) 8 Hz,1H), 7.41 (ddd, J ) 8, 8, 1 Hz,
1H), 7.53 (d, J ) 8 Hz, 1H), 8.29 (d, J ) 8 Hz, 1H). MS (ES+):
267 (MH+). Anal. for C18H22N2.
1
tetrahydrocarbazole as a yellow solid. Yield, 1.70 g (78%). H
NMR (CDCl3): δ 1.49 (d, 6H), 1.74-1.94 (m, 4H), 2.65 (t, 2H),
2.83 (t, 2H), 4.22 (s, 4H), 4.43 (sept, 1H), 6.80 (dd, J ) 12 Hz,
1 Hz, 1H), 7.14-7.45 (m, 10H). MS (ES+): 445 (MH+).
DDQ (818 mg, 3.60 mmol) was added to 9-(prop-2-yl)-7-
dibenzylamino-6,8-difluoro-1,2,3,4-tetrahydrocarbazole (800
mg, 1.80 mmol) in 1,4-dioxan (7.5 mL) and heated to 90 °C for
30 min and then cooled to room temperature. Further DDQ
(204 mg, 0.9 mmol) was added and again heated to 90 °C for
30 min. After it was cooled, the mixture was diluted with
EtOAc, washed with K2CO3 solution, dried, and concentrated.
Chromatography on silica gel (eluent gradient of i-hexane to
CH2Cl2:i-hexane (2:3)) gave 3-dibenzylamino-2,4-difluoro-9-
(prop-2-yl)carbazole as a yellow solid. Yield, 501 mg (63%). 1H
NMR (CDCl3): δ 1.63 (d, 6H), 4.30 (s, 4H), 4.79 (sept, 1H),
6.89 (dd, J ) 12, 1 Hz, 1H), 7.14-7.50 (m, 13H), 8.13 (d, J )
8 Hz, 1H).
A solution of ammonium formate (284 mg, 4.50 mmol) in
water (1 mL) was added to a suspension of 9-(prop-2-yl)-7-
dibenzylamino-6,8-difluoro-1,2,3,4-tetrahydrocarbazole (0.50 g,
1.14 mmol) and 10% Pd/C (50% wet with water) (76 mg) in
MeOH (4.25 mL) and then refluxed for 1 h. After it was cooled,
the mixture was filtered through Celite, diluted with CH2Cl2,
washed with K2CO3 solution, dried, and concentrated. Chro-
matography on silica gel (eluent gradient of i-hexane to
CH2Cl2) gave 12n as a pale brown solid. Yield, 261 mg (88%).
4-E t h oxy-9-isop r op yl-9H -ca r b a zole-3-a m in e
(12q )
(Sch em e 7). Compound 12q was prepared in a similar manner
as described in reference 16. Under an inert atmosphere, a
hot solution of NaOH (2.27 g, 56.75 mmol) in water (2.27 mL)
was added to a refluxing solution of 9-isopropyl-3-nitrocarba-
zole (0.72 g, 2.83 mmol) in EtOH (68 mL). Zinc powder (1.47
g, 22.49 mmol) was added, and then, the mixture was refluxed
for 12 h. After it was cooled, the mixture was filtered through
Celite, diluted with CH2Cl2, washed with K2CO3 solution,
dried, and concentrated. Chromatography was performed on
silica gel (eluent gradient of toluene to toluene:Et2O (1:1) to
1
give 12q as a gum. Yield, 80 mg (11%). H NMR (CDCl3): δ
1.58 (t, 3H), 1.68 (d, 6H), 4.21 (q, 2H), 4.90 (m, 1H), 6.95 (d, J
) 8 Hz, 1H), 7.12 (d, J ) 8 Hz, 1H), 7.17 (dt, J ) 8, 1 Hz, 1H),
7.0 (dt, J ) 8, 1 Hz, 1H), 7.46 (d, J ) 8 Hz, 1H), 8.23 (d, J )
8 Hz, 1H). MS (ES+): 269 (MH+). HRMS for C17H20N2O.
9-Isop r op yl-1,4-d im eth yl-9H-ca r ba zole-3-a m in e (12r )
(Sch em e 5). 6-Bromo-1,4-dimethylcarbazole13 (3.5 g, 13 mmol)
was added in portions over 10 min to a solution of 18-crown-6
(0.4 g, 1.5 mmol) and potassium bis(trimethylsilyl)amide (2.8

3522 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Block et al.
g, 14.3 mmol) in DMF (25 mL). 2-Iodopropane (1.4 mL, 14
mmol) was added in a single portion, and the mixture was
heated to 90 °C for 18 h. The solvent was removed under
vacuum, and the residue was partitioned between CH2Cl2 (50
mL) and 1 N HCl (50 mL). The organic layer was separated,
washed with brine (50 mL), dried, and concentrated to leave
a red oil. The crude product was purified by flash chromatog-
raphy eluting with a 5:1 mixture of i-hexane:EtOAc to give
6-bromo-1,4-dimethyl-9-iso-propylcarbazole as a colorless solid
Hz, 1H), 7.21 (s, 1H), 7.27 (t, J ) 7 Hz, 1H), 7.54 (d, J ) 7 Hz,
1H), 8.12 (d, J ) 7 Hz, 1H). MS (ES
+): 253 (MH+). Anal. for
C17H20N2.
Ack n ow led gm en t. We thank the following people
for their invaluable practical and intellectual contribu-
tions: Madeleine Vickers and Rob Horton for spectro-
scopic data and interpretation, George Stratton, Eddie
Clayton, Britt-Marie Fihn, Gun-Britt Forsberg, and
Brian Law for DMPK support, Paul Clarkson with
regard to in vitro biology, and Chris Williams, Steve
Bleakley, and J ohn Ashby for valuable discussions
relating to genetic toxicology.
1
(1.0 g, 27%). H NMR (CDCl3): δ 1.56 (d, J ) 7 Hz, 6H), 2.65
(s, 3H), 2.68 (s, 3H), 5.44 (sep, J ) 7 Hz, 1H), 6.77 (d, J ) 7.5
Hz, 1H), 6.97 (d, J ) 7.5 Hz, 1H), 7.34 (dd, J ) 8.7 & 1.9 Hz,
1H), 7.41(d, J ) 8.7 Hz, 1H), 8.18 (d, J ) 1.9 Hz, 1H).
6-Bromo-1,4-dimethyl-9-iso-propylcarbazole (1.0 g, 3.2 mmol)
was dissolved in glacial acetic acid (20 mL), and the solution
was cooled in an ice-bath. Concentrated HNO3 (d ) 1.42, 0.4
mL) was added dropwise over 5 min, and the mixture was
stirred in an ice-bath for 1 h. The mixture was poured into
water (50 mL), and the resulting precipitate was collected by
filtration. The solid was washed with water (2 × 25 mL) and
then with MeOH (2 × 25 mL). The product was dried in air to
leave 6-bromo-1,4-dimethyl-9-iso-propyl-3-nitrocarbazole as a
yellow solid (0.405 g, 37%). 1H NMR (CDCl3): δ 1.66 (d, J ) 7
Hz, 6H), 2.75 (s, 3H), 2.96 (s, 3H), 5.51 (sep, J ) 7 Hz, 1H),
7.49 (dd, J ) 9, 2 Hz, 1H), 7.55 (d, J ) 9 Hz, 1H), 7.77 (s, 1H),
8.34 (d, J ) 2 Hz, 1H).
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1
solid (95 mg, 28%). H NMR (Me2SO-d6): δ 1.65 (d, J ) 7 Hz,
6H), 2.75 (s, 3H), 2.8 (s, 3H), 5.5 (sept, J ) 7 Hz, 1H), 7.22 (m,
1H), 7.25 (s, 1H), 7.45 (m, 1H), 7.83 (d, J ) 8 Hz, 1H), 8.25 (d,
J ) 8 Hz, 1H), 10.15 (br s, 3H). MS (ES+): 253 (MH+). HRMS
for C17H20N2.
9-Isop r op yl-2,4-d im eth yl-9H-ca r ba zole-3-a m in e (12s)
(Sch em e 4). The sequence used to prepare 12s was similar
to that described for 12l.
Compound 22 (R3 ) R4 ) Me) was prepared as for 22 (R3
) Cl, R4 ) H) but using 3,5-dimethylaniline instead of
3-chloroaniline. The product was isolated as a brown solid
(yield 77%). 1H NMR (Me2SO-d6): δ 1.75 (m, 4H), 2.27 (s, 3H),
2.49 (s, 3H), 2.63 (m, 2H), 2.86 (m, 2H), 6.43 (s, 1H), 6.80 (s,
1H), 10.30 (br s, 1H).
Compound 23 (R3 ) R4 ) Me) was prepared in a manner
similar to 23 (R3 ) Cl, R4 ) H). The product was isolated as
1
an orange solid (yield 51%). H NMR (Me2SO-d6): δ 1.77 (m,
4H), 2.26 (s, 3H), 2.45 (s, 3H), 2.67 (m, 2H), 2.98 (m, 2H), 7.02
(s, 1H), 10.95 (s, 1H). MS (ES-): 243 (M - H-).
1,2,3,4-Tetrahydro-5,7-dimethyl-9-isopropyl-6-nitrocarba-
zole was prepared in a manner similar to 1,2,3,4-tetrahydro-
9-isopropyl-7-methyl-6-nitrocarbazole. Product was recrystal-
lized from EtOAc/i-hexane to yield a yellow solid (20%). 1H
NMR (Me2SO-d6): δ 1.48 (d, J ) 7 Hz, 6H), 1.77 (m, 4H), 2.30
(s, 3H), 2.45 (s, 3H), 2.73 (m, 2H), 2.90 (m, 2H), 4.65 (sept, J
) 7 Hz, 1H), 7.34 (s, 1H). MS (ES-): 287 (MH-).
2,4-Dimethyl-9-isopropyl-3-nitrocarbazole was prepared in
a manner similar to 2-methyl-9-isopropyl-3-nitrocarbazole. A
yellow solid was recrystallized from EtOAc/i-hexane (69%). 1H
NMR (Me2SO-d6): δ 1.63 (d, J ) 7 Hz, 6H), 2.45 (s, 3H), 2.73
(s, 3H), 5.17 (sept, J ) 7 Hz, 1H), 7.26 (t, J ) 8 Hz, 1H), 7.48
(t, J ) 8 Hz, 1H), 7.64 (s, 1H), 7.78 (d, J ) 8 Hz, 1H), 8.20 (d,
J ) 8 Hz, 1H).
Compound 12s was prepared in a manner similar to 12l.
The product was isolated as a brown solid (92%). 1H NMR
(Me2SO-d6): δ 1.56 (d, J ) 7 Hz, 6H), 2.30 (s, 3H), 2.59 (s,
3H), 4.28 (br s, 2H), 4.97 (sept, J ) 7 Hz, 1H), 7.04 (t, J ) 7

Ureas as Antagonists for the Treatment of Obesity
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