Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)-1-azetidinyl]ethyl} -2-piperidones. 1. Selective antagonists of the neurokinin-2 receptor

Article abstract of DOI:10.1021/jm0209331

The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK₂) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)- 1-azetidinyl]ethyl}-2-piperidones (5-44) are described. These compounds are formally derived from 2 by incorporating the metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam 4, resulting in increased stability in human liver microsome (HLM) preparations relative to 2 (T_1/2(HLM) of 30 min vs <10 min for 2). This series was further optimized by replacing the 4,4-disubstituted piperidine functionality found in 4 with simple 3-substituted azetidines. This series, exemplified by 1-benzyl-5-(3,4-dichlorophenyl)-5-{2- [3-(4-morpholinyl)-1-azetidinyl]-ethyl}-2-piperidone 5, was found to possess excellent functional potency for the NK₂ receptor in the Rabbit pulmonary artery (RPA) assay (pA₂ = 9.3) and increased in vitro metabolic stability (T_1/2(HLM) = 70 min) relative to 4. Metabolic route identification studies revealed that N-benzyl oxidation was a major route in this relatively lipophilic lead (log D = 3.2). Further exploration of the N-lactam substituent SAR targeting reduced lipophilicity to attenuate P-450 metabolism revealed that incorporation of a cyclopropylmethyl group in this region of the molecule gave a balance of good potency and high metabolic stability. For example, the significantly less lipophilic analogue 29 (log D = 2.3) possessed both good functional potency (RPA, pA₂ = 8. 1) and high in vitro metabolic stability (T_1/2(HLM) = 120 min). Optimization in this N-cyclopropylmethyllactam series by modification of the nature of the azetidine 3-substituent as a strategy to further increase potency and moderate log D led to the identification of sulfamide analogue 33, which possessed both excellent metabolic stability in vitro (T_1/2(HLM) > 120 min) and high potency in both RPA (pA₂ = 8.9) and human bladder smooth muscle (pK_b = 8.9) functional assays. In addition, NK₂ antagonist 33 (IC₅₀ = 4 nM) showed excellent selectivity over both the related human neurokinin receptors h-NK₁ (IC₅₀ = 7.9 μM) and h-NK₃ (IC₅₀ = 1.8 μM) in radioligand binding studies.

Full text of DOI:10.1021/jm0209331

J . Med. Chem. 2002, 45, 5365-5377
5365
Str u ctu r e-Activity Rela tion sh ip s of 1-Alk yl-5-(3,4-d ich lor op h en yl)-
5-{2-[(3-su bstitu ted )-1-a zetid in yl]eth yl}-2-p ip er id on es. 1. Selective An ta gon ists
of th e Neu r ok in in -2 Recep tor
A. Roderick MacKenzie,†,‡ Allan P. Marchington,†,§ Donald S. Middleton,*,† Sandra D. Newman,† and
Barry C. J ones|
Departments of Discovery Chemistry and Drug Metabolism, Pfizer Global Research and Development,
Sandwich, Kent CT13 9NJ , U.K.
Received May 13, 2002
The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK2)
antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)-1-azetidinyl]ethyl}-2-piperidones
(5-44) are described. These compounds are formally derived from 2 by incorporating the
metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam
4, resulting in increased stability in human liver microsome (HLM) preparations relative to 2
(T1/2(HLM) of 30 min vs <10 min for 2). This series was further optimized by replacing the
4,4-disubstituted piperidine functionality found in 4 with simple 3-substituted azetidines. This
series, exemplified by 1-benzyl-5-(3,4-dichlorophenyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]-
ethyl}-2-piperidone 5, was found to possess excellent functional potency for the NK2 receptor
in the Rabbit pulmonary artery (RPA) assay (pA2 ) 9.3) and increased in vitro metabolic
stability (T1/2(HLM) ) 70 min) relative to 4. Metabolic route identification studies revealed
that N-benzyl oxidation was a major route in this relatively lipophilic lead (log D ) 3.2). Further
exploration of the N-lactam substituent SAR targeting reduced lipophilicity to attenuate P-450
metabolism revealed that incorporation of a cyclopropylmethyl group in this region of the
molecule gave a balance of good potency and high metabolic stability. For example, the
significantly less lipophilic analogue 29 (log D ) 2.3) possessed both good functional potency
(RPA, pA2 ) 8.1) and high in vitro metabolic stability (T1/2(HLM) ) 120 min). Optimization in
this N-cyclopropylmethyllactam series by modification of the nature of the azetidine 3-sub-
stituent as a strategy to further increase potency and moderate log D led to the identification
of sulfamide analogue 33, which possessed both excellent metabolic stability in vitro (T1/2(HLM)
>120 min) and high potency in both RPA (pA2 ) 8.9) and human bladder smooth muscle (pKb
) 8.9) functional assays. In addition, NK2 antagonist 33 (IC50 ) 4 nM) showed excellent
selectivity over both the related human neurokinin receptors h-NK1 (IC50 ) 7.9 µM) and h-NK3
(IC50 ) 1.8 µM) in radioligand binding studies.
In tr od u ction
Substance P and the other tachykinins are largely
located in neurons, principally capsaicin-sensitive pri-
mary afferent fibers (C fibers), but are also present in
enteric sensory neurons and in a variety of neuronal
structures in the central nervous system (CNS). The
NK1 receptor is widely distributed in tissues throughout
the periphery and the CNS, while the NK2 receptor is
mainly located in the smooth muscle of the urinary,3
respiratory,4 and gastrointestinal tracts, with limited
presence in the CNS. In contrast, the NK3 receptor is
primarily expressed in the CNS although it is also found
in the GI tract.5
Neurokinin (NK) research has remained an area of
sustained activity over the past decade.1 Three mam-
malian neurokinin (tachykinin) receptors, classified as
neurokinin-1 (NK1), neurokinin-2 (NK2), and neuroki-
nin-3 (NK3), have been cloned and expressed,2 each
possessing an endogenous (tachykinin) ligand that share
a common C terminus, “Phe-X-Gly-Leu-Met-NH2”. The
three mammalian tachykinins, substance P (SP), neu-
rokinin A (NKA), and neurokinin B (NKB), preferen-
tially activate NK1, NK2, and NK3 receptors, respec-
tively. However, although each of the tachykinins is the
preferred ligand at one of the NK receptors, all three
are capable of full agonist activity at each of the
receptors, albeit with reduced affinity.
Tachykinins and their receptors have been postulated
to play a significant role in the pathophysiology of a wide
variety of diseases including gastrointestinal disorders,6
emesis,7 chronic pain,8 depression,9 and asthma,10 and
the search for selective non-peptidic antagonists of these
receptors continues, to both further elucidate their role
and evaluate their potential as therapeutic targets.
* To whom correspondence should be addressed. E-mail:
don_s_middleton@pfizer.sandwich.com. Phone: +44 1304 648393.
Fax: +44 1304 651819.
† Department of Discovery Chemistry.
‡ Current address; Discovery Technology Center, Pfizer Inc, 620
Memorial Drive, Cambridge, MA 02139.
The disclosure of a series of N-methyl-N-(4,4-disub-
stituted)piperidinyl)-(3,4-dichlorophenyl)butyl)benz-
amides11 as potent non-peptidic NK2 antagonists, ex-
emplified by (S)-1 (SR-48,968)12 and 2,11 has stimulated
§ Current address; Millennium Pharmaceuticals, Memorial Drive,
Cambridge, MA.
| Department of Drug Metabolism.
10.1021/jm0209331 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/26/2002

5366 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
MacKenzie et al.
F igu r e 1. Cyclization strategy to improve metabolic stability in lead series exemplified by 2.
Sch em e 1a
a
Reagents and conditions: (a) 2-bromoethyl tetrahydro-(2H)-pyran-2-yl ether, NaH, THF, 0 °C; (b) 3-bromoethyl propionate, LDA,
Bu4NI, THF, -78 °C to room temperature; (c) Raney nickel, H2, NH3/MeOH, room temp; (d) benzyl bromide, NaH, DMF, 0 °C; (e) HCl/
MeOH, room temp; (f) (COCl)2, DMSO, NEt3, CH2Cl2, -78 °C to room temp; (g) 3-substituted azetidine, NaBH(OAc)3, AcOH, NEt3, THF,
room temp.
activity both in the clinic13 and in exploiting this
template as a starting point for chemical programs
seeking selective NK2 antagonists.1
metabolically stable agents from within this δ-lactam
template.17
Ch em istr y
As part of our long-standing interest in neurokinin
antagonists for the treatment of urological disorders,14
preliminary pharmacological and pharmacokinetic evalu-
ation of 2 (Figure) as a potential lead revealed the
compound to be highly potent in both NK2 binding
(pIC50 ) 8.9) and rabbit pulmonary artery (RPA)
functional assays (pA2 ) 9.5). In vitro metabolic stability
studies in human liver microsome (HLM) preparations,
however, showed the compound to be rapidly turned
over in this assay (T1/2 < 10 min). Metabolic route
identification work revealed that a major pathway in
this process was amide N-demethylation to give the
essentially inactive secondary amide.11
We reasoned that incorporation of this vulnerable
methyl group of the amide into a cyclic N-acylpiperidine
or pyrrolidine 315 or δ-lactam 416 ring system could
reduce the potential for metabolism at this site. Though
the rate of CYP-450-mediated methylene (CH2) oxida-
tion is often observed to be more rapid than for methyl,
we believed that the reduction in the number of avail-
able conformations accessible in this cyclic template,
relative to the acyclic form 2, could result in attenuation
of the rate of metabolism. Initial exploration of this
strategy revealed that 4 possessed enhanced in vitro
metabolic stability relative to 2 (for 4, T1/2 ) 30 min;
for 2, T1/2 < 10 min) while retaining high potency for
the NK2 receptor (pA2(RPA) ) 8.9). In this paper, we
report our preliminary work to identify potent, selective
Compounds 6-20 were accessed as shown in Scheme
1. 3,4-Dichlorophenylacetonitrile was cleanly alkylated
in sequential fashion with 2-bromoethyl tetrahydro-
(2H)-pyran-2-yl ether followed by 3-bromoethyl propi-
onate in THF to give 45. Hydrogenation in the presence
of Raney nickel at room temperature resulted in a clean
reduction of the nitrile to the primary amine followed
by in situ lactam cyclization to give the piperidone 46
in 75% yield. Alkylation with benzyl bromide gave 47,
which was deprotected to the primary alcohol using HCl/
MeOH and oxidized under Swern conditions18 to furnish
aldehyde 48. Reductive amination of this aldehyde with
the appropriate 3-substituted azetidine,19 using triace-
toxyborohydride as reducing agent, then yielded com-
pounds 6-20.
Compounds 22 and 24-26 were accessed as shown
in Scheme 2. Acid deprotection of the primary alcohol
of lactam 46 using HCl/MeOH and treatment with
methanesulfonyl chloride cleanly furnished mesylate 49.
Mesylate displacement using 4-(3-azetidinyl)morpholine
hydrochloride in acetonitrile at reflux then gave inter-
mediate piperidone 50, which was cleanly alkylated
with the appropriate alkyl halide, using either KOH in
DMSO or NaH in DMF as base, to give compounds 22
and 24-26.
Compounds 5, 21, and 23 were prepared from inter-
mediate 46 as shown in Scheme 3. N-Alkylation using

SAR of Piperidones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5367
Sch em e 2a
Compounds 29 and 31-44 were prepared from alde-
hyde 58 as shown in Scheme 6, using the reductive
amination conditions described in Scheme 1.
Resu lts a n d Discu ssion
SAR studies initially focused on exploring the role of
the 4-hydroxy-4-phenylpiperidine moiety in 4 in confer-
ring both potency and metabolic stability in this lactam
template. Our aims in this initial phase of the program
were to identify an agent that possessed both high
functional potency against the NK2 receptor in the RPA
assay (pA2 ≈ 9) and high in vitro metabolic stability (T1/2
> 120 min) in HLM preparations, to minimize first-pass
metabolism in planned in vivo studies. Initial investiga-
tions sought to replace the piperidine with the smaller
3-substituted azetidine group, which we reasoned would
mimic the general directionality of the 4-substituted
piperidine moiety found in 4 (Table 1). Pleasingly, this
strategy yielded a series of potent compounds and
revealed that the 4-hydroxy-4-phenylpiperidine could be
replaced with a range of 3-monosusbstituted azetidines
possessing a range of H-bond donor-acceptor function-
ality with good retention of functional potency. For
example, 3-(morpholino)azetidine 5 was found to be
equipotent with 4 and possessed improved in vitro
metabolic stability (T1/2(HLM) ) 70 min vs T1/2(4) ) 30
min). Furthermore, this compound was found to be
potent in the human bladder functional assay (pKb )
9.0). Metabolic route profiling revealed that CYP-450-
mediated oxidation of the N-benzyl group was a major
metabolic pathway in this relatively lipophilic (log D )
3.2) compound.
The related cyclic ethers, the 1,4-oxazepanyl analogue
6 (pA2 ) 8.7), morpholinone 7 (pA2 ) 8.6), and 2-phe-
nylmorpholine 8 (pA2 ) 8.0), all retained high levels of
potency, although they offered no potency advantage
over 5. The introduction of a second basic center (9 and
10) to reduce log D and to explore the role of further
H-bonding potential in this region was also well toler-
ated, although the tertiary amine 10 was somewhat
weaker (pA2 ) 7.8) than 5. To explore the role of
H-bonding potential still further in this region, second-
ary amine 9 was converted to both the acetamide 11
and sulfonamide 12, which resulted in a small increase
in potency relative to 9. Interestingly, the thiomorpho-
line 13 and related sulfoxide 14 and sulfone 15 were
essentially equipotent. A range of primary and second-
ary alcohols (16-20), as hydrogen-bond donors, were
also examined and found to be potent in the RPA
functional assay. Acyclic amino alcohol 19 displayed
good activity (pA2 ) 8.5), which increased 40-fold in the
conformationally constrained 4-hydroxypiperidine ana-
logue 16, although tropane 20 was found to be weaker
than 16. The directionality of the alcohol function was
also found to play a role in conferring potency, the
3-hydroxypiperidine 18 and 3-hydroxypyrrolidine 17
analogues both being >10-fold weaker than 16.
a
Reagents and conditions: (a) HCl/MeOH, room temp; (b)
MeSO2Cl, NEt3, CH2Cl2, 0 °C; (c) 4-(3-azetidinyl)morpholine
hydrochloride, K2CO3, NEt3, CH3CN, reflux; (d) alkyl halide, KOH,
DMSO or alkyl halide, NaH, DMF, room temp.
the appropriate benzylic bromide in DMF gave the
benzylated compounds 51, which were readily converted
to their respective mesylates 52. Treatment with 4-(3-
azetidinyl)morpholine hydrochloride in the presence of
potassium carbonate furnished the target compounds
5, 21, and 23.
Single enantiomer compounds 27 and 28 were pre-
pared as shown in Scheme 4. Sequential alkylation of
3,4-dichlorophenylacetonitrile with allyl bromide and
the sodium salt of bromopropionic acid, in THF using
sodium hydride as base, gave 53, which was converted
to the diastereomeric aminooxazolines 54 in two steps
via transformation of the acid to the oxazoline with (S)-
valinol under Dean and Stark conditions20 and reduction
of the nitrile to the amine with lithium aluminum
hydride in diethyl ether. The resulting diastereomeric
amines were then readily separated by column chro-
matography.
Conversion of each diastereomer to the single enan-
tiomer compounds (S)-27 and (R)-2821 was then achieved
in four steps via acid-mediated cyclization to the pi-
peridone 55, N-alkylation with cyclohexylmethylbro-
mide in DMSO using KOH as base, ozonolysis of the
terminal olefin to the aldehyde, and reductive amination
using 4-(3-azetidinyl)morpholine hydrochloride in the
presence of sodium triacetoxyborohydride.
N-Cyclohexyl-substituted piperidone 30 was prepared
from acid 53 in six steps as shown in Scheme 5.
Conversion to the homochiral ester-aldehyde 56 was
readily achieved via resolution22 with R-(+)-naphthyl-
ethylamine, reduction of the nitrile to the aldehyde
using diisobutylaluminum hydride in toluene, and
conversion of the acid to the methyl ester using MeOH
in the presence of hydroxybenzotriazole (HOBT) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (WSCDI). Treatment of 56 with cyclohexyl-
amine in THF in the presence of triacetoxyborohydride
at reflux yielded the cyclized product 57 in 48% yield,
which was converted to 30 (49% for two steps) via
ozonolysis and subsequent reductive amination using
the conditions described above.
The role of the N-lactam substituent in conferring
both potency and in vitro metabolic stability was next
explored within a series incorporating the azetidine
morpholine moiety identified earlier (Table 2). No
substitution at the piperidone 1-position (R ) H; 50)
resulted in a dramatic loss of activity (pA2 < 5). Methyl
substitution at the ortho (21), meta (22), and para (23)

5368 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
MacKenzie et al.
Sch em e 3a
a
Reagents and conditions: (a) benzylic bromide, NaH, DMF, 0 °C; (b) HCl/MeOH, room temp; (c) MeSO2Cl, NEt3, CH2Cl2, room temp;
(d) 4-(3-azetidinyl)morpholine hydrochloride, K2CO3, NEt3, CH3CN, reflux.
Sch em e 4a
Sch em e 5a
a
Reagents and conditions: (a) R-(+)-naphthylethylamine, EtOAc,
recrystallization; (b) DIBAL, toluene, -78 to -40 °C; (c) WSCDI,
HOBT, MeOH, CH2Cl2, room temp; (d) cyclohexylamine, NaB-
H(OAc)3, THF, AcOH, reflux; (e) O3, dimethylsulfide, MeOH, -78
°C; (f) 4-(3-azetidinyl)morpholine hydrochloride, NaBH(OAc)3,
NEt3, AcOH, THF, room temp.
a
Only the (S)-isomer is shown for clarity. Reagents and
conditions: (a) allyl bromide, NaH, THF, 0-50 °C; (b) bromopro-
pionic acid sodium salt, NaH, THF, room temp to 70 °C; (c)
s-valinol, toluene, Dean-Stark, reflux; (d) LiAlH4, Et2O, 0 °C,
separate diastereomers; (e) 8% H2SO4 in EtOH, reflux; (f) cyclo-
hexylmethyl bromide, KOH, DMSO, room temp; (g) O3, dimethyl
sulfide, MeOH, -78 °C; (h) 4-(3-azetidinyl)morpholine hydrochlo-
ride, NaBH(OAc)3, NEt3, AcOH, THF, room temp.
Sch em e 6a
positions of the N-benzyl ring in 5 was found to be well
tolerated with high functional potency generally re-
tained (pA2 > 8). 4-Fluoro-substituted analogue 24 and
the 4-pyridylmethyl analogue 25, however, were found
to cause a significant reduction in functional potency.
In particular, 25 was found to be 200-fold less potent
than the benzyl analogue 5. N-Benzyl substitution was
found to routinely retain high potency; however, the
lipophilic nature of this group and the previously
established vulnerability of this site to metabolism (vide
supra) led us to seek alternative and less lipophilic
replacements for this group. Saturated cycloalkyl sub-
stitution SAR in this region was therefore investigated.
a
Reagents and conditions: (a) 3-substituted azetidine, NaB-
H(OAc)3, NEt3, AcOH, THF, room temp.
Cyclohexylmethyl substitution (26) was found to be
equipotent to N-benzyl in the RPA functional assay (pA2
) 8.9). In addition, this cycloalkyl analogue retained
excellent potency in the human bladder functional assay
(pKb ) 8.5). Resolution of this analogue to give the
enantiomers 27 and 28 revealed that (S)-stereoisomer
27 possessed significantly greater potency than (R)-

SAR of Piperidones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5369
Ta ble 1. NK2 Functional Activity Data of
1-Benzyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)-1-
azetidinyl]ethyl}-2-piperidones 4-20 in Rabbit Pulmonary
Artery Assay
Ta ble 2. RPA Functional Potency and Human in Vitro
Microsomal Stability Profiles of 1-Aryl- and
1-Alkyl-5-(3,4-dichlorophenyl)-5-{2-[3-(4-morpholinyl)-1-
azetidinyl]ethyl}-2-piperidones 5 and 21-30
a
For all determinations, n g 2 (each experiment performed in
triplicate). pKb(human bladder) ) 9.0. c pKb(human bladder) )
8.2. NT: not tested.
b
d
ries revealed cycloalkyl ring oxidation as a major
pathway. The N-cyclohexyl analogue 30, designed to
reduce log D relative to that for 27 as a strategy to
improve metabolic stability, was found to be very potent
(pA2 ) 9.9). Unfortunately, this compound showed no
advantage in metabolic stability relative to 27 (T1/2
<
10 min). This preliminary SAR suggested to us that the
nature of the N-lactam substituent played a major role
in conferring both potency and metabolic stability in this
series and that identifying a suitably stable lipophilic
substituent at this position was key to achieving our
target of good metabolic stability in this series. To
explore this further, a series of saturated N-(methylene)-
cycloalkyl-substituted lactam analogues possessing a
range of lipophilicities were prepared and profiled,
seeking to balance potency and metabolic stability. In
general, increasing potency was found to correlate with
increasing cycloalkyl ring size (3-7), while metabolic
a
b
All compounds are racemates. For all determinations, n g 2
(each experiment performed in triplicate). c Synthesis reported
previously. See ref 16. log D ) 3.2; T1/2(HLM) ) 70 min. e Mixture
d
of diastereomers.
enantiomer (28) (pA2 ) 9.0 vs 6.2), with the weaker
enantiomer possessing the greater in vitro metabolic
stability (T1/2(HLM) ) 84 vs 14 min). Metabolic route
identification studies within this cyclohexylmethyl se-

5370 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
MacKenzie et al.
Ta ble 3. NK2 (RPA) Functional Potency and Human in Vitro
Microsomal Stability Data of 1-Cyclopropylmethyl-5-(3,4-dichlo-
rophenyl)-5-{2-[(3-substituted)-1-azetidinyl]ethyl}-2-piperidones
31-44
stability generally correlated with decreasing cycloalkyl
ring size (i.e., reduced log D). From this SAR, cyclopro-
pylmethyl analogue 29 emerged as the compound pos-
sessing the best balance of potency and metabolic
stability (pA2 ) 8.1; T1/2(HLM) ) 120 min). Further-
more, in the human bladder smooth muscle assay, the
compound retained good functional potency (pKb ) 8.2),
again correlating closely with RPA data (pA2 ) 8.1). The
greater metabolic stability observed with 29 is note-
worthy and may be due to cooperative factors. 29 (log D
) 2.3) is significantly less lipophilic than 27 (log D )
3.3), which may predispose 29 to be intrinsically less
susceptible to CYP-450-mediated metabolism.23 In ad-
dition, the electronics of the three-membered cyclopropyl
ring are quite distinct from other cycloalkyl ring systems
and may contribute to the reduced susceptibility to CYP-
450-mediated radical abstraction or R-oxidation.24
With the goal of minimizing metabolic turnover at the
N-lactam substituent achieved in 29, our attention
returned to the nature of the 3-azetidine substituent
with the aim of both further increasing potency and
optimizing the physical properties while retaining the
excellent in vitro metabolic stability seen with 29 (Table
3).
Both hydrogen bond donor and acceptor moieties were
well tolerated with 4-substituted piperidine alcohol 41
(pA2 ) 8.8), ether 42 (pA2 ) 8.2), ketone 44 (pA2 ) 8.9),
and acid 43 (pA2 ) 9.4), all highly potent. Primary
amine 37 (pA2 ) 8.7) was also highly potent; however,
the in vitro metabolic half-life of this dibasic compound
was found to be lower than the 3-morpholine azetidinyl
analogue 29 (T1/2 ) 30 vs 120 min). Both acylation to
give 38 (pA2 ) 7.8) and sulfonylation to give 39 (pA2 )
8.0) resulted in a reduction in potency relative to the
primary amine parent 37. The 4-N-acetyl-4-phenyl
analogue 40 was somewhat more potent than the des-
phenyl analogue 38, although this offered no advantage
over 37. Piperazine 31 (pA2 ) 7.9) was found to be
weaker than the H-bond acceptor morpholine 29. Simple
methanesulfonylation to give 32 resulted in a 4-fold
increase in potency. Unfortunately, this compound was
rapidly metabolized in vitro (T1/2(HLM) < 10 min) in
HLM. Formal replacement of the methyl group of the
sulfonamide moiety in 32 with a primary amine to give
sulfamide 33 resulted in a drop in log D (1.7 vs 2.2 for
32) and a marked increase in both in vitro metabolic
stability (T1/2(HLM) > 120 min) and also a 3-fold
increase in functional potency. Furthermore, this func-
tional activity was shown to translate well into the
human bladder functional assay (pKb ) 8.9). Attempts
to modulate the H-bonding potential in this sulfamide
through either mono-(34) or N,N-dimethylation (35)
resulted in a progressive drop in potency over the
primary sulfamide. Similarly, attempts to replace the
sulfamide with the primary urea 36 (pA2 ) 8.3) resulted
in a 4-fold reduction in potency. NK2 antagonist 33 (IC50
) 4 nM) was also found to possess excellent selectivity
over the related human NK1 (IC50 ) 7.9 µM) and NK3
(IC50 ) 1.8 µM) receptors in radioligand binding studies.
a
All compounds are single (S) enantiomers. b For all determina-
tions, n g 2 (each experiment performed in triplicate). c pKb(hu-
man bladder) ) 8.9. h-NK1 binding (IM9 cells) IC50 ) 7.9 µM;
h-binding (CHO cells) IC50 ) 4 nM; h-NK3 binding (CHO cells)
IC50 ) 1.8 µM.
major sites of CYP-450 metabolism. These data initially
identified amide N-demethylation in lead 2 as a major
route of metabolism and were subsequently used in SAR
studies to guide selection of piperidone N-substitution
in the piperidone series. This work identified the cyclo-
propylmethyl substituent as a group that possessed low
susceptibility to P-450-mediated metabolism while re-
taining good potency in the RPA and human bladder
smooth muscle functional assays.
Con clu sion
The design of the NK2 antagonists described above
was guided by both in vitro metabolic stability and
metabolic route data in HLM preparations to identify
Furthermore, 33 has also been shown to possess good
selectivity over both the related human NK1 and NK3

SAR of Piperidones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5371
of sodium hydride (60% dispersion in oil) (19.24 g, 481 mmol)
in THF (450 mL) cooled in an ice/water bath, was added a
solution of 3,4-dichlorophenylacetonitrile (89.5 g, 481 mmol)
in THF (450 mL) dropwise over 40 min. After a further 30
min, a solution of 2-bromoethyl tetrahydro-2H-pyran-2-yl ether
(100 g, 481 mmol) in THF (100 mL) was added and the reaction
mixture was allowed to warm to room temperature and stirred
overnight. A 30% aqueous NH4Cl solution (500 mL) was added,
and the mixture was extracted with Et2O. The organic phase
was washed with H2O (×2), dried (MgSO4), and filtered, and
the solvent was removed under reduced pressure. The crude
product was purified on silica gel, eluting with Et2O/hexane
to give the alkylated product (51 g, 34%) as a pale-yellow oil.
1H NMR (300 MHz, CDCl3): δ 1.47-1.66 (4H, m), 1.79 (2H,
m), 2.17 (2H, m), 3.34-3.62 (2H, m), 3.88 (2H, m), 4.08 (1H,
t), 4.58 (1H, m), 7.21 (1H, d), 7.48 (2H, m).
(b) A solution of the above compound (43.9 g, 138 mmol) in
THF (180 mL) was added to a solution of LDA (192 mmol, 1.4
equiv) in THF (80 mL) at -78 °C. The mixture was allowed to
warm to room temperature and was cooled again to -78 °C,
and a solution of 3-bromoethyl propionate (22.36 mL, 179.5
mmol) in THF (70 mL) was added dropwise. Tetrabutylam-
monium iodide (50 g) was then added, and the mixture was
allowed to stir at room temperature overnight. Water (300 mL)
was added, and the solution was concentrated under reduced
pressure. The residue was partitioned between EtOAc and
brine, the organic phase was washed with H2O, dried (MgSO4),
and filtered, and the solvent was removed under reduced
pressure. The crude product was purified on silica gel, eluting
with Et2O/hexane to give the ester 45 (35 g, 61%). 1H NMR
(300 MHz, CDCl3): δ 1.21 (3H, t), 1.39-1.77 (4H, m), 2.03-
2.58 (8H, m), 3.39 (2H, m), 3.74 (2H, m), 4.09 (2H, q), 4.46
(1H, m), 7.28 (1H, d), 7.49 (1H, d), 7.57 (1H, s).
receptors in radioligand binding studies. Following
further profiling, 33 (UK-224,671) was progressed into
clinical development.25 Our work to further optimize the
pharmacokinetic (DMPK) properties of this series26 will
be the subject of further communications from these
laboratories.
Exp er im en ta l Section
Biology. The activity of compound 33 at the tachykinin
receptor subtypes NK1 and NK3 was assessed in radioligand
binding studies using cell membranes prepared from IM9
monocytes (NK1) and from CHO cells expressing the recom-
binant human NK3 receptor.
The NK2 receptor antagonist activity of compounds 2 and
4-44 was determined in vitro by testing their ability to
antagonize the contractile effects of the selective NK2 receptor
agonist [â-ala8]NKA(4-10) in the rabbit pulmonary artery (RPA),
using the method of Pataccini and Maggi.27
RPA, rather than binding against the human NK2 receptor
stably expressed in the CHO cell line, was chosen as the in
vitro surrogate for human bladder based on
a series of
comparative experiments. In general, the correlation between
RPA and human bladder was superior to that observed with
data obtained from human the NK2 binding assay.
Transplant-quality human liver tissue was obtained from
the International Institute for the Advancement of Medicine
(Exton, PA). Hepatic microsomes were prepared according to
the method of J ones et al.28 Cytochrome P450 (CYP-450)
content was determined using the method of Omura and
Sato,29 and the protein concentration was determined using
the method of Lowry et al.30
Incubations were carried out at 1 µM substrate and 0.5 µM
cytochrome P-450 in a total incubation volume of 12 mL. The
incubation volume was made up of 50 mM Tris HCl (pH 7.4),
5 mM MgCl2, and 5 µM MnCl2. The reducing equivalents
required by cytochrome P-450 were provided by NADPH (1
mM), which was regenerated in situ using an isocitrate/
isocitrate dehydrogenase system. All the components were
preincubated at 37 °C prior to the addition of the NADPH.
Aliquots (1 mL) were removed from the incubation at 0, 3,
5, 10, 15, 20, 30, 45, and 60 min after the addition of NADPH.
The reaction was terminated by addition of the samples to a
tube containing 0.2 M sodium borate buffer (pH 10)/tert-butyl
methyl ether (1:3 v/v) and a suitable internal standard.
Samples were mixed and centrifuged, and the ether layer was
evaporated to dryness under a stream of nitrogen. Samples
were analyzed by HPLC, and the rate of metabolism was
determined by log-linear regression of peak height ratio
(substrate/internal standard) vs time. The half-life was cal-
culated from 0.693/slope.
Ch em istr y. Melting points were determined on a Gallen-
kamp melting point apparatus using glass capillary tubes and
are uncorrected. Unless otherwise indicated, all reactions were
carried out under a nitrogen atmosphere, using commercially
available anhydrous solvents. Thin-layer chromatography was
performed on glass-backed precoated Merck silica gel (60 F254)
plates, and flash column chromatography was carried out
using 40-63 µm silica gel. Proton NMR spectra were measured
on a Varian Inova 300 or 400 spectrometer in the solvents
specified. Mass spectra were recorded on a Fisons Trio 1000
using thermospray positive (TSP) ionization. Where analyses
are indicated only by the symbols of the elements, results
obtained are within 0.4% of the theoretical values. In the cases
where compounds were analyzed as hydrates, the presence of
water was evident in the enhanced peak because of water in
the proton NMR spectra. The purity of compounds was
carefully assessed using analytical TLC and proton NMR, and
the latter technique was used to calculate the amount of
solvent in solvated samples. In multistep sequences, the purity
and structure of intermediates were verified spectroscopically
by proton NMR.
(c) To a solution of 45 (14.87 g, 36 mmol) in saturated
ammoniacal ethanol (500 mL) was added Raney nickel (1.5
g), and the mixture was stirred under an atmosphere of
hydrogen at room temperature for 14 h. The catalyst was
removed by filtration, and the solvent was evaporated under
reduced pressure. The crude product was purified on silica gel,
eluting with MeOH/CH2Cl2 to give the lactam 46 (10.1 g, 75%).
MS m/z: 372. 1H NMR (300 MHz, CDCl3): δ 1.39-1.81 (6H,
m), 1.90-2.23 (5H, m), 2.40 (1H, m), 3.11 (1H, m), 3.39-3.61
(3H, m), 3.77 (2H, m), 4.38 (1H, d), 6.07 (1H, br, s), 7.18 (1H,
d), 7.42 (2H, m).
(d ) To a solution of lactam 46 (2.3 g, 6.18 mmol) in DMF
(30 mL) was added, with cooling in an ice/water bath, NaH
(60% dispersion in oil) (475 mg, 12.3 mmol). The reaction
mixture was allowed to warm to room temperature and after
40 min was cooled again in an ice/water bath, and benzylbro-
mide (1.47 mL, 12.3 mmol) was added. After a further 30 min,
water was added and the mixture was evaporated to dryness
under reduced pressure. The residue was partitioned between
H2O and saturated NaHCO3 and was extracted with EtOAc.
The organic phase was dried (MgSO4) and filtered, and the
solvent was removed under reduced pressure. The residue was
purified on silica gel, eluting with MeOH/CH2Cl2 to give the
alkylated product 47 (2.6 g, 91%).
(e) A solution of lactam 47 (2.60 g, 5.63 mmol) in HCl-
saturated MeOH (50 mL) was stirred for 2 h. The solvent was
removed under reduced pressure, and the residue was parti-
tioned between saturated NaHCO3 and EtOAc. The organics
were dried (MgSO4) and filtered, and the solvent was removed
under reduced pressure to give the alcohol (2.07 g), which was
used without further purification. MS m/z: 378 (MH)+. 1H NMR
(300 MHz, DMSO-d6): δ 1.62-2.07 (4H, m), 2.24 (2H, m), 3.02
(2H, m), 3.39 (1H, d), 3.79 (1H, d), 4.27 (1H, t), 4.44 (1H, d),
4.59 (1H, d), 7.16 (1H, d), 7.21-7.40 (6H, m), 7.47 (1H, d).
(f) To a solution of oxalyl chloride (4.95 mL, 57.1 mmol) in
CH2Cl2 (120 mL) at -78 °C was added DMSO (8.83 mL, 114.2
mmol). After 45 min, a solution of the above alcohol (19.62 g,
51.9 mmol) in CH2Cl2 (210 mL) was added and the tempera-
ture maintained at -78 °C. After 2 h, NEt3 (36.1 mL, 259.5
mmol) was added and the reaction mixture was allowed to
warm to room temperature. The reaction was washed with
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-{2-[3-(1,4-oxa zep a n -
4-yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (6). (a ) To a solution

5372 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
MacKenzie et al.
saturated NaHCO3 and brine. The organic layer was dried
(MgSO4) and filtered, and the solvent was removed under
reduced pressure. The crude product was purified on silica gel,
eluting with EtOAc/hexane to give the aldehyde 48 (9.47 g,
49%). 1H NMR (300 MHz, CDCl3): δ 2.09-2.30 (3H, m), 2.40-
2.63 (2H, m), 2.86 (1H, d), 3.39 (1H, d), 3.77 (1H, d), 4.42 (1H,
d), 4.81 (1H, d), 6.87 (1H, d), 7.17 (1H, s), 7.22-7.41 (6H, m),
9.40 (1H, s).
NMR (300 MHz, CDCl3): δ 1.24 (1H, m), 1.41-1.80 (3H, m),
1.96-2.34 (6H, m), 2.43 (4H, m), 2.77 (2H, m), 2.98 (1H, m),
3.07 (4H, m), 3.24 (1H, d), 3.38 (1H, m), 3.55 (1H, d), 4.39 (1H,
d), 4.83 (1H, d), 6.80 (1H, d), 7.08 (1H, s), 7.23-7.41 (6H, m).
Anal. (C27H34Cl2N4O‚1.4CH2Cl2) C, H. N: found, 6.84; calcd,
9.03.
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-{2-[3-(4-m eth yl-1-p i-
p er a zin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (10). Yield:
1
32%. MS m/z: 515 (MH)+. H NMR (300 MHz, CDCl3): δ 1.52
(g) To a solution of the aldehyde 48 (427 mg, 1.13 mmol) in
THF (9 mL) was added 4-(3-azetidinyl)-1,4-oxazepane bishy-
drochloride (260 mg, 1.13 mmol) and NEt3 (0.22 mL, 1.25
mmol). After 1 h, sodium triacetoxyborohydride (305 mg, 1.47
mmol) and AcOH (70 µL, 1.25 mmol) were added and the
reaction mixture was stirred at room temperature for 16 h.
Water was added, and the reaction mixture was made basic
with saturated aqueous Na2CO3 solution. The mixture was
extracted with EtOAc, the organic phase was dried (MgSO4)
and filtered, and the solvent was removed under reduced
pressure. The crude product was purified on silica gel, eluting
with MeOH/CH2Cl2 to give the title compound 6 (62 mg, 11%).
MS m/z: 516 (MH)+. 1H NMR (300 MHz, CDCl3): δ 1.43-1.79
(3H, m), 1.86 (2H, m), 1.92-2.24 (5H, m), 2.43 (4H, t), 2.60
(2H, m), 3.08 (1H, m), 3.28 (1H, d), 3.38 (2H, t), 3.55 (1H, t),
3.69 (2H, dd), 3.79 (2H, t), 4.39 (1H, d), 4.82 (1H, d), 6.80 (1H,
d), 7.08 (1H, s), 7.22-7.41 (6H, m).
(1H, m), 1.72 (2H, m), 1.92-2.50 (16H, m), 2.65 (2H, m), 2.87
(1H, m), 3.24 (1H, d), 3.32 (2H, m), 3.56 (1H, d), 4.39 (1H, d),
4.84 (1H, d), 6.79 (1H, d), 7.09 (1H, s), 7.24-7.41 (6H, m). Anal.
(C28H36Cl2N4O‚1/4CH2Cl2) C, N. H: found, 6.33; calcd, 6.85.
5-{2-[3-(4-Acet yl-1-p ip er a zin yl)-1-a zet id in yl]et h yl}-1-
ben zyl-5-(3,4-d ich lor op h en yl)-2-p ip er id on e (11). Yield:
1
19%. MS m/z: 543 (MH)+. H NMR (300 MHz, CDCl3): δ 1.54
(1H, m), 1.73 (1H, m), 1.92-2.28 (13H, m), 2.43 (1H, m), 2.66
(1H, m), 2.86 (1H, m), 3.30 (3H, m), 3.43 (2H, t), 3.58 (3H, m),
4.40 (1H, d), 4.83 (1H, d), 6.81 (1H, d), 7.10 (1H, s), 7.24-7.40
(6H, m). Anal. (C29H36Cl2N4O2‚1/4CH2Cl2) C, H, N.
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-(2-{3-[4-(m eth ylsu l-
fon yl)-1-piper azin yl]-1-azetidin yl}eth yl)-2-piper idon e (12).
1
Yield: 8%. MS m/z: 580. H NMR (300 MHz, CDCl3): δ 1.56
(1H, m), 1.72 (1H, m), 2.01 (3H, m), 2.18 (2H, m), 2.33-2.51
(5H, m), 2.63 (2H, m), 2.75 (3H, s), 2.92 (1H, m), 3.18-3.35
(7H, m), 3.52 (1H, m), 4.40 (1H, d), 4.82 (1H, d), 6.80 (1H, d),
7.11 (1H, d), 7.22-7.40 (6H, m). Anal. (C28H36Cl2N4O3S‚1/6CH2-
Cl2) C, H. N: found, 8.98; calcd, 9.43.
Compounds 7-20 were prepared using the above reductive
amination protocol and the appropriate 3-substituted azeti-
dine.
1-Ben zyl-5-(3,4-dich lor oph en yl)-5-{2-[3-(4-th iom or ph oli-
n yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (13). Yield: 11%. MS
4-(1-{2-[1-Ben zyl-3-(3,4-d ich lor op h en yl)-6-oxo-3-p ip er -
idin yl]eth yl}-3-azetidin yl)-3-m or ph olin on e (7). Yield: 11%.
1
m/z: 518 (MH)+. H NMR (300 MHz, CDCl3): δ 1.56 (1H, m),
1
MS m/z: 516 (MH)+. H NMR (300 MHz, CDCl3): δ 1.53 (1H,
1.74 (1H, m), 1.94-2.23 (5H, m), 2.46 (5H, m), 2.62 (6H, m),
2.92 (1H, m), 3.23 (1H, d), 3.38 (2H, m), 3.53 (1H, t), 4.40 (1H,
d), 4.82 (1H, d), 6.78 (1H, d), 7.08 (1H, s), 7.23-7.40 (6H, m).
Anal. (C27H33Cl2N3OS‚1/4CH2Cl2) H, N. C: found, 61.11; calcd,
60.63.
m), 1.70 (1H, m), 2.03 (3H, m), 2.38 (2H, m), 2.46 (1H, m),
2.92 (2H, m), 3.28 (1H, d), 3.39 (4H, m), 3.59 (1H, d), 3.79 (2H,
m), 4.14 (2H, s), 4.38 (1H, d), 4.85 (2H, d), 6.80 (1H, d), 7.09
(1H, s), 7.24-7.43 (6H, m). Anal. (C27H31Cl2N3O3‚1/3CH2Cl2) C,
H, N.
4-(1-{2-[1-Ben zyl-3-(3,4-d ich lor op h en yl)-6-oxo-3-p ip er -
1-Ben zyl-5-(3,4-dich lor oph en yl)-5-{2-[3-(2-ph en yl-4-m or -
p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (8). Yield: 9%.
idin yl]eth yl}-3-azetidin yl)-1λ4,4-th iazin an -1-on e (14). Yield:
1
6%. MS m/z: 534 (MH)+. H NMR (300 MHz, CDCl3): δ 1.55
1
MS m/z: 580 (MH)+. H NMR (300 MHz, CDCl3): δ 1.56 (1H,
(1H, m), 1.70 (1H, m), 2.03 (3H, m), 2.18 (2H, m), 2.48 (3H,
m), 2.64 (2H, m), 2.73-2.91 (4H, m), 3.02 (1H, m), 3.24 (1H,
d), 3.24 (1H, d), 3.32 (2H, t), 3.54 (1H, d), 4.40 (1H, d), 4.82
(1H, d), 6.80 (1H, d), 7.08 (1H, s), 7.24-7.40 (6H, m). Anal.
(C27H33Cl2N3O2S‚3/8CH2Cl2) C, H, N.
m), 1.72 (1H, m), 1.82-2.04 (7H, m), 2.43 (1H, m), 2.60 (1H,
d), 2.73 (3H, m), 2.91 (1H, m), 3.23 (1H, d), 3.33 (2H, m), 3.55
(1H, d), 3.79 (1H, t), 4.03 (1H, d), 4.39 (1H, d), 4.52 (1H, d),
4.82 (1H, d), 6.78 (1H, d), 7.08 (1H, s), 7.21-7.40 (11H, m).
Anal. (C33H37Cl2N3O2‚1/8CH2Cl2) C, H, N.
4-(1-{2-[1-Ben zyl-3-(3,4-d ich lor op h en yl)-6-oxo-3-p ip er -
id in yl]eth yl}-3-a zetid in yl)-1λ6,4-th ia zin a n -1,1-d ion e (15).
1-Ben zyl-5-(3,4-d ich lor oph en yl)-5-{2-[3-(1-p ip er a zin yl)-
1-a zetid in yl]eth yl}-2-p ip er id on e (9). (a ) To a solution of
the aldehyde described in the preparation of compound 4 (342
mg, 0.91 mmol) in THF (8 mL) was added tert-butyl 4-(3-
azetidinyl)-1-piperazinecarboxylate hydrochloride (278 mg, 1.0
mmol) and NEt3 (0.14 mL, 1.0 mmol). After 1 h, sodium
triacetoxyborohydride (270 mg, 1.27 mmol) and AcOH (60 µL,
1.1 mmol) were added and the reaction mixture was stirred
at room temperature for 16 h. Water was added, and the
reaction mixture was made basic with saturated aqueous Na2-
CO3 solution. The mixture was extracted with EtOAc, the
organic phase was dried (MgSO4) and filtered, and the solvent
was removed under reduced pressure. The crude product was
purified on silica gel, eluting with MeOH/CH2Cl2 to give the
BOC-protected product (101 mg, 18%). 1H NMR (300 MHz,
CDCl3): δ 1.46 (10H, m), 1.50-1.80 (3H, m), 2.01 (3H, m), 2.15
(5H, m), 2.46 (1H, m), 2.65 (2H, m), 2.86 (1H, m), 3.27 (1H, d),
3.38 (1H, m), 3.43 (4H, m), 3.56 (1H, d), 4.39 (1H, d), 5.32 (1H,
d), 6.78 (1H, d), 7.08 (1H, s), 7.22-7.40 (6H, m).
(b) To a solution of the above protected amine (101 mg, 0.17
mmol) in CH2Cl2 (3 mL) was added TFA (3.3 mL). After 20
min, the solvent was removed under reduced pressure and the
residue was azeotroped with CH2Cl2 (×3). The solution was
adjusted to about pH 9 using 10% aqueous Na2CO3, and the
mixture was extracted with EtOAc. The combined organics
were dried (MgSO4) and filtered, and the solvent was removed
under reduced pressure. CH2Cl2 was added, and the solvent
was decanted and concentrated under reduced pressure to give
the title compound 9 (12 mg, 14%). MS m/z: 501 (MH)+. 1H
1
Yield: 10%. MS m/z: 550 (MH)+. H NMR (300 MHz, CDCl3):
δ 1.45-1.77 (2H, m), 2.00 (3H, m), 2.17 (2H, m), 2.46 (1H, m),
2.62 (2H, q), 2.78 (4H, m), 3.02 (5H, m), 3.24 (1H, d), 3.31 (2H,
m), 3.56 (1H, d), 4.41 (1H, d), 4.81 (1H, d), 6.81 (1H, d), 7.09
(1H, s), 7.28-7.40 (6H, m). Anal. (C27H33Cl2N3O3S‚5/8CH2Cl2)
C, H, N.
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-{2-[3-(4-h yd r oxy-1-
p ip er id in yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (16). Yield:
37%. MS m/z: 516 (MH)+. 1H NMR (300 MHz, CDCl3): δ 1.20-
2.23 (17H, m), 2.37-2.74 (3H, m), 2.87 (1H, m), 3.24 (1H, d),
3.39 (1H, m), 3.55 (1H, d), 3.71 (1H, m), 4.38 (1H, d), 4.84 (1H,
d), 6.79 (1H, d), 7.08 (1H, s), 7.22-7.41 (6H, m). Anal. (C28H35
-
Cl2N3O2‚9/10CH2Cl2) C, H, N.
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-{2-[3-(3-h yd r oxy-1-
p yr r olid in yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (17). Yield:
1
70%. MS m/z: 502 (MH)+. H NMR (300 MHz, CDCl3): δ 1.57
(1H, m), 1.78 (2H, m), 1.96-2.33 (8H, m), 2.50 (3H, m), 2.81
(3H, m), 3.09 (1H, m), 3.25 (1H, d), 3.34 (2H, m), 3.57 (1H, d),
4.37 (1H, s), 4.39 (1H, d), 4.83 (1H, d), 6.78 (1H, d), 7.08 (1H,
s), 7.22-7.41 (6H, m). Anal. (C27H33Cl2N3O2‚1/4CH2Cl2) C, H,
N.
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-{2-[3-(3-h yd r oxy-1-
p ip er id in yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (18). Yield:
1
58%. MS m/z: 516. H NMR (300 MHz, CDCl3): δ 1.42-2.38
(16H, m), 2.48 (1H, m), 2.73 (2H, m), 2.93 (1H, m), 3.23 (1H,
d), 3.41 (2H, m), 3.59 (1H, d), 3.81 (1H, d), 4.38 (1H, d), 4.84
(1H, d), 6.79 (1H, d), 7.09 (1H, s), 7.23-7.41 (6H, m). Anal.
(C28H35Cl2N3O2‚11/16CH2Cl2) C, H. N: found, 6.81; calcd, 7.30.

SAR of Piperidones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5373
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-(2-{3-[(2-h yd r oxy-
et h yl)(m et h yl)a m in o]-1-a zet id in yl}et h yl)-2-p ip er id on e
(19). Yield: 34%. 1H NMR (300 MHz, CDCl3): δ 1.58 (1H, m),
1.76 (1H, m), 1.95-2.24 (9H, m), 2.36 (2H, t), 2.48 (1H, m),
2.66 (2H, m), 3.09 (1H, m), 3.29 (1H, d), 3.42 (2H, m), 3.59
(3H, m), 4.37 (1H, d), 4.88 (1H, d), 6.79 (1H, d), 7.07 (1H, s),
7.24-7.40 (6H, m). Anal. (C26H33Cl2N3O2‚3/8CH2Cl2) C, H. N:
found, 7.62; calcd, 8.05.
3.72 (1H, d), 4.66 (2H, br, s), 7.08 (1H, d), 7.37 (2H, m). Anal.
(C24H35Cl2N5O3S‚H2O) C, H, N.
4-(1-{2-[(3S)-1-(Cyclop r op ylm eth yl)-3-(3,4-d ich lor op h e-
n yl)-6-oxop ip er id in yl]et h yl}-3-a zet id in yl)-N-m et h yl-1-
p ip er a zin esu lfon a m id e (34). Yield: 79%. MS m/z: 558
1
(MH)+. H NMR (300 MHz, CDCl3): δ 0.32 (2H, m), 0.62 (2H,
m), 1.04 (1H, m), 1.83 (1H, m), 1.97-2.41 (9H, m), 2.74 (5H,
m), 2.95 (1H, m), 3.10-3.27 (6H, m), 3.41 (5H, m), 3.78 (1H,
1-Ben zyl-5-(3,4-d ich lor op h en yl)-5-{2-[3-(3-h yd r oxy-8-
a za b icyclo[3.2.1]oct -8-yl)-1-a zet id in yl]et h yl}-2-p ip er i-
d on e (20). (a ) To a solution of aldehyde 48 (287 mg, 0.76
mmol) in THF (7 mL) and CH2Cl2 (7 mL) was added 8-(3-
azetidinyl)-8-azabicyclo[3.2.1]oct-3-yl acetate dihydrochloride
(227 mg, 0.76 mmol), NEt3 (0.1 mL, 0.72 mmol), sodium
triacetoxyborohydride (226 mg, 1.06 mmol), and AcOH (48 µL,
0.84 mmol), and the reaction mixture was stirred at room
temperature for 3 days. The solvent was removed under
reduced pressure, and the residue was partitioned between
EtOAc and saturated NaHCO3 solution. The organic phase was
separated, and the aqueous phase was extracted with EtOAc.
The combined organics were dried (Na2SO4) and filtered, and
the solvent was removed under reduced pressure. The crude
product was purified on silica gel, eluting with CH2Cl2/MeOH
d), 4.00 (1H, d), 7.15 (1H, d), 7.42 (2H, m). Anal. (C25H37
-
Cl2N5O3S‚1/20H2O) C, H, N.
4-(1-{2-[(3S)-1-(Cyclop r op ylm eth yl)-3-(3,4-d ich lor op h e-
n yl)-6-oxop ip er id in yl]eth yl}-3-a zetid in yl)-N,N-d im eth yl-
1-p ip er a zin esu lfon a m id e (35). Yield: 16%. MS m/z: 572. 1H
NMR (300 MHz, CDCl3): δ 0.28 (2H, m), 0.61 (2H, m), 1.05
(1H, m), 1.62 (1H, m), 1.80 (1H, m), 1.92-2.20 (10H, m), 2.64-
2.96 (8H, m), 3.10-3.48 (10H, m), 3.78 (1H, d), 7.15 (1H, d),
7.41 (2H, m). Anal. (C26H39Cl2N5O3S‚1/2H2O) C, H, N.
4-(1-{2-[(3S)-1-(Cyclop r op ylm eth yl)-3-(3,4-d ich lor op h e-
n yl)-6-oxop ip er id in yl]eth yl}-3-a zetid in yl)-1-p ip er a zin e-
ca r boxa m id e (36). Yield: 63%. MS m/z: 508 (MH)+. 1H NMR
(300 MHz, CDCl3): δ 0.33 (2H, m), 0.62 (2H, m), 1.07 (1H, m),
1.63 (1H, m), 1.82 (1H, m), 1.98-2.43 (11H, m), 2.74 (2H, m),
2.91 (1H, m), 3.17 (1H, dd), 3.35-3.52 (7H, m), 3.78 (1H, d),
4.40 (2H, s), 7.15 (1H, d), 7.40 (1H, s), 7.42 (1H, d). Anal.
(C25H35Cl2N5O2‚2H2O) C, H, N.
(5S)-5-{2-[3-(4-Am in o-1-piper idin yl)-1-azetidin yl]eth yl}-
1-(cyclop r op ylm et h yl)-5-(3,4-d ich lor op h en yl)-2-p ip er i-
d on e (37). (a ) To a solution of aldehyde 58 (1.4 g, 4.11 mmol)
in THF (60 mL) was added tert-butyl 1-(3-azetidinyl)-4-
piperidinecarbamate bis-TFA salt (2.2 g, 4.52 mmol) and NEt3
(1.8 mL, 12.33 mmol). After 90 min, NaBH(OAc)3 (1.2 g, 5.34
mmol) and AcOH (0.64 mL) were added and the reaction
mixture was stirred at room temperature for 16 h. Saturated
NaHCO3 was then added, the reaction mixture was extracted
with EtOAc, the organics were dried (Na2SO4) and filtered,
and the solvent was removed under reduced pressure. The
crude product was purified on silica gel, eluting with CH2Cl2/
MeOH to give the BOC-protected product (1.45 g, 61%). MS
m/z: 580. 1H NMR (300 MHz, CDCl3): δ 0.32 (2H, m), 0.59
(2H, m), 1.04 (1H, m), 1.42 (10H, m), 1.63 (2H, m), 1.72-2.23
(11H, m), 2.33 (1H, m), 2.54-2.75 (4H, m), 2.86 (1H, m), 3.15
(1H, m), 3.42 (4H, m), 3.75 (1H, d), 4.40 (1H, br s), 7.13 (1H,
d), 7.40 (2H, m). Anal. (C30H44Cl2N4O3‚1/3CH2Cl2) C, H, N.
(b) To a solution of the above protected amine (1.4 g, 24.2
mmol) in CH2Cl2 (20 mL), cooled in an ice/water bath, was
added TFA (6.6 mL). The reaction mixture was then warmed
to room temperature and was stirred for 1 h. Et2O was added,
and the reaction mixture was allowed to stir overnight. The
solid was filtered off and triturated with Et2O. The solid was
filtered off and dried to give the title compound 37 (907 mg,
46%) as a pale-brown solid. MS m/z: 479 (MH)+. 1H NMR (300
MHz, MeOH-d4) (selected data): δ 0.40 (2H, m), 0.62 (2H, m),
1.16 (1H, m), 1.72 (2H, m), 1.86-2.22 (8H, m), 2.39 (2H, m),
2.82-3.56 (8H, m), 3.66 (1H, m), 3.97 (3H, m), 7.42 (1H, br,
s), 7.64 (2H, m). Anal. (C25H36Cl2N4O‚3TFA‚3H2O) C, H, N.
1
to give the acetate (86 mg, 19%). H NMR (300 MHz, CDCl3):
δ 1.48-2.22 (18H, m), 2.46 (1H, m), 2.66 (2H, m), 3.00 (2H,
m), 3.11 (1H, m), 3.29 (3H, m), 3.52 (1H, d), 4.39 (1H, d), 4.83
(1H, d), 4.96 (1H, m), 6.78 (1H, d), 7.08 (1H, s), 7.21-7.40 (6H,
m). Anal. (C32H39Cl2N3O2‚5/16CH2Cl2) C, H, N.
(b) To a solution of the above acetate (78 mg, 0.13 mmol) in
MeOH (1.5 mL) was added 6 N aqueous NaOH solution (0.5
mL). After 16 h, the MeOH was evaporated under reduced
pressure and H2O (5 mL) and CH2Cl2 (10 mL) were added.
The organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. The combined organics were dried (Na2-
SO4) and filtered, and the solvent was removed under reduced
pressure to give the title compound 20 (67 mg, 96%) as a white
foam. MS m/z: 543 (MH)+. 1H NMR (300 MHz, CDCl3): δ 1.18
(1H, m), 1.43-2.23 (15H, m), 2.43 (1H, m), 2.61 (2H, m), 3.00
(2H, m), 3.12 (1H, m), 3.26 (3H, m), 3.56 (1H, d), 4.01 (1H, m),
4.40 (1H, d), 4.82 (1H, d), 6.80 (1H, d), 7.08 (1H, s), 7.23-7.40
(6H, m). Anal. (C30H37Cl2N3O2‚1/2CH2Cl2) C, N. H: found, 5.95;
calcd, 6.55.
Compounds 29 and 31-44 were prepared from aldehyde 58
and the appropriate 3-substituted azetidine, using the reduc-
tive amination protocol described above.
(5S)-1-(Cyclop r op ylm et h yl)-5-(3,4-d ich lor op h en yl)-5-
{2-[3-(4-m or ph olin yl)-1-azetidin yl]eth yl}-2-piper idon e (29).
1
Yield: 32%. H NMR (300 MHz, CDCl3): δ 0.33 (2H, m), 0.62
(2H, m), 1.08 (1H, m), 1.63 (2H, m), 1.81 (1H, m), 1.95-2.42
(9H, m), 2.74 (2H, m), 2.93 (1H, m), 3.19 (1H, m), 3.37 (2H,
m), 3.44 (2H, m), 3.68 (4H, m), 3.78 (1H, d), 7.16 (1H, d), 7.41
(2H, m). Anal. (C24H33Cl2N3O2‚1/2CH2Cl2‚1/5H2O) C, H, N.
(5S)-1-(Cyclop r op ylm et h yl)-5-(3,4-d ich lor op h en yl)-5-
{2-[3-(1-piper azin yl)-1-azetidin yl]eth yl}-2-piper idon e (31).
1
Yield: 43%. MS m/z: 465 (MH)+. H NMR (300 MHz, CDCl3):
δ 0.32 (2H, m), 0.61 (2H, m), 1.05 (1H, m), 1.67 (1H, m), 1.75-
2.57 (15H, m), 2.78 (1H, m), 2.96 (3H, m), 3.17 (1H, dd), 3.42
N-[1-(1-{2-[(3S)-1-(Cyclop r op ylm et h yl)-3-(3,4-d ich lo-
r op e h n yl)-6-oxop ip e r id in yl]e t h yl}-3-a ze t id in yl)-4-p i-
p er id in yl]a ceta m id e (38). To a solution of amine 37 (300
mg, 0.36 mmol) in CH2Cl2 (40 mL) was added NEt3 (0.255 mL,
1.8 mmol) and acetic anhydride (40 µL, 0.40 mmol). After 16
h, a further amount of 2 equiv of Ac2O was added and the
reaction mixture was allowed to stir for 1 h. The reaction
mixture was washed with H2O and brine, dried (Na2SO4), and
filtered, and the solvent was removed under reduced pressure.
EtOAc (40 mL) was added, and the organic phase was
extracted with 2 N HCl. The aqueous phase was made basic
with NaHCO3 and extracted with EtOAc. The organic phase
was dried (Na2SO4) and filtered, the solvent was removed
under reduced pressure, and the product was dried over P2O5
(53 mg, 28%). MS m/z: 521 (MH)+. 1H NMR (300 MHz,
CDCl3): δ 0.30 (2H, m), 0.60 (2H, m), 1.05 (1H, m), 1.38 (2H,
m), 1.60 (1H, m), 1.76-2.24 (13H, m), 2.37 (1H, m), 2.63 (4H,
m), 2.86 (1H, m), 3.15 (1H, m), 3.41 (4H, m), 3.74 (2H, d), 5.28
(4H, m), 3.78 (1H, d), 7.14 (1H, d), 7.41 (2H, m). Anal. (C24H34
-
Cl2N4O‚1/2CH2Cl2‚1/3H2O) C, H, N.
(5S)-1-(Cyclop r op ylm et h yl)-5-(3,4-d ich lor op h en yl)-5-
(2-{3-[4-(m et h ylsu lfon yl)-1-p ip er a zin yl]-1-a zet id in yl}-
eth yl)-2-p ip er id on e (32). Yield: 47%. MS m/z: 543 (MH)+.
1H NMR (300 MHz, CDCl3): δ 0.32 (2H, m), 0.61 (2H, m), 1.07
(1H, m), 1.63 (1H, m), 1.78 (2H, m), 1.94-2.24 (4H, m), 2.38
(5H, m), 2.70 (5H, m), 2.94 (1H, m), 3.19 (5H, m), 3.39 (4H,
m), 3.78 (1H, d), 7.15 (1H, d), 7.41 (2H, m). Anal. (C25H36
-
Cl2N4O3S‚2/3H2O) C, H, N.
4-(1-{2-[(3S)-1-(Cyclop r op ylm eth yl)-3-(3,4-d ich lor op h e-
n yl)-6-oxop ip er id in yl]eth yl}-3-a zetid in yl)-1-p ip er a zin e-
su lfon a m id e (33). Yield: 37%. MS m/z: 544 (MH)+. 1H NMR
(400 MHz, CDCl3): δ 0.26 (2H, m), 0.55 (2H, m), 1.00 (1H, m),
1.58 (1H, m), 1.66 (1H, m), 1.82-2.18 (7H, m), 2.31 (4H, m),
2.65 (2H, m), 2.87 (1H, m), 3.12 (4H, m), 3.25-3.42 (4H, m),

5374 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
MacKenzie et al.
(1H, m), 7.12 (1H, d), 7.41 (2H, m). Anal. (C27H38Cl2N4O2‚CH2-
Cl2‚H2O) C, H, N.
5-(3,4-Dich lor op h en yl)-1-(4-flu or ob en zyl)-5-{2-[3-(4-
m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (24). (a ) A
solution of lactam (46) (8.0 g, 21.5 mmol) in HCl-saturated
MeOH (100 mL) was stirred at room temperature for 2 h. The
solvent was removed under reduced pressure, CH2Cl2/MeOH
was added, and the solution was washed with saturated
sodium bicarbonate solution and brine. The organic phase was
dried (MgSO4) and filtered, and the residue was purified on
silica gel, eluting with MeOH/EtOAc to give the alcohol (3.8
g, 61%) as a white solid. MS m/z: 288 (MH)+. 1H NMR (300
MHz, DMSO-d6): δ 1.64-2.21 (6H, m), 3.09 (2H, m), 3.39 (1H,
d), 3.64 (1H, d), 4.35 (1H, d), 7.38 (1H, d), 7.52 (1H, br), 7.63
(2H, m).
N-[1-(1-{2-[(3S)-1-(Cyclop r op ylm et h yl)-3-(3,4-d ich lo-
r op h e n yl)-6-oxop ip e r id in yl]e t h yl}-3-a ze t id in yl)-4-p i-
p er id in yl]m eth a n esu lfon a m id e (39). To a solution of amine
37 tris-TFA salt (60 mg, 0.073 mmol) in CH2Cl2 (2 mL) was
added NEt3 (49 µL, 0.35 mmol), and the reaction mixture was
cooled in an ice/water bath. Methanesulfonyl chloride (6.3 µL,
0.88 mmol) was added, and the reaction was warmed to room
temperature and stirred for 16 h. The reaction mixture was
partitioned between H2O and CH2Cl2, and the organic phase
was washed with H2O. The organic layer was dried (MgSO4)
and filtered, the solvent was removed under reduced pressure,
and the residue was purified on silica gel, eluting with CH2-
Cl2/MeOH/NH3 to give the title compound 39 (6 mg, 15%). MS
(b) To a solution of the above alcohol (3.4 g, 11.8 mmol) in
CH2Cl2 at room temperature was added NEt3 (2.5 mL, 17.7
mmol), and the mixture was cooled in an ice/water bath.
Methanesulfonyl chloride (1.2 mL, 15.3 mmol) was added, and
the reaction mixture was allowed to warm to room tempera-
ture and stirred for 2.5 h. The reaction mixture was washed
with H2O (×3), dried (MgSO4), and filtered, and the solvent
was removed under reduced pressure. The residue was purified
on silica gel, eluting with MeOH/CH2Cl2 to give the mesylate
49 (2.52 g, 58%) as a buff-colored solid. MS m/z: 270 (MH)+.
1H NMR (300 MHz, CDCl3): δ 2.06 (6H, m), 2.40 (1H, m), 2.90
(1H, s), 3.12 (1H, m), 3.50 (1H, d), 3.80 (1H, m), 3.86-4.08
(2H, m), 6.14 (1H, s), 7.21 (1H, d), 7.42 (1H, s), 7.50 (1H, d).
1
m/z: 557 (MH)+. H NMR (300 MHz, CDCl3): δ 0.33 (2H, m),
0.60 (2H, m), 0.86 (2H, m), 1.08 (1H, m), 1.17-2.40 (14H, m),
2.56-2.78 (3H, m), 2.87 (1H, m), 2.96 (3H, s), 3.18 (1H, m),
3.24-3.50 (4H, m), 3.77 (1H, d), 4.18 (1H, d), 7.15 (1H, d), 7.40
(2H, d).
N-[1-(1-{2-[(3S)-1-(Cyclop r op ylm et h yl)-3-(3,4-d ich lo-
r op h en yl)-6-oxop ip er id in yl]et h yl}-3-a zet id in yl)-4-p h e-
n yl-4-p ip er id in yl]a ceta m id e (40). Yield: 45%. MS m/z: 597
1
(MH)+. H NMR (300 MHz, CDCl3): δ 0.34 (2H, m), 0.61 (2H,
m), 1.04 (1H, m), 1.63 (1H, m), 1.82 (1H, m), 1.99 (3H, s), 2.01-
2.27 (9H, m), 2.36 (3H, m), 2.59 (2H, m), 2.74 (2H, m), 2.94
(1H, m), 3.18 (1H, m), 3.42 (4H, m), 3.78 (1H, d), 5.45 (1H, s),
7.12 (1H, d), 7.18-7.43 (7H, m). Anal. (C33H42Cl2N4O2‚7/10CH2-
Cl2) C, H, N.
(c) To a solution of the above mesylate (2.5 g, 6.8 mmol) in
CH3CN (75 mL) was added 4-(3-azetidinyl)morpholine hydro-
chloride (3.8 g, 20.4 mmol), K2CO3 (3.0 g, 20.4 mmol), and NEt3
(9.3 mL, 68 mmol), and the mixture was heated under reflux
for 16 h. The solvent was removed under reduced pressure,
water (250 mL) was added, and the mixture was extracted with
EtOAc and then 10% MeOH/EtOAc solution. The combined
organics were dried (MgSO4) and filtered, and the solvent was
removed under reduced pressure to give the crude product as
a white foam that was purified on silica gel, eluting with CH2-
Cl2/MeOH to give the azetidine product 50 (1.25 g, 45%) as a
(5S)-1-(Cyclop r op ylm et h yl)-5-(3,4-d ich lor op eh n yl)-5-
{2-[3-(4-h yd r oxy-1-p ip er id in yl)-1-a zetid in yl]eth yl}-2-p i-
p er id on e (41). Yield: 78%. MS m/z: 481 (MH)+. 1H NMR (300
MHz, CDCl3): δ 0.31 (2H, m), 0.61 (2H, m), 1.04 (1H, m), 1.58
(4H, m), 1.75-2.23 (10H, m), 2.34 (1H, m), 2.57 (2H, m), 2.64
(2H, m), 2.84 (1H, m), 3.17 (1H, m), 3.42 (4H, m), 3.67 (1H,
m), 3.79 (1H, d), 7.13 (1H, d), 7.41 (2H, m). Anal. (C25H35
-
Cl2N3O2‚4/10CH2Cl2) C, H, N.
1
white solid. MS m/z: 413 (MH)+. H NMR (300 MHz, CDCl3):
(5S)-1-(Cyclop r op ylm et h yl)-5-(3,4-d ich lor op h en yl)-5-
{2-[3-(4-et h oxy-1-p ip er id in yl)-1-a zet id in yl]et h yl}-2-p i-
p er id on e (42). Yield: 64%. MS m/z: 508 (MH)+. 1H NMR (300
MHz, CDCl3): δ 0.32 (2H, m), 0.60 (2H, m), 1.05 (1H, m), 1.19
(3H, m), 1.60 (4H, m), 1.83 (3H, m), 1.90-2.21 (6H, m), 2.37
(1H, m), 2.53 (2H, m), 2.68 (2H, m), 2.87 (1H, m), 3.13-3.53
δ 1.63 (1H, m), 1.82 (1H, m), 1.97-2.41 (12H, m), 2.72 (2H,
m), 2.92 (1H, m), 3.40 (2H, m), 3.72 (4H, m), 6.17 (1H, br),
7.16 (1H, d), 7.37 (1H, s), 7.42 (1H, d).
(d ) Crushed KOH (104 mg, 1.84 mmol) in DMSO (3 mL)
was stirred for 5 min, and to this mixture was added a solution
of the above lactam (240 mg, 0.46 mmol) in DMSO (5 mL),
followed by 4-fluorobenzyl bromide (58 µL, 0.46 mmol). After
50 min, EtOAc was added and the mixture was washed with
H2O (×3), dried (MgSO4), and filtered, and the solvent was
removed under reduced pressure. The residue was purified on
silica gel, eluting with EtOAc/MeOH/NHEt2 to give the title
(8H, m), 3.78 (1H, d), 7.12 (1H, d), 7.40 (2H, m). Anal. (C27H39
-
Cl2N3O2‚3/8CH2Cl2) C, H, N.
1-(1-{2-[(3S)-1-(Cyclop r op ylm eth yl)-3-(3,4-d ich lor op h e-
n yl)-6-oxop ip er id in yl]eth yl}-3-a zetid in yl)-4-p ip er id in e-
ca r boxylic Acid (43). (a ) Aldehyde 58 was reacted with
methyl 1-(3-azetidinyl)-4-piperidinecarboxylate dihydrochlo-
ride, using the reductive amination conditions described above.
1
compound (24) (100 mg, 42%). MS m/z: 520 (MH)+. H NMR
(300 MHz, CDCl3): δ 1.56 (1H, m), 1.72 (2H, m), 1.94-2.28
(8H, m), 2.42 (1H, m), 2.67 (2H, m), 2.88 (1H, m), 3.33 (2H,
m), 3.49 (2H, m), 3.68 (4H, m), 4.36 (1H, d), 4.82 (1H, d), 6.82
1
Yield: 39%. H NMR (300 MHz, CDCl3): δ 0.29 (2H, m), 0.60
(2H, m), 1.05 (1H, m), 1.62-1.93 (8H, m), 1.96-2.39 (7H, m),
2.62 (2H, m), 2.77 (2H, m), 2.91 (1H, m), 3.17 (1H, m), 3.38-
3.56 (4H, m), 3.63 (3H, s), 3.76 (1H, d), 7.15 (1H, d), 7.40 (2H,
m). Anal. (C27H37Cl2N3O3‚1/10CH2Cl2‚H2O) C, H, N.
(1H, d), 7.00-7.09 (3H, m), 7.24-7.34 (3H, m). Anal. (C27H32
-
Cl2FN3O2‚1/2EtOAc) C, H, N.
5-(3,4-Dich lor op h en yl)-1-(3-m et h ylb en zyl)-5-{2-[3-(4-
m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (22). To a
solution of lactam 50 (250 mg, 0.6 mmol) in DMF (5 mL) was
added NaH (60% dispersion in oil) (22 mg, 0.6 mmol), and the
mixture was stirred for 30 min. 3-Methylbenzyl bromide (86
mL, 0.63 mmol) was added, and the reaction mixture was
stirred for 75 min. H2O (1 mL) was added, followed by
saturated sodium bicarbonate solution (30 mL). The mixture
was extracted with CH2Cl2 (×3), and the organic layers were
dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified on silica gel, eluting with
MeOH/CH2Cl2 to give the title compound 22 (60 mg, 20%) as
a white foam. MS m/z: 516 (MH)+. 1H NMR (300 MHz,
CDCl3): δ 1.57 (1H, m), 1.94-2.20 (5H, m), 2.24 (4H, m), 2.36
(3H, s), 2.44 (1H, m), 2.67 (2H, m), 2.88 (1H, m), 3.23 (1H, d),
3.33 (2H, m), 3.56-3.68 (6H, m), 4.34 (1H, d), 4.79 (1H, d),
(b) To a solution of the above ester (300 mg, 0.57 mmol) in
MeOH (10 mL) was added 1 N aqueous NaOH (ca. 2.5 mL),
and the reaction mixture was stirred for 16 h. The reaction
mixture was acidified to about pH 5 using 2 N HCl, the solvent
was removed under reduced pressure, and the residue was
triturated with Et2O. The resulting white solid was filtered
1
off to give the acid 43 (268 mg, 92%). MS m/z: 508 (MH)+. H
NMR (300 MHz, selected data, DMSO-d6): δ 1.04 (1H, m), 3.49
(1H, d), 3.79 (1H, d), 7.39 (1H, d), 7.62 (2H, m). Anal. (C26H35
-
Cl2N3O3‚3/2CH2Cl2‚7/4H2O) C, H, N.
(5S)-1-(Cyclop r op ylm et h yl)-5-(3,4-d ich lor op h en yl)-5-
{2-[3-(4-oxo-1-p ip er id in yl)-1-a zet id in yl]et h yl}-2-p ip er i-
d on e (44). Yield: 7%. MS m/z: 478 (MH)+. 1H NMR (300 MHz,
CDCl3): δ 0.33 (2H, m), 0.60 (2H, m), 1.06 (1H, m), 1.73 (1H,
m), 1.88 (1H, m), 1.98-2.47 (10H, m), 2.58 (4H, m), 2.87 (2H,
m), 3.09 (1H, m), 3.19 (1H, m), 3.48 (4H, m), 3.77 (1H, d), 7.16
(1H, d), 7.42 (2H, m).
6.81 (1H, d), 7.04-7.17 (3H, m), 7.23 (3H, m). Anal. (C28H35
-
Cl2N3O2‚1/2H2O) C, H. N: found, 7.26; calcd, 7.99.

SAR of Piperidones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5375
Compounds 25 and 26 were prepared from lactam 50,
employing the alkylation method described for 22 and using
the appropriate alkylating agent.
1.08 mol) in THF (400 mL). The reaction mixture was allowed
to warm to room temperature and was stirred for 14 h. The
reaction was cooled again in an ice/water bath, and allyl
bromide (93 mL, 1.08 mol) was added. The reaction mixture
was stirred at room temperature for 5 h, then at 50 °C for 4 h.
The reaction mixture was cooled, water was added, and the
mixture was partitioned between water and Et2O. The organic
phase was evaporated and the residue was purified on silica
gel, eluting with Et2O/hexane to give the alkylated product
(104.8 g, 43%). H NMR (300 MHz, CDCl3): δ 2.63 (2H, dd),
3.87 (1H, t), 5.21 (2H, m), 5.78 (1H, m), 7.19 (1H, d), 7.47 (2H,
m).
(b) To a solution of NaH (60% dispersion in oil) (21.15 g,
505 mmol) in THF (3 L) cooled in an ice/water bath was added
a solution of bromopropionic acid (73.7 g, 482 mmol) in THF
(400 mL), and the reaction mixture was allowed to stir for 16
h.
To a solution of NaH (60% dispersion in oil) (21.15 g, 505
mmol) in THF (300 mL) cooled in an ice/water bath was added
a solution of the above allyl compound (103.8 g, 459 mmol) in
THF (300 mL). The reaction mixture was then allowed to
warm to room temperature and stirred for 16 h. This solution
was then cannulated into the sodium salt solution of bro-
mopropionic acid, stirred at room temperature for 16 h, and
then heated to 70 °C for 4 h. The reaction mixture was cooled,
water was carefully added, and the reaction mixture was
concentrated under reduced pressure (to ∼1 L). The mixture
was made basic using NaHCO3 and extracted with Et2O. The
aqueous phase was then acidified (concentrated HCl) and
extracted with Et2O (×3), dried (MgSO4), and filtered, and the
solvent was removed under reduced pressure. The residue was
purified on silica gel, eluting with EtOAc/hexane to give the
acid 53 (88.6 g, 65%). 1H NMR (300 MHz, CDCl3): δ 2.21 (2H,
m), 2.39 (1H, m), 2.54 (1H, m), 2.68 (2H, m), 5.18 (2H, m),
5.62 (1H, m), 7.22 (1H, d), 7.49 (2H, m).
(c) To a solution of the above acid (88.6 g, 297 mmol) in
toluene (800 mL) was added (S)-valinol (30.7 g, 297 mmol),
and the reaction mixture was heated under Dean and Stark
conditions for 72 h. The reaction mixture was cooled to room
temperature, and the solvent was removed under reduced
pressure. The residue was purified on silica gel, eluting with
Et2O/hexane to give the oxazoline product 54 as a mixture of
diastereomers. 1H NMR (300 MHz, CDCl3): δ 0.82 (3H, d),
0.96 (3H, d), 1.68 (1H, m), 2.00-2.30 (2H, m), 2.40 (2H, m),
2.68 (2H, m), 3.82 (2H, m), 4.17 (1H, m), 5.18 (2H, m), 5.62
(1H, m), 7.22 (1H, d), 7.42 (1H, s), 7.48 (1H, d).
5-(3,4-Dich lor op h en yl)-5-{2-[3-(4-m or p h olin yl)-1-a ze-
tid in yl]eth yl}-1-(4-p yr id in ylm eth yl)-2-p ip er id on e (25).
1
Yield: 80%. MS m/z: 503 (MH)+. H NMR (300 MHz, CDCl3):
δ 1.58 (1H, m), 1.77 (2H, m), 2.08 (2H, m), 2.15-2.38 (6H, m),
2.48 (1H, m), 2.64 (2H, m), 2.88 (1H, m), 3.32 (3H, m), 3.54
(1H, d), 3.70 (4H, m), 4.50 (1H, d), 4.74 (1H, d), 6.89 (1H, d),
7.12 (1H, s), 7.20 (2H, d), 7.37 (1H, d), 8.61 (2H, d). Anal.
(C26H32Cl2N4O2‚1/5CH2Cl2) C, H, N.
1
1-(Cycloh exylm eth yl)-5-(3,4-d ich lor op h en yl)-5-{2-[3-(4-
m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (26). Yield:
1
10%. MS m/z: 509 (MH)+. H NMR (300 MHz, CDCl3): δ 1.02
(2H, m), 1.22 (2H, m), 1.58-1.83 (9H, m), 1.96-2.43 (10H, m),
2.76 (2H, m), 2,92 (1H, m), 3.18 (1H, m), 3.88 (4H, m), 3.57
(1H, m), 3.75 (4H, m), 7.08 (1H, d), 7.32 (1H, s), 7.42 (1H, d).
Anal. (C27H39Cl2N3O2‚1/5CH2Cl2) C, H, N.
1-Ben zyl-5-(3,4-dich lor oph en yl)-5-{2-[3-(4-m or ph olin yl)-
1-a zetid in yl]eth yl}-2-p ip er id on e (5). (a ) To a solution of
the alcohol described in the synthesis of 6 (2.07 g, 5.48 mmol)
in CH2Cl2 (40 mL) was added NEt3 (1.14 mL, 8.22 mmol), and
the reaction mixture was cooled in an ice/water bath. Meth-
anesulfonyl chloride (0.51 mL, 6.58 mmol) was added, and the
reaction mixture was warmed to room temperature and stirred
for 1 h. Saturated NH4Cl was added, and the mixture was
extracted with CH2Cl2 (×3). The combined organics were dried
(MgSO4) and filtered, and the solvent was removed under
reduced pressure to give the mesylate (2.32 g, 93%), which was
used without further purification. 1H NMR (300 MHz,
CDCl3): δ 1.96-2.24 (5H, m), 2.47 (1H, m), 2.82 (3H, s), 3.37
(1H, d), 3.66 (1H, d), 3.81 (1H, m), 3.90 (1H, m), 4.32 (1H, d),
4.96 (1H, d), 6.69 (1H, d), 7.13 (1H, s), 7.23-7.41 (6H, m).
(b) To a solution of the above mesylate (500 mg, 1.1 mmol)
in MeCN (25 mL) was added 4-(3-azetidinyl)morpholine
hydrochloride (973 mg, 5.5 mmol), NEt3 (1.45 mL, 11 mmol),
and K2CO3 (404 mg, 3.3 mmol), and the reaction mixture was
heated at reflux for 6 h. The reaction mixture was cooled to
room temperature, water was added, and the MeCN was
evaporated under reduced pressure. The aqueous phase was
diluted with aqueous NaHCO3 solution and extracted with
EtOAc (×4). The combined organics were dried (MgSO4) and
filtered, and the solvent was removed under reduced pressure.
The crude product was purified on silica gel, eluting with CH2-
Cl2/MeOH to give the title compound 5 (260 mg, 47%). MS m/z:
1
502 (MH)+. H NMR (300 MHz, CDCl3): δ 1.55 (1H, m), 1.74
(2H, m), 1.93-2.32 (8H, m), 2.23 (1H, m), 2.68 (2H, m), 2.89
(1H, m), 3.24 (1H, d), 3.35 (2H, m), 3.56 (1H, d), 3.68 (4H, m),
4.39 (1H, d), 4.83 (1H, d), 6.80 (1H, d), 7.08 (1H, s), 7.23-7.42
(6H, m). Anal. (C27H33Cl2N3O2‚1/10CH2Cl2) C, H, N.
(d ) To a suspension of LiAlH4 (2.32 g, 61.1 mmol) in Et2O
(100 mL) cooled in an ice/water bath was added a solution of
the above oxazolines (18.2 g, 61.1 mmol) in Et2O (100 mL).
After 2 h, H2O (2.5 mL), 2 N NaOH (4 mL), and H2O (2.5 mL)
were then added sequentially, the solid was filtered off, and
the solvent was removed under reduced pressure. The residue
was partitioned between 2 N HCl and EtOAc, and the aqueous
phase was extracted with EtOAc. The combined organics were
dried (MgSO4) and filtered, and the solvent was removed under
reduced pressure. The residue was purified on silica gel,
eluting with CH2Cl2/MeOH to give first the (S,S)-amine (2.55
5-(3,4-Dich lor op h en yl)-1-(2-m et h ylb en zyl)-5-{2-[3-(4-
m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (21). Yield:
11%. Compound 21 was prepared using the method described
for 3 using 2-methylbenzyl bromide in the initial alkylation
1
step. MS m/z: 516 (MH)+. H NMR (300 MHz, CDCl3): δ 1.56
(1H, m), 1.71 (1H, m), 2.02 (4H, m), 2.12-2.52 (9H, m), 2.63
(2H, m), 2.84 (1H, m), 3.17 (1H, d), 3.32 (2H, m), 3.53 (1H, d),
3.68 (4H, m), 4.37 (1H, d), 4.98 (1H, d), 6.77 (1H, d), 7.02 (1H,
s), 7.16-7.33 (5H, m). Anal. (C28H35Cl2N3O2‚1/5H2O) C, H, N.
5-(3,4-Dich lor op h en yl)-1-(4-m et h ylb en zyl)-5-{2-[3-(4-
m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (23). Yield:
32%. Compound 23 was prepared using the method described
for 3 using 4-methylbenzyl bromide in the initial alkylation
1
g). H NMR (300 MHz, CDCl3): δ 0.78 (3H, m), 0.97 (3H, m),
1.74 (0.5H, m), 1.84-2.19 (3H, m), 2.33 (1H, m), 2.49 (1.5H,
m), 2.8-3.0 (1H, m), 3.09 (0.5H, m), 3.28-3.47 (2H, m), 3.61
(0.5H, m), 3.73 (0.5H, d), 3.84 (0.5H, d), 3.96 (1H, d), 4.95-
5.07 (2H, m), 5.34 (1H, m), 7.10 (0.5H, d), 7.21 (0.5H, d), 7.37
(0.5H, s), 7.43 (1.5H, m), 8.90 (0.5H, d), 9.34 (0.5H, d), 9.97
(0.5H, s), 10.12 (0.5H, s). Following this off the column was
1
step. MS m/z: 516 (MH)+. H NMR (300 MHz, CDCl3): δ 1.54
1
the (R,(S)-diastereomer (1.55 g). H NMR (300 MHz, CDCl3):
(1H, m), 1.69 (1H, m), 1.93-2.20 (5H, m), 2.24 (4H, m), 2.38
(3H, s), 2.43 (1H, m), 2.66 (2H, m), 2.86 (1H, m), 3.22 (1H, d),
3.32 (2H, t), 3.53 (1H, d), 3.68 (4H, m), 4.32 (1H, d), 4.81 (1H,
d), 6.81 (1H, d), 7.02 (1H, s), 7.19 (3H, m), 7.28 (2H, m). Anal.
(C28H35Cl2N3O2‚0.2H2O) C, H. N: found, 10.19; calcd, 8.08.
(5S)-1-(Cycloh exylm eth yl)-5-(3,4-d ich lor op h en yl)-5-{2-
[3-(4-m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (27).
(a ) To a suspension of NaH (60% dispersion in oil) (43 g, 1.08
mol) in THF (400 mL) cooled in an ice/water bath was added
dropwise a solution of 3,4-dichlorophenylacetonitrile (200 g,
δ 0.8-1.0 (8H, m), 1.76-2.70 (7H, m), 3.04-3.13 (1H, m),
3.42-4.04 (5H, m), 5.01 (3H, m), 5.37 (1H, m), 7.12 (1H, d),
7.37 (1H, m), 7.42 (1H, m), 8.65 (0.66H, d), 9.52 (0.33H, d),
9.92 (0.66H, s), 10.23 (0.33H, s).
(e) A solution of the above (S,S)-isomer (2.54 g, 6.88 mmol)
in 8% H2SO4 in EtOH (100 mL) was heated under reflux for 5
days. The reaction mixture was cooled, made basic with
NaHCO3, and extracted with EtOAc. The organics were dried
(MgSO4) and filtered, and the solvent was removed under

5376 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
MacKenzie et al.
reduced pressure. The residue was purified on silica gel,
eluting with CH2Cl2/MeOH to give the lactam 55 (1.00 g, 51%).
1H NMR (300 MHz, CDCl3): δ 2.00-2.22 (3H, m), 2.37 (2H,
m), 2.58 (1H, m), 3.40 (1H, d), 3.62 (1H, d), 5.02 (2H, m), 5.39
(1H, m), 6.07 (1H, br), 7.17 (1H, d), 7.40 (1H, s), 7.44 (1H, d).
(f) KOH (790 mg, 14.1 mmol) was added to DMSO (20 mL),
and the mixture was allowed to stir for 20 min. To this mixture
was added a solution of the above lactam (1.00 g, 3.52 mmol)
in DMSO (20 mL) followed by cyclohexylmethyl bromide (0.54
mL, 3.87 mmol). After 16 h, H2O was added and the mixture
was extracted with EtOAc (×3). The combined organics were
washed with H2O (×3), dried (MgSO4), and filtered, and the
solvent was removed under reduced pressure. The residue was
purified on silica gel, eluting with EtOAc/pentane to give the
solution in toluene) in three aliquots, and the reaction mixture
was allowed to warm to -40 °C over 3 h. The reaction mixture
was poured into 10% aqueous citric acid solution, and the
mixture was stirred for 30 min. The organic layer was
separated, dried (Na2SO4), and filtered, and the solvent was
removed under reduced pressure to give the aldehyde, which
was used without further purification.
(c) To a solution of the above aldehyde (1.34 g, 4.45 mmol)
in CH2Cl2 (50 mL) was added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (WSCDI) (1.19 g, 6.23 mmol)
and hydroxybenzotriazole (HOBT) (0.68 g, 4.45 mmol). After
10 min, MeOH (0.9 mL, 22.3 mmol) was added and the reaction
mixture was stirred for 3 h. The solvent was removed under
reduced pressure, and the residue was partitioned between
0.5 N HCl and EtOAc. The organic phase was dried (Na2SO4)
and filtered and the solvent was removed under reduced
pressure to give the ester 56 (1.6 g), which was used without
further purification.
1
alkylated product (1.25 g, 94%). H NMR (300 MHz, CDCl3):
δ 1.01 (2H, m), 1.22 (3H, m), 1.57-1.80 (6H, m), 1.97-2.57
(6H, m), 3.20 (1H, m), 3.37 (2H, m), 3.52 (1H, d), 5.01 (2H, m),
5.39 (1H, m), 7.09 (1H, d), 7.32 (1H, s), 7.42 (1H, d).
(g) Ozone was bubbled through a solution of the above olefin
(1.25 g, 3.29 mmol) in MeOH (40 mL) at -78 °C until the
solution turned blue. After a further 20 min, a solution of Me2S
(2.5 mL, 33 mmol) in MeOH (5 mL) was added and the reaction
mixture was allowed to warm to room temperature. The
solvent was removed under reduced pressure, the residue was
partitioned between H2O and EtOAc, and the organic phase
was dried (MgSO4) and filtered. The solvent was removed
under reduced pressure and the residue was purified on silica
gel, eluting with EtOAc/hexane to give the aldehyde (0.98 g,
78%). MS m/z: 382 (MH)+. 1H NMR (300 MHz, CDCl3): δ 1.01
(2H, m), 1.22 (3H, m), 1.55-1.90 (6H, m), 2.20 (3H, m), 2.41
(1H, m), 2.72 (1H, d), 2.97 (1H, d), 3.19 (1H, m), 3.40 (1H, m),
3.49 (1H, d), 3.79 (1H, d), 7.18 (1H, d), 7.42 (2H, m), 9.50 (1H,
s).
(d ) To a solution of the above ester (500 mg, 1.59 mmol) in
THF (30 mL) was added cyclohexylamine (200 µL, 1.75 mmol).
After 10 min, NaBH(OAc)3 (470 mg, 2.23 mmol) and AcOH
(91 µL, 1.59 mmol) were added and the reaction mixture was
heated under reflux for 4 h. The reaction mixture was cooled
to room temperature and made basic with saturated aqueous
NaHCO3 solution. The mixture was extracted with EtOAc, the
organics were washed with brine, dried (Na2SO4), and filtered,
and the solvent was removed under reduced pressure. The
residue was purified on silica gel, eluting with CH2Cl2/MeOH
1
to give the lactam 57 (281 mg, 48%). MS m/z: 366 (MH)+. H
NMR (300 MHz, CDCl3): δ 1.13 (1H, m), 1.47 (3H, m), 1.70
(4H, m), 1.84 (2H, m), 1.93-2.54 (6H, m), 3.32 (1H, d), 3.48
(1H, d), 4.58 (1H, m), 5.02 (2H, m), 5.40 (1H, m), 7.12 (1H, d),
7.36 (1H, s), 7.44 (1H, d).
(e) The above olefin was converted to the aldehyde using
the method described for 27 (98%, crude). MS m/z: 368 (MH)+.
1H NMR (selected data, 300 MHz, CDCl3): δ 9.52 (aldehyde).
(f) The above aldehyde was converted to 30 using the
method described in the preparation of 27 (49%). MS m/z: 494
(MH)+. 1H NMR (300 MHz, CDCl3): δ 1.43 (4H, m), 1.56-
1.88 (8H, m), 2.96 (1H, m), 2.03-2.34 (8H, m), 2.40 (1H, m),
2.76 (2H, m), 2.93 (1H, m), 3.21 (1H, d), 3.38 (2H, t), 3.49 (1H,
d), 3.66 (4H, m), 4.50 (1H, m), 7.11 (1H, d), 7.34 (1H, s), 7.41
(1H, d). Anal. (C26H37Cl2N3O2‚1/4CH2Cl2) C, H, N.
(h ) To a solution of the above aldehyde (0.98 g, 2.57 mmol)
in THF (40 mL) was added 4-(3-azetidinyl)morpholine hydro-
chloride (600 mg, 2.83 mmol) and NEt3 (0.79 mL, 5.65 mmol),
and the reaction mixture was stirred for 1 h. NaBH(OAc)3 (818
mg, 3.86 mmol) was then added followed immediately by AcOH
(147 µL, 2.57 mmol). After 5 min, H2O was added and the
mixture was extracted with EtOAc (×3). The combined organ-
ics were dried (MgSO4) and filtered, and the solvent was
removed under reduced pressure. The residue was purified on
silica gel, eluting with MeOH/CH2Cl2 to give the title com-
pound 27 (771 mg, 58%). MS m/z: 508 (MH)+. 1H NMR (300
MHz, CDCl3): δ 1.02 (2H, m), 1.23 (3H, m), 1.54-1.87 (9H,
m), 2.02 (1H, m), 2.08-2.26 (4H, m), 2.29 (4H, m), 2.40 (1H,
m), 2.77 (2H, m), 2.93 (1H, m), 3.17 (1H, dd), 3.29-3.44 (3H,
m), 3.57 (1H, d), 3.70 (4H, m), 7.08 (1H, d), 7.32 (1H, s), 7.41
(1H, d). Anal. (C27H39Cl2N3O2‚1/10CH2Cl2) C, H. N: found, 8.55;
calcd, 8.13.
The (R)-enantiomer 28 was prepared in an identical fashion
from the more polar oxazoline-amine diastereomer 54.
(5R)-1-(Cycloh exylm eth yl)-5-(3,4-d ich lor op h en yl)-5-{2-
[3-(4-m or p h olin yl)-1-a zetid in yl]eth yl}-2-p ip er id on e (28).
MS m/z: 508 (MH)+. 1H NMR (300 MHz, CDCl3): spectral data
identical to data for 27. Anal. (C27H39Cl2N3O2‚1/4CH2Cl2) C, H,
N.
(5S)-1-(Cycloh exyl)-5-(3,4-d ich lor op h en yl)-5-{2-[3-(4-
m or p h olin yl)-1-a zet id in yl]et h yl}-2-p ip er id on e (30). (a )
To a solution of racemic acid 53 (100 g, 335 mmol) in EtOAc
(∼100 mL) was added a solution of R-(+)-naphthylethylamine
(24.9 g) in EtOAc (50 mL), and the solvent was removed under
reduced pressure. The solid residue was recrystallized three
times from EtOAc to give a white solid (20 g). The solid was
suspended in CH2Cl2 (500 mL), and 1 N HCl (∼300 mL) was
added. The aqueous layer was removed, and the organic layer
was washed with 1 N HCl, dried (MgSO4), and filtered, and
the solvent was removed under reduced pressure to give the
acid as the single (S)-enantiomer (>98% ee) (column, Diacel
Chiralcel OD, 250 mm × 4.6 mm; mobile phase 70% v/v
hexane, 30% v/v IPA + 0.1% v/v TFA; flow ) 1.0 mL/min; run
time ) 30 min, wavelength, results at 220 nM).
Ack n ow led gm en t. The authors thank Dr. Mark
Bushfield for advice and acknowledge the able as-
sistance of J . Banks, D. Davey, S. Broadbent, and M.
Stanley for ligand binding and functional assays. We
also thank M. Corless, C. M. Maxwell, C. Luckhurst,
C. Howard, and A. Warren for compound preparation.
We also thank the staff of the Structural and Separation
Sciences Department for analytical and spectroscopic
data and P. S. J ohnson for valuable help in preparing
this manuscript.
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