Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity

Article abstract of DOI:10.1021/jm990335v

Synthesis of a library of secondary benzylic amines based on the Sebti- Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC₅₀ of 8 nM) which lacked the p

Full text of DOI:10.1021/jm990335v

4844
J . Med. Chem. 1999, 42, 4844-4852
Discover y of a Ser ies of Cycloh exyleth yla m in e-Con ta in in g P r otein
F a r n esyltr a n sfer a se In h ibitor s Exh ibitin g P oten t Cellu la r Activity
Kenneth J . Henry, J r.,*,† J ames Wasicak, Andrew S. Tasker, J erome Cohen, Patricia Ewing, Michael Mitten,
J ohn J . Larsen, Douglas M. Kalvin, Rolf Swenson, Shi-Chung Ng, Badr Saeed, Sajeev Cherian, Hing Sham, and
Saul H. Rosenberg*
Departments of Cancer Research, D-47B, Combinatorial Chemistry, D-4CP, and Anti-infective Research, D-47T,
Abbott Laboratories, Abbott Park, Illinois 60064-3500
Received J une 28, 1999
Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type
peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6
as a potent enzyme inhibitor (IC50 of 8 nM) which lacked the problematic thiol residue which
had been a common theme in many of the more important FTase inhibitors reported to date.
It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the
general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras
prenylation in whole cells. Combination of these two observations led us to synthesize 7, a
potent FTase inhibitor which displayed an IC50 of 0.16 nM for in vitro inhibition of FTase and
an EC50 of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by classical
medicinal chemistry led to the discovery of a series of potent FTase inhibitors, culminating in
the identification of 25 which exhibited an IC50 of 0.20 nM and an EC50 of 4.4 nM. In vivo tests
in a nude mouse xenograft model of human pancreatic cancer (MiaPaCa cells) showed that
oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor
cell line.
Ch a r t 1
In tr od u ction
Ras p21 is a GTPase which acts as a molecular switch
and plays a central role in the transduction of extra-
cellular mitogenic signals to the nucleus.1,2 Ras mutants
which are stuck in the “on” state have been found in a
high percentage of several important human tumors,
including pancreatic, colon, and lung,2 and certain types
of ovarian cancers.3 Several posttranslational modifica-
tions normally occur before Ras can take part in the
signaling cascade,4-9 but the only critical modification
is prenylation by protein farnesyltransferase (FTase) of
the cysteine of a conserved carboxyl-terminal CA1A2X
motif, which is followed by localization to the inner
surface of the cellular membrane. This observation has
led several groups to examine inhibitors of FTase as
potential anticancer agents.10-26 There is now signifi-
cant evidence that Ras may not be the only substrate
of FTase germane to the issue of oncogenesis,27 but
FTase inhibitors have been demonstrated to slow the
growth of Ras-dependent tumors in nude mice.12,23,25
In 1995, Sebti and Hamilton disclosed the structure
of FTI-276 (1; Chart 1), which was conceived as a non-
peptide CA1A2M mimic in which the lipophilic amino
acid units (A1A2) were replaced with a rigid biphenyl
spacer. It exhibited a potent in vitro IC50 (0.5 nM
inhibition of farnesylation of an H-ras ligand) and
slowed the growth of human lung tumor cells in nude
mice.22-25 Recently, Augeri et al. disclosed that com-
pounds of the general description 2 (either anilines or
benzylic amines), in which the cysteinamine portion of
FTI-276 was replaced with a pyridyl ring, could dra-
matically and unexpectedly be improved in their ability
to act as FTase inhibitors by including an o-methyl
substituent on the flanking phenyl ring of the biphenyl
unit (i.e. 2, R ) Me).26a
Ch em istr y
Drawing on some of the more promising aspects of
the aforementioned work, a focused combinatorial li-
brary of benzylic amines was constructed to explore
replacements for the 3-pyridyl moiety in structure 2.
The requisite acid-aldehyde was prepared from com-
mercially available dimethyl iodoterephthalate in five
steps and coupled to L-methionine Wang resin (Scheme
1).28 The coupling was attempted under several stan-
dard conditions (Table 1), and use of HATU29 was
determined to be superior based on analysis of the
acid recovered from TFA cleavage from the polymer
support.30 The polymer-bound aldehyde was used as
the starting point for the synthesis of a small library
of secondary amines by reductive amination with so-
dium cyanoborohydride followed by TFA-mediated cleav-
age from the resin. Reductive amination with cyclohex-
* To whom correspondence should be addressed.
† Present address: Lilly Research Laboratories, Lilly Corporate
Center, Indianapolis, IN 46285. E-mail: Henryk@lilly.com.
10.1021/jm990335v CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/16/1999

Cyclohexylethylamine-Containing FTase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4845
Sch em e 1a
Sch em e 2a
a
(A) i. PhB(OH)2, Pd(OAc)2, Ph3P, Na2CO3, H2O-PhMe reflux,
a
(A) i. L-Met(OMe), EDCI, HOBt, NMM, ii. Swern; (B) i. RNH2,
NaBH(OAc)3, ii. LiOH, MeOH, H2O.
98%, ii. KOH, H2O/MeOH/THF, rt, 70%, iii. BH3-THF, 98%, iv.
Swern, quant., v. KOH, H2O/MeOH/THF; (B) see Table 1; (C) i.
RNH2, NaBH3CN, DMA, ii. TFA-H2O.
amination procedure was obtained by saturating the
corresponding aryl derivative under catalytic reduction
conditions or by modification of commercially available
cyclohexylalanol by way of the corresponding N-Boc-O-
mesylate. In a few instances, the final compound was
prepared by modification of the reductive amination
product (e.g. acylation or alkylation) before saponifica-
tion of the methionine ester. In a limited number of in-
stances we examined the properties of compounds where
the methionine residue was replaced by methionine
sulfone. Those compounds were prepared according to
Scheme 2, substituting methionine sulfone for methion-
ine. After reductive amination, the methionine esters
were saponified, and the final compounds were isolated
in the appropriate salt form.
Ta ble 1. Conditions for Coupling of Biphenyl Core Acid to
Methionine Residue on Wang Resina
Resu lts a n d Discu ssion
First, the biphenyl core of 6 (IC50 ) 8.0 nM) was
appended to contain an o-methyl substituent giving
structure 7. Whereas previous examples of this type of
modification resulted in 10-40-fold enhancement in
IC50, we observed a 50-fold increase in activity resulting
in an IC50 of 0.16 nM. In an effort to explore what
modifications were tolerable on the amine portion,
several similar structures were prepared, varying the
sense of chirality and the length of the alkyl chain and
testing the requirement for the cyclohexyl group (Table
2). Each of these changes resulted in loss of greater than
1 order of magnitude of activity. On the basis of this
information, we chose to limit further studies to com-
pounds with an o-tolylbiphenyl core, which conserve a
benzylic cyclohexylethylamine unit with a chiral center
adjacent to the amine possessing the S configuration
(as in 7).
We next examined the requirements for the branched
portion of the amine (Table 3). Etherification of the
hydroxyl group to give 12 was explored, in addition to
replacement of the oxygen with a variety of lipophilic
chains, and all such modifications resulted in subna-
nomolar FTase inhibitors. It was also discovered that
the hydroxyl group, and even the entire hydroxymethyl
group, could be omitted without sacrificing in vitro
activity (14, 13). Nitrogen substitution on 13, the
simplest member of this series (Table 4), retained
subnanomolar activity only in a limited number of cases.
It is curious that, in this limited number of compounds,
the side chains with the most disparate properties (BOC
- 20 and methyl - 24) had the best IC50 and EC50 data,
a
Reactions performed with 5 equiv of biphenyl acid.
Ch a r t 2
ylalanol gave rise to 6 (Chart 2), which after preliminary
screening and HPLC purification was identified as a
nanomolar inhibitor of FTase (vide infra).
This initial lead was optimized using standard solu-
tion-phase medicinal chemistry. The chemistry essen-
tially followed the reductive amination strategy outlined
above on solid phase. The hydroxy acid core (3) was
prepared by the method previously reported,26a replac-
ing phenylboronic acid with o-methylphenylboronic acid.
Coupling of the acid to L-methionine methyl or ethyl
ester followed by Swern oxidation31 gave 4, which was
a common intermediate for reductive amination with a
wide variety of mono- or disubstituted amines using
sodium triacetoxyborohydride in dichloroethane.32 In
most cases, the requisite amine partner for the reductive

4846 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Henry et al.
Ta ble 2. Initial SAR of Cyclohexylethyl Region of Lead
Structure 7a
Ta ble 4. SAR of Nitrogen Substitutiona
a
Unless otherwise indicated, all compounds were assayed once.
The reliability of the in vitro assay is (50%. The reliability of the
cellular assay is (50-100%. Compounds differing by 3-fold should
b
be considered statistically different. n ) 2.
Ta ble 5. Chalcogen Substitution of Cyclohexylalanol
Fragmenta
a
All compounds were assayed once. The reliability of the in vitro
assay is (50%. The reliability of the cellular assay is (50-100%.
Compounds differing by 3-fold should be considered statistically
different.
Ta ble 3. SAR of Substitution on Cyclohexylethylaminea
a
Unless otherwise indicated, all compounds were assayed once.
The reliability of the in vitro assay is (50%. The reliability of the
cellular assay is (50-100%. Compounds differing by 3-fold should
b
be considered statistically different. IC50 ) 0.20 ( 0.003 nM (n
) 8). c EC50 ) 4.4 ( 1.4 nM (n ) 8).
assay is a higher-order phenomenon and depends on a
number of different factors such as cellular transport
and intracellular distribution in addition to enzyme
inhibition. We have learned that, in general, only
compounds exhibiting subnanomolar FTase activity are
likely to express good cellular potency, but that even
some compounds with exceptional IC50’s may have very
poor cellular activity. Compound 16 is particularly
noteworthy since it had very good activity in the FTase
assay and displayed a remarkable EC50 of 4.3 nM in
our whole cell Ras processing assay.
Despite our success with compounds containing rela-
tively few heteroatoms on the “left” portion, we were
intrigued by the presence of a zinc atom in the active
site of FTase33 and chose to explore a series of com-
pounds which might have a higher propensity to inter-
act with a nearby metal atom (Table 5). The aforemen-
tioned methyl ether 12 fits this paradigm and indeed
exhibits a good level of enzyme inhibition. We prepared
a series of thioethers (25-29), in which the sulfur atom
is situated in the same manner relative to the biphenyl
core as the sulfhydryl group in FTI-276 (1). All members
of this series exhibited exceptional FTase inhibition, and
most had very good cellular activity. We then chose to
survey analogues of 25 in higher oxidation states (Table
a
Unless otherwise indicated, all compounds were assayed once.
The reliability of the in vitro assay is (50%. The reliability of the
cellular assay is (50-100%. Compounds differing by 3-fold should
be considered statistically different. n ) 2. c n ) 4.
b
while intermediate members of the series were rela-
tively poor.
Despite the fact that compounds of this general
description (i.e. benzylic cyclohexylethylamines) tended
to have very good in vitro activity against FTase, their
cellular activity varied considerably. This is not unex-
pected since by nature the readout from a cell-based

Cyclohexylethylamine-Containing FTase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4847
Ta ble 6. Sulfone Permutations of Compound 25
values (ppm) downfield relative to tetramethylsilane as an
internal standard. Mass spectra were obtained with a Hewlett-
Packard HP5965 spectrometer; CI/NH3 indicates chemical
ionization mode in the presence of ammonia, and APCI
indicates atmospheric pressure chemical ionization mode.
Combustion analyses were performed by Robertson Microlit
Laboratories, Inc., Madison, NJ . Purification was performed
by flash column chromatography using silica gel 60 (230-400
mesh) from E. Merck. Compounds synthesized by combinato-
rial techniques which displayed biological activity were re-
synthesized by solution-phase techniques in order to obtain
authenticated samples for biological assay. All compounds
synthesized by solution-phase methods were determined to be
>95% pure by analytical reverse-phase HPLC.
Gen er a l P r oced u r e: Cou p lin g of 4-F or m yl-2-p h en yl-
ben zoic Acid to L-Meth ion in e-Wa n g-P olystyr en e Resin .
A 100-mL manual peptide synthesis flask was charged with
7.70 g of L-Met-Wang-polystyrene resin (Novabiochem; 0.47
mmol/g, 3.62 mmol). The resin was suspended in N-meth-
ylpyrrolidinone (NMP). The flask was then placed on a manual
120° shaker and was gently rocked for 5 min. The flask was
then drained and the resin was washed with additional NMP
(2 × 5 min). The resin was resuspended in a minimal volume
of NMP followed by addition of diisopropylethylamine (9.5 mL,
54.4 mmol, 15 equiv), 4-formyl-2-phenylbenzoic acid as a
solution in NMP (4.10 g, 18.1 mmol, 5 equiv), and O-(7-
azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate (HATU)29 (6.90 g, 18.1 mmol, 5 equiv). The resin-
slurry was then shaken for 16 h at ambient temperature. The
reaction vessel was drained and washed as follows: acetone
(1 × 2 min), dimethylformamide (DMF) (5 × 5 min), 2-propanol
(5 × 5 min), DMF (3 × 5 min), methanol (2 × 5 min), and
diethyl ether (2 × 5 min). The resin was dried in vacuo
overnight at ambient temperature. Quantitative ninhydrin
analysis30 of a portion of the resin indicated 98% completion
for this coupling reaction.
Gen er a l P r oced u r e: Solid -P h a se Syn th esis of Secon d -
a r y Am in e-typ e F Ta se In h ibitor s by Red u ctive Am in a -
tion . All reactions were performed either in a manual solid-
phase synthesis flask using a 120° rotary shaker or on an
Advanced ChemTech model 396 multiple peptide synthesizer
(Advanced ChemTech Inc., Louisville, KY) at ambient tem-
perature. Resin (80 mg, substitution of 0.40 mmol/g) containing
4-formyl-2-phenylbenzamide-L-methionine-Wang-polysty-
rene resin was swollen with dimethylacetamide (DMA; 1.0 mL,
3 min). The solvent was drained and the resin was washed
with additional DMA (2 × 1.0 mL, 3 min). The resin was
suspended in DMA (0.20 mL) followed by addition of the
desired primary amine (0.48 mmol, 10 equiv) as a 1.0-mL
solution in 3:1 DMA/acetic acid. The resin was shaken for 2 h
and treated with sodium cyanoborohydride (0.25 mL of a 2.4
mM solution in DMA, 10 equiv). The resin-slurry was shaken
for an additional 2 h. The solvents were drained and the resin
was washed with DMA (6 × 1.0 mL, 3 min), DMF (6 × 1.0
mL, 3 min), IPA (6 × 1.0 mL, 3 min), DMF (6 × 1.0 mL, 3
min), MeOH (6 × 1.0 mL, 3 min), and diethyl ether (6 × 1.0
mL, 3 min). The resin was air-dried and subjected to subse-
quent cleavage.
a
Unless otherwise indicated, all compounds were assayed once.
The reliability of the in vitro assay is (50%. The reliability of the
cellular assay is (50-100%. Compounds differing by 3-fold should
b
be considered statistically different. n ) 2.
6) to assess the relative importance of the two sulfur
atoms for FTase inhibition. Oxidation of the left-side
thioether of 25 to the sulfone had no effect on in vitro
potency but resulted in slightly reduced cellular potency.
Oxidation of the methionine sulfur or the combination
of both oxidation events was not well-tolerated. Al-
though there is no direct evidence that indicates how
this type of molecule interacts with the enzyme, these
data do not support the idea that the sulfur on the “left”
portion of the inhibitors interacts with a metal atom.
On the other hand, the difficulty which we and others
have experienced finding useful replacements for the
methionine portion of the inhibitor does suggest a vital
role for the methionine atom.26,34 It should also be
considered that the requisite cyclohexylethyl portion of
the compounds described in this paper might occupy the
farnesylpyrophosphate binding site of FTase, but the
kinetic experiments required to explore this issue have
not yet been undertaken. It is interesting that compound
30 (IC50 ) 0.14 nM) contains all the structural elements
of a transition-state analogue for the alkylation of CAAX
with farnesylpyrophosphate.
It was hoped that the high cellular potency of many
of these compounds would allow for a clear demonstra-
tion of efficacy in an animal model of cancer. In
preliminary efficacy studies, compound 25 did in fact
exhibit exciting properties. When nude mice were
inoculated subcutaneously with MiaPaCa-2 cells, oral
dosing of compound 25 at 100 mpk, qd effected a 54%
reduction in tumor size relative to untreated control on
day 13 (mean tumor size of control, 669 mg). In a similar
experiment, compound 24 also demonstrated measur-
able in vivo efficacy. Oral dosing of 24 at 100 mpk, qd
effected a 23% reduction in tumor size on day 16, and
dosing of 24 at 6.25 mpk, qd, ip gave a 40% reduction
in tumor size on day 16 (mean tumor size for untreated
control on day 16, 980 mg). Although the exact magni-
tude of the efficacy of FTase inhibitors has been difficult
to reproducibly quantify, these results clearly demon-
strate a measurable level of in vivo efficacy against
human pancreatic cancer cells. Further in vivo efficacy
studies with this type of FTase inhibitor will be reported
in due course.26d
Gen er a l P r oced u r e: Clea va ge of F Ta se In h ibitor s
fr om th e Resin . Air-dried resin (80-90 mg) containing the
desired secondary amine was treated with a 1.50-mL solution
of 95/5 trifluoroacetic acid/water for 1.5 h at ambient temper-
ature. The spent resin was removed by filtration and the
resulting cleavage solution was poured into pretared storage
vials. An aliquot of the solution (0.150-0.250 mL) was removed
and evaporated in vacuo into a separate vial for analysis. The
remaining bulk solution was evaporated in vacuo and saved
for biological screening. In most cases, 5-20 mg of the crude
compound was obtained. Those compounds that contained the
desired product as determined by electrospray mass spectros-
copy and which had an HPLC purity of 40-90% were screened
for FTase inhibition.
Exp er im en ta l Section
Gen er a l. Proton magnetic resonance spectra were obtained
on a Nicolet QE-300 (300 MHz) or General Electric GN-300
(300 MHz) instrument. Chemical shifts are reported as δ
N-[4-(3-Cycloh exyl-1-h ydr oxypr opan -2-ylam in om eth yl)-
2-p h en ylben zoyl]-L-m eth ion in e (6): HPLC purity 65%; MS

4848 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Henry et al.
ESI(+) 499 (MH)+; resynthesized by the general procedure
described below; 1H NMR (DMSO-d6) δ 0.78-0.88 (m, 3H),
1.10-1.40 (m, 10H), 1.64-1.73 (m, 6H), 2.10-2.18 (m, 1H),
2.72 (m, 1H), 3.43 (m, 1H), 3.87-3.99 (m, 2H), 4.10-4.17 (m,
2H), 7.05-7.25 (m, 5H), 7.43 (d, J ) 7 Hz, 1H), 7.46 (d, J ) 7
Hz, 1H), 7.90 (m, 1H); MS (CI/NH3) m/z 499 (MH)+. Anal.
(C28H38N2O4S‚2.0 H2O) C, H, N.
N-[4-(1(S)-1-Cycloh exyl-2-h ydr oxyeth -1-ylam in om eth yl)-
2-(2-m et h ylp h en yl)b en zoyl]-L-m et h ion in e lit h iu m sa lt
(10): 1H NMR (DMSO-d6) δ 0.93-1.19 (m, 6H), 1.35-1.77 (m,
4H), 1.77-2.06 (m, 7H), 1.91 (s, 3H), 2.18 (brs, 1H), 2.26 (m,
3H), 3.40-3.48 (m, 1H), 3.59-3.70 (m, 1H), 3.73 (d, J ) 14.2
Hz, 1H), 3.81 (d, J ) 13.9 Hz, 1H), 4.36 (brs, 1H), 6.87-7.00
(m, 1H), 7.11-7.27 (m, 5H), 7.36 (d, J ) 8 Hz, 1H), 7.47 (d, J
) 8 Hz, 1H); MS (ESI(+)) m/e 499 (MH)+. Anal. (C28H37N2O4-
SLi‚0.75H2O) C, H, N.
N-[4-(1(R)-1-Cycloh exyl-2-h yd r oxyeth -1-yla m in om eth -
yl)-2-(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e lith iu m salt
(11): 1H NMR (DMSO-d6) δ 0.92-1.18 (m, 5H), 1.37-1.77 (m,
8H), 1.80-2.02 (m, 7H), 2.12-2.28 (m, 2H), 3.31 (m, 1H), 3.46
(m, 1H), 3.65-3.82 (m, 3H), 4.40 (t, J ) 5 Hz, 1H), 6.90 (m,
1H), 7.08-7.20 (m, 4H), 7.37 (dd, J ) 8, 1 Hz, 1H), 7.48 (d, J
) 8 Hz, 1H); MS (ESI(+)) m/e 499 (MH)+. Anal. (C28H37N2O4-
SLi‚1.5H2O) C, H, N.
N-[4-(2(S)-3-Cycloh exyl-1-m eth oxyp r op a n -2-yla m in o-
m eth yl)-2-(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e lith iu m
sa lt (12): 1H NMR (DMSO-d6) δ 0.65-0.88 (m, 2H), 1.00-1.88
(m, 15H), 1.91 (s, 3H), 1.95-2.19 (m, 3H), 2.61-2.68 (m, 1H),
3.20 (s, 3H), 3.20-3.26 (m, 2H), 3.62-3.84 (m, 3H), 6.85-7.00
(m, 2H), 7.09-7.24 (m, 5H), 7.36 (d, J ) 7.8 Hz, 1H), 7.48 (d,
J ) 7.8 Hz, 1H); MS (APCI(-)) m/e 525 (M - H)-. Anal.
(C30H41N2O4SLi‚0.60H2O) C, H, N.
N -[4-(2-Cycloh e xyle t h yla m in om e t h yl)-2-(2-m e t h yl-
p h en yl)ben zoyl]-L-m eth ion in e tr iflu or oa ceta te sa lt (13):
1H NMR (DMSO-d6) δ 0.72-0.87 (m, 2H), 1.00-1.26 (m, 4H),
1.37-1.45 (m, 2H), 1.47-1.78 (m, 7H), 1.86 (s, 3H), 1.90-2.11
(m, 5H), 2.80-2.87 (m, 2H), 4.11 (s, 2H), 4.14 (m, 1H), 6.98-
7.16 (m, 3H), 7.26 (m, 1H), 7.42-7.49 (m, 2H), 8.09 (m, 1H);
MS (CI/NH3) m/z 483 (MH)+. Anal. (C28H38N2O3S‚C2HF3O2‚
1.5H2O) C, H, N.
N-[4-(2(R)-1-Cycloh exylp r op -2-yla m in om et h yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e (14): 1H NMR (DM-
SO-d6) δ 0.77-0.90 (m, 2H), 1.02-1.50 (m, 9H), 1.52-1.84 (m,
7H), 1.94 (s, 3H), 1.94-2.17 (m, 5H), 2.85 (m, 1H), 3.89 (d, J
) 14 Hz, 1H), 3.97 (d, J ) 14 Hz, 1H), 4.06 (m, 1H), 7.04-
7.25 (m, 4H), 7.43-7.52 (m, 2H), 7.63 (m, 1H); MS (CI/NH3)
m/z 497 (MH)+. Anal. (C29H40N2O3S‚1.45H2O) C, H, N.
N -[4-(2(R )-1-Cycloh e xylb u t -2-yla m in om e t h yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e (15): 1H NMR (DM-
SO-d6) δ 0.70-0.90 (m, 2H), 0.79 (t, J ) 7 Hz, 3H), 1.06-1.41
(m, 8H), 1.50-2.20 (m, 15H), 2.42 (m, 1H), 3.65-3.80 (m, 3H),
6.88 (m, 1H), 7.09-7.25 (m, 4H), 7.36 (d, J ) 6 Hz, 1H), 7.48
(d, J ) 8 Hz, 1H); MS (CI/NH3) m/z 511 (MH)+. Anal.
(C30H41N2O3SLi‚1.25H2O) C, H, N.
N -[4-(2(R )-1-Cycloh e xylh e x-2-yla m in om e t h yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e (16): 1H NMR (DM-
SO-d6) δ 0.75-0.88 (m, 5H), 1.07-1.40 (m, 12H), 1.50-2.18
(m, 15H), 2.45 (m, 1H), 3.62-3.75 (m, 3H), 6.90 (m, 1H), 7.07-
7.24 (m, 4H), 7.36 (dd, J ) 8, 1 Hz, 1H), 7.47 (d, J ) 8 Hz,
1H); MS (CI/NH3) m/z 537 (M - H)-. Anal. (C32H45N2O3SLi‚
1.0H2O) C, H, N.
N-[4-(2(R)-1-Cycloh exyl-6-m eth ylh ep t-2-yla m in om eth -
yl)-2-(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e (17): 1H NMR
(DMSO-d6) δ 0.80 (d, J ) 5 Hz, 3H), 0.82 (d, J ) 5 Hz, 3H),
1.02-1.40 (m, 12H), 1.40-1.65 (m, 12H), 1.75-1.83 (m, 1H),
1.92 (s, 3H), 1.99 (m, 1H), 2.16 (m, 1H), 2.43 (m, 1H), 3.60-
3.77 (m, 3H), 6.86-6.95 (m, 1H), 7.08-7.22 (m, 5H), 7.35 (d,
J ) 8.0 Hz, 1H), 7.47 (d, J ) 8.0 Hz, 1H); MS (APCI(+)) m/e
567 (MH)+. Anal. (C34H49N2O3SLi‚2.0H2O) C, H, N.
N -[4-(2(R )-(Z)-1-Cycloh e xyl-6-m e t h ylh e p t -3-e n -2-yl-
a m in om e t h yl)-2-(2-m e t h ylp h e n yl)b e n zoyl]-L-m e t h io-
n in e lith iu m sa lt (18): 1H NMR (DMSO-d6) δ 0.86-1.74 (m,
7H), 1.02-1.19 (m, 4H), 1.27-1.38 (m, 2H), 1.46-1.87 (m,
14H), 1.93 (s, 3H), 1.99 (s, 3H), 2.17 (m, 1H), 3.51-3.82 (m,
3H), 5.11 (m, 1H), 5.43 (m, 1H), 6.83-6.96 (m, 1H), 7.00-7.24
(m, 5H), 7.24-7.36 (m, 1H), 7.47 (d, J ) 7 Hz, 1H); MS (APCI-
(+)) m/e 565 (MH)+. Anal. (C34H47N2O3SLi‚2.0H2O) C, H, N.
N -[4-(1,3-Dicycloh e xylp r op -2-yla m in om e t h yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e lith iu m sa lt (19):
1H NMR (DMSO-d6) δ 0.70-0.88 (m, 4H), 1.01-1.17 (m, 8H),
1.20-1.38 (m, 4H), 1.46-1.64 (m, 12H), 1.64-1.75 (m, 2H),
Gen er a l P r oced u r e: Red u ctive Am in a tion of Eth yl
N-[4-for m yl-2-(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e (4)
w ith a n Am in e. Eth yl N-[4-(2(S)-3-cycloh exyl-1-h yd r ox-
yp r op a n -2-yla m in om eth yl)-2-(2-m eth ylp h en yl)ben zoyl]-
L-m eth ion in e. To a solution of cyclohexylalanol (33 mg, 0.21
mmol) and 4 (84 mg, 0.21 mmol) in dichloroethane (0.7 mL)
was added sodium triacetoxyborohydride (62 mg, 0.29 mmol).
The reaction was stirred at ambient temperature for 3 h, at
which time it was judged to be complete by TLC. The reaction
was quenched by addition of 15% NaOH (1 mL), and the
mixture was extracted twice with ethyl acetate (5 mL). The
organic solution was dried (MgSO4), filtered, and concentrated.
The residue was purified by silica gel chromatography eluting
with 5% methanol/chloroform to afford the ethyl ester of 7 as
a clear oil (56 mg, 49%): 1H NMR (CDCl3) δ 0.83-0.95 (m, 2H),
1.10-1.73 (m, 17H), 1.85 (m, 1H), 2.01-2.11 (m, 6H), 2.77 (m,
1H), 3.27 (dd, J ) 6, 11 Hz, 1H), 3.64 (dd, J ) 4, 11 Hz, 1H),
3.82 (d, J ) 14 Hz, 1H), 3.90 (d, J ) 14 Hz, 1H), 4.11 (q, J )
7 Hz, 2H), 4.60 (m, 1H), 5.91 (d, J ) 7.5 Hz, 1H), 7.16 (s, 1H),
7.25-7.33 (m, 3H), 7.41 (dd, J ) 2, 8 Hz, 1H), 7.92 (dd, J ) 8,
15 Hz, 1H); MS (CI/NH3) m/z 541 (MH)+.
Gen er a l P r oced u r e: Sa p on ifica tion of Meth ion in e
Ester s. N-[4-(2(S)-3-Cycloh exyl-1-h ydr oxypr opan -2-ylam i-
n om eth yl)-2-(2-m eth ylp h en yl)ben zoyl]-L-m eth ion in e (7).
To a solution of ethyl N-[4-(3-cyclohexyl-1-hydroxypropan-2-
ylaminomethyl)-2-(2-methylphenyl)benzoyl]-L-methionine (86.0
mg, 0.159 mmol) in THF (0.53 mL) was added a 1 M aqueous
solution of lithium hydroxide (175 µL, 1.1 equiv), and the
solution was stirred at ambient temperature until judged to
be complete by TLC analysis (ca. 5 h). The solvent was
removed under reduced pressure, and the residue was dis-
solved in water (2 mL). The solution was neutralized with a 1
M aqueous solution of sodium bisulfate, and the product was
extracted into chloroform. The chloroform solution was dried
(MgSO4) and filtered, and the solvent was removed under
reduced pressure. If the salt-free compound was desired, the
residue was dissolved in aqueous acetonitrile and lyophilized
to give a white powder (65 mg, 80%): 1H NMR (DMSO-d6) δ
0.77-0.89 (m, 3H), 1.08-1.38 (m, 10H), 1.55-1.85 (m, 6H),
2.00-2.18 (m, 4H), 2.65 (m, 1H), 3.45 (m, 1H), 3.84-3.92 (m,
2H), 4.12-4.18 (m, 2H), 7.05-7.23 (m, 4H), 7.42 (d, J ) 7 Hz,
1H), 7.49 (d, J ) 7 Hz, 1H), 7.85 (m, 1H); MS (CI/NH3) m/z
513 (MH)+. Anal. (C29H40N2O4S‚1.5H2O) C, H, N.
In other compounds, it was determined on a case-by-case
basis that the lithium carboxylate or the ammonium trifluo-
roacetate salts gave well-behaved powders with superior solu-
bility properties. If the lithium carboxylate or the ammonium
trifluoroacetate salts were desired, the residue from the chloro-
form extraction was dissolved in aqueous acetonitrile (1-2 mL)
followed by addition of lithium hydroxide monohydrate (1
equiv) or dilute aqueous trifluoroacetic acid and lyophilization.
N-[4-(2(R)-3-Cycloh exyl-1-h yd r oxyp r op a n -2-yla m in o-
m eth yl)-2-(2-m eth ylp h en yl)ben zoyl]-L-m eth ion in e tr i-
flu or oa ceta te sa lt (8): 1H NMR (DMSO-d6) δ 0.77-0.89 (m,
3H), 1.08-1.38 (m, 10H), 1.55-1.85 (m, 6H), 2.00-2.18 (m,
4H), 2.65 (m, 1H), 3.45 (m, 1H), 3.84-3.92 (m, 2H), 4.12-4.18
(m, 2H), 7.05-7.23 (m, 4H), 7.42 (d, J ) 7 Hz, 1H), 7.49 (d, J
) 7 Hz, 1H), 7.85 (m, 1H); MS (CI/NH3) m/z 513 (MH)+. Anal.
(C29H40N2O4S‚C2HF3O2‚1.5H2O) C, H, N.
N-[4-(2(S)-3-P h en yl-1-h yd r oxyp r op a n -2-yla m in om eth -
yl)-2-(2-m eth ylp h en yl)ben zoyl]-L-m eth ion in e (9): 1H NMR
(DMSO-d6) δ 1.50-1.76 (m, 2H), 1.76-2.04 (m, 5H), 1.91 (s,
3H), 2.15 (brs, 1H), 2.60-2.74 (m, 2H), 3.25 (m, 1H), 3.70 (m,
1H), 3.80 (m, 2H), 4.14 (brs, 1H), 4.55 (brs, 1H), 6.87 (m, 2H),
7.07-7.22 (m, 10H), 7.29 (d, J ) 8 Hz, 1H), 7.44 (d, J ) 8 Hz,
1H); MS (ESI(+)) m/e 507 (MH)+. Anal. (C29H33N2O4SLi‚
1.8H2O) C, H, N.

Cyclohexylethylamine-Containing FTase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4849
1.92 (s, 3H), 1.94-2.02 (m, 2H), 2.13-2.18 (m, 2H), 3.60-3.76
(m, 3H), 6.84-6.97 (m, 1H), 7.04-7.24 (m, 5H), 7.36 (dd, J )
8, 1 Hz, 1H), 7.45 (d, J ) 8 Hz, 1H); MS (ESI(+)) m/e 579
(MH)+. Anal. (C35H49N2O3SLi‚0.75H2O) C, H, N.
Hz, 1H), 7.18 (m, 1H), 7.27-7.40 (m, 9H), 7.91 (dd, J ) 8, 16
Hz, 1H). The methyl ester was saponified according to the
general procedure to afford 74 mg of the lithium carboxylate
as a white powder: 1H NMR (DMSO-d6) δ 0.55-0.68 (m, 2H),
1.15-1.70 (m, 14H), 1.94-2.17 (m, 7H), 3.10-3.18 (m, 2H),
3.61-3.67 (m, 1H), 4.68-4.73 (m, 2H), 6.94 (m, 1H), 7.08-
7.25 (m, 4H), 7.32-7.45 (m, 6H), 7.53 (m, 1H); MS (APCI(-))
m/z 585 (M - H)-. Anal. (C35H41N2O4SLi‚1.8H2O) C, H, N.
N-[4-(N-ter t-Bu toxycar bon yl-2-cycloh exyleth ylam in om -
eth yl)-2-(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e Lith iu m
Sa lt (20). To a solution of methyl N-[4-(2-cyclohexylethylami-
nomethyl)-2-(2-methylphenyl)benzoyl]-L-methionine (methyl
ester of 13, 89 mg, 0.18 mmol) in THF (0.6 mL) was added
di-tert-butyl dicarbonate (47 mg, 0.21 mmol), and the reaction
was stirred at ambient temperature for 1 h. The reaction was
partitioned between saturated sodium bicarbonate and ethyl
acetate (5 mL each), and the organic phase was collected, dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography eluting
with 20% ethyl acetate in hexanes to afford methyl N-[4-(N-
tert-butoxycarbonyl-2-cyclohexylethylaminomethyl)-2-(2-meth-
ylphenyl)benzoyl]-L-methionine (92 mg, 91%): 1H NMR (CDCl3)
δ 0.82-0.93 (m, 2H), 1.10-1.70 (m, 23H), 1.95 (m, 1H), 2.01-
2.08 (m, 6H), 3.14-3.25 (m, 2H), 3.65 (s, 3H), 4.42-4.50 (m,
2H), 4.62 (m, 1H), 5.86 (m, 1H), 7.04 (s, 1H), 7.20-7.34 (m,
4H), 7.92 (m, 1H). The methyl ester was saponified according
to the general procedure to provide the title compound 20: 1H
NMR (DMSO-d6) δ 0.75-0.88 (m, 2H), 1.05-1.45 (m, 16H),
1.51-1.66 (m, 8H), 1.91 (s, 3H), 1.91-2.02 (m, 2H), 2.14 (m,
1H), 3.13-3.25 (m, 2H), 3.61-3.69 (m, 1H), 4.41 (s, 2H), 6.93-
7.31 (m, 6H), 7.51 (m, 1H); MS (APCI(-)) m/z 581 (M - H)-.
Anal. (C33H45N2O5SLi‚1.5H2O) C, H, N.
N-[4-(N-Acet yl-2-cycloh exylet h yla m in om et h yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e Lith iu m Sa lt (21).
To a solution of ethyl N-[4-(2-cyclohexylethylaminomethyl)-2-
(2-methylphenyl)benzoyl]-L-methionine (ethyl ester of 13, 102
mg, 0.20 mmol) in THF (0.67 mL) were added acetyl chloride
(20 µL, 0.30 mmol) and diisopropylethylamine (70 µL, 0.40
mmol). After stirring 1 h at ambient temperature the reaction
was quenched by addition of saturated aqueous sodium
bicarbonate. The mixture was extracted with ethyl acetate,
and the organic solution was dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified
by silica gel chromatography eluting with 50% ethyl acetate
in hexanes to afford ethyl N-[4-(N-acetyl-2-cyclohexylethyl-
aminomethyl)-2-(2-methylphenyl)benzoyl]-L-methionine (111
mg, 100%) as an amber oil: 1H NMR (CDCl3) δ 0.85-1.00 (m,
2H), 1.10-1.73 (m, 17H), 1.95 (m, 1H), 2.00-2.19 (m, 8H),
3.19-3.42 (m, 2H), 4.07-4.17 (m, 2H), 4.56-4.66 (m, 4H), 5.88
(m, 1H), 7.00 minor conformer 7.05 major conformer (s, 1H),
7.14-7.36 (m, 4H), 7.90 major conformer 7.95 minor conformer
(dd, J ) 8, 14 Hz, 1H). The ethyl ester was saponified according
to the general procedure to provide the title compound 21: 1H
NMR (DMSO-d6) δ 0.83-0.95 (m, 2H), 1.07-1.25 (m, 4H),
1.30-1.44 (m, 3H), 1.56-1.77 (m, 7H), 1.85-2.21 (m, 10H),
3.25-3.33 (m, 2H), 3.80 (m, 1H), 4.57 major conformer 4.63
minor conformer (s, 2H), 6.96-7.07 (m, 2H), 7.14-7.25 (m, 3H),
7.31 (d, J ) 8 Hz, 1H), 7.53 major conformer 7.59 minor
conformer (d, J ) 8 Hz, 1H); MS (APCI(-)) m/z 523 (M - H)-.
Anal. (C30H39N2O4SLi‚1.5H2O) C, H, N.
N-[4-(N-Ben zyl-2-cycloh exylet h yla m in om et h yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e Lith iu m Sa lt (23).
N-Benzylcyclohexylethylamine was prepared by reductive
amination of cyclohexylethylamine (330 mg, 2.6 mmol) and
benzaldehyde (240 µL, 2.3 mmol) with sodium triacetoxyboro-
hydride according to the general procedure to afford the
secondary amine (110 mg, 22%) after silica gel purification
with 5% methanol/chloroform: 1H NMR (CDCl3) δ 0.83-0.95
(m, 2H), 1.12-1.35 (m, 4H), 1.40-1.47 (m, 2H), 1.60-1.73 (m,
5H), 2.66 (d, J ) 8 Hz, 2H), 3.80 (s, 2H), 7.22-7.34 (m, 5H).
This amine was employed in a reductive amination with 4
according to the general procedure to provide ethyl N-[4-(N-
benzyl-2-cyclohexylethylaminomethyl)-2-(2-methylphenyl)ben-
zoyl]-L-methionine: 1H NMR (CDCl3) δ 0.74-0.86 (m, 2H),
1.05-1.42 (m, 9H), 1.47-1.66 (m, 8H), 1.84 (m, 1H), 2.00-
2.08 (m, 6H), 2.43 (t, J ) 7 Hz, 2H), 3.56 (s, 2H), 3.58 (s, 2H),
4.11 (q, J ) 7 Hz, 2H), 4.60 (m, 1H), 5.87 (m, 1H), 7.18-7.33
(m, 9H), 7.44 (d, J ) 8 Hz, 1H), 7.89 (dd, J ) 8, 14 Hz, 1H).
The ethyl ester was saponified according to the general
procedure to provide 23: 1H NMR (DMSO-d6) δ 0.68-0.81 (m,
2H), 1.02-1.38 (m, 7H), 1.42-1.58 (m, 7H), 1.91 (s, 3H), 1.95-
2.15 (m, 4H), 2.38 (t, J ) 7 Hz, 2H), 3.53 (s, 2H), 3.56 (s, 2H),
3.69 (m, 1H), 6.92 (d, J ) 6 Hz, 1H), 7.12-7.38 (m, 10H), 7.50
(d, J ) 8 Hz, 1H); MS (APCI(-)) m/z 571 (M - H)-. Anal.
(C35H43N2O3Sli‚1.75H2O) C, H, N.
N-[4-(N-2-Cycloh exylet h yl-N-m et h yla m in om et h yl)-2-
(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e lith iu m salt (24):
1H NMR (DMSO-d6) δ 0.76-0.90 (m, 2H), 1.05-1.35 (m, 7H),
1.50-1.74 (m, 7H), 1.92 (s, 3H), 1.80-2.06 (m, 3H), 2.12 (s,
3H), 2.15 (m, 1H), 2.32 (t, J ) 7 Hz, 2H), 3.49 (s, 2H), 3.64-
3.73 (m, 1H), 6.93 (d, J ) 6 Hz, 1H), 7.06-7.25 (m, 4H), 7.32
(dd, J ) 8, 1 Hz, 1H), 7.49 (d, J ) 8 Hz, 1H); MS (CI/NH3) m/z
497 (MH)+. Anal. (C29H39N2O3SLi‚1.0H2O) C, H, N.
Gen er a l P r oced u r e: Disp la cem en t of Cycloh exyla la -
n in e N-Boc-O-m esyla te w ith Th iola tes. (2S)-Amino-3-
cyclohexyl-1-propanol hydrochloride (1.9 g, 10.0 mmol), diiso-
propylethylamine (1.9 mL, 11.0 mmol), and di-tert-butyl
dicarbonate (2.7 g, 12.5 mmol) were combined in a (1:1)
mixture of 1,4-dioxane:water (20 mL) and allowed to stir for
18 h at ambient temperature. The reaction mixture was
partitioned between a solution of aqueous 2 N hydrochloric
acid/ethyl acetate and the phases were separated. The ethyl
acetate phase was washed with saturated potassium carbonate
solution, dried (MgSO4), and concentrated to afford a clear
oil: 1H NMR (CDCl3) δ 0.90-1.00 (m, 2H), 1.14-1.35 (m, 5H),
1.45 (s, 9H), 1.55-1.86 (m, 6H), 3.50 (m, 1H), 3.63-3.80 (m,
2H); MS (CI/NH3) m/z 258 (MH)+.
Methanesulfonyl chloride (820 µL, 10.5 mmol) was added
dropwise to a solution of the crude product from the above step
and triethylamine (1.5 mL, 10.5 mmol) in THF (40 mL) at 0
°C. The mixture was allowed to stir for 30 min and then a
solution of saturated NaHCO3 was added. The reaction
mixture was then extracted with ethyl acetate and the organic
phase was washed with 2 N hydrochloric acid, dried (MgSO4),
and concentrated. The residue was chromatographed (silica
gel; hexane/ethyl acetate, 80:20) to afford a clear oil (2.3 g,
67%): 1H NMR (CDCl3) δ 0.90-1.02 (m, 2H), 1.16-1.40 (m,
5H), 1.45 (s, 9H), 1.61-1.82 (m, 6H), 3.95 (m, 1H), 4.14 (dd, J
) 4, 10 Hz, 1H), 4.27 (m, 1H); MS (CI/NH3) m/z 336 (MH)+.
Ethanethiol (1.0 mL, 13.5 mmol) was added to a slurry of
sodium hydride (425 mg of an 80% dispersion, 13.9 mmol) in
THF (40 mL). After 15 min, a solution of the N-Boc-O-
mesylate of cyclohexylalanine in THF (1.5 g, 4.5 mmol, in 5
mL) was added dropwise. The reaction was warmed to reflux
for 1 h and cooled. The reaction was quenched by addition of
saturated aqueous sodium bicarbonate. The mixture was
N-[4-(N-Ben zoyl-2-cycloh exyleth yla m in om eth yl)-2-(2-
m eth ylp h en yl)ben zoyl]-L-m eth ion in e Lith iu m Sa lt (22).
To a solution of methyl N-[4-(2-cyclohexylethylaminomethyl)-
2-(2-methylphenyl)benzoyl]-L-methionine (methyl ester of 13,
88 mg, 0.18 mmol) in THF (0.6 mL) were added benzoyl
chloride (31 µL, 0.27 mmol) and diisopropylethylamine (63 µL,
0.36 mmol). After stirring 1 h at ambient temperature the
reaction was quenched by addition of saturated aqueous
sodium bicarbonate. The mixture was extracted with ethyl
acetate, and the organic solution was dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluting with 33%
ethyl acetate in hexanes to afford methyl N-[4-(N-benzoyl-2-
cyclohexylethylaminomethyl)-2-(2-methylphenyl)benzoyl]-L-
methionine as a clear viscous oil (82 mg, 76%): 1H NMR
(CDCl3) δ 0.70-1.23 (m, 9H), 1.53-1.85 (m, 6H), 1.87 (m, 1H),
2.00-2.10 (m, 6H), 2.18 (m, 1H), 3.18 (m, 1H), 3.48 (m, 1H),
3.66 (s, 3H), 4.50-4.67 (m, 2H), 4.80 (m, 1H), 5.88 (d, J ) 8

4850 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Henry et al.
extracted with ethyl acetate, and the organic solution was
dried (MgSO4), filtered, and concentrated under reduced
pressure to afford crude 2(S)-N-tert-butoxycarbonyl-3-cyclo-
hexyl-1-ethylthio-2-propylamine. The residue was dissolved in
methylene chloride (15 mL) followed by addition of trifluoro-
acetic acid (15 mL). After 30 min of stirring, solvent was
removed and the residue redissolved in methylene chloride,
washed with a solution of saturated potassium carbonate,
dried (MgSO4), and concentrated. The crude product was
chromatographed (silica gel; chloroform/methanol, 90:10) to
afford 2(S)-3-cyclohexyl-1-ethylthio-2-propylamine as a clear
oil (810 mg, 75%): 1H NMR (CDCl3) δ 0.90-1.00 (m, 2H), 1.26
(t, J ) 7.5 Hz, 3H), 1.10-1.50 (m, 6H), 1.61-1.80 (m, 5H),
2.34 (dd, J ) 13, 8.5 Hz, 1H), 2.55 (q, J ) 7.5 Hz, 2H), 2.68
(dd, J ) 13, 4 Hz, 1H), 2.97 (m, 1H); MS (CI/NH3) m/z 202
(MH)+.
N -[4-(2(S)-1-Cycloh e xyl-3-e t h ylt h iop r op -2-yla m in o-
m eth yl)-2-(2-m eth ylp h en yl)ben zoyl]-L-m eth ion in e (25).
The title compound was prepared from 2(S)-3-cyclohexyl-1-
ethylthio-2-propylamine and 4 according to the general pro-
cedure for reductive amination: 1H NMR (DMSO-d6) δ 0.70-
0.90 (m, 2H), 1.12 (t, J ) 7.5 Hz, 3H), 1.02-1.21 (m, 3H), 1.25-
1.45 (m, 4H), 1.50-1.88 (m, 7H), 1.95-2.22 (m, 5H), 2.44 (q,
J ) 7.5 Hz, 2H), 2.51 (s, 3H), 2.60-2.74 (m, 2H), 3.78-3.88
(m, 2H), 4.21 (m, 1H), 7.05-7.22 (m, 4H), 7.38-7.50 (m, 2H),
8.02 (m, 1H); MS (CI/NH3) m/z 557 (MH)+. Anal. (C31H44N2O3S2‚
1.0H2O) C, H, N.
N -[4-(2(S )-1-C y c lo h e x y l-3-t er t -b u t y lt h io p r o p -2-y l-
a m in om e t h yl)-2-(2-m e t h ylp h e n yl)b e n zoyl]-L-m e t h io-
n in e Lith iu m Sa lt (26). 2(S)-3-Cyclohexyl-1-tert-butylthio-
2-propylamine was prepared from tert-butylmercaptan accord-
ing to the general procedure: 1H NMR (CDCl3) δ 0.82-0.95
(m, 2H), 1.06-1.40 (m, 15H), 1.62-1.83 (m, 5H), 2.40 (dd, J
) 8, 12 Hz, 1H), 2.67 (dd, J ) 4, 12 Hz, 1H), 2.97 (m, 1H). The
title compound was then prepared according to the general
procedures for reductive amination with 4 and saponifica-
tion: 1H NMR (DMSO-d6) δ 0.68-0.91 (m, 2H), 1.00-1.74 (m,
24 H), 1.77-2.18 (m, 8H), 2.63 (m, 1H), 3.65 (m, 1H), 3.72-
3.87 (m, 2H), 6.97 (m, 1H), 7.13-7.23 (m, 4H), 7.37 (dd, J ) 8,
1 Hz, 1H), 7.47 (d, J ) 8 Hz, 1H); MS (CI/NH3) m/z 584 (MH)+.
Anal. (C33H47N2O3S2Li‚4.0H2O) C, N; H: calcd, 8.38; found,
7.43.
amination with 4: 1H NMR (DMSO-d6) δ 0.75-0.87 (m, 2H),
1.02-1.87 (m, 26H), 1.90 (s, 3H), 1.90-2.15 (m, 4H), 2.54-
2.64 (m, 2H), 3.66-3.83 (m, 3H), 6.88-6.96 (m, 1H), 7.06-
7.21 (m, 4H), 7.34 (m, 1H), 7.48 (d, J ) 7.7 Hz, 1H); MS (CI/
NH3) m/z 609 (M
-
H)-. Anal. (C35H49N2O3S2Li‚
1.05H2O‚1.60C2HF3O2) C, H, N.
N -[4-(2(S )-1-C y c lo h e x y l-3-e t h y ls u lfo n y lp r o p -2-y l-
a m in om e t h yl)-2-(2-m e t h ylp h e n yl)b e n zoyl]-L-m e t h io-
n in e Lith iu m Sa lt (30). 2(S)-N-tert-Butoxycarbonyl-3-cyclo-
hexyl-1-ethylthio-2-propylamine (vide supra, 565 mg, 1.87
mmol) was dissolved in methylene chloride (7.5 mL), followed
by addition of mCPBA (1.3 g, 7.5 mmol), and the heterogeneous
mixture was stirred overnight at ambient temperature. The
reaction was quenched by addition of saturated aqueous
sodium bicarbonate. The mixture was extracted with methyl-
ene chloride, and the organic solution was dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting with 20%
ethyl acetate in hexanes to afford the sulfone (480 mg, 77%)
as a white solid: 1H NMR (CDCl3) δ 0.83-1.06 (m, 2H), 1.16-
1.47 (m, 17H), 1.57-1.85 (m, 6H), 3.03-3.11 (m, 3H), 3.30 (m,
1H), 4.10 (m, 1H). This compound was dissolved in methylene
chloride (5 mL) followed by addition of trifluoroacetic acid (5
mL). After 1 h, the reaction was concentrated under reduced
pressure. The residue was redissolved in methylene chloride
and extracted to neutrality with aqueous potassium carbonate.
The organic solution was dried (MgSO4), filtered, and concen-
trated under reduced pressure to afford 2(S)-3-cyclohexyl-1-
ethanesulfonyl-2-propylamine as a white solid: 1H NMR
(CDCl3) δ 0.84-1.04 (m, 2H), 1.08-1.23 (m, 9H), 1.60-1.81
(m, 5H), 2.89 (dd, J ) 9, 14 Hz, 1H), 2.98 (dd, J ) 3, 14 Hz,
1H), 3.00 (q, J ) 7 Hz, 2H), 3.58 (m, 1H). The title compound
was prepared from 2(S)-3-cyclohexyl-1-ethanesulfonyl-2-pro-
pylamine according to the general procedure for reductive
amination with 4 and for saponification of the methionine
ester: 1H NMR (DMSO-d6) δ 0.75-0.92 (m, 2H), 1.08-1.78
(m, 16H), 1.81-2.28 (m, 8H), 2.97 (dd, J ) 14, 5 Hz, 1H), 3.07-
3.20 (m, 3H), 3.33 (m, 1H), 3.68-3.83 (m, 3H), 6.97 (m, 1H),
7.10-7.27 (m, 4H), 7.38 (dd, J ) 8, 1 Hz, 1H), 7.52 (d, J ) 8
Hz, 1H); MS (CI/NH3) m/z (MH)+ 589. Anal. (C31H43N2O5S2-
Li‚1.5H2O‚1.9LiOH) C, H, N.
N -[4-(2(S)-1-Cycloh e xyl-3-e t h ylt h iop r op -2-yla m in o-
m e t h yl)-2-(2-m e t h ylp h e n yl)b e n zoyl]-2(S )-2-a m in o-4-
m eth ylsu lfon ylbu ta n oa te Lith iu m Sa lt (31). A solution of
methyl 4-hydroxymethyl-2-(2-methylphenyl)benzoate (1.0 g,
4.1 mmol) in methanol (12 mL) was combined with a solution
of saturated lithium hydroxide (4.0 mL) and heated at reflux
for 3.5 h. The mixture was allowed to cool to ambient
temperature and then extracted with diethyl ether. The phases
were separated followed by addition of concentrated hydro-
chloric acid to the aqueous phase which was extracted with
ethyl acetate (2×). The organic solution was dried (MgSO4)
and concentrated to dryness to afford the 4-hydroxymethyl-
2-(2-methylphenyl)benzoic acid as a white solid: MS (CI/NH3)
m/z 243 (MH)+. A solution of crude acid, 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDCI; 940 mg, 4.5
mmol), N-hydroxybenzotriazole (1.1 g, 8.2 mmol), L-methionine
sulfone methyl ester hydrochloride (1.0 mg, 4.5 mmol), and
diisopropylethylamine (2.1 mL, 12.3 mmol) in dimethylforma-
mide (15 mL) was stirred at ambient temperature for 16 h.
The reaction was diluted with ethyl acetate (100 mL) and
washed with 2 M HCl, saturated sodium bicarbonate, and
brine. The organic solution was dried (MgSO4) and concen-
trated to dryness. The crude residue was chromatographed
(silica gel; methanol/chloroform, 5:95) to afford methyl N-[4-
hydroxymethyl-2-(2-methylphenyl)benzoyl]-2-amino-4-methyl-
sulfonylbutanoate (963 mg, 56%). Dimethyl sulfoxide (325 µL,
4.6 mmol) was added to a solution of oxalyl chloride (200 µL,
2,5 mmol) at -78 °C. After stirring for 5 min, methyl N-[4-
hydroxymethyl-2-(2-methylphenyl)benzoyl]-2-amino-4-methyl-
sulfonylbutanoate (955 mg, 2.3 mmol) in methylene chloride
(2.5 mL) was added to the reaction vessel. After 15 min,
triethylamine (950 µL, 6.8 mL) was added and the cold bath
was removed. After stirring for 30 min, a solution of 2 N
N-[4-(2(S)-1-Cycloh exyl-3-p h en ylt h iop r op -2-yla m in o-
m eth yl)-2-(2-m eth ylph en yl)ben zoyl]-L-m eth ion in e Lith iu m
Sa lt (27). 2(S)-3-Cyclohexyl-1-phenylthio-2-propylamine was
prepared from thiophenol according to the general procedure
procedures for reductive amination with 4 and saponifica-
tion: 1H NMR (CDCl3) δ 0.79-1.00 (m, 2H), 1.08-1.75 (m,
11H), 2.74 (dd, J ) 8, 13 Hz, 1H), 3.02 (m, 1H), 3.09 (dd, J )
4, 13 Hz, 1H), 7.18 (m, 1H), 7.25-7.33 (m, 2H), 7.35-7.40 (m,
2H). The title compound was then prepared according to the
general procedure for reductive amination with 4: 1H NMR
(DMSO-d6) δ 0.60-2.17 (m, 23H), 2.67 (m, 1H), 2.87 (m, 1H),
3.11 (dd, J ) 13, 5 Hz, 1H), 3.65-3.86 (m, 3H), 6.85-7.34 (m,
11H), 7.46 (d, J ) 8 Hz, 1H); MS (CI/NH3) m/z 605 (MH)+.
Anal. (C35H43N2O3S2Li‚1.20H2O) C, H, N.
N-[4-(2(S)-1-Cycloh exyl-3-(2-m et h ylp h en yl)t h iop r op -
2-yla m in om eth yl)-2-(2-m eth ylp h en yl)ben zoyl]-L-m eth io-
n in e Lith iu m Sa lt (28). 2(S)-3-Cyclohexyl-1-(2-methylphen-
yl)thio-2-propylamine was prepared from 2-methylthiophenol
according to the general procedure. The title compound was
then prepared according to the general procedure for reductive
amination with 4: 1H NMR (DMSO-d6) δ 0.63-0.90 (m, 2H),
0.98-1.85 (m, 14H), 1.90-1.97 (m, 2H), 1.92 (s, 3H), 2.08-
2.16 (m, 2H), 2.23 (s, 3H), 2.62-2.74 (m, 1H), 2.78-2.88 (m,
1H), 3.06 (dd, J ) 12.5, 4.4 Hz, 1H), 3.64-3.82 (m, 3H), 6.85-
7.32 (m, 10H), 7.45 (d, J ) 7.8 Hz, 1H); MS (CI/NH3) m/z 617
(M - H)-. Anal. (C36H45N2O3S2Li‚1.0H2O) C, H, N.
N -[4-(2(S )-1-Cycloh e xyl-3-cycloh e xylt h iop r op -2-yl-
a m in om e t h yl)-2-(2-m e t h ylp h e n yl)b e n zoyl]-L-m e t h io-
n in e Lith iu m Sa lt (29). 2(S)-3-Cyclohexyl-1-cyclohexylthio-
2-propylamine was prepared from cyclohexylmercaptan ac-
cording to the general procedure. The title compound was then
prepared according to the general procedure for reductive

Cyclohexylethylamine-Containing FTase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4851
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Lee, T.-J .; Smith, R. L.; Graham, S. L.; Hartman, G. D.; Gibbs,
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Analysis of Potent Non-Thiol Inhibitiors of Farnesyl Protein
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hydrochloric acid was added to the mixture and the phases
were separated. The organic phase was dried (MgSO4) and
concentrated. The residue was chromatographed (silica gel;
methanol/chloroform, 2:98) to afford methyl N-[4-formyl-2-(2-
methylphenyl)benzoyl]-2-amino-4-methylsulfonylbutanoate as
a clear oil (866 mg, 91%): 1H NMR (CDCl3) δ 1.88 (m, 1H),
2.11-2.30 (m, 4H), 2.47-2.73 (m, 2H), 2.71 (s, 3H), 3.71 (s,
3H), 4.65 (m, 1H), 6.12 (t, J ) 8 Hz, 1H), 7.20 (d, J ) 7 Hz,
1H), 7.27-7.41 (m, 2H), 7.76 (s, 1H), 7.95-8.06 (m, 2H), 10.10
(s, 1H); MS (CI/NH3) m/z 418 (MH)+. To a solution of methyl
N-[4-formyl-2-(2-methylphenyl)benzoyl]-2-amino-4-methylsul-
fonylbutanoate (285 mg, 1.4 mmol) and 2(S)-3-cyclohexyl-1-
ethylthio-2-propylamine (618 mg, 1.5 mmol) in ethylene
chloride (6 mL) was added sodium triacetoxyborohydride (415
mg, 2.0 mmol) at ambient temperature, and the mixture was
allowed to stir for 18 h. A solution of saturated sodium
bicarbonate was added and the mixture was extracted with
ethyl acetate (2×). The organic solutions were combined, dried
(MgSO4), and concentrated. The residue was chromatographed
(silica gel; MeOH/CHCl3, 2:98) to afford methyl N-[4-(N-3-
cyclohexyl-1-ethylthioprop-2-ylaminomethyl)-2-(2-methyl-
phenyl)benzoyl]amino-4-methylsulfonylbutanoate as a clear oil
(753 mg, 89%): MS (CI/NH3) m/z 418 (MH)+. The methyl ester
was saponified according to the general procedure to give the
title compound 31 as a white powder: 1H NMR (DMSO-d6) δ
0.70-0.91 (m, 2H), 1.12-1.65 (m, 14H), 1.75-2.20 (m, 5H),
2.35-2.67 (m, 7H), 2.82 (s, 3H), 3.66-3.86 (m, 3H), 6.95 (m,
1H), 7.10-7.25 (m, 4H), 7.38 (d, J ) 8 Hz, 1H), 7.53 (d, J ) 8
Hz, 1H); MS (APCI(-)) m/z 587 (M - H)-. Anal. (C31H43N2O5S2-
Li‚1.90H2O) C, H, N.
N-[4-(2(S)-1-Cycloh exyl-3-et h ylsu lfon ylp r op -2-yla m i-
n om et h yl)-2-(2-m et h ylp h en yl)b en zoyl]-2(S)-2-a m in o-4-
m eth ylsu lfon ylbu ta n oa te Lith iu m Sa lt (32). The title
compound was prepared from methyl N-[4-formyl-2-(2-meth-
ylphenyl)benzoyl]-2-amino-4-methylsulfonylbutanoate and 2(S)-
3-cyclohexyl-1-ethanesulfonyl-2-propylamine (vide supra) ac-
cording to the general procedures for reductive amination and
saponification: 1H NMR (DMSO-d6) δ 0.84-0.92 (m, 2H),
1.07-2.28 (m, 21H), 2.80 (s, 3H), 2.91-3.21 (m, 4H), 3.25 (m,
1H), 3.65-3.78 (m, 3H), 6.97 (m, 1H), 7.09-7.25 (m, 4H), 7.37
(d, J ) 8 Hz, 1H), 7.53 (d, J ) 8 Hz, 1H); MS (ESI(+)) m/z 621
(MH)+. Anal. (C31H43N2O7S2Li‚1.0H2O) C, H, N.
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