Diamine derivatives containing imidazolidinylidene propanedinitrile as a new class of histamine H3 receptor antagonists: conformationally restricted derivatives

Article abstract of DOI:10.1248/cpb.57.288

Novel conformationally restricted diamine derivatives containing imidazolidinylidene propanedinitrile were synthesized and evaluated for human and rat histamine H₃ receptor (H₃R) binding affinities. Among them, compounds 2b, 2c, 2j,

Full text of DOI:10.1248/cpb.57.288

288
Notes
Chem. Pharm. Bull. 57(3) 288—293 (2009)
Vol. 57, No. 3
Diamine Derivatives Containing Imidazolidinylidene Propanedinitrile as a
New Class of Histamine H3 Receptor Antagonists: Conformationally
Restricted Derivatives
Setsuya SASHO, ,1) Takashi SEISHI, Mariko KAWAMURA, Misato TOMURO, Ryo HIROSE,
*
Shinichiro TOKI, and Junich SHIMADA
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd.; 1188
Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411–8731, Japan.
Received October 7, 2008; accepted December 26, 2008; published online January 5, 2009
Novel conformationally restricted diamine derivatives containing imidazolidinylidene propanedinitrile were
synthesized and evaluated for human and rat histamine H3 receptor (H3R) binding affinities. Among them, com-
pounds 2b, 2c, 2j, 2k and 2m were found to be potent ligands for both H3Rs with Ki values in the sub-nanomolar
range, and showed potent H3 receptor antagonism.
Key words histamine H3 receptor; antagonist; imidazolidinylidene propanedinitrile; diamine
In the central nerve system, the histamine H3 receptor pounds 2a—f having a piperidinopropyl moiety were pre-
(H3R) is thought to control the release of a various neuro- pared (i.e. Amineꢀpiperidino, mꢀ3, nꢀ0). As shown in
transmitters such as histamine, serotonin, dopamine and Chart 1, commercially available [bis(methylthio)methyl-
acetylcholine. H3R antagonists induce release of these neuro- ene]malononitrile 3 and 4-amino-1-benzylpiperidine were re-
transmitters, and in animal models they have been shown to
enhance attention and cognition, and influence feeding.
Therefore, they may be useful in treatment of, for example,
attention-deficit disorder, Alzheimer’s disease, schizophrenia
and obesity.2—8)
Recently, we reported novel diamine derivatives containing
an imidazolidinylidene propanedinitrile moiety as potent
H3R antagonists.9) For example, compound 1 showed good
affinities both for human and rat H3Rs (Kiꢀ2.4 nM and
2.6 nM, respectively) with excellent selectivity for human H1,
Reagents and conditions: (a) 4-amino-1-benzylpiperidine, THF, room temperature,
19 h, then 2-aminoethanol, reflux, 10 h, 58% (2 steps); (b) MsCl, TEA, CH2Cl2, room
H2 and H4 receptors. Furthermore, a functional assay estab- temperature, 69 h, 40%; (c) 1,3-dibromopropane, 71% (6a) or 1,2-dibromoethane, 59%
(6b), K2CO3, DMF, room temperature; (d) piperidine, KI, 1,4-dioxane, 51% (7a) or
72% (7b); (e) 1-chloroethyl chloroformate, 1,2-dichloroethane, reflux, then MeOH, re-
flux, 85% (2a); (f) acetone, Na(OAc)3BH, THF, room temperature, 44 h, 37% (2b), 2-
iodopropane, K2CO3, DMF, room temperature, 111 h, 14% (2g from 7b, 2 steps).
lished that compound 1 was a rat neuronal H3R antagonist. In
2005, researchers from Johnson & Johnson identified a series
of conformationally restricted JNJ-5207852 derivatives as
potent H3R antagonists. For example, JNJ-7737782 repre-
Chart 1
sented pKi of 9.32 (0.48 nM) and 8.67 (2.14 nM) for human
and rat H3Rs, respectively, and showed wake-promoting ac-
tivity.10) These observations motivated us to design a novel
diamine series 2 in which a 1-alkylated-4-piperidinyl moiety
was introduced as a conformationally restricted linker in the
Reagents and conditions: (a) 1-bromo-2-fluoroethane, K2CO3, DMF, room tempera-
imidazolidinylidene propanedinitrile core in place of the
aminopropyl chain of compound 1. Analogs were prepared
with various alkyl substituents (R), linker lengths (mꢀ2, 3;
nꢀ0, 1) and amines (Fig. 1).
ture, 64 h, 19% (2d), 2,2,2-trifluoroethyl trifluoromethanesulfonate,11) K2CO3, DMF,
room temperature, 6 h, 50% (2e), 1-iodoacetonitrile, K2CO3, DMF, room temperature,
64 h, 17% (2f).
Chart 2
Syntheses of compounds 2a—m are shown in Charts 1—
5. First, in order to examine the effect of substituent R of the
4-piperidinyl part on human and rat H3R affinities, com-
Reagents and conditions: (a) (3-bromopropoxy)-tert-butyldimethylsilane, K2CO3,
DMF, 50 °C, 20 h, 90%; (b) 1-chloroethyl chloroformate, 1,2-dichloroethane, reflux,
1 h, then MeOH, reflux, 1 h, 93%; (c) (1-ethoxycyclopropoxy)trimethylsilane,
NaBH3CN, TEA, AcOH, THF, 60 °C, 3 h, 70%; (d) MsCl, TEA, CH2Cl2, room temper-
ature, 2 h, 83%; (e) corresponding amine, K2CO3, 1,4-dioxane, 80 °C, 12—24 h, 83%
(2c), 59% (2l), 29% (2m).
Fig. 1. Design of Conformationally Restricted Diamine-Based Novel Hist-
amine H3 Receptor Antagonists
Propanedinitrile Moiety
2 with Imidazolidinylidene
Chart 3
∗ To whom correspondence should be addressed. e-mail: setsuya.sasho@kyowa-kirin.co.jp
© 2009 Pharmaceutical Society of Japan

March 2009
289
nitrile 5 and N-(3-hydroxypropyl)ethylenediamine, was re-
acted with 1-tert-butoxylcarbonyl-4-methanesulfonyloxy-
methylpiperidine12) to give compound 14 with a yield of
50%. Mesylation of compound 14, and then introduction of
piperidine to the mesylate afforded compound 15. Finally,
the Boc protecting group was removed by TFA and the re-
sulting amine treated with 2-iodopropane to yield compound
2h (Chart 4).
Modification of the piperidino moiety of compound 2b or
2c was performed as illustrated in Charts 3 and 5. By virtue
of the use of an intermediate 12 or 17, three kinds of amines
were effectively introduced in the last step to yield com-
pounds 2i—m.
Reagents and conditions: (a) N-(3-hydroxypropyl)ethylenediamine, THF, room tem-
perature, 3 h, 82%; (b) 1-tert-butoxylcarbonyl-4-methanesulfonyloxymethylpiperi-
dine,12) K2CO3, DMF, 80—100 °C, 46 h, 50%; (c) MsCl, TEA, CH2Cl2, room tempera-
ture, 5 h, 97%, then piperidine, KI, 1,4-dioxane, 80 °C, 2.5 h, 64%; (d) TFA, CH2Cl2,
room temperature, 0.5 h, then 2-iodopropane, K2CO3, DMF, 50 °C, 5 h, 20% (2 steps).
Chart 4
The binding assay results for compounds 2a–m in human
and rat H3Rs are shown in Table 1. The effects of the alkyl
group R modification were analyzed first. Although com-
pound 2a (RꢀH) exhibited negligible affinities, introduction
of iso-propyl (2b) and cyclo-propyl (2c) substituents at the
N-1 position of a 4-piperidinyl moiety in compound 2a
caused an increase in affinities for both H3Rs. For example,
compound 2b showed six-fold and nine-fold affinity to
human and rat H3Rs (Kiꢀ0.37 nM and 0.28 nM, respectively)
than those of parent compound 1. Furthermore, compound
2b showed excellent selectivity over human H1, H2 and H4 re-
ceptors (percent inhibition of hH1R, hH2R, hH4R at 10 mM;
20%, ꢁ12%, ꢁ4%). Compound 2c also showed high affini-
Reagents and conditions: (a) 2-iodopropane, K2CO3, DMF, 60 °C, 23 h, 30%; (b)
MsCl, TEA, CH2Cl2, room temperature, 1.5 h, 55%; (c) corresponding amine, K2CO3,
1,4-dioxane, 80 °C, 12—24 h, 77% (2i), 58% (2j), 49% (2k).
Chart 5
acted in THF at room temperature and the resulting mixture ties to both H3Rs (Kiꢀ0.20 nM for human and 0.23 nM for rat,
refluxed with 2-aminoethanol to yield alcohol 4. Mesylation respectively). In contrast to 2b and 2c, compounds 2d—f,
of primary hydroxyl group of compound 4 and the resulting having alkyl substituents with electron withdrawing charac-
mesylate was stirred at ambient temperature to give imidazo- teristics, exhibited low affinities for human and rat H3Rs.
lidinylidene propanedinitrile 5 by spontaneous intramolecu-
Modification of linker length (i.e. compounds 2g, 2h)
lar cyclization. Compound 5 was then treated with 1,3-dibro- caused decrease in affinity for both human and rat H3Rs.
mopropane and introduction of piperidine to the bromide 6a These results indicate that the distance between two basic ni-
yielded compound 7a. The benzyl group of compound 7a trogen atoms is important for high affinities to both H3Rs.
was removed to yield compound 2a (RꢀH) in 85% yield.
With regard to modification of the variable amine moiety
Reductive alkylation of compound 2a with acetone in pres- (Table 1), compounds 2j, 2k and 2m, in which the piperidine
ence of Na(OAc)3BH gave compound 2b (Rꢀiso-Pr). Fur- moiety was replaced with thiomorpholine or 4-oxopiperi-
thermore, as illustrated in Chart 2, compound 2a was treated dine, retained good affinities for human and rat H3Rs with Ki
with corresponding electrophiles and K2CO3 in DMF to pro- values roughly equal to those of their parent compounds 2b
vide compounds 2d, 2e11) and 2f. The cyclopropyl containing and 2c. Conversely, compounds 2i and 2l possessing mor-
compound 2c was synthesized as depicted in Chart 3. Com- pholine had less affinity for both H3Rs than 2b or 2c.
pound 5 was reacted with (3-bromopropoxy)-tert-butyl-
Compounds 2b, 2c, 2d, 2i, 2j, 2k, 2l and 2m were selected
dimethylsilane to give compound 9 in 90% yield. Simultane- for a functional assay.13) Among them, compounds 2b and 2c
ous debenzylation and desilylation of compound 9 afforded reversed NAMH-mediated inhibition of [3H]-histamine re-
amino alcohol 10 in 93% yield. Then, cyclopropylation of lease from rat forebrain synaptosomes with IC50 values of
compound 10 by use of (1-ethoxycyclopropoxyl)trimethylsi- 10.2 nM and 11.6 nM, respectively (Table 1). Therefore, these
lane under reductive alkylation condition gave compound 11 compounds were found to be twice as potent as antagonists
in 70% yield. Finally, alcohol 11 was mesylated and the re- of rat neuronal H3R than compound 1. Somehow, there is a
sulting mesylate 12 heated with excess piperidine in 1,4- poor correlation between Ki values and IC50 values. Although
dioxane to give target molecule 2c with a yield of 83%.
the reason is not clear, remarkable differences between thiop-
In order to examine the effect of the distance between two eramide (known as an inverse agonist) and proxyfan (known
basic nitrogen atoms on human and rat H3R affinities, com- as a neutral antagonist) in these assays were found as shown
pounds 2g (Chart 1: mꢀ2, nꢀ0) and 2h (Chart 4: mꢀ3, in Table 1. In the functional assay, thioperamide and proxy-
nꢀ1) were synthesized. As shown in Chart 1, compound 2g fan showed IC50 values of 54.1 nM and 3397 nM, respectively,
was obtained by a method similar to that of preparation of in spite of their similar affinities for rat H3Rs (Ki; 5.14 nM,
compound 2b. Namely, 1,2-dibromoethane was used instead 3.95 nM, respectively). These results have led to speculation
of 1,3-dibromopropane in step c to give compound 6b in that the potency of inverse agonistic activity might affect the
59% yield. Then, compound 6b was transformed to target reverse activity toward NAMH-mediated inhibition of [3H]-
compound 2g by addition of piperidine, debenzylation and histamine release. Further study of characterization of com-
iso-propylation. On the other hand, compound 2h was syn- pounds 2 and this speculation are necessary.
thesized as follows. Compound 13,9) obtained from malono-
In conclusion, we have developed a new series of imidazo-

290
Vol. 57, No. 3
Table 1. Human and Rat H3R Binding Affinities and H3R Antagonistic Activities of Compounds 2a—m
Ki (nM)
Synaptosomeb)
IC50 (nM)
Linker
m, n
Compound
Amine
R
a)
a)
hH3
0.48c)
43.1
9.14
rH3
2.14c)
5.14
3.95
d)
JNJ-7737782
Thioperamide
Proxyfan
1
54.1ꢃ13.1f)
3397ꢃ713f)
2.4 (78/98)e)
(ꢁ8/50)e)
0.37
2.6 (88/96)e)
(32/50)e)
0.28
27.9ꢃ4.2f)
d)
2a
Piperidino
H
3, 0
3, 0
3, 0
3, 0
3, 0
3, 0
2, 0
3, 1
3, 0
3, 0
3, 0
3, 0
3, 0
2b
2c
2d
2e
2f
2g
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
iso-Pr
10.2ꢃ2.9f)
11.6ꢃ1.8f)
cyclo-Pr
CH2CH2F
CH2CF3
CH2CN
iso-Pr
0.20
1.48
0.23
1.55
63.8ꢃ28.3f)
d)
(42/66)e)
(18/67)e)
(72/96)e)
(60/87)e)
2.58
(40/76)e)
(40/86)e)
(54/88)e)
(70/96)e)
2.81
d)
d)
d)
2h
2i
2j
2k
2l
2m
Piperidino
iso-Pr
iso-Pr
iso-Pr
iso-Pr
cyclo-Pr
cyclo-Pr
Morpholino
Thiomorpholino
4-Oxopiperidino
Morpholino
Thiomorpholino
23.8ꢃ8.4f)
16.9ꢃ1.2f)
18.5ꢃ1.1f)
80.8ꢃ14.2f)
26.7g)
0.33
0.51
1.6
0.38
0.22
0.48
2.3
0.37
a) Binding potencies were assessed by displacement of [3H]-Na-methylhistamine (NAMH). The human H3 values were from cloned human H3R expressed in COS-7 cells,
while rat H3R values were from rat striatal membranes. b) H3R antagonism was assessed by reverse effect on NAMH-mediated inhibition of [3H]-histamine release from rat fore-
brain synaptosomes. c) Data from ref. 10. d) Not tested. e) Percent inhibition at 0.1 mM/1 mM. f ) Values with standard error of the mean (SEM): nꢀ3 or 4. g) nꢀ1.
piperidine 4-CH), 7.22—7.36 (5H, m, Ph).
Step c To a solution of compound 5 (0.705 g, 2.29 mmol) and K2CO3
(0.475 g, 3.44 mmol) in DMF (7 ml) was added 1,3-dibromopropane
(1.39 ml, 13.7 mmol) and the mixture was stirred at room temperature for
lidinylidene propanedinitrile based novel H3R ligands pos-
sessing a 1-alkylated-4-piperidinyl moiety as a conforma-
tionally restricted linker. This shows potent affinity to both
human and rat H3Rs, some of which are proven potent antag-
onists at H3Rs in rat cortical synaptosomes. Further struc-
tural modification and pharmacological evaluation of these
compounds are in progress.
26 h. The reaction mixture was diluted with ethyl acetate and washed with
brine. The combined organic extracts were dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was triturated with n-hexane to afford 6a
(0.694 g, 71%) as a white solid. 1H-NMR (CDCl3) d: 1.72—1.88 (4H, m,
piperidine 3-CH2 and 5-CH2), 2.08—2.32 (4H, m, piperidine 2-CH and 6-
CH and Br–CH2–CH2–CH2–), 2.93—3.03 (2H, m, piperidine 2-CH and 6-
Experimental
1H-NMR spectra were obtained on a JEOL JNM-EX270 (270 MHz) in- CH), 3.45—3.75 (10H, m, Ph–CH2–, Br–CH2–CH2–CH2–, imidazolidine
strument with chemical shifts (d) reported relative to tetramethylsilane as an ring CH2ꢂ2), 4.21 (1H, m, piperidine 4-CH), 7.23—7.36 (5H, m, Ph).
internal standard. Melting points were determined on a Yanaco micro melt-
ing point apparatus and are uncorrected. Mass spectra were recorded using a
Step d Compound 6a (0.694 g, 1.62 mmol) was dissolved in 1,4-diox-
ane (7 ml), and K2CO3 (0.448 g, 3.24 mmol), KI (0.269 g, 1.62 mmol) and
MICROMASS Quattro. Elemental analyses were performed by Perkin- piperidine (0.481 ml, 4.86 mmol) were added. After the solution was stirred
Elmer Series II CHNS/O Analyzer 2400 or Thermo Quest Flash EA1112.
Column chromatography was carried out on YMC GEL SIL-60-S150. Thin-
at 80 °C for 7 h, the mixture was allowed to cool to room temperature and di-
luted with ethyl acetate. The organic layer was washed with brine, dried
layer chromatography (TLC) was performed using 250 mm silica gel 60 (MgSO4), filtered and concentrated under vacuum. The residue was recrys-
glass-backed plates with F254 as indicator.
Synthesis of Compound 2a (Chart 1). Step a To a solution of
tallized from acetone and diisopropyl ether to give 7a (360 mg, 51%) as a
white solid. mp 156—158 °C. H-NMR (CDCl3) d: 1.37—1.93 (12H, m, 3-
CH2, 4-CH2 and 5-CH2 of piperidino group, 3-CH2 and 5-CH2 of 4-
1
[bis(methylthio)methylene]malononitrile
3
(3.00 g, 17.6 mmol) in THF
(30 ml) was added 4-amino-1-benzylpiperidine (3.59 ml, 17.6 mmol). After piperidinyl group, piperidino–CH2–CH2–CH2–), 2.08—2.22 (2H, m, 2-CH
the mixture was stirred at room temperature for 19 h, 2-aminoethanol
(0.70 ml, 11.6 mmol) was added to the solution and refluxed for a further
10 h. The resulting mixture was concentrated under reduced pressure and the
and 6-CH of 4-piperidinyl group), 2.29—2.43 (6H, m, 2-CH2 and 6-CH2 of
piperidino group, piperidino–CH2–CH2–CH2–), 2.9—3.02 (2H, m, 2-CH
and 6-CH of 4-piperidinyl group), 3.47—3.65 (8H, m, Ph–CH2–,
residue was triturated with ethyl acetate and diisopropyl ether to give 4 piperidino–CH2–CH2–CH2–, imidazolidine ring CH2ꢂ2), 4.21 (1H, m,
1
(3.18 g, 58%) as a brown solid. H-NMR (CD3OD) d: 1.52—1.68 (2H, m, piperidine 4-CH), 7.23—7.36 (5H, m, Ph).
piperidine 3-CH and 5-CH), 1.92—2.04 (2H, m, piperidine 3-CH and 5-
CH), 2.10—2.22 (2H, m, piperidine 2-CH and 6-CH), 2.82—2.93 (2H, m,
piperidine 2-CH and 6-CH), 3.31 (2H, t, Jꢀ4.5 Hz, –NH–CH2CH2–OH),
3.52 (2H, s, Ph–CH2–), 3.62—3.80 (3H, m, –NH–CH2CH2–OH and piperi-
dine 4-CH), 7.20—7.35 (5H, m, Ph).
Step b To a solution of compound 4 (1.88 g, 5.78 mmol) and triethy-
lamine (3.38 ml, 24.3 mmol) in dichloromethane (20 ml) was added
methanesulfonyl chloride (0.805 ml, 10.4 mmol). The mixture was stirred at
Step e To a solution of 7a (200 mg, 0.463 mmol) in 1,2-dichloroethane
(3 ml) was added 1-chloroethyl chloroformate (0.18 ml, 1.7 mmol). The mix-
ture was refluxed for 4.5 h and concentrated in vacuo. The residue was dis-
solved in methanol (3 ml) and resulting solution refluxed for further 1.5 h.
The resulting mixture was concentrated under reduced pressure and the
residue dissolved in 1 mol/l NaOH aq. The alkaline solution was extracted
with ethyl acetate twice and the combined organic layer was dried (MgSO4),
filtered and concentrated in vacuo to give compound 2a (0.134 g, 85%) as
1
room temperature for 69 h and diluted with brine. The mixture was extracted brown oil. H-NMR (CD3OD) d: 1.46—1.54 (2H, m, 4-CH2 of piperidino
with chloroform. The combined organic extracts were washed with brine group), 1.58—1.96 (10H, m, 3-CH2 and 5-CH2 of piperidino group, 3-CH2
and dried (MgSO4), filtered, and concentrated under vacuum to give com- and 5-CH2 of 4-piperidinyl group, piperidino–CH2–CH2–CH2–), 2.08—2.20
1
pound 5 (0.705 g, 40%) as a white solid. H-NMR (CDCl3) d: 1.68—1.90 (2H, m, 2-CH and 6-CH of 4-piperidinyl group), 2.64—2.78 (6H, m, 2-CH2
(4H, m, piperidine 3-CH2 and 5-CH2), 2.08—2.22 (2H, m, piperidine 2-CH
and 6-CH), 2.92—3.05 (2H, m, piperidine 2-CH and 6-CH), 3.50 (2H, s,
and 6-CH2 of piperidino group, piperidino–CH2–CH2–CH2–), 3.11—3.22
(2H, m, 2-CH and 6-CH of 4-piperidinyl group), 3.60—3.70 (6H, m,
Ph–CH2–), 3.55—3.76 (4H, m, imidazolidine ring CH2ꢂ2), 4.26 (1H, m, piperidino–CH2–CH2–CH2–, imidazolidine ring CH2ꢂ2), 4.22 (1H, m,

March 2009
291
piperidine 4-CH).
22.68. Found: C, 68.11; H, 9.34; N, 22.95.
Synthesis of Compound 2b (Chart 1). Step f To a solution of 2a
(196 mg, 0.572 mmol) and acetone (0.418 ml, 5.73 mmol) in THF (10 ml)
Synthesis of Compound 2c (Chart 3). Step a To a solution of com-
pound 5 (9.00 g, 29.3 mmol) and K2CO3 (8.1 g, 58.6 mmol) in DMF (30 ml)
was added sodium triacetoxyborohydride (604 mg, 2.85 mmol) and the mix- was added (3-bromopropoxy)-tert-butyldimethylsilane (8.15 ml, 35.2 mmol)
ture was stirred at room temperature for 44 h. After the reaction was com- and the mixture was stirred at 50 °C for 20 h. The reaction mixture was di-
pleted, the solution was diluted with Na2CO3 aq. and extracted with ethyl ac- luted with ethyl acetate and washed with brine. The combined organic ex-
etate. The organic extracts were dried (MgSO4), filtered, and concentrated in
tracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue
vacuo. The residue was recrystallized from diisopropyl ether to give com- was triturated with diisopropyl ether to afford 9 (12.3 g, 90%) as a white
1
pound 2b (81 mg, 37%) as a white solid. mp 199—201 °C. 1H-NMR solid. H-NMR (CDCl3) d: 0.05 (6H, s, 2ꢂCH3 of TBS), 0.89 (9H, s, tert-
(CDCl3) d: 1.03 (6H, d, Jꢀ6.4 Hz, CH3 of iso-Pr), 1.37—1.50 (2H, m, 4-
butyl of TBS), 1.70—1.93 (6H, m, TBSO–CH2CH2CH2–, piperidine 3-CH2
CH2 of piperidino group), 1.51—1.93 (10H, m, 3-CH2 and 5-CH2 of and 5-CH2), 2.10—2.23 (2H, m, piperidine 2-CH and 6-CH), 2.92—3.02
piperidino group, 3-CH2 and 5-CH2 of 4-piperidinyl group, piperidino–
CH2–CH2–CH2–), 2.22—2.42 (8H, m, 2-CH and 6-CH of 4-piperidinyl
group, 2-CH2 and 6-CH2 of piperidino group, piperidino–CH2–CH2–CH2–),
2.75 (1H, m, CH of iso-Pr), 2.89—3.01 (2H, m, 2-CH and 6-CH of 4-
piperidinyl group), 3.50—3.65 (6H, m, piperidino–CH2–CH2–CH2–, imida-
(2H, m, piperidine 2-CH and 6-CH), 3.56 (2H, s, Ph–CH2–), 3.53—3.72
(8H, m, TBSO–CH2CH2CH2–, imidazolidine ring CH2ꢂ2), 4.21 (1H, m,
piperidine 4-CH), 7.22—7.36 (5H, m, Ph).
Step b To a solution of 9 (500 mg, 1.02 mmol) in 1,2-dichloroethane
(5 ml) was added 1-chloroethyl chloroformate (0.275 ml, 2.55 mmol). The
zolidine ring CH2ꢂ2), 4.17 (1H, m, piperidine 4-CH). APCI-MS m/z: 385 mixture was refluxed for 1 h and concentrated in vacuo. The residue was dis-
(MꢄHꢄ). Anal. Calcd for C22H36N6: C, 68.71; H, 9.44; N, 21.85. Found: C, solved in methanol (5 ml) and the solution was refluxed for further 1 h. The
68.95; H, 9.51; N, 22.01.
resulting mixture was concentrated under reduced pressure and the residue
was triturated with ethyl acetate to give compound 10 (HCl salt; 0.295 g,
93%) as a white solid. 1H-NMR (CD3OD) d: 1.84—2.15 (6H, m, HO–
CH2CH2CH2–, piperidine 3-CH2 and 5-CH2), 3.04—3.15 (2H, m, HO–
Synthesis of Compound 2d (Chart 2). Step a Compound 2a (78 mg,
0.23 mmol) was dissolved in DMF (2 ml), and K2CO3 (190 mg, 1.38 mmol)
and 1-bromo-2-fluoroethane (0.051 ml, 0.69 mmol) were added. After the
solution was stirred at room temperature for 64 h, the mixture was diluted CH2CH2CH2), 3.45—3.58 (2H, m, piperidine 2-CH and 6-CH), 3.61—3.80
with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), (8H, m, HO–CH2CH2CH2–, piperidine 2-CH and 6-CH-, imidazolidine ring
filtered and concentrated under vacuum. The residue was purified by silica CH2ꢂ2), 4.39 (1H, m, piperidine 4-CH).
gel column chromatography, eluting with 10% 2 mol/l NH3–CH3OH/CHCl3
Step c To a solution of 10 (720 mg, 2.31 mmol), triethylamine (0.32 ml,
to provide crude 2d, which was recrystallized from diisopropyl ether to af- 2.3 mmol), acetic acid (3.96 ml) and (1-ethoxycyclopropoxy)trimethylsilane
ford pure 2d (17 mg, 19%) as a white solid. mp 56—57 °C. 1H-NMR (0.93 ml, 4.6 mmol) in THF (35 ml) and methanol (0.36 ml) was added
(CDCl3) d: 1.38—1.50 (2H, m, 4-CH2 of piperidino group), 1.50—1.93 sodium cyanoborohydride (310 mg, 4.62 mmol) and the mixture was stirred
(10H, m, 3-CH2 and 5-CH2 of piperidino group, 3-CH2 and 5-CH2 of 4- at 60 °C for 3 h. After the reaction was completed, the solution was diluted
piperidinyl group, piperidino–CH2–CH2–CH2–), 2.20—2.45 (8H, m, 2-CH with H2O (110 ml) and 2 mol/l HCl aq. and washed with ethyl acetate. The
and 6-CH of 4-piperidinyl group, 2-CH2 and 6-CH2 of piperidino group,
piperidino–CH2–CH2–CH2–), 2.70 (2H, dt, Jꢀ28.4, 5.0 Hz, N–CH2CH2F),
3.00—3.10 (2H, m, 2-CH and 6-CH of 4-piperidinyl group), 3.50—3.67
aqueous layer was neutralized with K2CO3, and then extracted with ethyl ac-
etate. The organic extracts were washed with brine, dried (MgSO4), filtered,
and concentrated in vacuo. The residue triturated with n-hexane and ethyl
(6H, m, piperidino–CH2–CH2–CH2–, imidazolidine ring CH2ꢂ2), 4.21 (1H, acetate (20 : 1) to give compound 11 (510 mg, 70%) as a white solid. 1H-
m, piperidine 4-CH), 4.54 (2H, dt, Jꢀ47.5, 5.0 Hz, N–CH2CH2F). APCI-MS NMR (CDCl3) d: 0.34—0.39 and 0.42—0.51 (each 2H, each m, cyclo-Pr
m/z: 389 (MꢄHꢄ). Anal. Calcd for C21H33FN6·0.5H2O: C, 63.45; H, 8.62; CH2ꢂ2), 1.63—1.68 (3H, m, HO–CH2CH2CH2–, cyclo-Pr CH), 1.71—1.99
N, 21.14. Found: C, 63.47; H, 8.81; N, 21.30.
(4H, m, piperidine 3-CH2 and 5-CH2), 2.36 (2H, m, piperidine 2-CH
Synthesis of Compounds 2e and 2f (Chart 2) Compounds 2e and 2f and 6-CH), 3.11 (2H, m, HO–CH2CH2CH2–), 3.54—3.76 (8H, m, HO–
were synthesized using a method similar to that for preparation of com- CH2CH2CH2–, piperidine 2-CH and 6-CH-, imidazolidine ring CH2ꢂ2),
pound 2d.
4.21 (1H, m, piperidine 4-CH).
Compound 2e (White Solid): mp 103—105 °C (n-hexane/ethyl acetate).
Step d To a solution of compound 11 (500 mg, 1.60 mmol) and triethyl-
amine (0.89 ml, 6.41 mmol) in dichloromethane (6 ml) was added methane-
1H-NMR (CDCl3) d: 1.36—1.62 (6H, m, 3-CH2, 4-CH2 and 5-CH2 of
piperidino group), 1.73—1.92 (6H, m, 3-CH2 and 5-CH2 of 4-piperidinyl sulfonyl chloride (0.19 ml, 2.4 mmol). The mixture was stirred at room tem-
group, piperidino–CH2–CH2–CH2–), 2.34—2.57 (8H, m, 2-CH and 6-CH of perature for 2 h and diluted with brine. The mixture was extracted with ethyl
4-piperidinyl group, 2-CH2 and 6-CH2 of piperidino group, piperidino–
CH2–CH2–CH2–), 2.88—3.07 (4H, m, 2-CH and 6-CH of 4-piperidinyl
acetate. The organic extracts were washed with brine, dried (MgSO4), fil-
tered and concentrated under reduced pressure to afford the mesylate 12
group, N–CH2CF3), 3.52—3.66 (6H, m, piperidino–CH2–CH2–CH2–, imida- (520 mg, 83%) as a white solid. 1H-NMR (CDCl3) d: 0.41—0.50 (4H,
zolidine ring CH2ꢂ2), 4.21 (1H, m, piperidine 4-CH). APCI-MS m/z: 425 m, cyclo-Pr CH2ꢂ2), 1.64—1.86 (5H, m, piperidine 3-CH and 5-CH,
(MꢄHꢄ). Anal. Calcd for C21H31F3N6: C, 59.42; H, 7.36; N, 19.80. Found: HO–CH2CH2CH2–, cyclo-Pr CH), 2.12—2.22 (2H, m, piperidine 3-CH and
C, 59.68; H, 7.61; N, 20.13.
5-CH), 2.38 (2H, m, piperidine 2-CH and 6-CH), 3.05 (3H, s, CH3SO2–),
Compound 2f (White Solid): mp 135—136 °C (2-propanol). 1H-NMR 3.06—3.15 (2H, m, piperidine 2-CH and 6-CH), 3.57—3.72 (6H, m,
(CDCl3) d: 1.40—1.50 (2H, m, 4-CH2 of piperidino group), 1.50—2.00 MsO–CH2CH2CH2–, imidazolidine ring CH2ꢂ2), 4.22 (1H, m, piperidine 4-
(10H, m, 3-CH2 and 5-CH2 of piperidino group, 3-CH2 and 5-CH2 of 4- CH), 4.34 (2H, t, Jꢀ5.8 Hz, MsO–CH2CH2CH2–).
piperidinyl group, piperidino–CH2–CH2–CH2–), 2.32—2.56 (8H, m, 2-CH
and 6-CH of 4-piperidinyl group, 2-CH2 and 6-CH2 of piperidino group,
Step e The mesylate 12 (0.21 g, 0.52 mmol) was dissolved in 1,4-diox-
ane (12 ml), and K2CO3 (145 mg, 1.04 mmol) and piperidine (0.104 ml,
piperidino–CH2–CH2–CH2–), 2.90—3.00 (2H, m, 2-CH and 6-CH of 4- 1.04 mmol) were added. After the solution was stirred at 80 °C for 15 h, the
piperidinyl group), 3.46 (2H, s, N–CH2CN), 3.50—3.70 (6H, m, piperidino–
mixture was allowed to cool to room temperature and diluted with brine.
The mixture was extracted with ethyl acetate and the combined organic ex-
CH2–CH2–CH2–, imidazolidine ring CH2ꢂ2), 4.24 (1H, m, piperidine 4-
CH). APCI-MS m/z: 382 (MꢄHꢄ). Anal. Calcd for C21H31N7: C, 66.11; H, tracts washed with brine, dried (MgSO4), filtered and concentrated in vacuo.
8.19; N, 25.70. Found: C, 66.40; H, 8.22; N, 25.87.
The residue was recrystallized from n-hexane and ethyl acetate to give com-
pound 2c (166 mg, 83%). mp 104—105 °C. 1H-NMR (CDCl3) d: 0.34—0.51
(4H, m, cyclo-Pr CH2ꢂ2), 1.42—1.44 (2H, m, 4-CH2 of piperidino group),
1.53—1.73 (8H, m, 3-CH2 and 5-CH2 of piperidino group, 3-CH and 5-CH
of 4-piperidinyl group, piperidino–CH2–CH2–CH2–), 1.81—1.91 (2H, m,
Synthesis of Compound 2g (Chart 1) Compound 2g was synthesized
using a method similar to that for compound 2b and 2d by use of 1,2-dibro-
moethane and 2-iodopropane instead of 1,3-dibromopropane and 1-bromo-
2-fluoroethane, respectively.
Compound 2g (White Solid): mp 93—95 °C (diisopropyl ether). 1H-NMR 3-CH and 5-CH of 4-piperidinyl group), 2.31—2.36 (9H, m, 2-CH2 and
(CDCl3) d: 1.04 (6H, d, Jꢀ6.6 Hz, CH3 of iso-Pr), 1.38—1.95 (10H, m, 3-
CH2, 4-CH2 and 5-CH2 of piperidino group, 3-CH2 and 5-CH2 of 4- piperidino–CH2–CH2–CH2–, cyclo-Pr CH), 3.08—3.12 (2H, m, 2-CH and 6-
piperidinyl group), 2.24—2.50 (6H, m, 2-CH and 6-CH of 4-piperidinyl CH of 4-piperidinyl group), 3.53—3.60 (6H, m, piperidino–CH2–CH2–
6-CH2 of piperidino group, 2-CH and 6-CH of 4-piperidinyl group,
group, 2-CH2 and 6-CH2 of piperidino group), 2.53—2.65 (2H, m, CH2–, imidazolidine ring CH2ꢂ2), 4.27 (1H, m, piperidine 4-CH). APCI-
piperidino–CH2–CH2–), 2.76 (1H, m, CH of iso-Pr), 2.90—3.00 (2H, m, 2-
CH and 6-CH of 4-piperidinyl group), 3.50—3.72 (6H, m, piperidino–CH2–
CH2–, imidazolidine ring CH2ꢂ2), 4.16 (1H, m, piperidine 4-CH). APCI-
MS m/z: 383 (MꢄHꢄ). Anal. Calcd for C22H34N6: C, 69.07; H, 8.96; N,
21.97. Found: C, 69.15; H, 9.21; N, 22.35.
Synthesis of Compounds 2l and 2m (Chart 3) The following com-
MS m/z: 371 (MꢄHꢄ). Anal. Calcd for C21H34N6: C, 68.07; H, 9.25; N, pounds were prepared using a method similar to that of synthesis of com-

292
Vol. 57, No. 3
pound 2c.
3.28—3.50 (2H, m, piperidino–CH2–CH2–CH2–), 3.55—3.70 (6H, m, 4-
Compound 2l (White Solid): mp 104—106 °C. 1H-NMR (CDCl3) d: piperidinyl–CH2–, imidazolidine ring CH2ꢂ2), 4.08—4.24 (2H, m, 2-CH
0.34—0.41 and 0.43—0.51 (each 2H, each m, cyclo-Pr CH2ꢂ2), 1.65—1.75 and 6-CH of piperidine).
(3H, m, morpholino–CH2–CH2–CH2–, cyclo-Pr CH), 1.81—1.91 (4H, m,
piperidine 3-CH2 and 5-CH2), 2.30—2.45 (8H, m, morpholino–CH2– chloride (2 ml) was added trifluoroacetic acid (1 ml) and the mixture was
CH2–CH2–, morpholine 3-CH2 and 5-CH2, piperidine 2-CH and 6-CH), 3.11 stirred at room temperature for 0.5 h. The reaction mixture was concentrated
(2H, m, piperidine 2-CH and 6-CH), 3.52—3.63 (6H, m, morpholino–CH2– in vacuo and the residue dissolved in DMF (2 ml). K2CO3 (110 mg,
CH2–CH2–, imidazolidine ring CH2ꢂ2), 4.23 (1H, m, piperidine 4-CH). 0.800 mmol) and 2-iodopropane (0.031 ml, 0.32 mmol) were added to the
APCI-MS m/z: 385 (MꢄHꢄ). Anal. Calcd for C21H32N6O: C, 65.59; H, 8.39; solution and stirred at 50 °C for 5 h. The reaction mixture was diluted with
Step d To a solution of compound 15 (72 mg, 0.16 mmol) in methylene
N, 21.86. Found: C, 68.97; H, 8.44; N, 22.23.
ethyl acetate and washed with brine. The combined organic extracts were
Compound 2m (White Solid): mp 129—130 °C. 1H-NMR (CDCl3) d: dried (MgSO4), filtered, and concentrated in vacuo. The residue was puri-
0.36—0.41 and 0.43—0.51 (each 2H, each m, cyclo-Pr CH2ꢂ2), 1.62—1.75 fied by silica gel column chromatography, eluting with 20% 2 mol/l
(5H, m, thiomorpholino–CH2–CH2–CH2–, piperidine 3-CH and 5-CH,
cyclo-Pr CH), 1.81—1.90 (4H, m, thiomorpholine 2-CH and 6-CH, piperi-
dine 3-CH and 5-CH), 2.31—2.44 (4H, m, thiomorpholino–CH2–CH2–
CH2–, thiomorpholine 2-CH and 6-CH), 2.65—2.72 (6H, m, thiomorpholine
3-CH2 and 5-CH2, piperidine 2-CH and 6-CH), 3.11 (2H, m, piperidine 2-
NH3–CH3OH/CHCl3 to yield compound 2h (13 mg, 20%) as a white solid.
mp 115—117 °C. H-NMR (CDCl3) d: 1.03 (6H, d, Jꢀ6.6 Hz, CH3 of iso-
Pr), 1.23—1.50 (2H, m, 4-CH2 of piperidino group), 1.51—1.63 (6H, m,
piperidino–CH2–CH2–CH2–, 3-CH2 and 5-CH2 of piperidino group), 1.68—
1.94 (5H, m, 3-CH2, 4-CH and 5-CH2 of 4-piperidinylmethyl group), 2.10—
1
CH and 6-CH), 3.51—3.60 (6H, m, thiomorpholino–CH2–CH2–CH2–, imi- 2.23 (2H, m, 2-CH and 6-CH of 4-piperidinylmethyl group), 2.25—2.47
dazolidine ring CH2ꢂ2), 4.22 (1H, m, piperidine 4-CH). APCI-MS m/z: 401 (6H, m, 2-CH2 and 6-CH2 of piperidino group, piperidino–CH2–CH2–CH2–),
(MꢄHꢄ). Anal. Calcd for C21H32N6S: C, 62.96; H, 8.05; N, 20.98. Found: C, 2.67—2.79 (1H, m, CH of iso-Pr), 2.84—2.95 (2H, m, 2-CH and 6-CH of 4-
63.07; H, 8.14; N, 21.21.
Synthesis of Compound 2h (Chart 4). Step a To an ice-cooled solu-
tion of 3 (10.2 g, 59.9 mmol) in THF (68 ml) was added THF solution
piperidinylmethyl group), 3.38 (2H, d, Jꢀ7.3 Hz, piperidino–CH2–CH2–
CH2–), 3.53—3.67 (6H, m, 4-piperidinyl–CH2–, imidazolidine ring
CH2ꢂ2). APCI-MS m/z: 399 (MꢄHꢄ). Anal. Calcd for C23H38N6: C, 69.31;
(10 ml) of N-(3-hydroxypropyl)ethylenediamine (7.24 g, 61.3 mmol). The H, 9.61; N, 21.08. Found: C, 69.47; H, 9.92; N, 21.45.
mixture was stirred at room temperature for 3 h and diluted with ethyl
Synthesis of Compound 2i (Chart 5). Step a To a solution of com-
acetate/diisopropyl ether (each 35 ml). This solution was stirred in an ice pound 10 (HCl salt; 6.36 g, 20.4 mmol) in DMF (50 ml) were added K2CO3
bath for 1 h and the resulting white precipitate filtered and dried to give (14.1 g, 102 mmol) and 2-iodopropane (6.1 ml, 61.2 mmol). After the mix-
compound 13 (9.48 g, 82%). 1H-NMR (DMSO-d6) d: 1.65—1.79 (2H, m, ture was stirred at 60 °C for 23 h, the reaction mixture was diluted with ethyl
HO–CH2CH2CH2–), 3.38—3.55 (6H, m, HO–CH2CH2CH2–, imidazolidine
ring CH2), 3.63—3.75 (2H, m, imidazolidine ring CH2), 4.54 (1H, t,
Jꢀ4.6 Hz, OH), 7.87 (1H, br s, NH).
acetate and washed with brine. The organic extracts were dried (MgSO4), fil-
tered, and concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography, eluting with 10% CH3OH/CHCl3 to yield compound
1
Step b To a solution of compound 13 (1.19 g, 6.19 mmol) and K2CO3
16 (1.96 g, 30%) as a pale yellow solid. H-NMR (CDCl3) d: 1.05 (6H, d,
(1.71 g, 12.4 mmol) in DMF (12 ml) was added 1-tert-butoxycarbonyl-4- Jꢀ6.6 Hz, CH3 of iso-Pr), 1.72—1.98 (6H, m, HO–CH2CH2CH2–, piperi-
methanesulfonyloxymethylpiperidine12) (2.94 g, 9.29 mmol) and the mixture
was stirred at 80 °C for 21 h and 100 °C for 25 h. The reaction mixture was
dine 3-CH2 and 5-CH2), 2.28—2.35 (2H, m, piperidine 2-CH and 5-CH),
2.73—2.81 (1H, m, CH of iso-Pr), 2.97 (2H, m, piperidine 2-CH and 5-CH),
diluted with ethyl acetate and washed with brine. The combined organic 3.61 (4H, s, imidazolidine ring CH2ꢂ2), 3.66—3.71 (2H, m, HO–
extracts were dried (MgSO4), filtered, and concentrated in vacuo. The re- CH2CH2CH2–), 3.74 (2H, t, Jꢀ6.8 Hz, HO–CH2CH2CH2–), 4.18 (1H, m,
sidue was purified by silica gel column chromatography, eluting with piperidine 4-CH).
1
CH3OH/CHCl3 (from 3 to 8%) to provide compound 14 (1.21 g, 50%). H-
Step b To a solution of compound 16 (1.96 g, 6.19 mmol) and triethy-
NMR (CDCl3) d: 1.20—1.40 (2H, m, HO–CH2CH2CH2–), 1.46 (9H, s, tert- lamine (3.45 ml, 24.8 mmol) in dichloromethane (20 ml) was added
butyl), 1.65—1.75 (2H, m, 3-CH and 5-CH of piperidine), 1.88—2.04 (3H,
m, 3-CH, 4-CH and 5-CH of piperidine), 2.62—2.80 (2H, m, 2-CH and 6-
methanesulfonyl chloride (0.72 ml, 9.3 mmol). The mixture was stirred at
room temperature for 1.5 h and diluted with brine. The mixture was ex-
CH of piperidine), 3.30—3.50 (2H, m, HO–CH2CH2CH2–), 3.60—3.78 (8H, tracted with ethyl acetate. The organic extracts were washed with brine,
m, 4-piperidinyl–CH2–, HO–CH2CH2CH2–, imidazolidine ring CH2ꢂ2), dried (MgSO4), filtered and concentrated under reduced pressure to afford
4.05—4.24 (2H, m, 2-CH and 6-CH of piperidine).
Step c To a solution of compound 14 (600 mg, 1.60 mmol) and triethy- (6H, d, Jꢀ6.6 Hz, CH3 of iso-Pr), 1.75—1.80 (4H, m, piperidine 3-CH2 and
the mesylate 17 (1.34 g, 55%) as a white solid. 1H-NMR (CDCl3) d: 1.06
lamine (0.445 ml, 3.20 mmol) in dichloromethane (6 ml) was added 5-CH2), 2.13—2.21 (2H, m, MsO–CH2CH2CH2–), 2.30—2.37 (2H, m,
methanesulfonyl chloride (0.186 ml, 2.40 mmol). The mixture was stirred at
piperidine 2-CH and 6-CH), 2.80 (1H, m, CH of iso-Pr), 2.99 (2H, m,
room temperature for 5 h and diluted with brine. The mixture was extracted piperidine 2-CH and 6-CH), 3.05 (3H, s, CH3SO2–), 3.62 (4H, s, imidazoli-
with ethyl acetate. The combined organic extracts were washed with brine dine ring CH2ꢂ2), 3.72 (2H, t, Jꢀ7.2 Hz, MsO–CH2CH2CH2–), 4.20 (1H,
and dried (MgSO4), filtered, and concentrated under vacuum to give {1-[[1- m, piperidine 4-CH), 4.35 (2H, t, Jꢀ5.9 Hz, MsO–CH2CH2CH2–).
(tert-butoxycarbonyl)piperidin-4-yl]methyl]-3-(3-methanesulfony-
loxypropyl)imidazolidine-2-ylidene}malononitrile (700 mg, 97%). H-NMR ane (20 ml), and K2CO3 (1.23 g, 8.94 mmol) and morpholine (0.78 ml,
Step c The mesylate 17 (1.77 g, 4.47 mmol) was dissolved in 1,4-diox-
1
(CDCl3) d: 1.12—1.28 (2H, m, HO–CH2CH2CH2–), 1.46 (9H, s, tert-butyl),
1.65—1.75 (2H, m, 3-CH and 5-CH of piperidine), 1.90—2.05 (1H, m, 4-
CH of piperidine), 2.12—2.45 (2H, m, 3-CH and 5-CH of piperidine),
8.9 mmol) were added. After the solution was stirred at 80 °C for 13 h, the
mixture was allowed to cool to room temperature and diluted with brine.
The mixture was extracted with ethyl acetate and the combined organic ex-
2.63—2.78 (2H, m, 2-CH and 6-CH of piperidine), 3.06 (3H, s, CH3SO2–), tracts were washed with brine, dried (MgSO4), filtered and concentrated in
3.30—3.78 (8H, m, 4-piperidinyl–CH2–, HO–CH2CH2CH2–, imidazolidine
ring CH2ꢂ2), 4.05—4.24 (2H, m, 2-CH and 6-CH of piperidine), 4.35 (2H,
t, Jꢀ6.0 Hz, MsO–CH2CH2CH2–).
vacuo. The residue was recrystallized from n-hexane and ethyl acetate to
give compound 2i (1.32 g, 77%) as a white solid. mp 109—110 °C. 1H-NMR
(CDCl3) d: 1.04 (6H, d, Jꢀ6.6 Hz, CH3 of iso-Pr), 1.70—1.93 (6H, m,
The mesylate (780 mg, 1.67 mmol) was dissolved in 1,4-dioxane (8 ml), piperidine 3-CH2 and 5-CH2, morpholino–CH2–CH2–CH2–), 2.24—2.50
and KI (415 mg, 2.50 mmol) and piperidine (0.496 ml, 5.01 mmol) were
added. After the solution was stirred at 80 °C for 2.5 h, the mixture was al-
(8H, m, piperidine 2-CH and 6-CH, morpholine 3-CH2 and 5-CH2, mor-
pholino–CH2–CH2–CH2–), 2.76 (1H, m, CH of iso-Pr), 2.90—3.01 (2H, m,
lowed to cool to room temperature and diluted with brine. The mixture was piperidine 2-CH and 6-CH), 3.55—3.77 (10H, m, morpholine 2-CH2 and 6-
extracted with ethyl acetate and the combined organic extracts were washed CH2, morpholino–CH2–CH2–CH2–, imidazolidine ring CH2ꢂ2), 4.18 (1H,
with brine, dried (MgSO4), filtered and concentrated under reduced pres-
sure. The residue was chromatographed on silica gel (from 1 to 15%
CH3OH/CHCl3) to give compound 15 (490 mg, 64%). H-NMR (CDCl3) d:
1.12—1.29 (2H, m, 4-CH2 of piperidino group), 1.43—1.52 (11H, m, pounds were prepared using a method similar to that of synthesis of com-
m, piperidine 4-CH). APCI-MS m/z: 387 (MꢄHꢄ). Anal. Calcd for
C21H34N6O: C, 65.25; H, 8.87; N, 21.74. Found: C, 65.60; H, 9.10; N, 22.09.
Synthesis of Compounds 2j and 2k (Chart 5) The following com-
1
HO–CH2CH2CH2–, tert-butyl), 1.58—1.75 (6H, m, 3-CH2 and 5-CH2 of
piperidino group, 3-CH and 5-CH of 4-piperidinylmethyl group), 1.87—
2.05 (3H, m, 3-CH, 4-CH and 5-CH of 4-piperidinylmethyl group), 2.40—
pound 2i.
Compound 2j (White Solid): mp 124—125 °C. 1H-NMR (CDCl3) d: 1.04
(6H, d, Jꢀ6.6 Hz, CH3 of iso-Pr), 1.67—1.88 (6H, m, piperidine 3-CH2 and
2.55 (6H, m, 2-CH2 and 6-CH2 of piperidino group, piperidino–CH2–CH2– 5-CH2, thiomorpholino–CH2–CH2–CH2–), 2.27—2.37 (2H, m, thiomorpho-
CH2–), 2.62—2.79 (2H, m, 2-CH and 6-CH of 4-piperidinylmethyl group), line 2-CH and 6-CH), 2.41 (2H, t, Jꢀ7.0 Hz, thiomorpholino–CH2–CH–

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293
CH2–), 2.65—2.79 (9H, m, piperidine 2-CH and 6-CH, thiomorpholine 2-
CH, 6-CH, 3-CH2 and 5-CH2, CH of iso-Pr), 2.94—2.98 (2H, m, piperidine
2-CH and 6-CH), 3.54—3.60 (6H, m, thiomorpholino–CH2–CH2–CH2–, im-
idazolidine ring CH2ꢂ2), 4.19 (1H, m, piperidine 4-CH). APCI-MS m/z:
403 (MꢄHꢄ). Anal. Calcd for C21H34N6S: C, 62.65; H, 8.51; N, 20.87.
Found: C, 62.81; H, 8.60; N, 20.92.
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berg T., Biochem. Pharmacol., 73, 1084—1096 (2007).
9) Sasho S., Seishi T., Kawamura M., Hirose R., Toki S., Shimada J.,
Bioorg. Med. Chem. Lett., 18, 2288—2291 (2008).
Compound 2k (White Solid): mp 103—105 °C. 1H-NMR (CDCl3) d: 1.04
(6H, d, Jꢀ6.6 Hz, CH3 of iso-Pr), 1.75 (2H, m, 4-oxopiperidino–CH2–CH2–
CH2–), 1.87—1.99 (4H, m, piperidine 3-CH2 and 5-CH2), 2.27—2.34 (2H,
m, 3-CH and 5-CH of 4-oxopiperidine), 2.46 (4H, t, Jꢀ6.0 Hz, 4-oxopiperi-
dine 2-CH, 3-CH, 4-CH and 5-CH), 2.53 (2H, t, Jꢀ6.8 Hz, 4-oxopiperidino–
CH2–CH2–CH2–), 2.75 (5H, m, 4-oxopiperidine 3-CH and 5-CH, piperidine
2-CH and 6-CH, CH of iso-Pr), 2.96 (2H, m, piperidine 2-CH and 6-CH),
3.60—3.67 (6H, m, 4-oxopiperidino–CH2–CH2–CH2–, imidazolidine ring
CH2ꢂ2), 4.19 (1H, m, piperidine 4-CH). APCI-MS m/z: 399 (MꢄHꢄ).
Anal. Calcd for C22H34N6O: C, 66.30; H, 8.60; N, 21.09. Found: C, 66.51; H, 10) Dvorak C. A., Apodaca R., Barbier A. J., Berridge C. W., Wilson S. J.,
8.56; N, 21.18.
Boggs J. D., Xiao W., Lovenberg T. W., Carruthers N. I., J. Med.
Chem., 48, 2229—2238 (2005).
Acknowledgments We thank Ms. Atsuko Kobayashi and Ms. Miyako 11) 2,2,2-Trifluoroethyl trifluoromethanesulfonate, used for the synthesis
Mizuguchi for technical assistances on chemical synthesis, Ms. Ari Okabe
and Ms. Naomi Kamiya for performing binding assays and functional as-
says.
of compound 2e, was prepared by the method represented in; J. Burdo
J., McLoughli V. C. R., Tetrahedron, 21, 1—4 (1965).
12) Lu T., Tomczuk B., Illig C. R., Bone R., Murphy L., Spurlino J.,
Salemme F. R., Soil R. M., Bioorg. Med. Chem. Lett., 8, 1595—1600
(1998).
References and Notes
1) Present address: Innovative Drug Research Laboratories, Kyowa 13) Garbarg M., Arrang J. M., Rouleau A., Ligneau X., Tuong M. D.,
Hakko Kirin Co., Ltd.; 3–6–6, Asahi-machi, Machida-shi, Tokyo 194–
Schwartz J. C., Ganellin C. R., J. Pharmacol. Exp. Ther., 263, 304—
8533, Japan.
310 (1992).