Novel, non-acylguanidine-type Na+/H+ exchanger inhibitors: Synthesis and pharmacology of 5-tetrahydroquinolinylidene aminoguanidine derivatives

Article abstract of DOI:10.1021/jm0104567

In the course of our research into new types of non-acylguanidine Na⁺/H⁺ exchanger (NHE) inhibitors, we designed and synthesized aryl-fused tetrahydropyranylidene and cyclohexylidene aminoguanidine derivatives I (X = O, CH₂), which were tested for their inhibitory effects on rat platelet NHEs. After optimization, we found that the S isomer of tetrahydroquinoline derivatives that possess a methyl group in the 4-position and a halogen or methyl group in the o-position of Ar² exhibited high inhibitory activity. In these compounds, (5E,7S)-[[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H) -quinolinylidene]amino]guanidine dimethane-sulfonate (18, T-162559) was found to be a potent inhibitor of both rat and human platelet NHEs, with IC₅₀ values of 14 and 13 nM, respectively. Furthermore, in a rat myocardial infarction model in vivo (1 h ischemia-24 h reperfusion), 18 (0.1 mg/kg, intravenously administered 5 min or 2 h before coronary occlusion) showed significant activity (33% or 23% inhibition, respectively). These results suggested that 18 may exhibit a potent and long-lasting protective activity against cardiac injuries induced by ischemia-reperfusion.

Full text of DOI:10.1021/jm0104567

J . Med. Chem. 2002, 45, 3009-3021
3009
Novel, Non -a cylgu a n id in e-typ e Na +/H+ Exch a n ger In h ibitor s: Syn th esis a n d
P h a r m a cology of 5-Tetr a h yd r oqu in olin ylid en e Am in ogu a n id in e Der iva tives
Shoji Fukumoto,* Eiko Imamiya, Keiji Kusumoto, Shuji Fujiwara, Toshifumi Watanabe, and Mitsuru Shiraishi
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, J usohonmachi, Yodogawa-ku,
Osaka 532-8686, J apan
Received October 2, 2001
In the course of our research into new types of non-acylguanidine Na+/H+ exchanger (NHE)
inhibitors, we designed and synthesized aryl-fused tetrahydropyranylidene and cyclohexylidene
aminoguanidine derivatives I (X ) O, CH2), which were tested for their inhibitory effects on
rat platelet NHEs. After optimization, we found that the S isomer of tetrahydroquinoline
derivatives that possess a methyl group in the 4-position and a halogen or methyl group in the
o-position of Ar2 exhibited high inhibitory activity. In these compounds, (5E,7S)-[[7-(5-fluoro-
2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylidene]amino]guanidine dimethane-
sulfonate (18, T-162559) was found to be a potent inhibitor of both rat and human platelet
NHEs, with IC50 values of 14 and 13 nM, respectively. Furthermore, in a rat myocardial
infarction model in vivo (1 h ischemia-24 h reperfusion), 18 (0.1 mg/kg, intravenously
administered 5 min or 2 h before coronary occlusion) showed significant activity (33% or 23%
inhibition, respectively). These results suggested that 18 may exhibit a potent and long-lasting
protective activity against cardiac injuries induced by ischemia-reperfusion.
Ch a r t 1
In tr od u ction
NHEs are integral plasma membrane proteins that
play an important role in the regulation of intracellular
pH of the myocardium. NHEs interchange one intra-
cellular H+ with one extracellular Na+ when the intra-
cellular pH decreases.1,2
In ischemia-reperfusion injuries, the accumulation
of intracellular protons leads to the activation of NHEs,
and the consequent increase of intracellular Na+ con-
centration causes the activation of another ion ex-
changer, the Na+/Ca2+ exchanger. This results in intra-
cellular Ca2+ overload, causing detrimental effects
including myocardial contracture, stunning, necrosis,
and reperfusion arrhythmia.3-5
Ch a r t 2. Synthetic Design of Aminoguanidine
Derivatives
Inhibition of NHE overactivity would be an effective
obstruction of this chain of events and would prevent
damage to the myocardium in ischemia-reperfusion. A
number of compounds6-9 with an acylguanidine struc-
ture, including amiloride, have been reported as NHE
inhibitors (Chart 1). Among these, cariporide10,11(23)
and others12 are currently under clinical evaluations,
and it has been demonstrated that NHE inhibitors are
therapeutically effective for ischemia-reperfusion in-
juries in humans. However, only a few examples of non-
acylguanidine-type NHE inhibitors such as SL59.122713
have been reported.
To find compounds possessing more potent inhibitory
activities, we synthesized several non-acylguanidine
derivatives and tested their NHE inhibitory activities
in rat platelets. We found that [[(2-benzyloxy-3-meth-
oxyphenyl)methylidene]amino]guanidine (1) possesses
a moderate activity (IC50 ) 2.3 µM). To increase the
NHE inhibitory activity and improve the stability due
to the imine structure of 1, we designed and synthesized
dihydropyranylidene and cyclohexylidene aminoguani-
dine derivatives I (X ) O, CH2) fused with an aromatic
ring (Chart 2). Optimization of the two aromatic rings
(Ar1 and Ar2), their substituents, and the stereo-
chemistry of the asymmetric carbon atom was carried
out. It was found that these compounds were potent
NHE inhibitors and a selected compound, (5E,7S)-[[7-
(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-
quinolinylidene]amino]guanidine dimethanesulfonate
(18, T-162559), exhibited long-lasting effects (iv, rat).
Herein, we report the design, synthesis, structure-
activity relationships, and pharmacological properties
of these aminoguanidine derivatives.
Ch em istr y. The designed aminoguanidine deriva-
tives I were prepared by reaction of ketones II with
aminoguanidine in the presence of hydrochloric acid in
good yields (Scheme 1). All the racemic aminoguanidine
derivatives except 9b were isolated and purified as
* Corresponding author: phone +81-6-6300-6909; fax +81-6-6300-
6306; e-mail Fukumoto_Shoji@takeda.co.jp.
10.1021/jm0104567 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002

3010 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Fukumoto et al.
Sch em e 1
Sch em e 3a
hydrochloride salts and their structure and physical
data are shown in Tables 1-4. The configuration of the
imine bond produced under these reaction conditions
was E, and no compounds with Z-configuration were
detected, which may be due to the steric repulsion
between the aminoguanidine and the substituent or
hydrogen atom in the peri position. This was confirmed
by means of X-ray crystallographic analysis of products
16, 19, and 21. All cyclic ketones II except flavanone
and flavone derivatives were obtained from 5-aryl-
cyclohexane-1,3-diones14,15 as starting materials, as
summarized in Schemes 2-5.
Four methods were used to synthesize the tetra-
hydroquinolin-5-ones, and these are shown in Schemes
2 and 3. Method A involved condensation of diketones
24 with 1-amino-2-butyne to give enamines 25, which
was followed by cyclization at high temperature to give
the desired aromatic compounds 26.16 Alternatively
tetrahydroquinolin-5-ones could be synthesized under
milder conditions according to method B by conden-
sation of 3-aminocyclohexenones 27 with 3-oxobutyl-
aldehyde dimethylacetal, which avoided the require-
ment for oxidation of the cyclized product.17 Also, two
chlorothiophene derivatives 26s,u were prepared by
chlorination of 26r ,t, respectively.
a
(a) 1,1,3,3-tetramethoxypropane, 1-butyn-3-one or acetyl-
acetone, NH4OAc, EtOH.
Tetrahydroquinolin-5-one derivatives with a chloro or
alkoxy group in the 4-position were synthesized by
method C. 3-Aminocyclohexenones 27 were reacted with
5-(methoxymethylene)-2,2-dimethyl-[1,3]-dioxane-4,6-di-
one18 followed by heating at 260 °C to yield 4-hydroxy-
tetrahydroquoinolin-5-one (29b). Chlorination of 29b
followed by treatment with sodium methoxide in methyl
alcohol provided 4-methoxy compound 30b . Diketone
24a was reacted with tetramethoxypropane, 1-butyn-
3-one, or acetylacetone in the presence of ammonium
acetate without isolation of 27a to afford 31a -33a ,
19,20
respectively (method D).
Other cyclohexanones fused with heteroaromatic rings
were prepared according to Schemes 4 and 5. Tetra-
hydroindol-4-ones 35a ,e were obtained by palladium-
catalyzed oxidation of enamines 34a ,e followed by
cyclization and dehydration.21 Enamines 34a ,e were
obtained by reaction of 5-phenylcyclohexane-1,3-diones
24a ,e and 2-aminoethanol or 2-aminopropanol in THF
in the presence of molecular sieves 4A. Condensation
of diketone 24b with acetic acid in the presence of DCC
and DMAP gave triketone 36b,22 which was reacted
Sch em e 2a
a
(a) CH3CtCCH2NH2‚HCl; (b) 220 °C; (c) NH4OAc, EtOH; (d) CH3COCH2CH(OMe)2, KOH; (e) SO2Cl2; (f) 5-(methoxymethylene)-2,2-
dimethyl-[1,3]-dioxane-4,6-dione; (g) 260 °C, Ph2O; (h) POCl3; (i) MeONa.

Non-acylguanidine-type Na+/ H+ Exchanger Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3011
Sch em e 4a
a
(a) H2NCH2CH2OH or H2NCH2CH(OH)CH3, MS 4A; (b) bromomesitylene, cat. Pd(PPh3)4, K2CO3; (c) AcOH, DMAP, DCC; (d)
NH2NH2‚H2O; (e) pyrrolidine; (f) formamidine; (g) TosNHNH2; (h) CH3COCH2Cl, K2CO3.
Sch em e 5a
a
(a) CH3COCH2Cl, EtONa, DMF; (b) PCl3; (c) Na2S‚9H2O; (d) CH3COCH2Cl, NaOEt-EtOH; (e) xylene, reflux.
with hydrazine hydrate in EtOH to provide tetra-
hydroindazol-4-one 37b in good yield. In addition, the
enamine obtained from 36b and pyrrolidine was reacted
with formamidine to afford tetrahydroquinazolin-5-one
38b. Tosyl hydrazide 39b generated from diketone 24b,
and p-toluenesulfonyl hydrazide was converted to 4-
methyltetrahydrocinnolin-5-one 40b by reaction with
chloroacetone followed by cyclization in 42% yield. This
is a new, facile synthetic method for the preparation of
tetahydrocinnolin-5-one. Alkylation of diketone 24b
with chloroacetone in the presence of sodium ethoxide
in DMF followed by cyclization provided tetrahydro-
benzofuran-4-one 41b. Tetrahydrobenzothiophen-4-one
44b was synthesized in several steps,23,24 in which
3-mercapto-2-cyclohexen-1-one 42b was first obtained
from diketone 24b and then alkylated with chloro-
acetone to give thioether 43b. Subsequent cyclization
of this compound produced the desired heterocyclic
compound 44b.
The flavanone and flavone derivatives 47b and 50b
were prepared by standard procedures as shown in
Scheme 6.
The optical isomers 16 and 18-22 were prepared by
optical resolution of 8b, 8n , and 8v with D- or L-
pyroglutamic acid, respectively (Scheme 7). Compound
17 was synthesized from the (-)-isomer of 26b, which
was obtained by resolution of 26b by means of Chiralcel
OD with i-PrOH-hexane as the eluent. The pure
enantiomers were converted to the corresponding
dimethanesulfonate salts. These salts showed optimal

3012 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Fukumoto et al.
Sch em e 6a
a
(a) 4-chlorobenzaldehyde, aq NaOH, EtOH; (b) AcOH, reflux; (c) 4-chlorobenzoyl chloride; (d) NaH, t-BuOH; (e) MeSO3H, AcOH.
Sch em e 7
solubilities and physical properties, whereas the corre-
The initial lead compound 1 was converted into a
bicyclic derivative, i.e., flavanone 2a to improve stability
and restrict the conformation. And the related bicyclic
compounds, including flavone, tetrahydroindole and
tetrahydroquinoline derivatives (3a -5a ) were prepared
(see Table 1). Among these compounds, flavanone 2a ,
flavone 3a , and tetrahydroindole 4a retained similar
activity to 1, whereas tetrahydroquinoline 5a was about
10 times more potent. These results indicated that
bicyclic aminoguanidine derivatives I were effective as
NHE inhibitors.
sponding HCl salts or free bases were used for X-ray
crystallographic analysis. The absolute configurations
of these compounds are listed in Table 5, and the
molecular structure of compound 19 (HCl salt) is shown
in Figure 1.
Resu lts a n d Discu ssion
The synthesized aminoguanidine derivatives were
evaluated for their inhibitory effects on acidosis-induced
increases in rat platelet cell volume. Namely, the
increase in the cell volume caused by the addition of
sodium propionate buffer was observed by measurement
of the increase in the optical density (OD). The results
are displayed in Tables 1-5 as IC50 values (i.e., the
concentration needed to inhibit the increase in the OD
by 50%).
Optimization of 5a was initially investigated by
changing the substituents on the pyridine and benzene
rings. Tetrahydroquinoline derivatives that possess
methyl or methoxy groups on the tetrahydroquinoline
ring and/or a chlorine atom on Ar2 are shown in Table
2. Introduction of a methyl group into the 4-position of
the tetrahydroquinoline ring led to an improvement of
the in vitro activity. Compound 8a was about 5 times
more potent than 5a , and 7a was 15 times more potent
than 6a . On the other hand, the compounds with the
methyl group in the 2-position exhibited weaker activi-
ties than 2-unsubstituted compounds (6a vs 5a , 7a vs
8a ).
Compound 8b, having a chlorine atom in the o-
position of Ar2, exhibited highly potent activity (IC50
value was 0.040 µM) and was twice as potent as 8a and
10 times more potent than the lead compound 5a . Also,
a chlorine atom in the 3-position of Ar2 (8c) increased
the activity (IC50 value of 8c was 0.061 µM), but a
chlorine atom in the 4-position (8d ) reduced the activity
(IC50 value was 0.55 µM). Substitution of the methoxy
group (9b) for the methyl group of 8b retained the
activity. These results suggest that substituents, espe-
cially a methyl group in the 4-position of Ar1 and a
F igu r e 1. Molecular structure of 19 as determined by X-ray
crystallographic analysis.

Non-acylguanidine-type Na+/ H+ Exchanger Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3013
Ta ble 1. Physical Properties and in Vitro NHE Inhibitory Activities of Compounds 2a -5a
a
b
AG ) N-NH-C(dNH)-NH2. No attempt was made to optimize yields. Numbers represent the yield for the last step. c E ) EtOH.
Analyses for C, H, and N are within (0.4% of the expected value for the formula. e NHE assay in rat platelets. IC50 is the concentration
required to inhibit the acid-induced swelling in rat platelets by 50%. All data represent means of triplicate separate experiments.
d
Ta ble 2. Physical Properties and in Vitro NHE Inhibitory Activities of Tetrahydroquinoline Derivatives 6a -9b
in vitro
compda
R1
R2
R3
R4
R5
yieldb (%)
mp (°C)
recryst solvc
formulad
IC50e (µM)
6a
7a
8a
8b
8c
8d
9b
Me
Me
H
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
H
71
55
79
71
90
48
84
>300
E
E
C
C
17H19N5·2HCl·0.1H2O
18H21N5·2HCl
2.8
0.18
0.091
0.040
0.061
0.55
Me
Me
Me
Me
Me
OMe
270 dec
184-186
204 dec
295 dec
197 dec
158-159
H2O-E
E-EA
E
H2O
H2O-E
C17H19N5·2HCl·H2O
C
C
C17H18ClN5·2HCl·0.5H2O
C17H18ClN5O·2CH3SO3H·H2O
17H18ClN5·2HCl·0.8H2O
17H18ClN5·2HCl
H
H
H
Cl
0.050
a
b
AG ) N-NH-C(dNH)-NH2. No attempt was made to optimize yields. Numbers represent the yield for the last step. c E ) EtOH,
EA ) ethyl acetate. Analyses for C, H, and N are within (0.4% of the expected value for the formula. e NHE assay in rat platelets. IC50
is the concentration required to inhibit the acid-induced swelling in rat platelets by 50%. All data represent means of triplicate separate
experiments.
d
chlorine atom in the o-position of Ar2, were important
for potent activity.
in Table 4. Introduction of certain substituents in the
2-position of Ar2 increased the potency. The IC50 values
of compound 8e (2-Me), 8g (2-F), and 8h (2-Br) were
0.057, 0.032, and 0.056 µM, respectively, whereas
compound 8f with a 2-methoxy group showed weaker
activity (IC50 ) 0.10 µM).
For the disubstituted series of compounds, the pres-
ence of two chlorine atoms in the 2- and 5-position (8k )
maintained potent activities (IC50 ) 0.058 µM). On the
other hand, a 2,3-dichloro compound (8i) exhibited
relatively weaker activity (IC50 ) 0.089 µM), and other
dichloro derivatives (8j,l) were less active. The com-
pounds with a fluorine atom in the 5-position of Ar2
(8m -p ) exhibited highly potent activities (IC50 values
were about 0.02-0.04 µM). These results indicated that
both the size and lipophilicity of the Ar2 substituents
are important for optimal activity.
Introduction of a thiophene ring as Ar2 also resulted
in compounds with potent NHE inhibitory activities
(IC50 values of 8q and 8t were 0.047 and 0.030 µM,
respectively). Furthermore, this activity was increased
by the presence of a chlorine atom in the o-position of
the thiophene ring of 8q and 8t, and compounds 8r and
8v exhibited the most potent activities (IC50 values of
both compounds were 0.019 µM). These results agreed
Next, aromatic ring 1 (Ar1) was modified for a series
of compounds with a methyl group in the peri position
of the aminoguanidine moiety and a chlorine atom in
the o-position in Ar2. The NHE inhibitory activities of
these compounds are shown in Table 3. Pyridine,
pyridazine, pyrrole, and pyrazole derivatives (8b, 10b,
12e, and 13b) showed potent activities, although furan
14b was slightly less potent. In comparison with these
compounds, flavanone 2b, flavone 3b (Ar1 ) benzene),
and benzothiophene derivatives (15b) exhibited much
weaker activities. These results suggest that the basicity
of the nitrogen atom in the 1-position of compounds (8b,
10b, 12e, and 13b) is important for potent activity.
Tetrahydroquinazoline 11b was only weakly active,
which may be due to the presence of a nitrogen atom at
the 3-position. Among the compounds that exhibited
potent NHE inhibitory activity, tetrahydroquinolines
were selected for further examination on the basis of
their potency, ease of preparation, and physical proper-
ties.
Tetrahydroquinoline derivatives (8e-y) with various
aromatic rings (Ar2) were prepared in order to optimize
Ar2 and the substituents in the o-position and are shown

3014 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Fukumoto et al.
Ta ble 3. Physical Properties and in Vitro NHE Inhibitory Activities of Aminoguanidine Derivatives 2b-15b
in vitro
compda
X
Y
Z
R3
yieldb (%)
mp (°C)
recryst solvc
formulad
IC50e (µM)
2b
3b
8b
10b
11b
12e
13b
14b
15b
88
35
71
79
63
4
79
80
87
276-277
287-289 dec
204 dec
241-243
284 dec
187 dec
220 dec
300 dec
246 dec
E
EA
E-EA
E
IPE
E-EA
H2O-E
IPE
E
C
C
C
C
C
C
17H17ClN4O·HCl
0.20
0.36
17H15ClN4O·2HCl·0.5H2O
17H18ClN5·2HCl·0.8H2O
16H17ClN6·2HCl
N
N
N
NH
NH
O
CH
N
CH
CH
N
CH
CH
N
0.040
0.026
0.24
0.034
0.055
0.082
0.22
16H17ClN6·2HCl·0.5H2O
17H21N5·2HCl·0.5H2O
Me
Cl
Cl
Cl
C15H17ClN6·2HCl·0.5H2O
C
C
CH
CH
16H17ClN4·HCl
16H17ClN4S·HCl
S
a
b
AG ) N-NH-C(dNH)-NH2. No attempt was made to optimize yields. Numbers represent the yield for the last step. c E ) EtOH,
EA ) ethyl acetate, IPE ) diisopropyl ether. Analyses for C, H and N are within (0.4% of the expected value for the formula. e NHE
assay in rat platelets. IC50 is the concentration required to inhibit the acid-induced swelling in rat platelets by 50%. All data represent
means of triplicate separate experiments.
d
Ta ble 4. Physical Properties and in Vitro NHE Inhibitory Activities of Tetrahydroquinoline Derivatives
in vitro
IC50 (µM)
Ar2
yielda (%)
mp (°C)
recryst solvb
formulac
d
compd
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
2-methylphenyl
2-methoxyphenyl
2-fluorophenyl
88
50
61
70
98
90
91
89
39
86
86
90
73
67
57
93
69
96
76
77
86
218 dec
192 dec
240 dec
233 dec
270-272
193-195
>300
E-EA
C
C
C
18H21N5·2HCl·0.5H2O
18H21N5O·2HCl·0.2H2O
17H18FN5·2HCl·0.2H2O
0.057
0.10
0.032
0.056
0.089
0.34
E-EA
E
2-bromophenyl
H2O-E
E
H2O-E
H2O
C17H18BrN5·2HCl·0.5H2O
2,3-dichlorophenyl
2,4-dichlorophenyl
2,5-dichlorophenyl
2,6-dichlorophenyl
2-chloro-5-fluorophenyl
5-fluoro-2-methylphenyl
5-fluoro-2-methoxyphenyl
2,5-difluorophenyl
2-thienyl
3-chloro-2-thienyl
3,5-dichloro-2-thienyl
3-thienyl
2-chloro-3-thienyl
2,5-dichloro-3-thienyl
2-pyridyl
C17H17Cl2N5·2HCl
C17H17Cl2N5·2HCl·0.5H2O
C17H17Cl2N5·2HCl·0.5H2O
0.058
23%(0.3)e
0.019
0.037
0.032
0.039
0.047
0.019
0.049
0.030
0.022
0.019
23%(0.3)e
25%(1)e
0.11
>300
E
C17H17Cl2N5·2HCl·0.25H2O
268 dec
202-205
>300
290 dec
225 dec
204 dec
184-187
>300
281 dec
>300
E-EA
E
E
E
H2O-E
CH2Cl2
E
E
C17H17ClFN5·2HCl·0.5H2O
C
C
C
18H20FN5·2HCl·0.5H2O
18H20FN5O·2HCl
17H17F2N5·2HCl
C15H17N5S·2HCl·H2O
C15H16ClN5S·2HCl
C
C
C
C
C16H18N6·3HCl·0.2H2O
C16H18N6·3HCl·0.5H2O
C15H17N5O·2HCl
8s
8t
15H15Cl2N5S·2HCl·0.5H2O
15H17N5S·2HCl·0.3EtOH
15H16ClN5S·2HCl
8u
8v
8w
8x
8y
E
E
15H15Cl2N5S·2HCl
260 dec
267 dec
>300
H2O-E
H2O-E
E
4-pyridyl
2-furyl
a
b
No attempt was made to optimize yields. Numbers represent the yield for the last step. E ) EtOH, EA ) ethyl acetate. c Analyses
d
for C, H, and N are within ( 0.4% of the expected value for the formula. NHE assay in rat platelets. IC50 is the concentration required
to inhibit the acid-induced swelling in rat platelets by 50%. All data represent means of triplicate separate experiments. e Percent inhibition
at the concentration (micromolar) represented in parentheses.
with the structure-activity relationships observed for
compounds with a benzene ring as Ar2. In contrast,
compounds with basic heterocycles such as 2- or 4-pyr-
idyl (8w or 8x) in the 7-position of the tetrahydroquino-
line showed poor activities, and the activity of 7-(2-
furyl)tetrahydroquinoline 8y was relatively weak.
Optical isomers (16-18, 20-22) of three tetrahydro-
quinoline racemates (8b, 8n , and 8v) that exhibited
potent NHE inhibitory activities were also tested and
the results are summarized in Table 5. The IC50 values
of S enantiomers (16, 18, and 21) were 20, 14, and 17
nM, respectively. The S isomers showed about 2-35
times more potent activity than the R isomers. And
these activities were 115-150 times more potent than
the initial lead compound 1 and about 4-6 times more
potent than 23 (IC50 ) 75 nM).
These three enantiomers (16, 18, 21) were evaluated
for their NHE inhibitory effects on human platelets in
vitro. The results showed that these compounds exhib-
ited excellent activities on human platelets, and they
were about 16-30 times more potent than 23, with IC50
values of 9.0, 13, 7.0, and 210 nM, respectively. Com-
pound 23 exhibited weak activity in human platelets
compared with rat platelets. The compounds were then
tested in a rat myocardial infarction model in vivo, in
which the left coronary artery was occluded for 1 h and
then reperfused for 24 h. Aminoguanidine derivative 16,
18, or 21 (0.1 mg/kg) or acylguanidine derivative 23 (0.3

Non-acylguanidine-type Na+/ H+ Exchanger Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3015
Ta ble 5. Physical Properties and in Vitro NHE Inhibitory
Activities of Enantiomers of Tetrahydroquinoline Derivatives
16-22
tion by guanidine compounds, it is necessary that the
guanidino moiety is protonated and mimics the sodium
cation hydrated with three water molecules. The pKa
values of the aminoguanidine derivative 18 and acyl-
guanidine derivative 23 measured in water were 8.4 and
6.2, respectively. Thus, 18 is expected to inhibit NHE
at higher pH, that is, at a lower level of acidosis, and to
prevent the myocardium damage in the ischemia-
reperfusion more effectively.
In summary, in our search for potent and non-
acylguanidine-type NHE inhibitors, we investigated
aryl-fused tetrahydropyranylidene and cyclohexylidene
aminoguanidine derivatives I (X ) O, CH2), which were
designed on the basis of the structure of an initial lead
compound 1. It was found that S isomers of tetra-
hydroquinoline derivatives that possess a methyl group
in the 4-position and a halogen or methyl group in the
o-position in Ar2 exhibited potent NHE inhibitory ac-
tivities. In this series of compounds, (5E,7S)-[[7-
(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-
quinolinylidene]amino]guanidine dimethanesulfonate
(18) displayed significant NHE inhibitory activities on
the rat and human platelets and showed long-lasting
properties in vitro and in vivo. These results suggested
that 18 may exhibit significant and long-lasting NHE-1
inhibitory activity and show potent protective effects
against cardiac injuries induced by ischemia-reperfu-
sion in clinical application.
d
recryst IC50
compda
formulab
mp (°C)
solvc
E
(nM)
16
8b
17
C
17H18ClN5·2CH3SO3H
194-195
20
40
C
C
17H18ClN5·2CH3SO3H
18H20FN5·2CH3SO3H
194-196
202-204
E-A
700
18
8n
20
E
14
37
C
C
18H20FN5·2CH3SO3H
202-204
E
E
220
21
8v
22
15H15Cl2N5S·2CH3SO3H 229-231
17
19
33
C
15H15Cl2N5S·2CH3SO3H 225-229
E
23
cariporide
75
a
b
Structures are given in Tables 2 and 4. Analyses for C, H,
and N are within (0.4% of the expected value for the formula.c E
) EtOH, A ) acetone. NHE assay in rat platelets. IC50 is the
d
concentration required to inhibit the acid-induced swelling in rat
platelets by 50%. All data represent means of triplicate separate
experiments.
Ta ble 6. NHE Inhibitory Activities in Human Platelets in
Vitro and Inhibitory Effect on the Myocardial Infarct Size of
Ischemia-Reperfusion Injury Model of Rat in Vivo
ischemia-reperfusion
human plateletb
IC50c (nM)
injury modeld
compda
% inhibition
n
16
9.0
13
7.0
44
33
43
5
7
6
18
21e
28f
6
Exp er im en ta l Section
23
210
a
b
Structures are given in Scheme 7. NHE assay in human
platelets. c IC50 is the concentration required to inhibit the acid-
induced swelling in human platelets by 50%. All data represent
Melting points were obtained with a Yanaco micro melting
apparatus and are uncorrected. Proton nuclear magnetic
resonance (1H NMR) spectra not specified were recorded on a
Varian Gemini 200 instrument at 200 MHz, with tetra-
methylsilane as an internal standard. Elemental analyses
were carried out by Takeda Analytical Laboratories, Ltd., and
are within (0.4% of the theoretical values unless otherwise
noted. Solutions of organic solvents were dried over anhydrous
MgSO4. Column chromatography was carried out on silica gel
(Wakogel C-300, particle size 45-75 mm) by the flash chro-
matography technique. Yields were not maximized. All TLC
analyses were carried out on Merck silica gel 60 (F254) plates.
The enantiomeric excess was measured by HPLC with Ultron
ES-OVM.
[[7-(5-F lu or o-2-m et h ylp h en yl)-4-m et h yl-7,8-d ih yd r o-
5(6H)-q u in olin ylid en e]a m in o]gu a n id in e Dih yd r och lo-
r id e (8n ), Typ ica l P r oced u r e. The mixture of 26n (1.1 g,
4.1 mmol), aminoguanidine hydrochloride (0.54 g, 4.9 mmol),
concentrated HCl (1.0 mL), and water (1.0 mL) in EtOH (30
mL) was refluxed for 6 h. The solvent was evaporated under
reduced pressure. The residue was dissolved in water and
washed with EtOAc. To the solution was added aqueous
NaHCO3, and the mixture was extracted with EtOAc, and the
organic layer was washed with water, dried, and evaporated.
The residue was dissolved in EtOH, and 1 N HCl (10 mL) was
added. The mixture was concentrated, and the residue was
recrystallized from EtOH to give 8n (1.4 g, 86%) as colorless
crystals: 1H NMR(DMSO-d6) δ 2.31 (3H, s), 2.72-3.03 (1H,
m), 2.90 (3H, s), 3.13-3.57 (4H, m), 6.93-7.06 (1H, m), 7.17-
7.4 (2H, m), 7.5-8.4 (4H, br s), 7.85 (1H, d, J ) 6 Hz), 8.65
(1H, d, J ) 6 Hz), 11.39 (1H, s).
d
means of triplicate separate experiments. Compounds (0.1 mg/
kg) were administered intravenously 5 min before occlusion. e The
hydrate was used in this experiment. f Compound 23 (0.3 mg/kg)
was administered intravenously 5 min before occlusion.
mg/kg) was administered intravenously 5 min before
occlusion. Potent cardioprotective effects were observed
with 16, 18, and 21 inhibiting the extension of infarct
size by 44%, 33%, and 43%, respectively (Table 6).
Compound 23 (0.3 mg/kg) showed weaker activity (28%
inhibition) than the aminoguanidine derivatives.
From these results and other factors including phar-
macokinetics, toxicity, and physicochemical properties,
18 was selected for further evaluation. 18 showed long-
lasting inhibitory properties. In the rat ischemia-
reperfusion injury model described above, compound 18,
administered intravenously 2 h before coronary occlu-
sion, exhibited potent inhibitory effects. The minimum
effective dose in this condition was 0.1 mg/kg, due to
the desirable pharmacokinetic profile of this compound.
The half-life period of 18 was 3.6 h in IGS/SD rat (1
mg/kg iv). In addition, the metabolic velocity in rat (IGS/
SD male rat) and human liver microsomes was low (40
and 18 pmol min-1 mg-1, respectively).
In the Na+-dependent pHi recovery assay, 18 inhib-
ited hNHE in a concentration-dependent manner, with
IC50 values for hNHE1, hNHE2, and hNHE3 of 0.96,
430, and 11000 nM, respectively. The inhibitory activity
of 18 was selective for the human NHE-1 isoform.25
The potent NHE inhibitory activities of aminoguani-
dine derivatives are dependent on both the structures
and the pKa values of the compounds. For NHE inhibi-
The following compounds (1-15b) were prepared by a
manner similar to that used for 8n .
1: mp 175-176 °C; 1H NMR (DMSO-d6) δ 3.89 (3H, s), 5.02
(2H, s), 7.06-7.22 (2H, m), 7.28-7.51 (5H, m), 7.52-8.03 (4H,
br s), 7.64-7.75 (1H, m), 8.38 (1H, s), 11.96 (1H, s).
1
2a : H NMR (DMSO-d6) δ 7.2-8.0 (4H, br s), 7.37 (1H, dt,
J ) 2, 8 Hz), 7.50-7.68 (7H, m), 8.09-8.21 (2H, m), 8.45 (1H,
dd, J ) 1, 8 Hz), 11.93 (1H, s).

3016 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Fukumoto et al.
1
2b: H NMR (DMSO-d6) δ 2.65 (3H, s), 2.95 (1H, dd, J )
8.4 (4H, br s), 7.83 (1H, d, J ) 6 Hz), 8.64 (1H, d, J ) 6 Hz),
13, 17 Hz), 3.43 (1H, dd, J ) 3, 17 Hz), 5.41 (1H, dd, J ) 3, 13
Hz), 6.85-7.01 (2H, m), 7.20-8.32 (1H, m), 7.30-8.05 (4H, br
s), 7.40-7.60 (3H, m), 7.70-7.80 (1H, m), 11.18 (1H, s).
3a : 1H NMR (DMSO-d6) δ 2.92 (1H, dd, J ) 12, 17 Hz), 5.30
(1H, dd, J ) 3, 12 Hz), 6.95-7.08 (2H, m), 7.20-8.20 (4H, br
s), 7.30-7.62 (6H, m), 8.34 (1H, dd, J ) 2, 8 Hz), 11.2 (1H, s).
4a : 1H NMR (DMSO-d6) δ 2.68-3.16 (4H, m), 3.24-3.48 (1H,
m), 6.84 (1H, s), 6.95 (1H, s), 7.21-7.50 (5H, m), 7.74 (4H, br
s), 10.15 (1H, br s), 11.77 (1H, br s).
11.58 (1H, s).
1
8q: H NMR (DMSO-d6) δ 2.60-3.08 (1H, m), 2.86 (3H, s),
3.28-3.80 (4H, m), 6.96-7.08 (1H, m), 7.14 (1H, s), 7.43 (1H,
d, J ) 5 Hz), 7.6-8.2 (4H, br s), 7.81 (1H, d, J ) 6 Hz), 8.63
(1H, d, J ) 6 Hz), 11.69 (1H, s).
1
8r : H NMR (DMSO-d6) δ 2.7-2.97 (1H, m), 2.86 (3H, s),
3.22-4.4 (4H, m), 7.08 (1H, d, J ) 5 Hz), 7.4-8.4 (4H, br s),
7.63 (1H, d, J ) 5 Hz), 7.8 (1H, d, J ) 5 Hz), 8.62 (1H, d, J )
6 Hz), 11.43 (1H, s).
5a : 1H NMR (DMSO-d6) δ 2.74-2.92 (1H, m), 3.16-3.53 (4H,
m), 7.24-7.46 (5H, m), 7.81 (1H, dd, J ) 4, 8 Hz), 8.04 (4H, br
s), 8.78 (1H, d, J ) 4 Hz), 9.31 (1H, d, J ) 8 Hz), 11.51 (1H,
s).
1
8s: H NMR (DMSO-d6) δ 2.72-2.94 (1H, m), 2.83 (3H, s),
3.20-4.0 (4H, m), 7.24 (1H, s), 7.75 (1H, d, J ) 6 Hz), 7.87
(4H, br s), 8.60 (1H, d, J ) 6 Hz), 11.47 (1H, s).
1
8t: H NMR (DMSO-d6) δ 2.86 (3H, s), 2.80-3.02 (1H, m),
1
6a : H NMR (DMSO-d6) δ 2.65-2.96 (1H, m), 2.78 (3H, s),
3.36 (4H, m), 7.24 (1H, dd, J ) 1, 5 Hz), 7.49 (1H, d, J ) 2
Hz), 7.56 (1H, m), 7.82 (1H, d, J ) 6 Hz), 7.90 (4H, br s), 8.64
(1H, d, J ) 6 Hz), 11.65 (1H, br s).
3.15-3.61 (4H, m), 7.25-7.55 (5H, m), 7.6-8.7 (4H, br s), 7.78
(1H, d, J ) 8 Hz), 9.72 (1H, d, J ) 8 Hz), 11.51 (1H, s).
7a : 1H NMR (DMSO-d6) δ 2.5-3.8 (5H, m), 2.72 (3H, s), 2.82
(3H, s), 7.23-7.60 (6H, m), 7.6-8.2 (4H, br s), 7.71 (1H, s),
11.33 (1H, s).
8u : 1H NMR (DMSO-d6) δ 2.86 (4H, m), 3.04-3.22 (1H, m),
3.39 (3H, m), 7.25 (1H, d, J ) 6 Hz), 7.55 (1H, d, J ) 6 Hz),
7.82 (1H, d, J ) 6 Hz), 7.92 (4H, br s), 8.62 (1H, d, J ) 6 Hz),
11.43 (1H, br s).
1
8a : H NMR (DMSO-d6) δ 2.76-2.98 (1H, m), 2.87 (3H, s),
8v: 1H NMR (DMSO-d6) δ 2.85 (4H, m), 3.03-3.22 (1H, m),
3.36 (3H, m), 7.42 (1H, s), 7.79 (1H, d, J ) 6 Hz), 7.90 (4H, br
s), 8.62 (1H, d, J ) 6 Hz), 11.44 (1H, br s).
3.14-3.46 (4H, m), 7.24-7.48 (5H, m), 7.82 (1H, d, J ) 6 Hz),
7.91 (4H, br s), 8.63 (1H, d, J ) 6 Hz), 11.45 (1H, s).
1
8b: H NMR (DMSO-d6) δ 2.65-3.00 (1H, m), 2.88 (3H, s),
8w : 1H NMR (DMSO-d6) δ 2.82 (3H, s), 3.03-3.78 (5H, m),
7.4-8.3 (4H, br s), 7.53-7.63 (1H, m), 7.78 (1H, d, J ) 8 Hz),
7.84 (1H, d, J ) 6 Hz), 8.06-8.17 (1H, m), 8.65 (1H, d, J ) 6
Hz), 8.70 (1H, d, J ) 5 Hz), 11.57 (1H, s).
3.15-3.78 (4H, m), 7.2-8.2 (4H, br s), 7.28-7.53 (3H, m),
7.58-7.66 (1H, m), 7.83 (1H, d, J ) 6 Hz), 8.63 (1H, d, J ) 6
Hz), 11.45 (1H, s).
1
8c: H NMR (DMSO-d6) δ 2.76-3.03 (1H, m), 2.88 (3H, s),
1
3.16-3.52 (4H, m), 7.32-7.62 (4H, m), 7.86 (1H, d, J ) 6 Hz),
7.99 (4H, br s), 8.65 (1H, d, J ) 6 Hz), 11.60 (1H, s).
8x: H NMR (DMSO-d6) δ 2.70-4.2 (5H, m), 2.85 (3H, s),
7.60-8.4 (4H, br s), 7.76 (1H, d, J ) 6 Hz), 8.17 (2H, d, J ) 5
1
8d : H NMR (DMSO-d6) δ 2.70-2.96 (1H, m), 2.85 (3H, s),
Hz), 8.61 (1H, d, J ) 6 Hz), 8.97 (2H, d, J ) 5 Hz), 11.82 (1H,
3.14-3.50 (4H, m), 7.47 (4H, s), 7.79 (1H, d, J ) 6 Hz), 7.88
(4H, br s), 8.62 (1H, d, J ) 6 Hz), 11.46 (1H, s).
s).
1
8y: H NMR (DMSO-d6) δ 2.85 (3H, s), 2.98 (1H, dd, J )
1
8e: H NMR (DMSO-d6) δ 2.35 (3H, s), 2.64-2.96 (1H, m),
10, 18 Hz), 3.30 (2H, m), 3.56 (2H, m), 6.42 (2H, d, J ) 1 Hz),
7.63 (1H, d, J ) 1 Hz), 7.82 (1H, d, J ) 6 Hz), 7.98 (4H, br s),
8.64 (1H, d, J ) 6 Hz), 11.79 (1H, s).
2.91 (3H, s), 3.07-3.61 (4H, m), 6.9-8.4 (4H, br s), 7.03-7.30
(3H, m), 7.37-7.48 (1H, m), 7.86 (1H, d, J ) 6 Hz), 8.65 (1H,
d, J ) 6 Hz), 11.36 (1H, s).
1
9b: H NMR (DMSO-d6) δ 2.54 (6H, s), 2.72-2.84 (1H, m),
1
8f: H NMR (DMSO-d6) δ 2.70-3.90 (5H, m), 2.87 (3H, s),
3.06-3.57 (3H, m), 3.63-4.3 (1H, m), 4.21 (3H, s), 7.2-8.0 (4H,
br s), 7.36-7.63 (5H, m), 8.61 (1H, d, J ) 7 Hz).
3.83 (3H, s), 6.93-7.06 (2H, m), 7.23-7.40 (2H, m), 7.50-8.02
(4H, br s), 7.78 (1H, d, J ) 6 Hz), 8.61 (1H, d, J ) 6 Hz), 11.20
(1H, s).
1
10b: H NMR (DMSO-d6) δ 2.78 (3H, s), 2.91 (1H, dd, J )
12, 18 Hz), 3.21-3.34 (1H, m), 3.40-3.56 (2H, m), 3.61-3.78
(1H, m), 7.31-7.70 (4H, m), 8.00 (4H, br s), 9.32 (1H, s).
1
8g: H NMR (DMSO-d6) δ 2.80-4.0 (5H, m), 2.83 (3H, s),
1
7.19-7.44 (3H, m), 7.50-8.02 (4H, br s), 7.51-7.63 (1H, m),
7.77 (1H, d, J ) 6 Hz), 8.60 (1H, d, J ) 6 Hz), 11.28 (1H, s).
11b: H NMR (DMSO-d6) δ 2.7-3.0 (2H, m), 2.83 (3H, s),
3.1-3.4 (2H, m), 3.59 (1H, m), 7.32-7.64 (4H, m), 7.76 (4H,
br s), 8.89 (1H, s).
1
8h : H NMR (DMSO-d6) δ 2.75-3.03 (1H, m), 2.88 (3H, s),
12e: 1H NMR (DMSO-d6) δ 2.33 (3H, s), 2.34 (3H, s), 2.53-
3.08 (4H, m), 3.67-3.85 (1H, m), 6.46 (1H, s), 7.05-7.34 (4H,
m), 8.30 (1H, br s).
3.16-3.60 (4H, m), 7.22-7.35 (1H, m), 7.41-7.56 (1H, m),
7.69-7.75 (2H, m), 7.4-8.6 (4H, br s), 7.82 (1H, d, J ) 6 Hz),
8.63 (1H, d, J ) 6 Hz), 11.39 (1H, s).
8i: 1H NMR (DMSO-d6) δ 2.88 (4H, m), 3.27 (1H, dd, J ) 5,
18 Hz), 3.45 (2H, m), 3.74 (1H, m), 7.46 (1H, t, J ) 8 Hz), 7.63
(2H, d, J ) 8 Hz), 7.82 (1H, d, J ) 6 Hz), 7.94 (4H, br s), 8.63
(1H, d, J ) 6 Hz), 11.50 (1H, br s).
1
13b: H NMR (DMSO-d6) δ 2.48 (3H, s), 2.68 (1H, dd, J )
12, 17 Hz), 2.94 (2H, d, J ) 8 Hz), 3.05 (1H, dd, J ) 2, 16 Hz),
3.53-3.72 (1H, m), 6.9-7.9 (4H, br s), 7.24-7.53 (3H, m),
7.56-7.63 (1H, m), 10.86 (1H, s).
8j: 1H NMR (DMSO-d6) δ 2.72-2.96 (1H, m), 2.86 (3H, s),
3.14-3.73 (4H, m), 7.47-7.72 (3H, m), 7.81 (1H, d, J ) 6 Hz),
7.93 (4H, br s), 8.62 (1H, d, J ) 6 Hz), 11.53 (1H, s).
1
14b: H NMR (DMSO-d6) δ 2.21 (3H, s), 2.69 (1H, dd, J )
12.0, 16.2 Hz), 2.99-3.09 (3H, m), 3.71 (1H, m), 7.0-7.8 (4H,
br s), 7.27-7.51 (3H, m), 7.42 (1H, s), 7.61 (1H, dd, J ) 2.0,
7.4 Hz).
1
8k : H NMR (DMSO-d6) δ 2.83-3.03 (1H, m), 2.88 (3H, s),
1
3.14-3.77 (4H, m), 7.43 (1H, dd, J ) 2, 9 Hz), 7.5-8.4 (4H, br
s), 7.55 (1H, d, J ) 9 Hz), 7.76 (1H, d, J ) 2 Hz), 7.83 (1H, d,
J ) 5 Hz), 8.63 (1H, d, J ) 5 Hz), 11.51 (1H, s).
15b: H NMR (DMSO-d6) δ 2.45 (3H, s), 2.73 (1H, dd, J )
12, 17 Hz), 3.0-3.20 (3H, m), 3.56-3.77 (1H, m), 6.9-8.1 (4H,
br s), 7.03 (1H, s), 7.25-7.66 (4H, m), 10.77 (1H, s).
1
8l: H NMR (DMSO-d6) δ 2.85 (3H, s), 3.07 (1H, dd, J ) 4,
(5E ,7S )-[[7-(2-Ch lor op h e n yl)-4-m e t h yl-7,8-d ih yd r o-
5(6H )-q u in olin ylid en e]a m in o]gu a n id in e Met h a n esu l-
fon a te (16). To the suspension of 8b (123.9 g, 0.31 mol) in
MeOH (1200 mL) was added dropwise 28% NaOMe in MeOH
(119 mL). The mixture was stirred at 50 °C for 30 min and
concentrated under reduced pressure. The residue was washed
with water and dried to give free base (109.3 g) as colorless
crystals. To a solution of this free base in i-PrOH (700 mL)
was added dropwise a solution of L-pyroglutamic acid (10 g,
77.5 mmol) in i-PrOH (700 mL) at 50 °C for 1.5 h, and the
mixture was stirred at 50 °C for 1 h and then at room
temperature for 2 days. The precipitates formed were filtered
and washed with i-PrOH to give diastereomeric salt (55.5 g,
46%, 88% ee), which was recrystallized from EtOH to give
crystals (44.3 g, 36%, 97% ee). This crystals of salt were
16 Hz), 3.28 (1H, d, J ) 15 Hz), 3.38 (1H, dd, J ) 12, 18 Hz),
4.10 (2H, m), 7.41 (1H, t, J ) 8 Hz), 7.57 (2H, d, J ) 8 Hz),
7.80 (1H, d, J ) 6 Hz), 7.89 (4H, br s), 8.62 (1H, d, J ) 6 Hz),
11.46 (1H, br s).
8m : 1H NMR (DMSO-d6) δ 2.76-3.05 (1H, m), 2.84 (3H, s),
3.13-3.75 (4H, m), 7.0-8.4 (4H, br s), 7.2-7.34 (1H, m), 7.52-
7.66 (2H, m), 7.76 (1H, d, J ) 6 Hz), 8.6 (1H, d, J ) 6 Hz),
11.36 (1H, s).
8o: 1H NMR (DMSO-d6) δ 2.77-2.92 (4H, m), 3.16 (1H, dd,
J ) 4, 17 Hz), 3.33-3.61 (3H, m), 3.81 (3H, s), 7.01-7.15 (2H,
m), 7.28-7.33 (1H, m), 7.82 (1H, d, J ) 6 Hz), 7.91 (4H, br s),
8.62 (1H, d, J ) 6 Hz), 11.42 (1H, br s).
1
8p : H NMR (DMSO-d6) δ 2.6-3.03 (1H, m), 2.87 (3H, s),
3.14-3.72 (4H, m), 7.12-7.38 (2H, m), 7.42-7.56 (1H, m), 7.6-

Non-acylguanidine-type Na+/ H+ Exchanger Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3017
18 to give 20 as colorless crystals: 99.4% ee; [R]D +60.5 (c 1.0,
suspended in MeOH (500 mL), and a solution of 28% NaOMe
in MeOH (10.9 mL) was added. The mixture was stirred at 50
°C for 30 min and evaporated. The residue was washed with
water and dried to give the free base of 16 (38.9 g). To the
solution of this free base (38.9 g, 0.11 mol) in EtOH (400 mL)
was added methanesulfonic acid (14.3 g, 0.22 mol), and the
mixture was evaporated to give crystals, which were recrystal-
lized from EtOH to give 16 (46.8 g) as colorless crystals: 99.2%
ee; [R]D -57.8 (c 1.0, MeOH); 1H NMR (DMSO-d6) δ 2.40 (6H,
s), 2.78 (1H, dd, J ) 12, 18 Hz), 2.89 (3H, s), 3.08-3.32 (2H,
m), 3.44-3.80 (2H, m), 7.2-8.1 (4H, br s), 7.31-7.56 (3H, m),
7.58-7.66 (1H, m), 7.86 (1H, d, J ) 6 Hz), 8.66 (1H, d, J ) 6
Hz), 10.77 (1H, s).
1
MeOH); H NMR (DMSO-d6) was in agreement with that of
18.
The following compounds (21, 22) were prepared by a
manner similar to that used for 18 and 20.
1
21: 99.5% ee; [R]D -38.7 (c 1.0, MeOH); H NMR (DMSO-
d6) δ 2.41 (6H, s), 2.70-2.94 (1H, m), 2.86 (3H, s), 2.97-3.26
(2H, m), 3.27-3.57 (2H, m), 7.2-8.4 (4H, br s), 7.41 (1H, s),
7,82 (1H, d, J ) 6 Hz), 8.65 (1H, d, J ) 6 Hz), 10.80 (1H, s).
1
22: 99.9% ee; [R]D +39.5 (c 1.0, MeOH); H NMR (DMSO-
d6) was in agreement with that of 21.
7-(2-Ch lor op h en yl)-4-m eth yl-5,6,7,8-tetr a h yd r oqu in o-
lin -5-on e (26b), Typ ica l P r oced u r e. To a mixture of 24b
(1.1 g, 4.7 mmol), 1-amino-2-butyne hydrochloride (0.5 g, 4.7
mmol), and molecular sieves 4A (2 g) in THF (20 mL) was
added triethylamine (0.48 g, 4.7 mmol). The mixture was
stirred at room temperature for 1 h and then refluxed for 12
h and cooled. Insoluble material was filtered off, and the
solvent was removed under reduced pressure. The residue was
stirred at 220 °C for 4 h. To the mixture were added EtOAc
and aqueous NaHCO3. The organic layer was washed with
water, dried, and evaporated. The residue was chromato-
graphed on silica gel with EtOAc-hexane as eluent to afford
crystals, which were recrystallized from EtOAc-hexane to give
26b (0.20 g, 16%) as colorless crystals: mp 97-98 °C; 1H NMR
(CDCl3) δ 2.71 (3H, s), 2.84 (1H, dd, J ) 13, 16 Hz), 3.02 (1H,
ddd, J ) 2, 4, 16 Hz), 3.30 (1H, dd, J ) 12, 17 Hz), 3.48 (1H,
ddd, J ) 2, 4, 17 Hz), 3.88-4.07 (1H, m), 7.11 (1H, d, J ) 5
(5E ,7R )-[[7-(2-Ch lor op h e n yl)-4-m e t h yl-7,8-d ih yd r o-
5(6H )-q u in olin ylid en e]a m in o]gu a n id in e Met h a n esu l-
fon a te (17). The mixture of (-)-8b (0.33 g, 1.2 mmol), amino-
guanidine hydrochloride (0.16 g, 1.5 mmol), concentrated HCl
(0.3 mL), and water (0.3 mL) in EtOH (25 mL) was refluxed
for 6 h. The solvent was evaporated under reduced pressure.
The residue was dissolved in water and washed with Et2O.
Aqueous NaHCO3 was added, and the solution was extracted
with EtOAc. The organic layer was washed with water, dried,
and evaporated. The residue was dissolved in EtOH, and
methanesulfonic acid (0.23 g, 2.4 mmol) was added. The
mixture was concentrated, and the residue was recrystallized
from EtOH-acetone to afford 17 (0.52 g, 83%) as colorless
crystals: >99.9% ee; [R]D +54.3 (c 1.0, MeOH); 1H NMR
(DMSO-d6) was in agreement with that of 16.
Hz), 7.16-7.34 (4H, m), 8.50 (1H, d, J ) 5 Hz). Anal. (C16H14
ClNO) C, H, N.
-
(5E,7S)-[[7-(5-F lu or o-2-m eth ylp h en yl)-4-m eth yl-7,8-d i-
hydro-5(6H)-quinolinylidene]amino]guanidine Dimethane-
su lfon a te (18). To the suspension of 8n (100.3 g, 0.25 mol) in
MeOH (900 mL) was added dropwise 28% NaOMe in MeOH
(107.8 g). The solvent was removed under reduced pressure,
and the residue was washed with water and dried to give free
base (67.5 g) as colorless crystals. To a solution of this free
base in EtOH (1000 mL) was added dropwise a solution of
D-pyroglutamic acid (27.1 g, 0.21 mol) in EtOH (60 mL) at 80
°C. The mixture was allowed to cool to room temperature
slowly and was stirred at the same temperature for 14 h. The
precipitate formed was filtered and washed with EtOH to give
diastereomeric salt (43.0 g, 45%, 95.7% ee). These crystals of
salt were suspended in MeOH (700 mL), and a solution of 28%
NaOMe in MeOH (18.3 g) was added. The mixture was
evaporated, and the residue was washed with water and dried
to give the free base of 18 (30.9 g). To the solution of this free
base (3.0 g, 9.2 mmol) in EtOH (20 mL) was added methane-
sulfonic acid (1.9 g, 19.4 mmol), and the mixture was evapo-
rated and recrystallized from EtOH to afford 18 (3.8 g, 36%
from 8n ) as colorless crystals: 99.8% ee; [R]D -61.4 (c 1.0,
MeOH); 1H NMR (DMSO-d6) δ 2.30 (3H, s), 2.35 (6H, s), 2.62-
2.95 (1H, m), 2.86 (3H, s), 2.99-3.24 (2H, m), 3.3-3.6 (2H,
m), 6.96-7.11 (1H, m), 7.19-7.42 (2H, m), 7.7 (4H, br s), 7.81
(1H, d, J ) 5 Hz), 8.65 (1H, d, J ) 5 Hz), 10.68 (1H, s).
The following compounds (26e-h ,q,w -y) were prepared by
a manner similar to that used for 26b.
1
26e: mp 104-106 °C; H NMR (CDCl3) δ 2.36 (3H, s), 2.70
(3H, s), 2.75-3.03 (2H, m), 3.17-3.48 (2H, m), 3.54-3.77 (1H,
m), 7.08 (1H, d, J ) 5 Hz), 7.10-7.34 (4H, m) 8.47 (1H, d, J )
5 Hz). Anal. (C17H17NO) C, H, N.
26f: colorless oil; 1H NMR (CDCl3) δ 2.70 (3H, s), 2.75-3.05
(2H, m), 3.23-3.48 (2H, m), 3.71-3.93 (1H, m), 3.83 (3H, s),
6.86 (2H, m), 7.07 (1H, d, J ) 5 Hz), 7.18-7.32 (2H, m) 8.47
(1H, d, J ) 5 Hz).
26g: colorless oil; 1H NMR (CDCl3) δ 2.70 (3H, s), 2.83-
3.08 (2H, m), 3.29-3.46 (2H, m), 3.71-3.77 (1H, m), 7.02-
7.36 (5H, m), 8.49 (1H, d, J ) 4 Hz).
26h : mp 106-107 °C; 1H NMR (CDCl3) δ 2.71 (3H, s), 2.82
(1H, dd, J ) 13, 16 Hz), 3.03 (1H, ddd, J ) 2, 4, 10 Hz), 3.28
(1H, dd, J ) 12, 17 Hz), 3.49 (1H, ddd, J ) 2, 4, 11 Hz), 3.86-
4.06 (1H, m), 7.08-7.47 (4H, m), 7.57-7.66 (1H, m), 8.50 (1H,
d, J ) 5 Hz). Anal. (C16H14BrNO) C, H, N.
1
26q: mp 105-107 °C; H NMR (CDCl3) δ 2.69 (3H, s), 2.90
(1H, dd, J ) 11, 16 Hz), 3.14 (1H, ddd, J ) 2, 4, 11 Hz), 3.37
(1H, dd, J ) 11, 16 Hz), 3.61 (1H, ddd, J ) 2, 4, 11 Hz), 3.69-
3.88 (1H, m), 6.86-7.04 (2H, m), 7.09 (1H, d, J ) 5 Hz), 7.21
(1H, dd, J ) 1, 5 Hz), 8.49 (1H, d, J ) 5 Hz). Anal. (C14H13
NOS) C, H, N.
-
26w : colorless oil; 1H NMR(CDCl3) δ 2.69 (3H, s), 2.98 (1H,
ddd, J ) 1, 4, 16 Hz), 3.15 (1H, dd, J ) 11, 16 Hz), 3.37-3.76
(3H, m), 7.08 (1H, d, J ) 5 Hz), 7.18 (1H, ddd, J ) 1, 5, 8 Hz),
7.24 (1H, d, J ) 8 Hz), 7.66 (1H, dt, J ) 2, 8 Hz), 8.47 (1H, d,
J ) 5 Hz), 8.58 (1H, ddd, J ) 1, 2, 5 Hz).
(5E,7S)-[[7-(5-F lu or o-2-m eth ylp h en yl)-4-m eth yl-7,8-d i-
h yd r o-5(6H)-qu in olin ylid en e]a m in o]gu a n id in e Hyd r o-
ch lor id e (19). To the solution of the free base of 18 (1.5 g,
4.6 mmol) in EtOH (20 mL) was added concentrated HCl (1.2
mL), and the mixture was concentrated. The residue was
recrystallized from EtOH-water to afford 19 (0.96 g, 99.3%)
as colorless crystals. This compound was confirmed to be the
S isomer by X-ray crystal structure analysis: mp 192-198 °C;
1H NMR (DMSO-d6) δ 2.31 (3H, s), 2.66-3.03 (1H, m), 2.89
(3H, s), 3.12-3.6 (4H, m), 6.94-7.06 (1H, m), 7.16-7.37 (2H,
m), 7.4-8.3 (4H, br s), 7.85 (1H, d, J ) 6 Hz), 8.64 (1H, d, J )
6 Hz), 11.41 (1H, s).
26x: colorless oil; 1H NMR(CDCl3) δ 2.69 (3H, s), 2.87 (1H,
dd, J ) 12, 16 Hz), 2.92-3.08 (1H, m), 3.25-3.62 (3H, m), 7.12
(1H, d, J ) 5 Hz), 7.22-7.35 (1H, m), 8.50 (1H, d, J ) 5 Hz),
8.57-8.65 (1H, m).
26y: mp 70-71 °C; 1H NMR(CDCl3) δ 2.68 (3H, s), 2.92 (1H,
dd, J ) 10, 17 Hz), 3.08 (1H, ddd, J ) 2, 4, 7 Hz), 3.40 (1H,
dd, J ) 10, 17 Hz), 3.59 (2H, m), 6.08 (1H, d, J ) 3 Hz), 6.31
(1H, dd, J ) 2, 3 Hz), 7.08 (1H, d, J ) 5 Hz), 7.36 (1H, d, J )
2 Hz), 8.49 (1H, d, J ) 5 Hz). Anal. (C14H13NO2) C, H, N.
7-(5-F lu or o-2-m e t h ylp h e n yl)-4-m e t h yl-5,6,7,8-t e t r a -
h yd r oqu in olin -5-on e (26n ), Typ ica l P r oced u r e. A mixture
of 24n (3.0 g, 13.6 mmol) and ammonium acetate (3.1 g, 40.9
mmol) in EtOH (50 mL) was refluxed for 14 h. The solvent
was removed under reduced pressure, and the residue was
dissolved in EtOAc. The mixture was washed with water,
(5E,7R)-[[7-(5-F lu or o-2-m eth ylp h en yl)-4-m eth yl-7,8-d i-
hydro-5(6H)-quinolinylidene]amino]guanidine Dimethane-
su lfon a te (20). To the combined filtrate obtained in prepa-
ration of 18 was added 28% NaOMe in MeOH (25.5 g). The
solvent was removed under reduced pressure, and the residue
was washed with water and dried to give free base (41.5 g) as
colorless crystals. This free base was resolved with L-pyro-
glutamic acid in the same manner as for the preparation of

3018 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Fukumoto et al.
dried, and evaporated under reduced pressure to give 27n (2.7
g). The mixture of 27n (2.7 g, 12.3 mmol), 3-oxobutylaldehyde
dimethylacetal (4.1 g, 30.8 mmol), and powdery KOH (0.57 g,
10.2 mmol) in EtOH (70 mL) and toluene (120 mL) was
refluxed for 3.5 h. In this period powdery KOH (0.12 g, 2.1
mmol) was added three times for 30 min each, and 3-oxo-
butylaldehyde dimethylacetal (0.33 g, 2.5 mmol) was added 1
h later. The solvent was removed under reduced pressure. The
residue was dissolved in EtOAc and washed with water, dried,
and evaporated. The residue was chromatographed on silica
gel with EtOAc-hexane as eluent to afford crystals, which
were recrystallized from EtOAc-hexane to give 26n (1.5 g,
41%) as colorless crystals: mp 113-114 °C; 1H NMR (CDCl3)
δ 2.33 (3H, s), 2.71 (3H, s), 2.78-2.98 (2H, m), 3.24 (1H, dd, J
) 11, 16 Hz), 3.28-3.44 (1H, m), 3.55-3.74 (1H, m), 6.82-
7.04 (2H, m), 7.12 (1H, d, J ) 5 Hz), 7.07-7.22 (2H, m), 8.50
(1H, d, J ) 5 Hz). Anal. (C17H16FNO) C, H, N.
26r : colorless oil; 1H NMR (CDCl3) δ 2.70 (3H, s), 2.82 (1H,
dd, J ) 12, 17 Hz), 3.08 (1H, ddd, J ) 2, 4, 16 Hz), 3.32 (1H,
dd, J ) 11, 17 Hz), 3.54 (1H, ddd, J ) 2, 4, 17 Hz), 3.86-4.06
(1H, m), 6.93 (1H, d, J ) 5 Hz), 7.12 (1H, d, J ) 5 Hz), 7.2
(1H, d, J ) 5 Hz), 8.50 (1H, d, J ) 5 Hz).
26t: mp 92-93 °C; 1H NMR (CDCl3) δ 2.69 (3H, s), 2.85 (1H,
dd, J ) 12, 17 Hz), 3.09 (1H, ddd, J ) 2, 4, 16 Hz), 3.28 (1H,
dd, J ) 11, 17 Hz), 3.61 (2H, m), 7.08 (3H, m), 7.38 (1H, m),
8.49 (1H, d, J ) 5 Hz). Anal. (C14H13NOS) C, H, N.
26v: mp 138-140 °C; 1H NMR (CDCl3) δ 2.70 (3H, s), 2.75
(1H, dd, J ) 12, 17 Hz), 2.93 (1H, ddd, J ) 2, 4, 16 Hz), 3.22
(1H, dd, J ) 11, 17 Hz), 3.39 (1H, ddd, J ) 2, 5, 17 Hz), 3.57-
3.76 (1H, m), 6.72 (1H, s), 7.11 (1H, d, J ) 5 Hz), 8.50 (1H, d,
J ) 5 Hz). Anal. (C14H11Cl2NOS) C, H, N.
7-(3,5-Dich lor ot h iop h en -2-yl)-4-m et h yl-5,6,7,8-t et r a -
h yd r oqu in olin -5-on e (26s). To the solution of 26r (0.74 g,
2,7 mmol) in EtOAc (10 mL) were added pyridine (0.22 mL,
0.21 g, 2.7 mmol) and SO2Cl2 (0.22 mL, 0.38 g, 2.8 mmol), and
the mixture was stirred for 3 h at room temperature. The
solution was diluted with EtOAc and washed successively with
aqueous NaHCO3 and water, dried, and evaporated. The
residue was chromatographed on silica gel with EtOAc-
hexane as eluent to give 26s (0.56 g, 66%) as colorless crystals:
The following compounds (26a -d ,i-p ,r -v) were prepared
by a manner similar to that used for 26n .
1
26a : mp 73-74 °C; H NMR (CDCl3) δ 2.70 (3H, s), 2.80-
3.07 (2H, m), 3.23-3.60 (3H, m), 7.10 (1H, d, J ) 5 Hz), 7.23-
7.46 (5H, m), 8.50 (1H, d, J ) 5 Hz). Anal. (C16H15NO) C, H,
N.
26c: mp 112-113 °C; 1H NMR (CDCl3) δ 2.70 (3H, s), 2.77-
3.06 (2H, m), 3.22-3.58 (3H, m), 7.11 (1H, d, J ) 5 Hz), 7.13-
7.37 (4H, m), 8.50 (1H, d, J ) 5 Hz). Anal. (C16H14ClNO) C,
H, N.
1
mp 109-111 °C; H NMR(CDCl3) δ 2.68 (3H,s), 2.76 (1H, dd,
J ) 12, 16 Hz), 3.04 (1H, ddd, J ) 2, 4, 17 Hz), 3,24 (1H, dd,
J ) 11, 17 Hz), 3,51 (1H, ddd, J ) 2, 4, 17 Hz), 3.82-3.99
(1H, m), 6.76 (1H, s), 7.11 (1H, d, J ) 5 Hz), 8.49 (1H, d, J )
5 Hz). Anal. (C14H11Cl2NOS) C, H, N.
26d : mp 124-125 °C; 1H NMR (CDCl3) δ 2.70 (3H, s), 2.84
(1H, dd, J ) 12, 17 Hz), 2.98 (1H,ddd, J ) 2, 4, 17 Hz), 3.29
(1H, dd, J ) 12, 17 Hz), 3.35-3.6 (2H, m), 7.1 (1H, d, J ) 5
Compound 26u was prepared by a manner similar to that
used for 26s.
1
Hz), 7.2-7.4 (4H, m), 8.49 (1H, d, J ) 5 Hz). Anal. (C16H14
-
26u : amorphous; H NMR(CDCl3) δ 2.70 (3H, s), 2.77 (1H,
ClNO) C, H, N.
dd, J ) 12, 17 Hz), 2.97 (1H, ddd, J ) 2, 5, 17 Hz), 3.29 (1H,
dd, J ) 11, 17 Hz), 3.32 (1H, ddd, J ) 2, 5, 18 Hz), 3.72 (1H,
m), 6.89 (1H, d, J ) 6 Hz), 7.12 (2H, m), 8.50 (1H, d, J ) 6
Hz).
1
26i: mp 123-124 °C; H NMR (CDCl3) δ 2.72 (3H, s), 2.81
(1H, dd, J ) 12, 16 Hz), 3.03 (1H, ddd, J ) 2, 4, 8 Hz), 3.29
(1H, dd, J ) 11, 17 Hz), 3.49 (1H, ddd, J ) 2, 4, 8 Hz), 4.03
(1H, m), 7.13 (1H, d, J ) 5 Hz), 7.24 (2H, m), 7.43 (1H, m),
8.51 (1H, d, J ) 5 Hz). Anal. (C16H13Cl2NO) C, H, N.
2,2-Dim eth yl-5-[([3-oxo-5-(2-ch lor op h en yl)-1-cycloh ex-
en yl]a m in o)m eth ylen e]-[1,3]-d ioxa n e-4,6-d ion e (28b). A
mixture of 5-(methoxymethylene)-2,2-dimethyl-[1,3]-dioxane-
4,6-dione (1.7 g, 9.0 mmol) and 27b (2.2 g, 9.9 mmol) in CH3CN
(15 mL) was stirred at room temperature for 13 h. Precipitated
crystals were filtered and washed with CH3CN to give 28b
(1.7 g, 50%) as colorless crystals: mp 112 °C dec; 1H NMR
(CDCl3) δ 1.75 (6H, s), 2.62-2.84 (3H, m), 2.95 (1H, dd, J ) 5,
17 Hz), 3.89-4.09 (1H, m), 6.0 (1H, d, J ) 2 Hz), 7.14-7.52
(4H, m), 8.38 (1H, d, J ) 14 Hz), 11.03 (1H, d, J ) 14 Hz).
Anal. (C19H18ClNO5) C, H, N.
7-(2-Ch lor oph en yl)-4-h yd r oxy-5,6,7,8-h exa h yd r oqu in o-
lin -5-on e (29b). A solution of 28b (1.6 g, 4.3 mmol) in Ph2O
(20 mL) was stirred at 260 °C for 30 min. The solvent was
removed under reduced pressure, and the residue was washed
with petroleum ether and recrystallized from EtOH to give
29b (1.1 g, 93%) as colorless crystals: mp 243 °C dec; 1H NMR
(DMSO-d6) d 2.59-2.77 (1H, m), 2.92-3.6 (3H, m), 3.77-4.0
(1H, m), 6.53 (1H, br s), 7.23-7.58 (4H, m), 8.03 (1H, br s).
Anal. (C15H12ClNO2) C, H, N.
1
26j: mp 136-137 °C; H NMR (CDCl3) δ 2.71 (3H, s), 2.81
(1H, dd, J ) 12, 16 Hz), 3.00 (1H, ddd, J ) 2, 4, 16 Hz), 3.27
(1H, dd, J ) 12, 17 Hz), 3.46 (1H, ddd, J ) 2, 4, 17 Hz), 3.83-
4.03 (1H, m), 7.12 (1H, d, J ) 5 Hz), 7.22-7.33 (2H, m), 7.45
(1H, d, J ) 2 Hz), 8.51 (1H, d, J ) 5 Hz). Anal. (C16H13Cl2NO)
C, H, N.
26k : mp 116-117 °C; 1H NMR (CDCl3) δ 2.72 (3H, s), 2.80
(1H, dd, J ) 12, 16 Hz), 3.00 (1H, ddd, J ) 2, 4, 17 Hz), 3.26
(1H, dd, J ) 12, 17 Hz), 3.46 (1H, ddd, J ) 2, 4, 16 Hz), 3.83-
4.04 (1H, m), 7.12 (1H, d, J ) 5 Hz), 7.21 (1H, dd, J ) 2, 8
Hz), 7.31 (1H, d, J ) 2 Hz), 7.36 (1H, d, J ) 8 Hz), 8.50 (1H,
d, J ) 5 Hz). Anal. (C16H13Cl2NO) C, H, N.
26l: isolated as HCl salt; mp 184-185 °C; 1H NMR (DMSO-
d6) δ 2.55-2.65 (1H, m), 2.79 (3H, s), 3.35 (1H, ddd, J ) 2, 4,
11 Hz), 3.74 (1H, dd, J ) 14, 17 Hz), 4.19 (1H, dd, J ) 13, 17
Hz), 4.48-4.58 (1H, m), 7.33-7.57 (1H, m), 7.50-7.54 (2H,
m), 7.75 (1H, d, J ) 6 Hz), 8.77 (1H, d, J ) 6 Hz). Anal. (C16H13
ClNO·HCl) C, H, N.
-
26m : colorless oil; 1H NMR (CDCl3) δ 2.71 (3H, s), 2.79 (1H,
dd, J ) 13, 16 Hz), 3.01 (1H, ddd, J ) 2, 4, 17 Hz), 3.26 (1H,
dd, J ) 12, 17 Hz), 3.48 (1H, ddd, J ) 2, 4, 17 Hz), 3.83-4.03
(1H, m), 6.87-7.07 (2H, m), 7.13 (1H, d, J ) 5 Hz), 7.34-7.43
(1H, m), 8.51 (1H, d, J ) 5 Hz). Anal. (C16H13ClFNO) C, H, N.
26n : mp 113-114 °C; 1H NMR (CDCl3) δ 2.33 (3H, s), 2.71
(3H, s), 2.78-2.98 (2H, m), 3.24 (1H, dd, J ) 11, 16 Hz), 3.28-
3.44 (1H, m), 3.55-3.74 (1H, m), 6.82-7.04 (2H, m), 7.12 (1H,
d, J ) 5 Hz), 7.07-7.22 (2H, m), 8.50 (1H, d, J ) 5 Hz). Anal.
(C17H16FNO) C, H, N.
26o: isolated as HCl salt; mp 174-175 °C; 1H NMR (DMSO-
d6) δ 2.71-2.86 (4H, m), 3.10 (1H, dd, J ) 13, 17 Hz), 3.5-
3.64 (2H, m), 3.68-4.03 (4H, m), 6.99-7.24 (3H, m), 7.76 (1H,
d, J ) 6 Hz), 8.78 (1H, d, J ) 6 Hz). Anal. (C17H15FNO2·HCl)
C, H, N.
7-(2-Ch lor oph en yl)-4-m eth oxy-5,6,7,8-tetr ah ydr oqu in o-
lin -5-on e (30b). The mixture of phosphorus oxychloride (5.4
g, 35.1 mmol) and 29b (0.60 g, 2.2 mmol) was stirred at 100
°C for 2 h. The mixture was cooled and concentrated under
reduced pressure. To the residue was added 1 N NaOH. The
mixture was extracted with EtOAc, and the organic layer was
washed with water, dried, and evaporated to afford the
4-chloro derivative (0.55 g, 86%) as colorless crystals. The
mixture of these crystals (0.2 g, 0.68 mmol) and NaOMe (0.074
g, 1.4 mmol) in MeOH (20 mL) was refluxed for 2 h. The
solvent was removed, and EtOAc was added. The organic layer
was washed with water, dried, and evaporated. The residue
was chromatographed on silica gel with EtOAc-hexane as
elutent to yield 30b (0.1 g, 61%) as colorless crystals: mp 116-
1
117 °C; H NMR (CDCl3) δ 2.81 (1H, dd, J ) 12, 16 Hz), 3.0
26p : mp 75-76 °C; 1H NMR (CDCl3) δ 2.71 (3H, s), 2.86
(1H, dd, J ) 12, 17 Hz), 2.9-3.07 (1H, m), 3.33 (1H, dd, J )
11, 17 Hz), 3.37-3,53 (1H, m), 3.68-3.87 (1H, m), 6.86-7.15
(4H, m), 8.50 (1H, d, J ) 5 Hz). Anal. (C16H13F2NO) C, H, N.
(1H, ddd, J ) 2, 4, 17 Hz), 3.25 (1H, dd, J ) 12, 17 Hz), 3.45
(1H, ddd, J ) 2, 4, 17 Hz), 3.80-4.16 (1H, m), 4.00 (3H, s),
6.85 (1H, d, J ) 6 Hz), 7.16-7.45 (4H, m), 8.53 (1H, d, J ) 6
Hz) Anal. (C16H14ClNO2) C, H, N.

Non-acylguanidine-type Na+/ H+ Exchanger Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3019
7-P h en yl-5,6,7,8-tetr a h yd r oqu in olin -5-on e (31a ). The
mixture of 24a (5.0 g, 26.6 mmol), 1,1,3,3-tetramethoxypropane
(8.7 g, 53.1 mmol), and ammonium acetate (6.1 g, 79.7 mmol)
in AcOH (100 mL) was refluxed for 48 h. The solvent was
removed under reduced pressure, and the residue was neutral-
ized with aqueous NaHCO3. The mixture was extracted with
EtOAc, and the organic layer was washed with water, dried,
and evaporated. The residue was chromatographed on silica
gel with EtOAc-hexane as eluent to afford crystals, which
were recrystallized from EtOAc-hexane to give 31a (1.1 g,
19%) as colorless crystals: mp 78-79 °C dec; 1 H NMR (CDCl3)
δ 2.89 (1H, dd, J ) 12, 17 Hz), 2.95-3.12 (1H, m), 3.04 (1H,
dd, J ) 11, 17 Hz), 3.4-3.63 (2H, m), 7.20-7.43 (6H, m), 8.33
(1H, dd, J ) 1.8, 7.6 Hz), 8.73 (1H, dd, J ) 1.8, 4.7 Hz). Anal.
(C15H13NO) C, H, N.
water, dried, and evaporated. The residue was recrystallized
from EtOAc-hexane to afford 36b (1.4 g, 79%) as colorless
crystals: mp 100-101 °C; 1H NMR (CDCl3) δ 2.66 (3H, s),
2.53-3.04 (4H, m), 3.76-3.95 (1H, m), 7.17-7.45 (5H, m).
Anal. (C14H13ClO3) C, H.
6-(2-Ch lor oph en yl)-3-m eth yl-4,5,6,7-tetr ah ydr oin dazol-
4-on e (37b). A solution of 36b (0.31 g, 1.2 mmol) and
hydrazine hydrate (0.065 g, 1.3 mmol) in EtOH (10 mL) was
refluxed for 30 min. The solvent was removed under reduced
pressure, and the residue was recrystallized from EtOAc-
hexane to give 37b (0.26 g, 83%) as colorless crystals: mp 168-
170 °C; 1H NMR (CDCl3) δ 2.59 (3H, s), 2.6-2.8 (2H, m), 2.94
(1H, dd, J ) 11, 16 Hz), 3.22 (1H, dd, J ) 4, 16 Hz), 3.90-
4.06 (1H, m), 7.07-7.43 (4H, m). Anal. (C14H13ClN2O) C, H,
N.
2-Methyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (32a).
The mixture of 24a (1.2 g, 6.4 mmol), ammonium acetate (0.49
g, 6.4 mmol), and 3-butyn-2-one (0.44 g, 6.4 mmol) in EtOH
(20 mL) was stirred at room temperature for 1.5 h and refluxed
for 18 h. The solvent was removed under reduced pressure,
and the residue was dissolved in EtOAc. The solution was
washed successively with aqueous NaHCO3 and water, dried,
and evaporated. The residue was chromatographed on silica
gel with EtOAc-hexane as eluent to give 32a (0.88 g, 58%) as
colorless crystals: mp 79-81 °C; 1H NMR (CDCl3) δ 2.61 (3H,
s), 2.85 (1H, dd, J ) 12, 17 Hz), 3.00 (1H, ddd, J ) 1, 4, 17
Hz), 3.23-3.63 (3H, m), 7.18 (1H, d, J ) 8 Hz), 7.22-7.43 (5H,
m) 8.21 (1H, d, J ) 8 Hz). Anal. (C16H15NO) C, H, N.
7-(2-Ch lor oph en yl)-4-m eth yl-5,6,7,8-tetr ah ydr oqu in azo-
lin -5-on e (38b). A mixture of 36b (0.48 g, 1.8 mmol), pyrroli-
dine (0.14 g, 1.9 mmol), anhydrous Na2SO4 (1.0 g, 7.0 mmol)
and benzene (15 mL) was refluxed under argon atmosphere
for 2 h. The solvent was removed under reduced pressure. To
the residue were added formamidine acetate (0.19 g, 1.8 mmol),
K2CO3 (0.25 g, 1.8 mmol), and MeOH (10 mL). The mixture
was refluxed under argon atmosphere for 2 h, and the solvent
was removed under reduced pressure. The residue was ex-
tracted with EtOAc. The organic layer was washed, dried, and
chromatographed on silica gel with EtOAc-hexane as eluent
to give 38b (41 mg, 8%) as an oil: 1H NMR (CDCl3) δ 2.81-
3.11 (2H, m), 2.90 (3H, s), 3.19-3.50 (2H, m), 4.00 (1H, m),
7.21-7.33 (3H, m), 7.44 (1H, dd, J ) 1.4, 7.0 Hz), 9.06 (1H, s).
4-Meth yl-7-(2-ch lor op h en yl)-5,6,7,8-tetr a h yd r ocin n o-
lin -5-on e (40b). A mixture of 24b (5.5 g, 25 mmol), p-toluene
sulfonylhydrazide (4.6 g, 25 mmol), and EtOH (70 mL) was
refluxed for 70 min and cooled, and precipitated crystals were
filtered and washed with EtOH to afford colorless crystals (7.2
g). A mixture of these crystals (1.2 g, 3 mmol), anhydrous
K2CO3 (1.1 g, 8 mmol), chloroacetone (0.34 g, 3.6 mmol), NaI
(0.4 g, 2.7 mmol), EtOH (7.5 mL), and DME (7.5 mL) was
stirred at 80 °C for 4 h. The solvent was removed under
reduced pressure, and the residue was extracted with EtOAc.
The organic layer was concentrated, and the residue was
chromatographed on silica gel to give 40b (0.34 g, 42%) as pale
yellow crystals: mp 108-109 °C; 1H NMR (CDCl3) δ 2.71 (3H,
s), 2.88 (1H, dd, J ) 13, 17 Hz), 3.09 (1H, ddd, J ) 2, 4, 17
Hz), 3.49 (1H, dd, J ) 5, 17 Hz), 3.79 (1H, ddd, J ) 2, 4, 17
Hz), 3.93-4.1 (1H, m), 7.22-7.35 (3H, m), 7.45 (1H, dd, J )
2, 7 Hz), 9.16 (1H, s). Anal. (C15H13ClN2O) C, H, N.
6-(2-Ch lor op h en yl)-3-m eth yl-4,5,6,7-tetr a h yd r oben zo-
fu r a n -4-on e (41b). To a solution of 24b (1.11 g, 5.0 mmol) in
DMF (20 mL) was added 60% NaH (0.22 g, 5.5 mmol, washed
three times with hexane), and the mixture was stirred under
argon atmosphere at room temperature for 15 min. To the
mixture was added chloroacetone (0.52 g, 5.7 mmol), and the
mixture was stirred at 150 °C for 15 h. The solvent was
removed under reduced pressure. To the residue was added
ice-water, and the mixture was extracted with EtOAc. The
organic layer was washed, dried, and evaporated. The residue
was chromatograhed on silica gel with EtOAc-hexane as
eluent to afford 41b (0.35 g, 27%) as a colorless oil: 1H NMR
(CDCl3) δ 2.23 (3H, s), 2.73 (1H, s), 2.77 (1H, d, J ) 5.2 Hz),
2.97 (1H, dd, J ) 10.6, 17.0 Hz), 3.20 (1H, dd, J ) 5.2, 16.8
Hz), 4.05 (1H, m), 7.12 (1H, s), 7.20-7.34 (3H, m), 7.41 (1H,
dd, J ) 1.2, 7.0 Hz).
7-P h en yl-2,4-d im et h yl-5,6,7,8-t et r a h yd r oq u in olin -5-
on e (33a ). A mixture of 24a (2.0 g, 10.6 mmol), ammonium
acetate (0.9 g, 11.7 mmol), and acetylacetone (1.1 g, 10.6 mmol)
in EtOH (30 mL) was stirred at room temperature for 1 h and
refluxed for 21 h. The solvent was removed under reduced
pressure, and the residue was dissolved in EtOAc. The solution
was washed successively with aqueous NaHCO3 and water,
dried, and evaporated. The residue was chromatographed on
silica gel with EtOAc-hexane as eluent to give crystals, which
was recrystallized from IPE-hexane to afford 33a (0.6 g, 23%)
1
as colorless crystals: mp 97-99 °C; H NMR (CDCl3) δ 2.54
(3H, s), 2.66 (3H, s), 2.77-3.04 (2H, m), 3.24-3.44 (2H, m),
3.51-3.94 (1H, m), 6.96 (1H, s), 7.00-7.33 (5H, m). Anal.
(C17H17NO) C, H, N.
3-Meth yl-6-(2-m eth ylp h en yl)-4,5,6,7-tetr a h yd r oin d ol-
4-on e (35e). A mixture of 24e (2.0 g, 9.9 mmol), 1-amino-2-
propanol (0.97 g, 12.9 mol), molecular sieves 4A (12 g), and
THF (30 mL) was refluxed for 12 h. Insoluble materials were
filtered off. The solvent was removed under reduced pressure,
and the residue was dissolved in DMF (40 mL). To the solution
were added 2-bromomesitylene (2.0 g, 9.9 mmol), Pd(PPh3)4
(0.29 g, 0.25 mmol), and K2CO3 (2.7 g, 19.8 mmol), and the
mixture was stirred at 150 °C for 5 h. The solvent was removed
under reduced pressure. The residue was dissolved in EtOAc,
and the solution was washed successively with aqueous
NaHCO3 and water, dried, and evaporated. The residue was
chromatographed on silica gel with EtOAc-hexane as eluent
to afford 35e (1.5 g, 63%) as colorless crystals: mp 190-191
°C; 1H NMR (CDCl3) δ 2.33 (3H, s), 2.34 (3H, s), 2.53-3.08
(4H, m), 3.67-3.85 (1H, m), 6.46 (1H, s), 7.05-7.34 (4H, m),
8.30 (1H, br s). Anal. (C16H17NO•0.1H2O) C, H, N.
The following compound 35a were prepared by a manner
similar to that used for 35e.
1
35a : mp 187-189 °C; H NMR(CDCl3) δ 2.72 (1H, s), 2.76
(1H, dd, J ) 16, 20 Hz), 3.02 (1H, dd, J ) 16, 26 Hz), 3.06
(1H, dd, J ) 16, 20 Hz), 3.43-3.61 (1H, m), 6.56 (1H, t, J ) 3
Hz), 6.72 (1H, t, J ) 3 Hz), 7.10-7.48 (5H, m) 9.31 (1H, br s).
Anal. (C14H13NO) C, H, N.
2-(1-Hyd r oxyeth ylid en e)-5-(2-ch lor op h en yl)cycloh ex-
a n e-1,3-d ion e (36b). To a solution of 24b (1.5 g, 6.7 mmol),
acetic acid (0.73 g, 7.4 mmol), and 4-(dimethylamino)pyridine
(0.12 g, 6.7 mmol) in DMF (65 mL) was added dicyclohexyl-
carbodiimide (1.5 g, 7.4 mmol), and the mixture was stirred
at room temperature for 13 h. The solvent was removed under
reduced pressure, and the residue was dissolved in EtOAc. The
solution was washed successively with aqueous NaHCO3 and
5-(2-Chlor oph enyl)-3-m er capto-2-cyclohexen -1-on e (42b).
A mixture of 24b (3.0 g, 13.5 mmol) and PCl3 (0.62 g, 4.5 mmol)
in chloroform (10 mL) was stirred at 100 °C. After 2.5 h PCl3
(0.62 g, 4.5 mmol) was added, and the mixture was stirred at
100 °C for 2 h and concentrated under reduced pressure. The
mixture was poured onto ice-water and extracted with EtOAc.
The organic layer was washed, dried, and evaporated. To the
residue were added EtOH (3 mL) and the solution of Na2S·
9H2O (2.0 g, 8.3 mmol) in water (3 mL). The mixture was
stirred at room temperature for 2 h and evaporated. Water
was added to the residue, and the solution was washed with
Et2O. To the aqueous layer was added 4 N HCl to make the

3020 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Fukumoto et al.
solution acidic, and the solution was extracted with EtOAc.
The organic layer was washed, dried, and evaporated to yield
42b (1.8 g, 91%) as an oil: 1H NMR (CDCl3) δ 2.50-2.80 (4H,
m), 3.52 (1H, s), 3.83-4.01 (1H, m), 6.20 (1H, s), 7.14-7.43
(4H, m).
5-(2-Ch lor oph en yl)-3-[(2-oxopr opyl)th io]-2-cycloh exen -
1-on e (43b). To a solution of 42b (1.8 g, 7.6 mmol) and
chloroacetone (0.7 g, 7.6 mmol) in EtOH (20 mL) was added a
solution of 20% NaOEt in EtOH (0.48 g, 8.2 mmol), and the
mixture was stirred at room temperature for 5 h. The solvent
was removed under reduced pressure, the residue was ex-
tracted with EtOAc, and the organic layer was washed, dried,
and evaporated to afford 43b (2.3 g, quant) as colorless
crystals: mp 81-82 °C; 1H NMR (CDCl3) δ 2.33 (3H, s), 2.52-
2.80 (4H, m), 3.76 (2H, s), 3.79-3.99 (1H, m), 5.85 (1H, s),
7.16-7.43 (4H, m). Anal. (C15H15ClO2S) C, H.
6-(2-Ch lor op h en yl)-3-m eth yl-4,5,6,7-tetr a h yd r oben zo-
th iop h en e-4-on e (44b). A solution of 43b (1.0 g, 3.4 mmol)
in xylene (10 mL) was refluxed for 7.5 days. The reaction
mixture was chromatographed on silica gel with EtOAc-
hexane as eluent to give 44b (0.07 g, 8%) as an oil: 1H NMR
(CDCl3) δ 2.48 (3H, s), 2.64-2.92 (2H, m), 3.09 (1H, dd, J )
11, 17 Hz), 3.35 (1H, dd, J ) 4, 17 Hz), 3.96-4.13 (1H, m),
6.70 (1H, s), 7.14-7.50 (4H, m).
2-(2-Ch lor op h en yl)-5-m eth ylch r om a n -4-on e (47b). To
the solution of 2′-hydroxy-6′-methylacetophenone (0.2 g, 1.3
mmol) in EtOH (4 mL) were added 50% NaOH (260 mg) and
2-chlorobenzaldehyde (0.2 g, 1.4 mmol). The solution was
stirred at 50 °C for 1.5 h and acidified with 2 N HCl. Water
was added and the mixture was extracted with EtOAc, and
the organic layer was washed, dried, and evaporated. The
residue was washed with MeOH to afford 46b as yellow
crystals. This was dissolved in AcOH (5 mL) and refluxed for
6 h. The mixture was concentrated under reduced pressure
and chromatograhed on silica gel with EtOAc-hexane as
eluent to afford 47b (0.24 g, 27%) as a pale yellow oil: 1H NMR
(CDCl3) δ 2.69 (3H, s), 2.87 (1H, dd, J ) 13, 17 Hz), 3.02 (1H,
dd, J ) 3, 17 Hz), 5.83 (1H, dd, J ) 3, 13 Hz), 6.82-6.97 (2H,
m), 7.25-7.44 (4H, m), 7.71-7.77 (1H, m).
2-(2-Ch lor op h en yl)-5-m eth yl-4H-ch r om en -4-on e (50b).
The solution of 2′-hydroxy-6′-methylacetophenone (0.45 g, 3
mmol) and 2-chlorobenzoyl chloride (0.58 g, 3.3 mmol) in
pyridine (3 mL) was stirred at room temperature for 30 min.
To the solution was added water (0.2 mL), and the mixture
was extracted with EtOAc. The organic layer was washed
successively with dilute HCl, aqueous NaHCO3, and water,
dried, and evaporated to afford 48b as colorless oil. To the
solution of 48b in t-BuOH (8 mL) was added 60% NaH (0.24
g, 6 mmol). The mixture was stirred at room temperature for
30 min and concentrated under reduced pressure. The residue
was dissolved in water, washed with Et2O, and acidified with
HCl. The mixture was extracted with i-Pr2O, and the organic
layer was washed, dried, and evaporated to afford 49b as a
yellow oil. To the solution of 49b in AcOH (10 mL) was added
MeSO3H (0.3 mL, 4.5 mmol), and the mixture was stirred at
165 °C for 3 h. The mixture was concentrated and extracted
with EtOAc. The organic layer was washed with aqueous
NaHCO3 and water, dried, and evaporated. The residue was
recrystallized from i-Pr2O to give 50b (0.66 g, 81%) as pale
yellow crystals: mp 99-100 °C; 1H NMR (CDCl3) δ 2.90 (3H,
s), 6.58 (1H, s), 7.13-7.66 (7H, m). Anal. (C16H11ClO2) C, H.
glucose, 20 mM Hepes, 1 mM CaCl2, and 1 mM MgCl2; pH
6.7) was added while the mixture was stirred at 37 °C. The
change in the light transmission of PRP at 550 nm, which was
induced by the activation of NHE, was observed 1 min after
the treatment with sodium propionate. PPP was used to
correct for the light transmission of the nonplatelet part of
PRP. The test compound dissolved in dimethyl sulfoxide
(DMSO) was added to PRP 3 min before the treatment with
sodium propionate. At this stage, the compound concentration
was 4-fold higher than the final one in the assay and the
concentration of DMSO was 4% (final concentration of 1%).
The rate of inhibition of the compound on NHE-1 was
calculated, designating the difference obtained between the
treatments with vehicle and high concentration of HOE-642
(10-5M), as 100%.
In the human platelet assay, blood samples were collected
from the forearm vein of normal adult men, and the platelet
number was adjusted to 10 × 104/µL. In addition, the maxi-
mum upstroke velocity of the light transmission was calculated
during the first minute after application of sodium propionate
solution and used to determine the inhibitory effect of the
compound on human platelet NHE-1.
In h ibitor y Effects on th e Exten sion of Myoca r d ia l
In fa r ction in Ra ts. The details of the procedure of the
experiment were previously reported.27 Briefly, male Wistar
rats (11-12 weeks) were anesthetized, and acute myocardial
infarction was induced by occlusion of the left coronary artery
(1 h) followed by reperfusion (24 h). The rats were anesthetized
again and the heart was removed. The coronary artery was
ligated at the same position previously occluded. Area at risk
(AAR) was determined by the injection of 1% Evans blue. The
left ventricle was cut into six slices and was incubated with
1% 2,3,5-triphenyltetrazolium chloride at 37 °C for 10 min to
stain intact tissue. Infarct size was determined as a percentage
of AAR based on weight. Compounds were intravenously
administered 5 min before coronary occlusion.
X-r a y Cr ysta llogr a p h y. A colorless crystal of approximate
dimensions 0.40 × 0.40 × 0.30 mm was mounted on a glass
fiber and transferred to a Rigaku AFC5R diffractometer. The
intensity data were collected at 295 K by a 2θ/ω scan technique
with Cu KR radiation. The structure was solved by direct
methods and refined on F2 by full-matrix least-squares
techniques. Data processing and initial phase determination
were carried out on the teXsan28 system. The structure was
refined by SHELXL-93.29 This crystal contains two chlorine
ions and disordered water molecules per asymmetric unit.
Hydrogen atoms were included by use of a riding model. At
convergence, wR2 ) 0.0925 and GOF ) 1.024 for 257 variables
refined against all 3518 unique data. The absolute configura-
tion was reliably determined by the refined Flack30 parameter
[-0.004(13)].
Ack n ow led gm en t. We thank Drs T. Naka and Z.
Terashita for their encouragement and helpful advice.
We thank H. Igata for the in vivo assay, A. Abe for the
platelet assay, and T. Kawamoto for the hNHE assay,
as well as A. Fujishima and K. Higashikawa for their
X-ray crystallographic analysis.
Su p p or tin g In for m a tion Ava ila ble: Analytical data and
crystallographic data and details of refinement are available
for compound 19. This material is available free of charge via
the Internet at http://pubs.acs.org.
NHE Assa y in Ra t a n d Hu m a n P la telets. Inhibitory
effects of compounds on rat and human NHE were determined
by a platelet assay.26
Blood was obtained from male Wistar rats (13-15 weeks)
and was centrifuged at 3000 rpm for 5 s to obtain platelet-
rich plasma (PRP). The remainder of the blood sample was
then centrifuged at 3000 rpm for 5 min to prepare platelet-
poor plasma (PPP). The PRP was diluted with physiologi-
cal saline to a concentration of 40 × 104/µL. A platelet
aggregometer (Hematoracer, Niko Bioscience) was used for the
measurement of NHE activity. Two hundred microliters of the
PRP was poured into a cuvette and 600 µL of sodium
propionate solution (135 mM sodium propionate, 10 mM
Refer en ces
(1) Wakabayashi, S.; Shigekawa, M.; Pouyssegur, J . Molecular
Physiology of Vertebrate Na+/H+ Exchangers. Physiol. Rev. 1997,
77, 51-74.
(2) Frohlich, O.; Karmazyn, M. The Na-H exchanger revisted: an
update on Na-H exchange regulation and the role of the
exchanger in hypertension and cardiac function in health and
disease. Cardiovasc. Res. 1997, 36, 138-148.
(3) Piper, H. M.; Balser, C.; Ladilov, Y. V.; Schafer, M.; Siegmund,
B.; Garcia-Dorado, D. The role of Na+/H+ exchange in ischemia-
reperfusion. Basic Res. Cardiol. 1996, 91, 191-202.

Non-acylguanidine-type Na+/ H+ Exchanger Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3021
(4) Levitsky, J .; Gurell, D.; Frishman, W. Sodium Ion/Hydrogen Ion
Exchange Inhibition: A New Pharmacologic Approach to Myo-
cardial Ischemia and Reprefusion Injury. J . Clin. Pharmacol.
1998, 38, 887-897.
(16) Reimann, E.; Friesinger, J . M. Synthesis of 4-Methyl-5,6,7,8-
tetrahydro-5-quinolinone. Arch. Pharm. (Weinheim) 1985, 318,
871-878.
(17) Reimann, E.; Po¨schl, K. Regioselective Synthesis of 4-Methyl-
1-pyridin-5-one. Pharmazie 1995, 50, 589-592.
(5) Karmazyn, M.; Gan, X. T.; Humphreys, R. A.; Yoshida, H.;
Kusumoto, K. The Myocardial Na+-H+ Exchange Structure,
Regulation, and Its Role in Heart Disease. Circ. Res. 1999, 85,
777-786.
(18) Gatta, F.; Giudice, M. R.; Pomponi, M.; Marta, M. Synthesis of
1,2,3,4-tetrahydroacridine and 5,6,7,8-tetrahydroquinoline de-
rivatives as potential acetylcholinesterase inhibitors. Hetero-
cycles 1992, 34, 991-1004.
(19) Mulamba, T.; Boukili-Garre´, R. E.; Se´raphin, D.; Noe, E.;
Charlet-Fagne´re, C.; He´nin, J .; Laronze, J .; Sapi, J .; Barret, R.;
Laronze, J .; Le´vy, J . Synthesis of compounds with the novel
2,3,7-triazaphenalene ring system. Heterocycles 1995, 41, 29-
36.
(20) Ruangsiyanand, C.; Rimek, H. J .; Zymalkowski, F. Enamines
of Cyclic 1,3-Diketones as Starting Materials for Pyridine Ring
Synthesis. Chem. Ber. 1970, 103, 2403-2410.
(21) Aoyagi, Y.; Mizusaki, T.; Ohta, A. Facile and Efficient Synthesis
of Pyrroles and Indoles via Palladium-Catalyzed Oxidation of
Hydroxy-Enamines and Amines. Tetrahedron Lett. 1996, 37,
9203-9206.
(22) Kellam, B.; Chan, W. C.; Chhabra, S. R.; Bycroft, B. W. Transient
Affinity Tags Based on the Dde Protection/Deprotection Strat-
egy: Synthesis and Application of 2-Biotinyl- and 2-Hexanoyl-
dimedone. Tetrahedron Lett. 1997, 38, 5391-5394.
(23) Khan, A. Z.; Isaksson, R.; Sandstrom, J . Chromatographic
Enantiomer Separation and Spectroscopic Studies of a Chiral
Vinylogous Thiolcarboxylate. Acta Chem. Scand. 1992, 46, 897-
900.
(24) Adam, W.; Weinkotz, S. Synthesis of thiiranes through direct
sulfur transfer to cycloalkenes in the thermolysis of a thiophene
endoperoxide. Chem. Commun. 1996, 177-178.
(25) Kawamoto, T.; Kimura, H.; Kusumoto, K.; Fukumoto, S.; Shiraishi,
M.; Watanabe, T.; Sawada, H. Potent and selective inhibition
of the human Na+/H+ exchanger isoform NHE1 by a novel
aminoguanidine derivative T-162559. Eur. J . Pharmacol. 2001,
420, 1-8.
(26) Rosskopf, D.; Morgenstern, E.; Scholz, W.; Osswald, U.; Siffert,
W. Rapid determination of the elevated Na+-H+ exchange in
platelets of patients with essential hypertension using an optical
swelling assay. J . Hypertens. 1991, 9, 231-238.
(27) Watanabe, T.; Awane, Y.; Ikeda, S.; Fujiwara, S.; Kubo, K.;
Kikuchi, T.; Kusumoto, K.; Wakimasu, M.; Fujino, M. Pharma-
cology of a nonselective ETA and ETB receptor antagonist, TAK-
044 and the inhibition of myocardial infarct size in rats. Br. J .
Pharmacol. 1995, 114, 949-954.
(28) teXsan: a single-crystal structure analysis software, version 1.9;
Molecular Structure Corporation: The Woodlands, TX, 1998.
(29) Sheldrick, G. M. SHELXL-93: a program for crystal structure
refinement, University of Go¨ttingen: Go¨ttingen, Germany, 1993.
(30) Flack H. D. On enantiomorph-polarity estimation. Acta Crys-
tallogr. 1983, A39, 876-881.
(6) Banno, H.; Fujiwara, J .; Hosoya, J .; Kitamori, T.; Mori, H.;
Yamashita, H.; Ikeda, F. Effects of MS-31-038,
a Novel
Na+-H+ Exchange Inhibitor, on the Myocardial Infarct Size in
Rats after Postischemic Administration. Arzneim.-Forsch. Drug
Res. 1999, 49, 304-310.
(7) Ito, Y.; Imai, S.; Ui, G.; Nakano, M.; Imai, K.; Kamiyama, H.;
Naganuma, F.; Matsui, K.; Ohashi, N.; Nagai, R. A Na+-H+
exchange inhibitor (SM-20550) protects from microvascular
deterioration and myocardial injury after reperfusion. Eur. J .
Pharmacol. 1999, 374, 355-366.
(8) Gumina, R. J .; Buerger, E.; Eickmeier, C.; Moore, J .; Daemmgen,
J . D.; Gross, G. J . Inhibition of the Na+/H+ Exchanger Confers
Greater Cardioprotection Against 90 min of Myocardial Ischemia
Than Ischemic Preconditioning in Dogs. Circulation 1999, 100,
2519-2526.
(9) Ohara, F.; Sugimoto, T.; Yamamoto, N.; Ohkubo, K.; Maeda, K.;
Ozaki, T.; Seki, J .; Goto, T. Preischemic and Postischemic
Treatment with a New Na+/H+ Exchange Inhibitor, FR 183998,
Shows Cardioprotective Effects in Rats with Cardiac Ischemia
and Reperfusion. J . Cardiovasc. Pharmacol. 1999, 34, 848-856.
(10) Scholz, W.; Albus, U.; Counillin, L.; Go¨elein, H.; Lang, J .-J .; Linz,
W.; Weichert, A.; Scho¨lkens, B. A. Protective effects of HOE642,
a selective sodium-hydrogen exchange subtype 1 inhibitor, on
cardiac ischemia and reperfusion. Cardiovasc. Res. 1995, 29,
260-268.
(11) Theroux, P.; Chaitman, B. R.; Danchin, N.; Erhardt, L.; Meinertz,
T.; Schroeder, J . S.; Tognoni, G.; White, H. D.; Willerson, J . T.;
J essel, A. Inhibition of the Sodium-Hydrogen Exchanger with
Cariporide to Prevent Myocardial Infarction in High-Risk
Ischemic Situations. Main Results of the GUARDIAN Trial.
Circulation 2000, 102, 3032-3038.
(12) Baumgarth, M.; Beier, N.; Gericke, R. (2-Methyl-5-(methylsul-
fonyl)benzoyl)guanidine Na+/H+ Antiporter Inhibitors. J . Med.
Chem. 1997, 40, 2017-2034.
(13) Saleem, A.; Lidia, M. D.; Sundeep, D.; Nyeemah, G.; Khehyong,
N.; Shung, C. W.; Kenneth, J . Y.; Bang-Chi, C.; J ack, Z. G.; J ohn,
D. D.; Shih-J ung, L.; Brian, J . G.; Alice, Y. C.; Charles, R. D.;
Randy, S.; Mark, K.; Karnail, S. A. Arylcyclopropanecarboxyl
Guanidines as Novel, Potent, and Selective Inhibitors of the
Sodium Hydrogen Exchanger Isoform-1. J . Med. Chem. 2001,
44, 3302-3310.
(14) Rubinov, D. B.; Rubiova, I. L.; Akhrem, A. A. Chemistry of
2-Acylcycloalkane-1,3-diones. Chem. Rev. 1999, 99, 1047-1065.
(15) Kesten, S. J .; Degnan, M. J .; Hung, J .; McNamara, D. J .;
Ortwine, D. F.; Uhledorf, S. E.; Werbel, L. M. Synthesis and
Antimalarial Properties of 1-Imino Derivatives of 7-Chloro-3-
substituted-3,4-dihydro-1.9(2H,10H)-acridinediones and Related
Structures. J . Med. Chem. 1992, 35, 3429-3447.
J M0104567