Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists

Article abstract of DOI:10.1248/cpb.49.29

A series of 8′-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolin ecarboxamides were synthesized. The 5-HT₄ receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT₄ receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT₄ receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT₄ receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.

Full text of DOI:10.1248/cpb.49.29

January 2001
Chem. Pharm. Bull. 49(1) 29—39 (2001)
29
Synthesis and Evaluation of Novel 2-Oxo-1,2-dihydro-3-quinolinecar-
boxamide Derivatives as Potent and Selective Serotonin 5-HT4
Receptor Agonists
Masaji SUZUKI,* Yutaka OHUCHI, Hajime ASANUMA, Toshie KANEKO, Sadakazu YOKOMORI, Chika ITO,
Yoshihiko ISOBE, and Makoto MURAMATSU
Research Center Taisho Pharmaceutical Co., Ltd., 1–403 Yoshino-Cho, Ohmiya, Saitama 330–8530, Japan.
Received June 29, 2000; accepted October 12, 2000
A series of 8؅-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecar-
boxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig
ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-
isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 re-
ceptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no
affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in
conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951
may be useful in improving gastrointestinal dysfunction.
Key words quinolinecarboxamide; TS-951; serotonin 5-HT4 receptor agonist; structure–activity relationship
Serotonin (5-HT) is a neurotransmitter which is widely tropane derivatives (12—38). In the original route, the 8Ј-
distributed in the human body and has a variety of physiolog- methyl group is a protective group and required deprotection
ical effects. 5-HT receptors include seven subtypes.1,2) The 5- step. We examined direct synthesis of 3-amino-8-(3-hy-
HT4 receptor was discovered by Dumuis et al. in 19883) and droxy)propyl-8-azabicyclo[3.2.1]octane (9) in order to avoid
its existence in the gut was later proved. 5-HT4 receptors in
the gut are suggested to participate in the induction and
maintenance of gastrointestinal motility. It has been reported
that 5-HT4 receptor agonists, cisapride4) and renzapride,5,6)
are reported to increase gastrointestinal motility and improve
gastrointestinal condition. We recently reported N-(endo-8-
methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-
dihydro-3-quinolinecarboxamide (10a) as a potent 5-HT4 re-
ceptor agonist.7) In the course of study, 1-alkyl substituents
had a great influence upon 5-HT4 receptor agonistic activity.
Next, we took note of an influence of 8Ј-alkyl substituents
upon 5-HT4 receptor agonistic activity. In the present study,
we synthesized and evaluated 8Ј-position substituted N-
(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-di-
hydro-3-quinolinecarboxamide derivatives with the aim of
finding more potent and selective 5-HT4 receptor agonists.
Chemistry
Preparation of compounds 12—38 was performed follow-
ing the synthetic pathway depicted in Chart 1. 2-Amino-
benzyl alcohol (1) was reacted with acetone to obtain 1,2-di-
hydro-2,2-dimethyl-4H-3,1-benzoxazine (2) in 93% yield,
which was reduced to 2-isopropylaminobenzyl alcohol (3) by
catalytic hydrogenation in 79% yield.8) Compound 3 was oxi-
dized with manganese dioxide to give benzaldehyde (4),
which was reacted with Meldrum’s acid (2,2-dimethyl-1,3-
dioxane-4,6-dione) in the presence of ethylenediamine and
acetic acid in MeOH. Carboxylic acid (5) was led to carbonyl
chloride (6) through chlorination with thionylchloride. Car-
bonyl chloride (6) was coupled with 3-amino-8-methyl-8-aza-
bicyclo[3.2.1]octane (7)9) to give carboxamide (10a), or with
tropine (8) to give carboxylate (10b). Demethylation of com-
pound 10a and 10b with 1-chloroethyl chloroformate pro-
vided the corresponding desmethyltropane,10) which was
Chart 1
alkylated with various alkyl halides to give 8Ј-substituted
To whom correspondence should be addressed. e-mail: s13845@ccm.taisho.co.jp
© 2001 Pharmaceutical Society of Japan

30
Vol. 49, No. 1
ED50 (nM)
Table 1. Structures and Pharmacological Activities in Vitro
Compound
R
X
11a
10a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
29a
30a
31a
32a
33a
34a
35a
36a
37a
38a
Cisapride
H
Me
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
73.6
36.3
59.2
955
45.9
32.0
38.5
30.8
62.3
15.0
18.7
136
CH2CHϭCH2
CH2CϵCH
(CH2)2OH
(CH2)3OH
(CH2)4OH
(CH2)5OH
(CH2)6OH
(CH2)2OMe
(CH2)2OEt
(CH2)2O(CH2)2OMe
(CH2)2NEt2
(CH2)2SMe
(CH2)2SO2C6H5
CH2CH2-morphorino
CH2CH2-piperidino
CH2-(2-pyranyl)
CH2CH2OC6H5
CH2CO2Et
155
48.0
86.6
25.5
202
24.0
140
84.4
66.1
19.3
91.4
718
11.5
52.3
184
Chart 2
CH2CO2H
(CH2)3CO2Et
(CH2)3CO2H
COMe
CH2COMe
(CH2)3COMe
CH2CN
(CH2)2CN
CH2CONH2
35.8
61.9
271
Table 2. Structure and Pharmacological Activities in Vitro
Compound
R
X
ED50 (nM)
11b
10b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
27b
28b
29b
34b
35b
36b
37b
38b
H
Me
(CH2)2OH
(CH2)3OH
(CH2)4OH
(CH2)5OH
(CH2)6OH
(CH2)2OMe
(CH2)2OEt
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
40.1
21.3
16.1
11.9
16.6
25.5
50.9
18.4
15.2
73.7
72.6
29.5
46.5
30.8
55.9
39.0
249
Fig. 1
deprotection step (Chart 2). 2,5-Dimethoxytetrahydrofuran
(39) was hydrolyzed to succinaldehyde (40) under acidic
conditions. Succinaldehyde (40), 3-hydroxypropylamine and
acetonedicarboxylic acid were condensed in buffer solution
at pH 3—4 to give tropinone (41), which was converted to
tropinone oxime (42).11) The reduction of oxime (42) to
amine (9) was accomplished by catalytic reduction using
Adams catalyst.9) Compound (9) was reacted with 6 under
general conditions. Thus, 3-hydroxypropyl group on 8Ј-posi-
tion could be introduced beforehand and no further use for
deprotection step.
(CH2)2O(CH2)2OMe
(CH2)2NEt2
(CH2)2SMe
(CH2)2SO2C6H5
CH2CH2-morphorino
CH2-(2-pyranyl)
CH2CH2OC6H5
CH2CO2Et
CH2COMe
(CH2)3COMe
CH2CN
(CH2)2CN
CH2CONH2
24.6
26.4
740
27.3
31.4
Results and Discussion
The 5-HT4 receptor agonistic activities of 8Ј-position sub-
stituted compounds were measured on longitudinal muscle of
guinea pig ileum. The 50% effective doses (ED50) of these
compounds are shown in Tables 1 and 2. N-(endo-8-Methyl-
8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-
3-quinolinecarboxamide (11a) was used as a starting point to
evaluate the effect of 8Ј-position substitution. We selected
short-chain as substituents that included unsaturated bonds or
heteroatoms. Our preliminary study, simple alkyl substitution
of 8Ј-position had a slight effect on 5-HT4 receptor agonistic
activity.12) Just as in our preliminary study, removal of the 8Ј-
methyl group (10a) slightly decreased 5-HT4 receptor ago-
nistic activity. We first tested replacement of the methyl
group by an unsaturated alkyl group (12a, 13a). Introduction
of a double bond (12a) yielded results identical to those with
11a, but introduction of a triple bond led to decrease in activ-
ity. It appears that introduction of an unsaturated alkyl group
is not effective. We next replaced a carbon with a het-

January 2001
31
Table 3. Affinities of TS-951 and Other 5-HT4 Receptor Agonists in Receptor Binding Assay
% of Control specific binding
Cisapride Mosapride
TS-951
1
Receptor Subtype
Tissue membrane
Ligand
(mmol/l)
0.1
10
0.1
1
10
0.1
1
10
5-HT
5-HT1A
5-HT1B
5-HT1D
5-HT2A
5-HT2C
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
s1
Human recombinant (CHO cells)
Rat cerebral cortex
Bovine caudate
Human recombinant (CHO cells)
Human recombinant (CHO cells)
Rat cerebral cortex
[3H]8-OH-DPAT
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
51 82
—
—
—
—
—
—
—
—
—
60
—
—
57
[
125I]CYP
—
—
—
—
[3H]5-HT
[3H]Ketanserin
[3H]Mesulergine
[3H]GR65630
[3H]GR113808
[3H]LSD
80 98 101
50 82
—
52 93
1555.7Ϯ587.2
11.8Ϯ1.6
183.0Ϯ23.1
21.9Ϯ3.1
—
—
—
—
1020.2Ϯ101.3 (Ki, nmol/l)
51.6Ϯ9.6 (Ki, nmol/l)
—
—
—
—
—
Guinea pig striatum
Human recombinant (CHO cells)
Human recombinant (CHO cells)
Human recombinant (CHO cells)
Guinea pig cerebral cortex
Rat cerebral cortex
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
[49]
62
—
—
—
72 98
— 73
—
55
—
[3H]LSD
[3H]LSD
Sigma
[3H](ϩ)Pentazocine
[3H]DTG
65 87
s2
[47] 93
61 100 103
(ϩ300 nM (ϩ)Pentazocine)
—: Inhibitive potency was less than 50%.
eroatom. Hydroxy substitutions (14a—18a) were slightly easily hydrolyzed. We could not prepare caboxylic acid de-
more potent, with ED50 values of 32.0 nM (15a, TS-951) and rivatives (30b, 32b) because they readily underwent hydroly-
30.8 nM (17a). Ether substitutions (19a, 20a) resulted in more sis. It was therefore anticipated that ester compounds would
potent activity, with ED50 values of 15.0 nM (19a) and be decomposed easily in vivo.
18.7 nM (20a). However, compound 21a was 10 times less
Receptor Selectivity of TS-951 Standard techniques
potent than other ether compounds. This suggests that appro- were used to identify radioligand binding to each membrane
priate length of alkyl chain is important in obtaining potent tested.13) The tissues and radiolabelled ligands used are
activity. Replacement of the oxygen of the ether with nitro- presented in Tables 3, 4 and 5. In the displacement study,
gen (22a) or sulfur (23a) resulted in compounds that were TS-951 concentration-dependently inhibited specific [3H]-
less potent than 19a. Oxygen is preferable as a heteroatom GR113808 binding to 5-HT4 receptors in membranes derived
among 8Ј-position substituents, which is also preferable 2—3 from guinea pigs striatum.14) Other 5-HT4 receptor agonists,
atom distance from tropane nitrogen. About cyclic sub- cisapride and mosapride,15) also inhibited the specific binding
stituents, compound 25a (ED50ϭ25.5 nM) was 6 times as po- of [3H]GR113808 in a concentration-dependent manner. Ki
tent as 26a (ED50ϭ202 nM). The difference between 25a and values derived from these curves are presented in Table 3.
26a in structure was only morpholine oxygen. It appeared TS-951 had no affinity for other broad spectrum receptors,
that an additional oxygen atom at an approximately 6-atom although it had a weak affinity for 5-HT3 receptors (Tables
distance from tropane nitrogen yielded increase in activity. 3—5). On the other hand, cisapride and mosapride had
We next investigated carbonyl substituents. Compound 31a affinities for other neurotransmitter receptors, such as 5-
had an ester introduced at the distance of three methylenes HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, s1 and s2 receptors
from tropane nitrogen, a position of ester oxygen that corre- (Table 3).
sponded to the above additional oxygen atom. Compound
Intrinsic Activity of TS-951 We investigated the func-
31a exhibited potent activity, with an ED50 of 19.3 nM. Nev- tional effects of TS-951 using 5-HT4 receptor-mediated con-
ertheless, the agonistic activity of carboxylic acid (32a), the tractions in guinea pig distal colon. 5-HT, 5-MeOT, TS-951,
hydrolyzed compound of 31a, was mild. Compound 31a re- cisapride and BIMU816) caused concentration-dependent
quired ethyl group with ester function to exhibit potent 5- contraction of the longitudinal muscle of the guinea pig dis-
HT4 receptor agonistic activity. Short-chain ester (29a), the tal colon. However, mosapride was found to be inactive. The
corresponding carboxylic acid derivative (30a), and an amide indole agonists 5-HT and 5-MeOT had full agonist activity
derivative (38a) showed less potent activity than 31a. Of (intrinsic activity: 1.0). On the other hand, the intrinsic activ-
oxoalkyl compounds, compound 34a had the most potent 5- ities of TS-951, cisapride and BIMU8 were 0.72, 0.49 and
HT4 receptor agonistic activity (ED50ϭ11.5 nM). Thus, hy- 0.54, respectively. The results for all compounds tested are
droxyalkyl, alkoxyalkyl and oxoalkyl substituents at the 8Ј- summarized in Table 6.
position yielded potent 5-HT4 receptor agonistic activity. All
Effects of TS-951 on Gastric Antral Motility TS-951
heteroatoms of substituents must exist in the appropriate po- (0.003—0.3 mg/kg, p.o.) dose-dependently stimulated gastric
sitions. From among these compounds, we selected Com- antral motility in conscious fed dogs. Figure 2 shows typical
pound 15a (TS-951) as a candidate. Oxoalkyl substituted effects of TS-951 (0.1 mg/kg, p.o.). TS-951 (0.01—0.3 mg/kg,
compound (34a) was unstable, and alkoxyalkyl substituted p.o.) significantly increased motility index (M.I.) in the gas-
compounds (19a, 20a) seems to be possessed of side effect.
tric antrum (Fig. 3). Cisapride (0.3—3 mg/kg, p.o.) also stim-
To discriminate between amide and ester compounds, sev- ulated gastric antral motility in conscious fed dogs. Figure 2
eral ester compounds were synthesized. All ester compounds shows typical effects of cisapride (1 mg/kg, p.o.). Cisapride
exhibited more potent activity than amide compounds with (0.3—3 mg/kg, p.o.) significantly increased M.I. in the gas-
the same substituents. Nevertheless, ester compounds were tric antrum (Fig. 3).

32
Vol. 49, No. 1
Table 4. Affinities of TS-951 in Receptor Binding Assay
% of Control
TS-951 (mmol/l)
Receptor
Subtype
Tissue membrane
Ligand
0.1
1
10
Adenosine
Adrenergic
A1
A2
Rat cerebral cortex
Bovine striatum
Rat forebrain
Rat cerebral cortex
Rat cerebral cortex
Rat striatum
[3H]CPX
[3H]CGS 21680
[3H]Prazosin
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
53
—
—
—
—
—
—
53
—
55
—
—
—
—
—
—
—
—
—
—
—
a1
a2
[3H]RX 821002
[3H]Dihydroalprenolol
[3H]SCH 23390
[3H]Sulpiride
b
Dopamine
GABA
D1
D2
Rat striatum
GABAA
GABAB
H1
M1
M2
Neuronal
NMDA
Kainate
Quisqualate Rat forebrain
Rat spinal cord
Bovine cerebellum
Rat cerebral cortex
Bovine cerebellum
Bovine striatum
Rat heart
Rat cerebral cortex
Rat forebrain
Rat forebrain
[3H]GABA
[3H]GABA
Histamine
Muscarinic
[3H]Pyrilamine
[3H]Pirenzepine
[3H]AFDX 384
[3H]N-methyl-carbamyl choline iodide
[3H]CGS 19755
[3H]Kainic acid
[3H]AMPA
Nicotinic
Glutamate
Glycine (strychnine-sensitive)
Benzodiazepine
Glycine (strychnine-sensitive)
Phencyclidine
[3H]Strychnine
Central
Bovine cerebral cortex [3H]Flunitrazepam
Rat cerebral cortex
Rat forebrain
[3H]Glycine
PCP
Mu
Delta
Kappa
[3H]TCP
Opiate
Rat forebrain
[3H]Tyr-D-Ala-Gly-NMe-Phe-Gly-ol(DAMGO)
[3H]Enkephalin
Rat forebrain
Guinea pig cerebellum [3H]U69593
—: Inhibitive potency was less than 50%.
Table 5. Affinities of TS-951 and Other 5-HT4 Receptor Agonists in Receptor Binding Assay
% of Control
TS-951 (mmol/l)
Receptor
Subtype
Tissue membrane
Ligand
0.1
1
10
Thyroid Releasing Hormone
Corticotropin Releasing1 Factor
Neurokinin
Rat forebrain
Rat cerebral cortex
Rat SUBMX
[3H](3MeHis2)thyroidreleasing hormone
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
69
—
—
—
—
—
—
[
125I]Tyr-o-CRF
NK1
NK2
NK3
N
[3H]Substance P
Bovine duodenum
Rat cerebral cortex
Rat cerebral cortex
[
[
[
125I]Neurokinin A
125I]Eledoisin
Ca channel
125I]Omega-conotoxin
T & L
TBOB
ATP depentent
Low conductance
Voltage dependent
LTB4
LTD4
TXA2
Forskolin
Phorbol ester
DA
NE
5-HT
Choline
MAO-A
MAO-B
Rat cerebral cortex [3H]Nitrendipine
Rat cerebral cortex [3H]TBOB
Cl channel
K channel
Rat cerebral cortex [3H]Glibenclamide
Rat forebrain
Rat brain
[
[
125I]Apamin
125I]Charybdotoxin
Leukotriene
Guinea pig spleen
Guinea pig lung
Human platelets
Rat forebrain
Mouse brain
[3H]LTB4
[3H]LTD4
Prostanoid
[3H]SQ 29548
[3H]Forskolin
Adenylate Cyclase
Protein Kinase C
Uptake Site
[3H]Phorbol ester dibutyrate
Guinea pig striatum [3H]WIN 35428
Rat forebrain
Rat forebrain
[3H]Desmethylimipramine
[3H]Citalopram
Rat cerebral cortex [3H]Choline chloride
Mono-Amine Oxidase
Rat liver
Rat liver
[14C]5-HT
[14C]Phenylethylamine
[3H]Nitroarginine
NO Synthase
Acetylcholinesterase
Choline Acetyltransferase
Rat striatum
[14C]Acetyl coenzyme A
—: Inhibitive potency was less than 50%.
Effects of TS-951 on Colonic Motility The agonistic ef- transient high-amplitude contractions with rapid-propagating
fect of TS-951 on colonic motility was characterized by in- velocity (Fig. 4). TS-951 also induced the defecation in some
duction of giant migrating complex (GMC)-like patterns i.e., dogs without causing diarrhea and vomit (Fig. 5). TS-951

January 2001
33
Table 6. The Contractile Potency and Efficacy of 5-HT4 Receptor Agonists in the Guinea-Pig Ileum and Distal Colon
Ileuma)
Distal colon
i.ab)
EC50 (nmol/l)
n
EC50 (nmol/l)
n
5-HT
5-MeOT
TS-951
Cisapride
Mosapride
BIMU8
8.3Ϯ 2.0
19.5Ϯ 4.9
31.9Ϯ 9.5
237.1Ϯ39.3
163.5Ϯ35.7
93.4Ϯ18.3
3
3
4
3
4
6
6.3Ϯ 0.5
20.8Ϯ 7.0
20.1Ϯ 3.4
155.8Ϯ33.0
inactive
1
4
5
5
5
4
5
1.03Ϯ0.05
0.72Ϯ0.01
0.49Ϯ0.07
156.6Ϯ65.6
0.54Ϯ0.03
Each value represents the meanϮS.E. a) Electrically evoked twich response. b) i.a.: intrinsic activity.
Fig. 2. Effects of TS-951 and Cisapride on Gastric Antral Motility in Conscious Fed Dogs
Fig. 3. Effects of TS-951 and Cisapride on Gastric Antral Motility in Conscious Fed Dogs
(0.03 mg/kg, p.o.) induced high-amplitude contractions and/ Although cisapride (3 mg/kg, p.o.) induced defecation in
or defecation in four tested dogs out of seven. TS-951 (0.1 three tested dogs out of five, diarrhea, vomit or retrograde
and 0.3 mg/kg, p.o.) induced high-amplitude contractions peristaltic contractions were also observed in certain dogs
and/or defecation in six tested dogs out of seven (Fig. 5). (Fig. 5). It is suggested that TS-951 is superior to non-selec-
Cisapride (0.3, 1, 3 mg/kg, p.o.) induced high-amplitude con- tive 5-HT4 receptor agonists due to its reduced side effects.
tractions or defecation (Fig. 5). However, cisapride (1 mg/kg, Namely, the selective 5-HT4 receptor agonist TS-951 induced
p.o.) caused vomit and retrograde peristaltic contractions defecation without unfavorable effects that non-selective 5-
without inducing defecation in one tested dog out of five. HT4 receptor agonist cisapride has.

34
Vol. 49, No. 1
Fig. 4. Effect of TS-951 on Colonic Motility in Conscious Fed Dogs
Fig. 5. Effects of TS-951 and Cisapride on Colonic Function in Conscious Fed Dogs
Conclusion
compound to improve gastrointestinal dysfunction.
We have investigated the potencies of 2-oxo-1,2-dihydro-
3-quinolinecarboxamide derivatives as 5-HT4 receptor ago-
nists. Of the compounds synthesized, N-(endo-8-(3-hy-
droxy)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) was
optimal. It showed 7 times as potent 5-HT4 receptor agonistic
activity as cisapride in the regulation of electrically-evoked
contraction in guinea pig muscle. TS-951 is selective for 5-
HT4 receptors as shown in receptor binding assay. This com-
pound enhanced gastric antral and colonic motility in the fed
dogs. Furthermore it induced defecation without vomit and
Experimental
Melting points were determined by a Büchi 535 melting point apparatus
and are uncorrected. IR spectra (KBr) were taken on a Perkin-Elmer 1760
spectrometer. 1H-NMR spectra were recorded on a Varian VXL-200 spec-
trometer. Chemical shifts are reported in ppm (d) values, based on tetram-
ethylsilane as an internal standard. MS were taken on a JEOL JMS-SX102
spectrometer. Elemental analyses were taken on a Perkin-Elmer 2400. TLC
was performed on silica-gel pre-coated plates (Merck, Kieselgel 60F-254).
Column chromatography was carried out over silica gel (Asahi glass, M. S.
GEL. SIL.). Organic solutions during work-up were dried using anhydrous
Na2SO4.
1,2-Dihydro-2,2-dimethyl-4H-3,1-benzoxadine (2) Acetone (403 g,
retrograde peristeltic contractions. TS-951 is a promising 6.94 mol) was added to a mixture of 2-aminobenzyl alcohol (1) (500 g,

January 2001
35
1
4.63 mol), acetic acid (8.3 g, 0.14 mol) and water (4000 g). The reaction mix-
ture was stirred at room temperature for 1 h and was then stirred at 0 °C for
1 h. Resulting precipitates were collected by filtration, washed with water
and dried, to give 700 g (93%) of 2 as a yellow solid. mp 119—121 °C (re-
crystallized from acetone–H2O). 1H-NMR (CDCl3) d: 1.48 (6H, s), 3.97
(1H, s), 4.83 (2H, s), 6.64 (1H, d, Jϭ7.0 Hz), 6.79 (1H, t, Jϭ7.0 Hz), 6.95
(1H, d, Jϭ7.0 Hz), 7.08 (1H, t, Jϭ7.0 Hz). IR (KBr) cmϪ1: 3310, 1612,
1592. MS (EI) m/z: 163 (Mϩ). Anal. Calcd for C10H13NO: C, 73.59; H, 8.03;
N, 8.58. Found: C, 73.40; H, 7.97; N, 8.64.
mp 252—254 °C. H-NMR (DMSO-d6) d: 1.65 (6H, d, Jϭ7.0 Hz), 1.90—
2.20 (2H, m), 2.20—2.35 (3H, m), 2.78 (3H, d), 2.80—2.92 (1H, m), 3.06—
3.25 (2H, m), 5.41 (1H, t, Jϭ4.6 Hz), 5.30—5.65 (1H, br), 7.29—7.30 (1H,
m), 7.55—7.70 (3H, m), 8.32 (1H, s), 12.20—12.50 (1H, br). IR (KBr)
cmϪ1: 3538, 3424, 1709, 1656, 1619, 1565. MS (EI) m/z: 354 (Mϩ). Anal.
Calcd for C21H26N2O3·HCl·0.25H2O: C, 63.79; H, 7.01; N, 7.08. Found: C,
63.75; H, 7.40; N, 7.05.
N-(endo-8-Azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-
quinolinecarboxamide (11a) 1-Chloroethyl chloroformate (0.41 g, 2.8
2-Isopropylaminobenzyl Alcohol (3) A mixture of 2 (7.0 g, 43 mmol),
5%Pt/C (0.14 g) and MeOH (70 ml) was heated at 40 °C under a hydrogen
atmosphere. The reaction mixture was filtered and the filtrate was concen-
trated in vacuo. The residue was dissolved in toluene and washed with water.
The solution was evaporated in vacuo to give 5.6 g (79%) of 3 as a yellow
oil. bp 114 °C (4 mmHg). 1H-NMR (CDCl3) d: 1.24 (6H, d, Jϭ7.2 Hz), 3.78
(1H, sept, Jϭ7.2 Hz), 4.62 (2H, s), 6.57—6.72 (2H, m), 7.02—7.05 (1H, m),
7.15—7.27 (1H, m). IR (neat) cmϪ1: 3391, 1608, 1587. MS (EI) m/z: 165
(Mϩ). Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C,
72.30; H, 9.33; N, 8.88.
2-Isopropylaminobenzaldehyde (4) A mixture of 3 (33.62 g, 0.20 mol),
manganese (IV) oxide (44.12 g, 0.51 mol) and toluene (300 ml) was refluxed
for 2 h. The reaction mixture was filtered, and filtrate was evaporated in
vacuo. The residue was purified by column chromatography using hexane/
AcOEtϭ10 : 1 to give 20.59 g (62%) of 4 as a yellow oil. 1H-NMR (CDCl3)
d: 1.28 (6H, d, Jϭ6.4 Hz), 3.75 (1H, sept, Jϭ6.4 Hz), 6.61—6.72 (2H, m),
7.33—7.47 (2H, m), 8.28 (1H, br), 9.80 (1H, s). IR (neat) cmϪ1: 3317, 1652,
1610, 1579. MS (EI) m/z: 163 (Mϩ).
1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic Acid (5) Mel-
drum’s acid (2,2-dimethyl-1,3-dioxan-4,6-dione, 1.59 g, 11.0 mmol) was
added to a mixture of ethylenediamine (0.41 ml, 6.1 mmol), acetic acid
(0.70 ml, 12.2 mmol) and 4 (1.00 g, 6.13 mmol) at 0 °C. The reaction mixture
was stirred at room temperature overnight and was then acidified with di-
luted HCl. The resulting precipitate was collected by filtration and washed
with water to give 1.17 g (83%) of 5 as a colorless powder. mp 167—169 °C
(recrystallized from acetone–H2O). 1H-NMR (CDCl3) d: 1.71 (6H, d,
Jϭ7.2 Hz), 5.25—5.75 (1H, br), 7.36—7.45 (1H, m), 7.69—7.85 (3H, m),
8.88 (1H, s), 14.76 (1H, s). IR (KBr) cmϪ1: 1734, 1631. MS (EI) m/z: 231
(Mϩ). Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C,
67.42; H, 5.54; N, 6.07.
mmol) was added to
a solution of 10a (1.0 g, 2.8 mmol) in 1,2-
dichloroethane (10 ml) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and
then refluxed for 1 h. The reaction mixture was evaporated in vacuo and the
residue was dissolved in MeOH (10 ml). The MeOH solution was refluxed
for 1 h and the solution was evaporated in vacuo. The residue was purified
by column chromatography using CHCl3/MeOH saturated with NH3ϭ20 : 1,
and recrystallized from AcOEt to give 530 mg (55%) of 11a as a colorless
solid. mp 202—203 °C. 1H-NMR (CDCl3) d: 1.69 (6H, d, Jϭ7.2 Hz), 1.78—
2.40 (9H, m), 3.55—3.68 (2H, m), 4.38 (1H, q, Jϭ7.0 Hz), 5.40—5.82 (1H,
br), 7.23—7.35 (1H, m), 7.56—7.70 (2H, m), 7.75 (1H, d, Jϭ7.8 Hz), 8.83
(1H, s), 10.54 (1H, d, Jϭ7.2 Hz). IR (KBr) cmϪ1: 3257, 2971, 1674, 1622,
1569, 1531. MS (EI) m/z: 339 (Mϩ). Anal. Calcd for C20H25N3O2: C, 70.77;
H, 7.42; N, 12.38. Found: C, 70.57; H, 7.49; N, 12.44.
endo-8-Azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-1,2-dihydro-3-
quinoline carboxylate (11b) Demethylation of 10b was conducted using
a procedure similar to that employed in the synthesis of 11a. 50.2%, a
colorless solid. mp 137—140 °C (recrystallized from diisopropyl ether).
1H-NMR (CDCl3) d: 1.67 (6H, d, Jϭ7.2 Hz), 1.81—2.34 (8H, m), 2.45—
2.62 (br, 1H), 3.53—3.67 (2H, m), 5.33 (1H, t, Jϭ7.0 Hz), 5.30—5.75
(1H, br), 7.19—7.27 (1H, m), 7.54—7.68 (3H, m), 8.23 (1H, s). IR (KBr)
cmϪ1: 3286, 1694, 1647. MS (EI) m/z: 340 (Mϩ). Anal. Calcd for
C20H24N2O3·0.25H2O: C, 69.58; H, 7.16; N, 8.12. Found: C, 69.54; H, 7.19;
N, 7.98.
N-(endo-8-(3-Hydroxy)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951)
A
mixture of 11a (2.00 g, 5.9 mmol), 3-bromo-1-propanol (0.53 ml, 5.9 mmol),
K2CO3 (0.81 g, 5.9 mmol) and EtOH (50 ml) was refluxed for 10 h. The reac-
tion mixture was evaporated in vacuo to give a residue, which was parti-
tioned between water and CHCl3. The organic layer was dried and evapo-
rated in vacuo. The residue was purified by column chromatography using
CHCl3/MeOH saturated with NH3ϭ40 : 1, and recrystallized from AcOEt to
give 510 mg (21.8%) of 15a as a colorless solid. mp 171—172 °C. 1H-NMR
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.62—1.78 (2H, m), 1.80—196 (2H, m),
2.00—2.38 (6H, m), 2.72 (2H, t, Jϭ7.0 Hz), 3.32—3.52 (2H, m), 3.88 (2H,
t, Jϭ7.0 Hz), 4.30 (1H, q, Jϭ7.0 Hz), 5.45— 5.80 (1H, br), 7.23—7.33 (1H,
m), 7.56—7.70 (2H, m), 7.75 (1H, d, Jϭ7.8 Hz), 8.83 (1H, s), 10.51 (1H, d,
Jϭ7.2 Hz). IR (KBr) cmϪ1: 3431, 3240, 1669. MS (EI) m/z: 397 (Mϩ). Anal.
Calcd for C23H31N3O3: C, 69.49; H, 7.86; N, 10.57. Found: C, 69.22; H,
7.90; N, 10.43.
1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonylchloride (6)
A
mixture of 5 (10.0 g, 43.2 mmol) and thionyl chloride (20 ml, 274 mmol) was
refluxed for 4 h. The reaction mixture was evaporated in vacuo to leave a
residue, which was dissolved in toluene (30 ml). It was evaporated in vacuo
again to give 10.6 g (98%) of 6 as a pale yellow solid.
N-(endo-8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-
1,2-dihydro-3-quinolinecarboxamide (10a) A solution of 3-Amino-8-
methyl-8-azabicyclo[3.2.1]octane (7) (404 mg, 2.8 mmol) in toluene (3 ml)
was added to a solution of 6 (540 mg, 2.2 mmol) in toluene (2 ml). The reac-
tion mixture was stirred at room temperature for 1 h. The reaction mixture
was then poured into 5%NaOH and extracted with CHCl3. The extract was
washed with brine, dried and evaporated in vacuo. The residue was purified
by column chromatography using CHCl3, recrystallized from AcOEt to give
391 mg (51%) of 10a as a colorless solid. mp 173—177 °C. 1H-NMR
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.76—1.83 (2H, m), 2.00—2.40 (6H,
m), 2.34 (3H, s), 3.10—3.28 (2H, m), 4.30 (1H, q, Jϭ7.0 Hz), 5.40—5.90
(1H, br), 7.22—7.33 (1H, m), 7.55—7.70 (2H, m), 7.75 (1H, d, Jϭ7.8 Hz),
8.83 (1H, s), 10.48 (1H, d, Jϭ7.2 Hz). IR (KBr) cmϪ1: 3263, 2961, 1673,
1616, 1585, 1568, 1528. MS (EI) m/z: 353 (Mϩ). Anal. Calcd for
C21H27N3O2: C, 71.36; H, 7.70; N, 11.88. Found: C, 71.21; H, 7.67; N,
11.84.
endo-8-Methyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-1,2-dihy-
dro-3-quinolinecarboxylate Hydrochloride (10b) Tropine (8) (5.65 g,
40.0 mmol) was added to a suspension of sodium hydride (60% mineral oil
suspension, 1.60 g, 40.0 mmol) in tetrahydrofuran (THF) (100 ml), and the
reaction mixture was refluxed for 2 h. After being cooled to 0 °C, 6 (8.33 g,
33.4 mmol) was added. The reaction mixture was stirred at room tempera-
ture for 1 h. The reaction mixture was diluted with water, and the mixture
was acidified with diluted HCl. The aqueous layer was washed with AcOEt.
The aqueous layer was made basic with K2CO3 and extracted with CHCl3.
The extract was dried and evaporated in vacuo. The resulting residue was
crystallized from diisopropyl ether to give 2.12 g (18%) of a colorless pow-
der, which was dissolved in EtOH (10 ml) and concentrated HCl (1 ml) was
added. The mixture was evaporated in vacuo to afford a residue, which was
recrystallized from EtOH to give 1.25 g (8.0%) of 10b as a colorless solid.
N-(endo-8-(6-Hydroxy)hexyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxamide Hydrochloride (18a)
A
mixture of 11a (1.00 g, 2.7 mmol), 6-chloro-1-hexanol (0.30 ml, 2.7 mmol),
K2CO3 (1.11 g, 8.0 mmol), KI (0.44 g, 2.7 mmol) and N,N-dimethylform-
amide (DMF) (20 ml) was heated at 100 °C for 5 h. The reaction mixture was
poured into water and extracted with CHCl3. The extract was dried and
evaporated in vacuo to give a residue. The residue was purified by column
chromatography using CHCl3/MeOH saturated with NH3ϭ20 : 1, to give a
yellow gum. It was dissolved in MeOH and concentrated HCl was added.
The mixture was concentrated in vacuo and crystallized from 2-propanol
(IPA). The crude product was recrystallized from IPA to give 667 mg
(52.5%) of 18a as a colorless solid. mp 251—253 °C. 1H-NMR (dimethyl
sulfoxide (DMSO)-d6) d: 1.33—1.90 (8H, m), 1.68 (6H, d, Jϭ7.2 Hz),
2.10—2.65 (8H, m), 2.97—3.20 (2H, m), 3.58 (2H, t, Jϭ7.0 Hz), 4.02—
4.18 (2H, m), 4.32 (1H, q, Jϭ7.0 Hz), 5.35—5.80 (1H, br), 7.34—7.43 (1H,
m), 7.71—7.81 (1H, m), 7.83—7.92 (2H, m), 8.81 (1H, s). IR (KBr) cmϪ1
:
3368, 1671. MS (EI) m/z: 439 (Mϩ). Anal. Calcd for C26H37N3O3·HCl·
0.5H2O: C, 64.38; H, 7.90; N, 8.66. Found: C, 64.33; H, 8.17; N, 8.49.
N-(endo-8-Alkyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-di-
hydro-3-quinolinecarboxamides (12a—38a) The alkylation of com-
pound 11a was conducted in a similar procedure as employed in the synthe-
sis of 15a and 18a. HCl salts of alkylated compounds were made using a
procedure similar to that employed in the synthesis of 11b.
N-(endo-8-(2-Propenyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-
1,2-dihydro-3-quinolinecarboxamide (12a) 47.7%, colorless prism. mp
126—128 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.68 (6H, d,

36
Vol. 49, No. 1
C25H35N3O4·HCl·0.8H2O: C, 60.98; H, 7.70; N, 8.53. Found: C, 60.97; H,
8.07; N, 8.52.
Jϭ7.2 Hz), 1.74—1.88 (2H, m), 2.05—2.15 (4H, m), 2.21—2.38 (2H, m),
3.08 (2H, d, Jϭ7.0 Hz), 3.25—3.35 (2H, m), 4.33 (1H, q, Jϭ7.0 Hz), 5.10—
5.27 (2H, m), 5.40—5.80 (br, 1H), 5.95 (1H, ddd, Jϭ7.0, 10.0, 17.0 Hz),
7.22—7.33 (1H, m), 7.56—7.70 (2H, m), 7.75 (1H, d, Jϭ7.8 Hz), 8.83 (1H,
s), 10.50 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 3249, 1676. MS (EI) m/z: 379
(Mϩ). Anal. Calcd for C23H29N3O2: C, 72.79; H, 7.70; N, 11.07. Found: C,
72.51; H, 7.67; N, 11.03.
N-(endo-8-(2-Propargyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxamide (13a) 69.9%, colorless prism.
mp 201—203 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.69
(6H, d, Jϭ7.2 Hz), 1.80—1.95 (2H, m), 2.07—2.24 (4H, m), 2.27 (1H, t,
Jϭ2.0 Hz), 2.29—2.47 (2H, m), 3.27 (2H, d, Jϭ7.0 Hz), 3.43—3.53 (2H,
m), 4.32 (1H, q, Jϭ7.0 Hz), 5.35—5.87 (1H, br), 7.23—7.33 (1H, m),
7.57—7.70 (2H, m), 7.75 (1H, d, Jϭ7.8 Hz), 8.84 (1H, s), 10.52 (1H, d,
Jϭ7.5 Hz). IR (KBr) cmϪ1: 3193, 2113, 1672. MS (EI) m/z: 377 (Mϩ). Anal.
Calcd for C23H27N3O2: C, 73.18; H, 7.21; N, 11.13. Found: C, 72.94; H,
7.16; N, 11.12.
N-(endo-8-(2-Hydroxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxamide (14a) 30.1%, colorless solid.
mp 160—162 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.68
(6H, d, Jϭ7.2 Hz), 1.78—1.92 (2H, m), 1.98—2.40 (6H, m), 2.59 (2H, t,
Jϭ7.0 Hz), 3.25—3.35 (2H, m), 3.60 (2H, t, Jϭ7.0 Hz), 4.32 (1H, q,
Jϭ7.0 Hz), 5.48—5.80 (1H, br), 7.23—7.34 (1H, m), 7.57—7.70 (2H, m),
7.76 (1H, d, Jϭ7.8 Hz), 8.84 (1H, s), 10.50 (1H, d, Jϭ7.5 Hz). IR (KBr)
cmϪ1: 3232, 1669. MS (EI) m/z: 383 (Mϩ). Anal. Calcd for C22H29N3O3: C,
68.90; H, 7.62; N, 10.96. Found: C, 68.70; H, 7.60; N, 10.79.
N-(endo-8-(4-Hydroxy)butyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxamide (16a) 18.4%, colorless solid.
mp 162—164 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.68
(6H, d, Jϭ7.2 Hz), 1.60—1.92 (6H, m), 2.00—2.20 (4H, m), 2.24—2.40
(2H, m), 2.42—2.53 (2H, m), 3.29—3.38 (2H, m), 3.57—3.66 (2H, m), 4.33
(1H, q, Jϭ7.0 Hz), 5.50—5.80 (1H, br), 7.23—7.33 (1H, m), 7.56—7.70
(2H, m), 7.75 (1H, d, Jϭ7.8 Hz), 8.83 (1H, s), 10.51 (1H, d, Jϭ7.5 Hz). IR
(KBr) cmϪ1: 3411, 3260, 1667. MS (EI) m/z: 411 (Mϩ). Anal. Calcd for
C24H33N3O3: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.09; H, 8.12; N,
10.23.
N-(endo-8-(5-Hydroxy)pentyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxamide (17a) 18.4%, colorless solid.
mp 148—150 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.68
(6H, d, Jϭ7.2 Hz), 1.40—1.92 (8H, m), 2.10—2.30 (4H, m), 2.40—2.70
(4H, m), 3.40—3.60 (2H, m), 3.67 (2H, t, Jϭ6.8 Hz), 4.35 (1H, q,
Jϭ7.0 Hz), 5.50—5.80 (1H, br), 7.22—7.35 (1H, m), 7.59—7.70 (2H, m),
7.75 (1H, d, Jϭ7.8 Hz), 8.83 (1H, s), 10.55 (1H, d, Jϭ7.5 Hz). IR (KBr)
cmϪ1: 3452, 3257, 1668. MS (EI) m/z: 425 (Mϩ). Anal. Calcd for
C25H35N3O3·0.3H2O: C, 69.67; H, 8.32; N, 9.75. Found: C, 69.51; H, 8.21;
N, 9.66.
N-(endo-8-(2-Methoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxamide Hydrochloride (19a)
28.4%, colorless solid. mp 247—249 °C (recrystallized from EtOH). 1H-
NMR (DMSO-d6) d: 1.68 (6H, d, Jϭ7.2 Hz), 2.05—2.24 (2H, m), 2.25—
2.60 (4H, m), 3.10—3.20 (2H, m), 3.20—3.30 (1H, m), 3.38 (3H, s), 3.30—
3.55 (1H, m), 3.95—4.18 (4H, m), 4.07 (1H, q, Jϭ7.0 Hz), 5.30—5.80 (1H,
br), 7.26—7.36 (1H, m), 7.65 (1H, s), 7.67 (1H, s), 7.77 (1H, d, Jϭ7.6 Hz),
8.85 (1H, s), 10.68 (1H, d, Jϭ7.5 Hz), 11.90—12.25 (1H, br). IR (KBr)
cmϪ1: 3428, 1671. MS (EI) m/z: 397 (Mϩ). Anal. Calcd for C23H31N3O3·
HCl·H2O: C, 61.12; H, 7.58; N, 9.29. Found: C, 61.15; H, 7.70; N, 9.03.
N-(endo-8-(2-Ethoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxamide (20a) 58.7%, colorless solid.
mp 99—100 °C (recrystallized from diisopropyl ether). 1H-NMR (CDCl3) d:
1.20 (3H, t, Jϭ7.2 Hz), 1.68 (6H, d, Jϭ7.2 Hz), 1.70—1.85 (2H, m), 1.95—
2.20 (4H, m), 2.20—2.44 (2H, m), 2.67 (2H, t, Jϭ7.0 Hz), 3.31—3.39 (2H,
m), 3.53 (2H, q, Jϭ7.2 Hz), 3.61 (2H, t, Jϭ7.0 Hz), 4.30 (1H, q, Jϭ7.0 Hz),
5.40—5.80 (1H, br), 7.24—7.33 (1H, m), 7.56—7.70 (2H, m), 7.76 (1H, d,
Jϭ7.8 Hz), 8.84 (1H, s), 10.50 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 3269,
1671. MS (EI) m/z: 411 (Mϩ). Anal. Calcd for C24H33N3O3: C, 70.04; H,
8.08; N, 10.21. Found: C, 69.93; H, 8.14; N, 10.09.
N-(endo-8-(2-Diethylamino)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide Dihydrochloride (22a)
52.2%, colorless solid. mp 179—186 °C (recrystallized from EtOH–ace-
1
tone). H-NMR (CDCl3) d: 1.47 (6H, t, Jϭ7.2 Hz), 1.68 (6H, d, Jϭ7.2 Hz),
2.15—2.30 (2H, m), 2.40—2.80 (4H, m), 2.95—3.40 (6H, m), 3.65—3.90
(4H, m), 3.90—4.15 (2H, m), 4.44 (1H, q, Jϭ6.3 Hz), 5.40—5.80 (1H, br),
7.25—7.35 (1H, m), 7.64 (1H, s), 7.65 (1H, s), 7.76 (1H, d, Jϭ7.8 Hz), 8.81
(1H, s), 10.78 (1H. d, Jϭ7.5 Hz), 12.10—12.40 (2H, br). IR (KBr) cmϪ1
:
3420, 1673. MS (CI) m/z: 439 (Mϩ1). Anal. Calcd for C26H38N4O2·2HCl·
1.3H2O: C, 58.37; H, 8.02; N, 10.47. Found: C, 58.47; H, 8.13; N, 10.51.
N-(endo-8-(2-Methylthio)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (23a) 62.7%, color-
less solid. mp 168—169 °C (recrystallized from AcOEt–diisopropyl ether).
1H-NMR (CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.76—1.92 (2H, m), 2.17 (3H,
s), 2.00—2.50 (6H, m), 2.60—2.83 (4H, m), 3.20—3.55 (2H, m), 4.32 (1H,
q, Jϭ7.0 Hz), 5.40—5.80 (1H, br), 7.24—7.35 (1H, m), 7.57—7.70 (2H, m),
7.76 (1H, d, Jϭ7.8 Hz), 8.82 (1H, s), 10.53 (1H, d, Jϭ7.5 Hz). IR (KBr)
cmϪ1: 3283, 1674. MS (EI) m/z: 413 (Mϩ). Anal. Calcd for C23H31N3O2S·
0.5H2O: C, 65.37; H, 7.63; N, 9.94. Found: C, 65.45; H, 7.44; N, 9.94.
N-(endo-8-(2-Phenylsulfonyl)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (24a) 63.0%, color-
1
less solid. mp 210—211 °C (recrystallized from AcOEt). H-NMR (CDCl3)
d: 1.68 (6H, d, Jϭ7.2 Hz), 1.50—2.20 (8H, m), 2.60—2.90 (2H, m), 3.00—
3.55 (4H, m), 4.10—4.25 (1H, m), 5.40—5.80 (1H, br), 7.24—7.35 (1H, m),
7.52—7.80 (6H, m), 7.90—8.00 (2H, m), 8.82 (1H, s), 10.53 (1H, d,
Jϭ7.5 Hz). IR (KBr) cmϪ1: 3254, 1668. MS (EI) m/z: 507 (Mϩ). Anal. Calcd
for C28H33N3O4S·0.25H2O: C, 65.66; H, 6.59; N, 8.20. Found: C, 65.66; H,
6.47; N, 8.14.
N-(endo-8-(2-Morphorino)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (25a) 38.3%, color-
less solid. mp 177—178 °C (recrystallized from AcOEt–diisopropyl ether).
1H-NMR (CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.85—2.05 (4H, m), 2.05—
2.40 (4H, m), 2.40—3.00 (10H, m), 3.50—3.85 (6H, m), 4.36 (1H, q,
Jϭ7.0 Hz), 5.40—5.80 (1H, br), 7.27—7.35 (1H, m), 7.61—7.70 (2H, m),
7.76 (1H, d, Jϭ7.8 Hz), 8.84 (1H, s), 10.58 (1H, d, Jϭ7.5 Hz). IR (KBr)
cmϪ1: 3272, 1678. MS (EI) m/z: 452 (Mϩ). Anal. Calcd for C26H36N4O3·
H2O: C, 66.36; H, 8.14; N, 11.91. Found: C, 66.60; H, 7.84; N, 11.66.
N-(endo-8-(2-Piperidino)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (26a) 59.2%, color-
1
less solid. mp 159—160 °C (recrystallized from AcOEt). H-NMR (CDCl3)
d: 1.68 (6H, d, Jϭ7.2 Hz), 1.38—1.90 (8H, m), 2.05—2.15 (4H, m), 2.20—
2.40 (2H, m), 2.40—2.70 (8H, m), 3.33—3.42 (2H, m), 4.30 (1H, q,
Jϭ7.0 Hz), 5.40—5.80 (1H, br), 7.23—7.33 (1H, m), 7.56—7.70 (2H, m),
7.76 (1H, d, Jϭ7.8 Hz), 8.84 (1H, s), 10.49 (1H, d, Jϭ7.5 Hz). IR (KBr)
cmϪ1: 3272, 1677. MS (EI) m/z: 450 (Mϩ). Anal. Calcd for C27H38N4O2: C,
71.97; H, 8.50; N, 12.43. Found: C, 71.71; H, 8.58; N, 12.38.
N-(endo-8-(Tetrahydropyran-2-yl)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-
isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (27a) 32.8%, col-
orless solid. mp 163—164 °C (recrystallized from AcOEt). 1H-NMR
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.10—2.70 (16H, m), 3.20—3.60 (4H,
m), 3.91—4.03 (1H, m), 4.30 (1H, q, Jϭ7.0 Hz), 5.40—5.80 (1H, br),
7.23—7.35 (1H, m), 7.56—7.70 (2H, m), 7.75 (1H, d, Jϭ7.8 Hz), 8.82 (1H,
s), 10.48 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 3273, 1676. MS (EI) m/z: 437
(Mϩ). Anal. Calcd for C26H35N3O3: C, 71.37; H, 8.06; N, 9.60. Found: C,
71.09; H, 8.07; N, 9.48.
N-(endo-8-(2-Phenoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxamide (28a) 50.8%, colorless solid.
mp 146—147 °C (recrystallized from AcOEt–diisopropyl ether). 1H-NMR
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.55—1.85 (2H, m), 2.04—2.42 (6H,
m), 2.88 (2H, t, Jϭ5.5 Hz), 3.38—3.47 (2H, m), 4.15 (1H, t, Jϭ7.0 Hz),
4.21 (1H, t, Jϭ7.0 Hz), 5.20—5.80 (1H, br), 6.87—6.97 (3H, m), 7.20—
7.40 (3H, m), 7.67—7.90 (3H, m), 8.78 (1H, s). IR (KBr) cmϪ1: 3295, 1670.
MS (EI) m/z: 459 (Mϩ). Anal. Calcd for C28H33N3O3·0.25H2O: C, 72.46; H,
7.28; N, 9.05. Found: C, 72.24; H, 7.20; N, 9.08.
N-(endo-8-(Ethoxycarbonyl)methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (29a) 60.7%, color-
less solid. mp 106—108 °C (recrystallized from AcOEt–diisopropyl ether).
1H-NMR (CDCl3) d: 1.31 (3H, t, Jϭ7.2 Hz), 1.68 (6H, d, Jϭ7.2 Hz), 1.76—
1.90 (2H, m), 2.00—2.25 (4H, m), 2.32—2.52 (2H, m), 3.30 (2H, s), 3.36—
3.47 (2H, m), 4.21 (2H, q, Jϭ7.2 Hz), 4.32 (1H, q, Jϭ7.0 Hz), 5.40—5.80
(1H, br), 7.24—7.35 (1H, m), 7.57—7.70 (2H, m), 7.76 (1H, d, Jϭ7.0 Hz),
8.83 (1H, s), 10.52 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 3264, 1752, 1671.
N-(endo-8-(Methoxyethoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide Hydrochloride (21a)
72.0%, colorless solid. mp 95—97 °C (recrystallized from EtOH–diiso-
1
propyl ether). H-NMR (DMSO-d6) d: 1.68 (6H, d, Jϭ7.2 Hz), 2.15—2.62
(8H, m), 3.29—3.38 (2H, m), 3.41 (3H, s), 3.58—3.66 (2H, m), 3.68—3.73
(2H, m), 3.85—3.90 (2H, m), 4.19 (2H, br s), 4.33 (1H, t, Jϭ6.3 Hz), 5.40—
5.80 (1H, br), 7.34—7.42 (1H, m), 7.71—7.90 (3H, m), 8.81 (1H, s). IR
(KBr) cmϪ1: 3328, 1678. MS (EI) m/z: 441 (Mϩ). Anal. Calcd for

January 2001
37
MS (EI) m/z: 425 (Mϩ). Anal. Calcd for C24H31N3O4·0.25H2O: C, 67.03; H,
7.38; N, 9.77. Found: C, 67.04; H, 7.44; N, 9.69.
(Mϩ). Anal. Calcd for C23H28N4O2·0.25H2O: C, 69.58; H, 7.24; N, 14.11.
Found: C, 69.61; H, 7.17; N, 13.95.
N-(endo-8-Carboxylmethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-
N-(endo-8-Carbamoylmethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-
oxo-1,2-dihydro-3-quinolinecarboxamide (30a) 55.3%, colorless solid. 2-oxo-1,2-dihydro-3-quinolinecarboxamide (38a) 56.9%, colorless solid.
1
mp 244—247 °C (recrystallized from MeOH–AcOEt). 1H-NMR (CDCl3) d: mp Ͼ250 °C (recrystallized from EtOH). H-NMR (CDCl3) d: 1.68 (6H, d,
1.68 (6H, d, Jϭ7.2 Hz), 2.10—2.27 (2H, m), 2.30—2.70 (6H, m), 3.60 (2H, Jϭ7.2 Hz), 1.76—2.40 (8H, m), 2.90—3.40 (4H, m), 4.33 (1H, q,
s), 4.03—4.15 (2H, m), 4.32 (1H, t, Jϭ7.0 Hz), 5.30—5.70 (1H, br), 7.32— Jϭ7.0 Hz), 5.30—5.86 (1H, br), 7.23—7.34 (1H, m), 7.34—7.57 (2H, br),
7.42 (1H, m), 7.68—7.90 (2H, m), 7.90 (1H, s), 8.80 (1H, s). IR (KBr) 7.57—7.70 (2H, m), 7.76 (1H, d, Jϭ7.0 Hz), 8.82 (1H, s), 10.54 (1H, d,
cmϪ1: 3436, 1677, 1638. MS (FAB) m/z: 398 (Mϩ1). Anal. Calcd for Jϭ7.5 Hz). IR (KBr) cmϪ1: 3407, 1670. MS (EI) m/z: 396 (Mϩ). Anal. Calcd
C22H27N3O4·H2O: C, 64.15; H, 6.99; N, 10.20. Found: C, 64.08; H, 7.00; N,
10.28.
for C22H28N4O3: C, 66.65; H, 7.12; N, 14.13. Found: C, 66.54; H, 7.19; N,
14.03.
N-(endo-8-(3-Ethoxycarbonyl)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-
isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide Hydrochloride
endo-8-Alkyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-1,2-dihy-
dro-3-quinolinecarboxylates (12b—38b) The alkylation of compound
(31a) 27.1%, colorless solid. mp 251—252 °C (recrystallized from EtOH). 11b was conducted in a similar procedure as employed in the synthesis of
1H-NMR (DMSO-d6) d: 1.26 (3H, t, Jϭ7.2 Hz), 1.68 (6H, d, Jϭ7.2 Hz), 18a. HCl salts of alkylated compounds were made using a procedure similar
1.95—2.60 (10H, m), 2.91—3.07 (2H, m), 3.14—3.32 (2H, m), 3.88—3.97 to that employed in the synthesis of 11b.
(2H, m), 4.13 (2H, q, Jϭ7.2 Hz), 4.46 (1H, q, Jϭ7.0 Hz), 5.40—5.75 (1H,
endo-8-(2-Hydroxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
br), 7.28—7.38 (1H, m), 7.77 (2H, d, Jϭ7.0 Hz), 8.85 (1H, s), 10.68 (1H, d, oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (14b) 27%, col-
Jϭ7.5 Hz), 12.10—12.30 (1H, br). IR (KBr) cmϪ1: 1731, 1665. MS (EI) orless solid. mp 191—193 °C (recrystallized from EtOH–toluene). 1H-NMR
m/z: 453 (Mϩ). Anal. Calcd for C26H35N3O4·HCl·0.25H2O: C, 63.15; H,
7.44; N, 8.50. Found: C, 63.36; H, 7.55; N, 8.49.
N-(endo-8-(3-Carboxyl)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
(DMSO-d6) d: 1.65 (6H, d, Jϭ7.2 Hz), 2.10—2.30 (4H, m), 2.75—2.90 (2H,
m), 3.03—3.18 (2H, m), 3.18—3.27 (1H, m), 3.27—3.35 (1H, m), 3.35—
3.60 (1H, br), 3.95—4.20 (4H, m), 5.30—5.65 (1H, br), 5.42 (1H, t,
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (32a) 75.7%, color- Jϭ4.6 Hz), 7.20—7.30 (1H, m), 7.55—7.70 (3H, m), 8.32 (1H, s), 11.25—
less solid. mp Ͼ250 °C (recrystallized from EtOH–AcOEt). 1H-NMR 11.50 (1H, br). IR (KBr) cmϪ1: 3436, 1708, 1646. MS (EI) m/z: 384 (Mϩ).
(CDCl3) d: 1.60 (6H, d, Jϭ7.2 Hz), 1.83—2.10 (4H, m), 2.10—2.65 (6H, Anal. Calcd for C22H28N2O4·HCl·0.2H2O: C, 62.24; H, 7.03; N, 6.59.
m), 2.87—3.08 (2H, m), 3.20—3.40 (2H, m), 3.95—4.05 (2H, m), 4.08—
4.25 (1H, m), 5.30—5.70 (1H, br), 7.38 (1H, t, Jϭ7.0 Hz), 7.75 (1H, dt,
Jϭ1.0, 9.0 Hz), 7.90 (1H, d, Jϭ9.0 Hz), 8.03 (1H, dd, Jϭ1.0, 7.0 Hz), 8.81
(1H, s), 10.46 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 3430, 1734, 1681. MS
Found: C, 62.13; H, 6.99; N, 6.60.
endo-8-(3-Hydroxy)propyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxylate (15b) 48%, colorless solid. mp
129—131 °C (recrystallized from AcOEt–diisopropyl ether). 1H-NMR
(EI) m/z: 425 (Mϩ). Anal. Calcd for C24H31N3O4·0.6H2O: C, 66.06; H, 7.44; (CDCl3) d: 1.60—1.70 (3H, m), 1.66 (6H, d, Jϭ7.2 Hz), 1.90—2.10 (4H,
N, 9.63. Found: C, 66.21; H, 7.45; N, 9.61.
m), 2.10—2.40 (4H, m), 2.70 (2H, t, Jϭ7.0 Hz), 3.33—3.45 (2H, m), 3.87
(2H, t, Jϭ7.0 Hz), 5.27 (1H, t, Jϭ7.0 Hz), 5.30—5.70 (1H, br), 7.18—7.30
(1H, m), 7.55—7.68 (3H, m), 8.22 (1H, s). IR (KBr) cmϪ1: 3437, 3119,
1726, 1650. MS (EI) m/z: 398 (Mϩ). Anal. Calcd for C23H30N2O4: C, 69.32;
H, 7.58; N, 7.02. Found: C, 69.22; H, 7.65; N, 7.02.
N-(endo-8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-
dihydro-3-quinolinecarboxamide (33a) 19.4%, colorless solid. mp 208—
210 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.69 (6H, d,
Jϭ7.2 Hz), 2.09 (3H, s), 1.81—2.42 (8H, m), 4.13—4.22 (1H, m), 4.33—
4.48 (1H, m), 4.70—4.85 (1H, m), 5.35—5.90 (1H, br), 7.26—7.37 (1H, m),
7.58—7.70 (2H, m), 7.77 (1H, d, Jϭ7.0 Hz), 8.83 (1H, s), 10.70 (1H, d,
endo-8-(4-Hydroxy)butyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (16b) 10%, col-
Jϭ7.5 Hz). IR (KBr) cmϪ1: 3235, 1674, 1636. MS (EI) m/z: 381 (Mϩ). Anal. orless solid. mp 209—213 °C (recrystallized from EtOH–toluene). 1H-NMR
Calcd for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02. Found: C, 69.25; H, (DMSO-d6) d: 1.65 (6H, d, Jϭ7.2 Hz), 1.50—1.80 (2H, m), 1.95—2.30 (6H,
7.20; N, 11.30.
m), 2.50—3.35 (7H, m), 3.65—3.80 (2H, m), 3.80—4.05 (2H, m), 5.30—
5.60 (2H, m), 7.18—7.33 (1H, m), 7.52—7.75 (3H, m), 8.83 (1H, s). IR
N-(endo-8-(2-Oxopropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxamide Hydrochloride (34a) 7.7%, (KBr) cmϪ1: 3370, 1704, 1660. MS (EI) m/z: 412 (Mϩ). Anal. Calcd for
colorless solid. mp 208—211 °C (recrystallized from EtOH). 1H-NMR C24H32N2O4·HCl: C, 64.20; H, 7.18; N, 6.23. Found: C, 63.93; H, 7.45; N,
(DMSO-d6) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.95—2.80 (11H, m), 3.06—3.28 6.19.
(1H, m), 3.95—4.52 (4H, m), 5.35—5.75 (1H, br), 7.27—7.38 (1H, m),
endo-8-(5-Hydroxy)pentyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxamide Hydrochloride (17b) 29%,
7.60—7.73 (2H, m), 7.77 (1H, d, Jϭ7.0 Hz), 8.85 (1H, s), 10.72 (1H, d,
Jϭ7.5 Hz), 11.20—11.45 (1H, br). IR (KBr) cmϪ1: 1723, 1673. MS (FAB) colorless solid. mp 243—245 °C (recrystallized from EtOH–toluene). 1H-
m/z: 396 (Mϩ1). Anal. Calcd for C23H29N3O3·HCl·1.1H2O: C, 61.15; H, NMR (DMSO-d6) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.40—2.60 (15H, m), 3.25—
6.96; N, 9.30. Found: C, 61.04; H, 6.99; N, 9.30.
3.40 (2H, m), 3.68 (2H, t, Jϭ7.0 Hz), 5.30 (1H, t, Jϭ7.0 Hz), 5.30—5.70
N-(endo-8-(4-Oxopentyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-
(1H, br), 7.20—7.30 (1H, m), 7.55—7.70 (3H, m), 8.23 (1H, s). IR (KBr)
oxo-1,2-dihydro-3-quinolinecarboxamide (35a) 5.3%, colorless solid. cmϪ1: 3352, 1731, 1642. MS (EI) m/z: 426 (Mϩ). Anal. Calcd for
mp 101—103 °C (recrystallized from diisopropyl ether–hexane). 1H-NMR C25H34N2O4·HCl: C, 64.85; H, 7.61; N, 6.05. Found: C, 64.59; H, 7.67; N,
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.72—1.91 (4H, m), 1.95—2.15 (4H, 5.96.
m), 2.17 (3H, s), 2.20—2.60 (6H, m), 3.25—3.34 (2H, m), 4.30 (1H, q,
endo-8-(6-Hydroxy)hexyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
Jϭ7.0 Hz), 5.40—5.80 (1H, br), 7.24—7.33 (1H, m), 7.56—7.70 (2H, m), oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (18b) 21%, col-
7.75 (1H, d, Jϭ7.0 Hz), 8.83 (1H, s), 10.49 (1H, d, Jϭ7.5 Hz). IR (KBr) orless solid. mp 205—207 °C (recrystallized from EtOH–toluene). 1H-NMR
cmϪ1: 1712, 1671. MS (EI) m/z: 423 (Mϩ). Anal. Calcd for C25H33N3O3: C,
70.89; H, 7.85; N, 9.92. Found: C, 70.78; H, 7.92; N, 9.67.
(DMSO-d6) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.20—2.75 (8H, m), 2.75—3.00 (2H,
m), 3.10—3.45 (3H, m), 3.80—4.05 (3H, m), 4.39 (1H, t, Jϭ7.0 Hz), 5.12—
N-(endo-8-Cyanomethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2- 5.23 (1H, m), 5.23—5.50 (1H, br), 7.26—7.35 (1H, m), 7.67—7.95 (3H, m),
oxo-1,2-dihydro-3-quinolinecarboxamide (36a) 53.3%, colorless solid. 8.45 (1H, s), 10.02—10.25 (1H, m). IR (KBr) cmϪ1: 3426, 1714, 1661. MS
mp 178—181 °C (recrystallized from AcOEt–diisopropyl ether). 1H-NMR (EI) m/z: 440 (Mϩ). Anal. Calcd for C26H36N2O4·HCl: C, 65.46; H, 7.81; N,
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.80—1.93 (2H, m), 2.02—2.37 (6H, 5.87. Found: C, 65.15; H, 7.65; N, 5.76.
m), 3.39 (2H, s), 3.34—3.46 (2H, m), 4.31 (1H, q, Jϭ7.0 Hz), 5.40—5.80
endo-8-(2-Methoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
(1H, br), 7.25—7.33 (1H, m), 7.61—7.70 (2H, m), 7.76 (1H, d, Jϭ7.0 Hz), oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (19b) 23%, col-
8.83 (1H, s), 10.53 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 2244, 1676. MS (EI) orless solid. mp 206—208 °C (recrystallized from EtOH–toluene). 1H-NMR
m/z: 378 (Mϩ). Anal. Calcd for C22H26N4O2·0.25H2O: C, 69.00; H, 6.97; N,
14.63. Found: C, 68.90; H, 6.91; N, 14.31.
(DMSO-d6) d: 1.65 (6H, d, Jϭ7.2 Hz), 2.08—2.30 (4H, m), 2.40—2.82 (3H,
m), 3.08—3.30 (3H, m), 3.37 (3H, s), 3.90—4.12 (1H, m), 5.30—5.60 (1H,
N-(endo-8-(2-Cyano)ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2- br), 5.41 (1H, t, Jϭ7.0 Hz), 7.20—7.30 (1H, m), 7.55—7.70 (3H, m), 8.30
oxo-1,2-dihydro-3-quinolinecarboxamide (37a) 37.4%, colorless solid. (1H, s), 12.10—12.30 (1H, br). IR (KBr) cmϪ1: 3436, 1731, 1652. MS (EI)
mp 177—178 °C (recrystallized from AcOEt–diisopropyl ether). 1H-NMR m/z: 398 (Mϩ). Anal. Calcd for C23H30N2O4·HCl·H2O: C, 60.98; H, 7.34; N,
(CDCl3) d: 1.68 (6H, d, Jϭ7.2 Hz), 1.75—1.95 (2H, m), 1.95—2.82 (10H, 6.18. Found: C, 60.89; H, 7.47; N, 5.95.
m), 3.15—3.45 (2H, m), 4.31 (1H, q, Jϭ7.0 Hz), 5.45—5.75 (1H, br),
endo-8-(2-Ethoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-
7.24—7.34 (1H, m), 7.60—7.70 (2H, m), 7.75 (1H, d, Jϭ7.0 Hz), 8.83 (1H, 1,2-dihydro-3-quinolinecarboxamide Hydrochloride (20b) 34%, color-
s), 10.51 (1H, d, Jϭ7.5 Hz). IR (KBr) cmϪ1: 3266, 2246, 1677. MS m/z: 392 less solid. mp 185—187 °C (recrystallized from EtOH–toluene). 1H-NMR

38
Vol. 49, No. 1
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (29b)
54%, colorless solid. mp 191—194 °C (recrystallized from EtOH–toluene).
1H-NMR (DMSO-d6) d: 1.34 (3H, t, Jϭ7.2 Hz), 1.65 (6H, d, Jϭ7.2 Hz),
2.10—2.30 (4H, m), 2.80—2.95 (2H, m), 3.20—3.39 (2H, m), 3.71 (2H, d,
Jϭ5.6 Hz), 4.15—4.27 (2H, m), 4.34 (2H, q, Jϭ7.2 Hz), 5.30—5.65 (1H,
br), 5.44 (1H, t, Jϭ7.0 Hz), 7.20—7.30 (1H, m), 7.55—7.72 (3H, m), 8.33
(1H, s), 12.55—12.75 (1H, br). IR (KBr) cmϪ1: 3435, 1741, 1713, 1655. MS
(EI) m/z: 426 (Mϩ). Anal. Calcd for C24H30N2O5·HCl: C, 62.26; H, 6.74; N,
6.05. Found: C, 62.13; H, 6.82; N, 5.94.
endo-8-(2-Oxopropyl)-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-
1,2-dihydro-3-quinolinecarboxylate Hydrochloride (34b) 28%, color-
less solid. mp 217—225 °C (recrystallized from EtOH–toluene). 1H-NMR
(DMSO-d6) d: 1.68 (6H, d, Jϭ7.2 Hz), 2.05—2.65 (7H, m), 2.75—2.92 (2H,
m), 3.15—3.33 (2H, m), 3.90—4.35 (4H, m), 5.30—5.70 (2H, br), 7.20—
7.33 (1H, m), 7.55—7.73 (3H, m), 8.32 (1H, s), 11.70—12.00 (1H, br). IR
(KBr) cmϪ1: 3421, 1736, 1718, 1665. MS (CI) m/z: 397 (Mϩ1). Anal. Calcd
for C23H28N2O4·HCl: C, 63.80; H, 6.75; N, 6.47. Found: C, 63.51; H, 6.82;
N, 6.28.
endo-8-(4-Oxopentyl)-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-
1,2-dihydro-3-quinolinecarboxylate Hydrochloride (35b) 56%, color-
less solid. mp 230—236 °C (recrystallized from EtOH–toluene). 1H-NMR
(DMSO-d6) d: 1.66 (6H, d, Jϭ7.2 Hz), 1.90—2.15 (2H, m), 2.17 (3H, s),
2.15—2.45 (4H, m), 2.45—2.80 (6H, m), 2.95—3.15 (2H, m), 3.90—4.20
(2H, m), 5.31 (1H, t, Jϭ7.0 Hz), 5.25—5.60 (1H, br), 7.36 (1H, dt, Jϭ1.4,
6.4 Hz), 7.65—7.87 (3H, m), 8.45 (1H, s). IR (KBr) cmϪ1: 3426, 1708,
1652. MS (EI) m/z: 424 (Mϩ). Anal. Calcd for C25H32N2O4·HCl: C, 65.13;
H, 7.21; N, 6.07. Found: C, 65.07; H, 7.24; N, 5.99.
(DMSO-d6) d: 1.24 (3H, t, Jϭ7.2 Hz), 1.66 (6H, d, Jϭ7.2 Hz), 2.10—2.45
(4H, m), 2.45—2.72 (4H, m), 3.20—3.40 (2H, m), 3.59 (2H, q, Jϭ6.8 Hz),
3.82 (2H, t, Jϭ7.2 Hz), 4.00—4.25 (2H, m), 5.30 (1H, t, Jϭ7.0 Hz), 5.20—
5.60 (1H, br), 7.33 (1H, dt, Jϭ1.4, 7.6 Hz), 7.68—7.87 (3H, m), 8.45 (1H,
s). IR (KBr) cmϪ1: 3435, 1704, 1654. MS (EI) m/z: 412 (Mϩ). Anal. Calcd
for C24H32N2O4·HCl: C, 64.20; H, 7.40; N, 6.23. Found: C, 64.00; H, 7.42;
N, 6.26.
endo-8-(Methoxyethoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (21b) 71.0%,
colorless solid. mp 70—75 °C (recrystallized from EtOH–diisopropyl ether).
1H-NMR (DMSO-d6) d: 1.65 (6H, d, Jϭ7.2 Hz), 2.11—2.20 (4H, m),
2.72—2.76 (2H, m), 3.16—3.26 (4H, m), 3.38 (3H, s), 3.52—3.66 (2H, m),
3.65—3.70 (2H, m), 4.06—4.16 (4H, m), 5.40—5.42 (2H, m), 7.21—7.29
(1H, m), 7.60—7.67 (3H, m), 8.31 (1H, s), 12.13 (1H, br). IR (KBr) cmϪ1
:
3338, 2894, 1698, 1657. MS (EI) m/z: 442 (Mϩ). Anal. Calcd for
C25H34N2O5·HCl·2H2O: C, 58.30; H, 7.63; N, 5.44. Found: C, 58.22; H,
7.75; N, 5.52.
endo-8-(2-Diethylamino)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxylate Dihydrochloride (22b) 45%,
colorless solid. mp 240—243 °C (recrystallized from EtOH–AcOEt). 1H-
NMR (DMSO-d6) d: 1.47 (6H, t, Jϭ7.2 Hz), 1.64 (6H, d, Jϭ7.2 Hz), 2.15—
2.30 (2H, m), 2.40—2.60 (2H, m), 2.70—2.90 (2H, m), 2.95—3.40 (6H, m),
3.60—3.93 (4H, m), 3.93—4.10 (2H, m), 5.30—5.60 (1H, m), 7.20—7.30
(1H, m), 7.51—7.70 (3H, m), 8.28 (1H, s), 12.10—12.50 (2H, br). IR (KBr)
cmϪ1: 3427, 1718, 1638. MS (FAB) m/z: 440 (Mϩ1). Anal. Calcd for
C26H37N3O3·2HCl·0.5H2O: C, 59.88; H, 7.73; N, 8.05. Found: C, 59.67; H,
7.77; N, 8.00.
endo-8-Cyanomethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-oxo-
1,2-dihydro-3-quinolinecarboxylate Hydrochloride (36b) 50%, color-
less solid. mp 209—213 °C (recrystallized from EtOH–toluene). 1H-NMR
(DMSO-d6) d: 1.65 (6H, d, Jϭ7.2 Hz), 2.10—2.50 (4H, m), 2.70—3.00 (2H,
m), 3.00—3.25 (2H, m), 4.10—4.33 (2H, m), 4.33—4.60 (2H, m), 5.30—
5.60 (2H, m), 7.19—7.30 (1H, m), 7.50—7.73 (3H, m), 8.32 (1H, s),
13.30—13.50 (1H, br). IR (KBr) cmϪ1: 3401, 1729, 1654. MS (EI) m/z: 379
(Mϩ). Anal. Calcd for C22H25N3O3·HCl: C, 63.53; H, 6.30; N, 10.10. Found:
C, 63.28; H, 6.31; N, 9.94.
endo-8-(2-Methylthio)ethyl-8-azabicyclo[3.2.1]oct-3-yl) Isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxylate (23b) 12%, colorless solid. mp
130—140 °C (recrystallized from AcOEt–diisopropyl ether). 1H-NMR
(CDCl3) d: 1.65 (6H, d, Jϭ7.2 Hz), 1.90—2.35 (8H, m), 2.13 (3H, s),
2.60—2.89 (4H, m), 3.40—3.55 (2H, m), 5.22 (1H, t, Jϭ7.0 Hz), 5.30—
5.60 (1H, br), 7.32 (1H, dt, Jϭ1.4, 6.8 Hz), 7.65—7.85 (3H, m), 8.39 (1H,
s). IR (KBr) cmϪ1: 3435, 1695, 1655. MS (CI) m/z: 415 (Mϩ1). Anal. Calcd
for C23H30N2O3S·0.5H2O: C, 65.06; H, 7.60; N, 6.60. Found: C, 65.22; H,
7.48; N, 6.46.
endo-8-(2-Cyano)ethyl-8-azabicyclo[3.2.1]oct-3-yl) 1-Isopropyl-2-oxo-
1,2-dihydro-3-quinolinecarboxylate (37b) 28%, colorless solid. mp
132—134 °C (recrystallized from AcOEt). 1H-NMR (CDCl3) d: 1.66 (6H, d,
Jϭ7.2 Hz), 1.85—2.05 (4H, m), 2.05—2.40 (4H, m), 2.40—2.80 (4H, m),
3.15—3.40 (2H, m), 5.17 (1H, t, Jϭ7.0 Hz), 5.35—5.65 (1H, br), 7.19—
7.29 (1H, m), 7.55—7.69 (3H, m), 8.21 (1H, s), 10.51 (1H, d, Jϭ7.5 Hz). IR
(KBr) cmϪ1: 3401, 2248, 1730, 1656. MS (EI) m/z: 393 (Mϩ). Anal. Calcd
for C23H27N3O3: C, 70.20; H, 6.91; N, 10.67. Found: C, 70.00; H, 6.92; N,
10.54.
endo-8-(2-Phenylsulfonyl)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxylate (24b) 42%, colorless solid.
mp 131—133 °C (recrystallized from AcOEt–diisopropyl ether). 1H-NMR
(CDCl3) d: 1.64 (6H, d, Jϭ7.2 Hz), 1.70—2.15 (8H, m), 2.75 (2H, t,
Jϭ7.0 Hz), 3.00—3.20 (2H, m), 3.44 (2H, t, Jϭ7.0 Hz), 5.04 (1H, t,
Jϭ7.0 Hz), 5.25—5.60 (1H, br), 7.27—7.37 (1H, m), 7.59—7.85 (6H, m),
7.90—8.02 (2H, m), 8.33 (1H, s). IR (KBr) cmϪ1: 1730, 1696. MS (EI) m/z:
508 (Mϩ). Anal. Calcd for C28H32N2O5S: C, 66.12; H, 6.34; N, 5.50. Found:
C, 65.98; H, 6.37; N, 5.50.
endo-8-Carbamoylmethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxylate (38b) 60%, colorless solid. mp
261—264 °C (recrystallized from EtOH). H-NMR (CDCl3) d: 1.66 (6H, d,
Jϭ7.2 Hz), 1.90—2.10 (4H, m), 2.10—2.45 (4H, m), 2.45—3.15 (2H, m),
3.15—3.45 (2H, m), 5.30 (1H, t, Jϭ7.0 Hz), 5.30—5.80 (3H, br), 7.18—
7.30 (1H, m), 7.55—7.70 (3H, m), 8.22 (1H, s). IR (KBr) cmϪ1: 3408, 1679,
1657. MS (CI) m/z: 398 (Mϩ1). Anal. Calcd for C22H27N3O4: C, 66.48; H,
6.84; N, 10.57. Found: C, 66.32; H, 6.75; N, 10.43.
endo-8-(2-Morphorino)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-
2-oxo-1,2-dihydro-3-quinolinecarboxylate Dihydrochloride (25b) 41%,
colorless solid. mp Ͼ270 °C (recrystallized from EtOH–CHCl3). 1H-NMR
(DMSO-d6) d: 1.66 (6H, d, Jϭ7.2 Hz), 2.20—2.45 (4H, m), 2.60—2.90 (4H,
m), 3.10—3.50 (2H, m), 3.50—3.80 (6H, m), 3.90—4.12 (4H, m), 4.12—
4.30 (2H, m), 5.32 (1H, t, Jϭ7.0 Hz), 5.28—5.55 (1H, br), 7.33 (1H, dt,
Jϭ1.6, 6.4 Hz), 7.68—7.77 (3H, m), 8.46 (1H, s). IR (KBr) cmϪ1: 3436,
1723, 1643. MS (CI) m/z: 454 (Mϩ1). Anal. Calcd for C26H35N3O4·2HCl·
0.25H2O: C, 58.81; H, 7.11; N, 7.91. Found: C, 58.68; H, 7.10; N, 7.75.
endo-8-(Tetrahydropyran-2-yl)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Iso-
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (27b)
30%, colorless solid. mp 255—257 °C (recrystallized from EtOH–toluene).
1H-NMR (DMSO-d6) d: 1.15—1.30 (1H, m), 1.40—1.90 (5H, m), 1.65 (6H,
d, Jϭ7.2 Hz), 2.00—2.30 (4H, m), 2.60—2.95 (4H, m), 3.05—3.18 (1H, m),
3.27—3.41 (1H, m), 3.45—3.60 (1H, m), 3.65—3.75 (1H, m), 3.85—3.95
(1H, m), 4.30—4.50 (2H, m), 5.30—5.70 (2H, m), 7.20—7.30 (1H, m),
1
8-(3-Hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one (41) To a solu-
tion of 2,5-dimethoxytetrahydrofuran 39 (120 ml, 0.93 mol) in water
(300 ml) was added HCl (45 ml) with stirring at room temperature. Twenty
minutes later, the reaction solution became homogenous. Thereafter, water
(450 ml), a solution of 3-amino-1-propanol (105 ml, 1.37 mol) and HCl
(138 ml) in water (600 ml), a solution of 1,3-diacetonedicarboxylic acid
(150 g, 1.03 mol) in water (700 ml) and a solution of Na2HPO4 (66 g) in
water (300 ml) were successively added to the homogeneous reaction solu-
tion. The pH of the resulting solution was then adjusted to the range of 3 to
4 with 40% NaOH aqueous solution (215 ml). After bubbling was con-
firmed, the mixture was stirred overnight. Then HCl was added to adjust the
pH of the reaction solution to 3. The reaction solution was heated to 80 °C
and stirred until bubbling of carbon dioxide gas was no longer observed.
After completion of the reaction, the reaction solution was cooled and
NaOH aqueous solution was added thereto to render the solution alkaline.
Thereafter NaCl was added, followed by extraction with CHCl3. The organic
layer was washed with water and dried. The organic layer was evaporated in
7.55—7.70 (3H, m), 8.30 (1H, s), 11.90—12.30 (1H, br). IR (KBr) cmϪ1
:
3435, 1733, 1698. MS (EI) m/z: 438 (Mϩ). Anal. Calcd for C26H34N2O4·
HCl: C, 65.74; H, 7.42; N, 5.89. Found: C, 65.86; H, 7.49; N, 5.77.
endo-8-(2-Phenoxy)ethyl-8-azabicyclo[3.2.1]oct-3-yl 1-Isopropyl-2-
oxo-1,2-dihydro-3-quinolinecarboxylate Hydrochloride (28b) 44%, col-
orless solid. mp 214—217 °C (recrystallized from EtOH–toluene). 1H-NMR
(CD3OD) d: 1.66 (3H, d, Jϭ7.2 Hz), 1.68 (3H, d, Jϭ7.2 Hz), 1.95—2.80
(8H, m), 3.40—3.80 (2H, m), 3.96—4.30 (2H, m), 4.32—4.50 (2H, m),
5.25—5.70 (2H, m), 6.94—7.07 (3H, m), 7.27—7.45 (3H, m), 7.67—7.90
(3H, m), 8.49 (1H, d, Jϭ4.5 Hz). IR (KBr) cmϪ1: 3440, 1724, 1638. MS (EI)
m/z: 460 (Mϩ). Anal. Calcd for C28H32N2O4·HCl·0.5H2O: C, 66.46; H,
6.77; N, 5.53. Found: C, 66.69; H, 6.63; N, 5.48.
1
vacuo to give 41 as a crude product. mp 42—43 °C. H-NMR (CDCl3) d:
1.57—1.68 (2H, m), 1.73—1.83 (2H, m), 2.00—2.17 (4H, m), 2.20—2.29
(2H, m), 2.66 (2H, dd, Jϭ16.1, 4.4 Hz), 2.84 (2H, t, Jϭ5.7 Hz), 3.62—3.66
(2H, m), 3.90 (2H, t, Jϭ5.2 Hz), 5.12 (1H, brs). IR (KBr) cmϪ1: 1714. MS
endo-8-(Ethoxycarbonyl)methyl-8-azabicyclo[3.2.1]oct-3-yl 1-Iso-

January 2001
39
(EI) m/z: 183 (Mϩ). Anal. Calcd for C10H17NO2·0.1H2O: C, 64.91; H, 9.37;
N, 7.57. Found: C, 64.72; H, 9.31; N, 7.56.
8-(3-Hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one Oxime Hydrochlo-
sponses to agonists were measured in terms of their ability to restore the
twitch response to those obtained at supramaximal voltage. The responses
were expressed as a percentage of the maximum 5-HT-evoked contraction.
ride (42) A crude product of 41 was dissolved in EtOH (1200 ml), and The ED50 values for agonists were determined by nonliner regression.
50% hydroxylamine aqueous solution (72.9 g) was added to the solution at
Intrinsic Activity Guinea pigs were killed by a blow to the head and
room temperature. After completion of the reaction, the solvent was distilled cutting of the carotid arteries. The distal colon was excised 2—3 cm from
off and toluene was added. The solvent was again distilled off and the the rectum and longitudinal muscle strips with the myenteric plexus attached
residue was dissolved in EtOH. HCl was added to the remaining solution, were prepared. The tissue was vertically suspended in a organ bath contain-
and the precipitated crystals were collected by filtration to give 161 g (73.9% ing Krebs’ solution (composition in mmol/l: NaCl, 120; KCl, 5.9; NaHCO3,
from 39) of 42 as a colorless solid. mp 239—242 °C (dec.). 1H-NMR 15.5; NaH2PO4, 1.2; CaCl2, 2.5; MgCl2, 1.2; glucose, 11.5) gassed with a
(MeOH-d4) d: 1.75—2.08 (4H, m), 2.21—2.56 (4H, m), 2.83—2.93 (1H, mixture of 95% O2 and 5% CO2 and maintained at 37 °C. Methysergide
m), 3.19—3.45 (3H, m), 3.73 (2H, t, Jϭ5.7 Hz), 4.14—4.20 (2H, m). IR
(KBr) cmϪ1 1658. MS (EI) m/z: 198 (Mϩ). Anal. Calcd for effects of 5-HT1, 5-HT2 and 5-HT3 receptor agonism. Contractile responses
C10H18N2O2·HCl: C, 51.17; H, 8.16; N, 11.93. Found: C, 51.17; H, 8.15; N, were recorded using an isometric transducer. Concentration–effect curves
(1 mmol/l) and ondansetron (1 mmol/l) were added to exclude any potential
:
11.93.
endo-3-Amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane (9)
for agonists were constructed non-cumulatively by adding increasing con-
centrations of agonist at 15 min time intervals. Responses were expressed as
A
mixture of 42 (100 g, 0.43 mol), platinum oxide (5.0 g) and AcOH (500 ml) a percentage of the maximum 5-HT-evoked contraction.
were stirred for 18 h under a hydrogen pressure of 5.0 kg/cm2, with tempera-
Gastrointestinal Motility Beagle dogs of both sexes were housed at
ture maintained at 45 to 46 °C. Water was added to the reaction mixture, and 20—26 °C on a 12 h light/dark cycle with free access to food and water.
the mixture was filtered. The filtrate was evaporated in vacuo. The residue Dogs with strain gauge force transducers sutured to the serosa of gastric
was dissolved in water (50 ml) and MeOH (100 ml). To this solution was antrum, small intestine or colon were prepared to measure circular muscle
added a solution of oxalic acid (38.4 g) in MeOH (200 ml), followed by contractions. The experiments started at least 14 d after surgery. The animals
MeOH (200 ml). The mixture was stirred overnight at room temperature. were deprived of food, but not water, for 18 h before each experiment. Be-
The precipitated crystals were collected by filtration and dried to give 71.3 g fore application of test drugs, control recordings were performed in each
(53.9%) of endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane
dog. During this recording, a previously reported motility pattern i.e.,17) al-
hydrochloride oxalate as a colorless solid. mp. 230—233 °C (dec.). 1H- ternating contractile and quiescent states were confirmed at the gastric antral
NMR (DMSO-d6) d: 1.66—1.94 (6H, m), 1.94—2.25 (6H, m), 2.38—2.63 site in all dogs. All drugs and vehicle (5% lactic acid) were given 5—10 min
(2H, m), 2.71—3.10 (3H, m), 3.35—3.61 (3H, m), 3.63—4.00 (3H, m). IR after the termination of contractile state in the gastric antrum. The meal
cmϪ1: 3414, 2115, 1634. MS (EI) m/z: 184 (Mϩ). Anal. Calcd for (100 kcal) was then given immediately. Gastric antral motility from the
C12H23N2ClO4: C, 48.89; H, 7.86; N, 9.50. Found: C, 48.59; H, 8.10; N,
transducer was measured continuously with the measuring system and
9.77. To a solution of endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo- recorded and analyzed by means of a computer system (ESC-820: Star Med-
[3.2.1]octane hydrochloride oxalate (30.0 g, 0.097 mol) in water (300 ml) ical). Mean gastric antral motility was quantified at 12 sequential 15-min in-
was added KHCO3 (48.3 g). The mixture was stirred at room temperature for tervals after administration. The results of motility changes observed were
4 h. EtOH (300 ml) was then added. After stirring for 1 h, precipitated insol- expressed as percent contraction of phase III, during which maximum con-
uble matter was filtered off and the filtrate was concentrated. EtOH (300 ml)
tractions (100%) occurred. Statistical analysis of the data was performed by
was added again to the concentrate. The precipitated insoluble matter was Dunnett multiple range test.
filtered off and the filtrate was concentrated. The residue was dissolved in
All experiments were performed according to the regulations of the ani-
CHCl3 (300 ml). After drying over anhydrous sodium sulfate, the solvent mal ethical committee of Taisho Pharmaceutical.
was distilled off to give 18.5 g (96.9%) of 9 as a colorless gum. 1H-NMR
(CDCl3) d: 1.43—1.50 (2H, m), 1.54—1.71 (2H, m), 1.85—2.14 (6H, m), References and Notes
2.60 (2H, t, Jϭ5.6 Hz), 3.19—3.37 (3H, m), 3.85 (2H, t, Jϭ5.2 Hz).
N-(endo-8-(3-Hydroxy)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-iso-
1) Lanfumey L., Hamon M., Actual. Chim. Ther., 22, 115—126 (1996).
2) Grailhe R., Boschert U., Hen R., Pharmacochem. Libr., 27, 311—323
(1997).
propyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951)
A
mixture of 5 (0.99 g, 4.3 mmol) and toluene (10 ml) was added thionyl chlo-
ride (0.77 g, 6.5 mmol) and heated at 80 °C for 1 h. The reaction mixture was
used directly to following condensation step. To a solution of NaOH (0.93 g,
23.3 mmol) and 9 (0.72 g, 3.91 mmol) in water (10 ml) was added above acid
chloride solution under 10 °C. After stirred for 0.5 h, the reaction mixture
was concentrated in vacuo. To the resulting residue were added EtOH
(10 ml) and 10% aqueous NaOH solution (10 ml), and the whole was stirred
at room temperature for 0.5 h. After hydrolysis was completed, additional
water (20 ml) was added. The resulting precipitates was filtered to give
1.39 g (90%) of 15a as a colorless solid.
Serotonin 5-HT4 Receptor Agonist Activity Male guinea pigs of Hart-
ley strain (Nihon SLC Inc., Shizuoka) weighing 200—400 g were housed at
20—26 °C on a 12 h light/dark cycle with free access to food and water. Ani-
mals were killed by a blow to the head and cutting of the carotid arteries.
The ileum was excised 10—20 cm from the ileo-caecal junction and divided
3) Dumuis A., Bouhelal R., Sebben M., Cory R., Bockaert J., Mol. Phar-
macol., 34, 880—887 (1988).
4) McCallum R. W., Prakash C., Campoli-Richards D. M., Goa K. L.,
Drugs, 36, 652—681 (1988).
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Motility, 2, 281—286 (1990).
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macol. Exp. Ther., 281, 1312—1316 (1997).
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Kawamura R., Ohuchi Y., Fukushima H., Asanuma H., Muramatsu
M., The 119th Annual Meeting of the Pharmaceutical Society of
Japan, Abstracts, No. 2, p. 181.
8) Schellenberg K. A., J. Org. Chem., 28, 3259—3261 (1963).
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4198 (1957).
longitudinally into segments approximately 3 cm in length. The longitudinal 10) Olofson R. A., Martz J. T., J. Org. Chem., 49, 2081—2082 (1984).
muscle strips with the myenteric plexus attached were removed by gentle 11) Chou T., Cheng W., Bull. Inst. Chem. Acad. Sin., 29, 9—14, (1982).
stroking with a cotton swab. The tissue was vertically suspended in an organ 12) 8Ј-Ethyl (activityϭ51.5Ϯ6.1), 8Ј-n-propyl (activityϭ61.8Ϯ7.0, ED50ϭ
bath containing Krebs’ solution (composition in mmol/l: NaCl, 120; KCl,
5.9; NaHCO3, 15.5; NaH2PO4, 1.2; CaCl2, 2.5; MgCl2, 1.2; glucose, 11.5)
36.5 n
M
), 8Ј-n-butyl (activityϭ52.1Ϯ8.6), 8Ј-n-pentyl (activityϭ28.5Ϯ
/5-HT 100 n
2.1). Activity (%)ϭcompound 100 n
M
M.
gassed with a mixture of 95% O2 and 5% CO2 and maintained at 32 °C. 13) Kajita S., Ito C., Kawamura R., Yasuda S., Isobe Y., Fukushima S.,
Twitch responses were evoked by transmural electrical stimulation of the en-
Pharmacology, in press.
teric cholinergic nerves using square-wave pulses (0.2 Hz, 1 msec pulse du- 14) Tsuyuki Y., Saitoh M., Muramatsu M., Life Sci., 59, 2129—2137
ration). Twitch responses were recorded isometrically with a resting tension
(1996).
of 0.8 g. The tissue was stimulated at supramaximal voltage to equilibration 15) Kato S., Morie T., Kon T., Yoshida N., Karasawa T., Matsumoto J., J.
for 2—3 h. The twitch response was then decreased by voltage reduction.
Med. Chem., 34, 616—624 (1991).
After obtaining a stable submaximal response, the tissue was exposed to 16) Schaus J. M., Thompson D. C., Bloomquist W. E., Susemichel A. D.,
10 nmol/l of 5-HT. We confirmed that the tissue was sensitive to this concen-
Calligaro D. O., Cohen M. L., J. Med. Chem., 41, 1943—1955 (1998).
tration of 5-HT. This concentration of 5-HT produced a sustained increase in 17) Itoh Z., Honda R., Takeuchi S., Aizawa I., Takayanagi R., Gastroen-
the twitch response. Concentration-effect curves for agonists were con-
structed by exposing the strips to cumulative additions of agonists. The re-
terol. Jpn., 12, 275—283 (1977).