Synthesis of new 5-substituted hydantoins and symmetrical twin-drug type hydantoin derivatives

Article abstract of DOI:10.1248/cpb.c14-00017

In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transformation of 5-methylene hydantoins 4a-c to 5-aminomethyl-substituted hydantoins 5-10 or to 5-amino-5-methyl-disubstituted hydantoins 11-14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives 19-24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosaminoglycans are also described.

Full text of DOI:10.1248/cpb.c14-00017

May 2014
Regular Article
Chem. Pharm. Bull. 62(5) 429–438 (2014)
429
Synthesis of New 5-Substituted Hydantoins and Symmetrical Twin-Drug
Type Hydantoin Derivatives
Fumiko Fujisaki, Hatsumi Aki, Ayumi Naito, Enko Fukami, Nobuhiro Kashige,
Fumio Miake, and Kunihiro Sumoto*
Faculty of Pharmaceutical Sciences, Fukuoka University; Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan.
Received January 8, 2014; accepted March 1, 2014
In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transfor-
mation of 5-methylene hydantoins 4a–c to 5-aminomethyl-substituted hydantoins 5–10 or to 5-amino-5-meth-
yl-disubstituted hydantoins 11–14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives
19–24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosamino-
glycans are also described.
Key words hydantoin; regioselective; antibacterial activity; isothermal titration calorimetry; bivalent twin-
drug; sulfated glycosaminoglycan
The need for new antibacterial agents is largely due to the encouraged us to develop further modifications of this class of
increase of bacterial infections with resistant strains, especial- compounds.
ly Gram-positive strains, in both community and hospital set-
In this article, we describe the regioselective chemical
ting. Oxazolidinone antibacterial agents such as linezolid are modification of 5-methylene hydantoins to 5-aminomethyl-
a relatively new class of antibacterial agents, and the utility of substituted hydantoins 5–10 or to 5-amino-5-methyl-disubsti-
this class includes activity against multidrug-resistant infec- tuted hydantoins 11–14. Preparation of the bivalent twin-drug
tions.1–3) In the early stage of invasion of bacteria or viruses, type hydantoin derivatives 19–24 from β-aminoalanine methyl
the surface glycans of organisms recognize various host cell ester (1)20) and a new carbohydrate recognition binding prop-
lectins. In terms of molecular recognition, the participation of erty of symmetrical twin-drug type hydantoin derivative 24b
two-fold (C2) or three-fold (C3) symmetrical geometry macro- are also described.
molecules is one of the common features in many biological
responses,4–6) and small symmetric geometrical molecules
Results and Discussion
In connection with our synthetic studies on new bioac-
frequently appear in many biological active compounds.7–9)
From this interesting aspect of molecular symmetry, we have tive hydantoin derivatives, some molecular modifications of
already reported a few examples of such types of symmetrical β-aminoalanine methyl esters (1) to bioisosteric hydantoin
targeted molecules for the purpose of finding new bioactive derivatives have been reported.16–20) As starting materials for
leads or candidates.10–15)
further derivatizations in this series, 5-methylene hydantoins
Our previous studies on a bioisosteric replacement of the 4a–c were obtained from elimination (deamination) reactions
oxazolidinone ring in linezolid by a hydantoin nucleus provid- of the corresponding 5-dialkylaminomethyl-hydantoins (3)17)
ed a few interesting antibacterial leads.16–20) Among previously (Chart 1) (see Experimental).
targeted hydantoin derivatives, some derivatives including a
Two types of hydantoin derivatives (5–10 and 11–14)
twin-drug type symmetrical hydantoin derivative20,21) showed could be obtained from regioselective additions of amines to
significant antibacterial activity against Gram-positive organ- 5-methylene hydantoins 4a–c (Chart 2). Thus, reaction condi-
isms (Staphylococcus aureus). This finding of new antibac- tions without a solvent (neat) at room temperature (rt) (path
terially active molecules constructed on a hydantoin scaffold a) resulted predominantly in the formation of 5-pyrrolidino-
Chart 1. Preparation of 5-Methylene Hydantoins 4a–c
The authors declare no conflict of interest.
© 2014 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: kunihiro@adm.fukuoka-u.ac.jp

430
Vol. 62, No. 5
Chart 2. Regioselective Preparations of 5-Substituted Hydantoins 5–10 and 11–14 from 5-Methylene Hydantoin 4
Table 1. Preparation of 5-Aminoethyl Hydantoins 5–10 from 5-Methylene Hydantoins 4a–c
Compd. No.
R1
Amounts of aminesa)
Time
Yield (%)
5
6
H
H
3
10min
2h
62
78
64
46
53
53
–NHCH2Ph
–NHCH2Ph
–NHCH2Ph
1.4
2
7
Cl
2h
8
Cl
3
1h
9
OMe
OMe
2.8
2
0.5h
2h
10
a) Molar ratio of the used amine to compound 4.
methyl- or 5-benzylaminomethyl-hydantoin derivatives 5–10. hydantoin derivatives are particularly interesting, and diag-
In contrast, reactions in CH2Cl2 under rt or refluxing condi- nostically useful fragmentation processes were observed. The
tions (path b) afforded 5-amino-5-methylhydantoin derivatives prominent fragment iminium ion [a] for 5-dialkylaminomethyl-
11–14 in moderate to good yields. The results are summarized hydantoin derivatives 5–10 is from fission of the C(5)–C bond
in Tables 1 and 2. It is thought that the tautomeric isomer B (α-cleavage of the molecular ion). On the other hand, in the
of 5-methylene hydantoin in solution (A⇄B)17,19) is a crucial mass spectra of 5-methyl-5-dialkylamino-hydantoin deriva-
intermediate for the formation of 5,5-disubstituted hydantoins tives 11–14, the formation of a strong ammonium ion peak [b]
(11–14), as shown in Chart 2. When using an excess amount resulting from C(5)–N bond cleavage of the 5-amino substitu-
of an amine, a considerable amount of ring-opened urea de- ent is observed (Fig. 1).
rivatives 15–17 was isolated as a predominant reaction prod-
Furthermore, in NMR spectra of 5-methyl-5-dialkylamino-
uct (Chart 2).
substituted hydantoin derivatives, 5-methyl and 5-carbon ring
1
All of the structures of the above hydantoin derivatives signals of the products are easily distinguished. The H-NMR
were easily confirmed by elemental analysis and spectroscopic spectrum of these 5,5-disubstituted derivatives showed
data. The positive FAB mass spectroscopic behaviors of these 1.53–1.57ppm as a singlet assignable to the 5-methyl group,

May 2014
431
Table 2. Preparation of 5-Amino-5-methyl-disubstituted Hydantoins 11–14 from 5-Methylene Hydantoins 4a–c
Compd. No.
R1
Amounts of aminesa)
Reaction temp.
Time
Yield (%)
11
12
13
H
H
1
6
3
rt
5h
5h
2h
61
28
69
–NHCH2Ph
Reflux
Reflux
Cl
14
OMe
2
rt
1h
67
a) Molar ratio of the used amine to compound 4.
thetic trials, we confirmed that the above-described procedure
is a conventional route to prepare new types of bivalent sym-
metrical twin-drug type bivalent molecules.
It is thought that sulfated sugar chains play an important
role in mediating adhesion of many types of bacterial or-
ganisms to host cells or tissues. Regarding the interaction
of bacterial adhesion to glycans, a few examples of binding
carbohydrate specificities have been demonstrated, and some
Fig. 1. Fragment Ions a and b
and the 13C-NMR spectrum had two characteristic carbon sig- bacteria are known to bind to sulfated glycosaminoglycans
nals at 22.9–24.0 and 73.4–75.1ppm, easily ascribable to the such as heparan sulfate.24) We have been interested in small
substituent 5-methyl carbon and 5-position of the hydantoin molecules that interfere with such carbohydrate recognition
ring carbon, respectively. From these data, we could easily stages in order to find new bioactive leads.10,11,25,26) With the
confirm the structures of the products (see Experimental for aim of elucidating the chemical properties of the antibacterial
details).
active symmetrical twin drug type compound 24b,20) we car-
A novel N-acyl derivative 18 was obtained from direct N- ried out thermodynamic experiments on binding of sulfated
acylation of isolated 5-aminomethyl-hydantoin 6 with acetic glycosaminoglycans such as heparan sulfate and dermatan sul-
anhydride (Chart 3). This chemical modification of compound fate to a bivalent antibacterial active hydantoin derivative 24b
18 also provided chemical evidence for the validity of the by using isothermal titration calorimetry. Among the com-
structure as a secondary amine 6 and a new promising route pounds tested, the binding reaction between twin-drug type
to 5-acylaminomethyl-hydantoins.
compound 24b and heparan sulfate or dermatan sulfate was
In addition to the above-described modifications, we also exothermic and the obtained thermodynamic parameters were
attempted to prepare twin-drug type hydantoin derivatives K=2.75×104 1/M and ΔH=−9.46kJ/mol for heparan sulfate and
from β-aminoalanine methyl ester 1 in order to find more ac- K=1.11×103 1/M and ΔH=−10.9kJ/mol for dermatan sulfate at
tive antibacterial leads.20,21) The targeted bivalent twin-drug 298.15K. A representative thermogram of a hydantoin deriva-
type7,22) hydantoin derivatives 19–24 were obtained from tive 24b titrated with heparan sulfate is shown in Fig. 2.
reactions of the corresponding diisocyanate derivatives and
From the results of calorimetric experiments, we found that
β-aminoalanine esters (1) (Chart 4). Details of the protocol the twin-drug type small molecule 24b has an interesting
for preparation of twin-drug type compounds are shown in binding property to sulfated glycosaminoglycans.27) Regarding
Experimental. Double cyclization reactions affording bivalent the prepared hydantoin derivatives, symmetrical twin-drug
hydantoin derivatives 19–24 easily occurred under condi- type derivatives (24a and 23b) showed significant antibacterial
tions similar to those for preparation of 5-dialkylaminomethyl activity against a Gram-positive strain (Staphylococcus au-
hydantoins described previously.18) The results for designed reus) (MIC=0.026mM and 0.116mM, respectively), but these
twin-drug type compounds are summarized in Table 3. All of compounds were inactive against a Gram-negative strain
the obtained compounds exhibited very simple symmetrical (Escherichia coli) at a concentration of less than 0.211mM.
13C-NMR spectra in DMSO-d6, indicating little difference The difference in antibacterial activities seems to be affected
with respect to the signal assignable to substituted hydantoin by both structure of the linker and structure of the basic
rings and a linker moiety.23) The linker structures applied in amine moiety in a twin-drug type molecule. Further details of
these twin-drug type molecules are also shown in Table 3. an structure–activity relationship (SAR) study including other
The yields were good to excellent and the obtained products prepared hydantoin derivatives and additional thermodynamic
were stable solid or crystalline materials. Through these syn- experiments for the biological active compounds in this series

432
Vol. 62, No. 5
Chart 3. Preparation of 5-N-Acylaminomethyl Hydantoin 18 from Compound 6
Chart 4. Synthesis of Twin-Drug Type Hydantoin Derivatives 19–24 from Compound 1
Table 3. Chemical Structures and Yields for Symmetrical Twin-Drug Type Hydantoin Derivatives 19–24
Compd. No.
Linker
Yield (%)
67
19a
–(CH2)4–
19b
20a
–(CH2)4–
–(CH2)6–
62
40
20b
–(CH2)6–
43
21a
21b
–(CH2)8–
–(CH2)8–
71
84
22a
22b
–(CH2)12–
–(CH2)12–
78
71
23b
24a
40
45
24ba)
65
a) The data for compound 24b were taken from ref. 19.

May 2014
433
Fig. 2. Isothermal Titration Thermogram (A) and Calculated Fitting Curve (B) for a Twin-Drug Compound 24b Binding to Heparan Sulfate
will be described separately.
Muller–Hinton broth according to the Japanese Society of
Chemotherapy.28,29)
Preparation of 5-Methylene Hydantoins (4a–c) These
Experimental
Melting points are uncorrected. IR spectra were mea- compounds were prepared according to the procedure re-
1
sured by a Shimadzu FT/IR-8100 spectrometer. The H- and ported previously.16) Physical and spectroscopic data of these
13C-NMR spectra were obtained by a JEOL JNM A-500 at compounds are shown below.
35°C. Chemical shifts are expressed in d ppm downfield from
5-Methylene-3-phenylimidazolidine-2,4-dione (4a): Physical
an internal tetramethylsilane (TMS) signal. The signal as- and spectroscopic data of this compound were reported in our
signments were confirmed by 1H–1H two-dimensional (2D) previous paper.16)
1
correlation spectroscopy (COSY), H–13C heteronuclear mul-
5-Methylene-3-(4-chlorophenyl)imidazolidine-2,4-dione
tiple quantum coherence (HMQC), and H–13C heteronuclear (4b): This compound was obtained in 68% yield; a white
multiple-bond connectivity (HMBC) spectra. High FAB-MS solid; mp >215°C. IR (KBr) cm−1: 1775, 1728, 1671. FAB-MS
spectra were obtained by a JEOL JMS-HX110 mass spectrom- (positive) m/z: 223 (M+H)+. 1H-NMR (DMSO-d6) δ: 4.94,
eter. Dermatan sulfate sodium salt (GAG-DS01) and heparan 5.26 (each 1H, d, J=1.5Hz, =CH2), 7.45 (2H, d, J=2.4Hz, Ar
sulfate sodium salt (GAG-HS01) were purchased from Funa- H-2, H-6), 7.47 (2H, d, J=2.1Hz, Ar H-3, H-5), 10.8 (1H, br,
koshi Co., Ltd. All other chemicals used were of reagent grade NH). 13C-NMR (DMSO-d6) δ: 94.9 (=CH2), 128.3 (Ar C-3,
and were used without further purification. The abbreviations C-5), 128.7 (Ar C-2, C-6), 130.6 (Ar C-4), 132.3 (Ar C-1),
Pyr and Hyd are used for the pyrrolidine ring and hydantoin 134.9 (Hyd C-5), 152.6 (Hyd C-2), 161.8 (Hyd C-4). Anal.
1
ring, respectively.
Calcd for C10H8N2O2Cl: C, 53.95; H, 3.17; N, 12.58. Found: C,
Calorimetric Experiments Heat of binding between a 53.77; H, 3.24; N, 12.65.
twin-drug type compound 24b and a sulfated glycosami-
5-Methylene-3-(4-methoxyphenyl)imidazolidine-2,4-dione
noglycan such as heparan sulfate was measured in water at (4c): This compound was obtained in 85% yield; a white solid;
298.15K by using an isothermal titration calorimeter (Thermal mp >215°C. IR (KBr) cm−1: 1789, 1765, 1714, 1665. FAB-MS
1
Activity Monitor 2270). Titrations were performed by step- (positive) m/z: 219 (M+H)+. H-NMR (DMSO-d6) δ: 3.79 (3H,
wise injection of heparan sulfate solution or dermatan sulfate s, OMe), 4.91, 5.22 (each 1H, d, J=1.5Hz, =CH2), 7.02 (2H, d,
(5.3mg/mL) into a reaction cell loaded with a twin-drug type J=8.8Hz, Ar H-3, H-5), 7.30 (2H, d, J=8.8Hz, Ar H-2, H-6),
24b solution (0.2mg/mL). In the calorimetric experiments, 10.66 (1H, br, NH). 13C-NMR (DMSO-d6) δ: 55.3 (OMe), 94.4
each binding reaction was exothermic and compound 24b (=CH2), 114.0 (Ar C-3, C-5), 124.2 (Ar C-1), 128.1 (Ar C-2,
showed thermodynamic parameters of ΔG=−25.3kJ/mol, C-6), 135.0 (Hyd C-5), 153.1 (Hyd C-2), 158.7 (Ar C-4), 162.1
ΔH=−9.46kJ/mol and ΔS=53.2J/K/mol for heparan sulfate (Hyd C-4). Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62; N,
and ΔG=−17.4kJ/mol, ΔH=−10.9kJ/mol and ΔS=21.6 J/K/ 12.84. Found: C, 60.42; H, 4.87; N, 12.58.
mol for dermatan sulfate. A representative thermogram of a
hydantoin derivative 24b titrated with heparan sulfate is il- (5–10) from 5-Methylene Hydantoins (4a–c) 3-Phenyl-5-
lustrated in Fig. 2.
(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione (5): A mixture
Typical Procedure for the Preparation of Products
Assays for Antibacterial Activity We used Staphylococ- of a 5-methylene hydantoin 4a (0.050g, 0.27mmol) and pyr-
cus aureus ATCC6538P and Escherichia coli NBRC14237 rolidine (0.057g, 0.80mmol) was allowed to stand for 10min
(NIHJ) (Gram-positive and Gram-negative bacteria, respec- at rt. Et2O was added to the mixture and the precipitate
tively) as target organisms. Synthesized compounds were was collected by filtration to give 5 (0.043g, 62%); a white
dissolved in dimethyl sulfoxide (DMSO) to a concentration of solid; mp 118–119°C; IR (KBr) cm−1: 1774, 1723, 1721. FAB-
1.280 µg/mL. The minimum inhibitory concentration (MIC) MS (positive) m/z: 260 (M+H)+, 84 (CH2=Pyr)+. 1H-NMR
of a standard strain was measured by the authentic micro- (DMSO-d6) δ: 1.68 (4H, brs, Pyr H-3, H-4), 2.53–2.60 (4H,
dilution method to monitor the bacterial growth turbidity in m, Pyr H-2, H-5), 2.81–2.83 (1H, m, CHH-Pyr), 2.91–2.95

434
Vol. 62, No. 5
(1H, m, CHH-Pyr), 4.27–4.28 (1H, m, Hyd H-5), 7.31–7.47 CHCH2NHCH2Ph), 2.75–2.82 (2H, m, CHCH2NHCH2Ph),
(5H, m, Ar H), 8.33 (1H, brs, Hyd-1). 13C-NMR (DMSO-d6) δ: 3.27 (2H, s, CHCH2NHCH2Ph), 4.27 (1H, dd, J=15.0,
23.2 (Pyr C-3, C-4), 54.2 (Pyr C-2, C-5), 56.3 (CH2-Pyr), 56.9 6.0Hz, CONHCHHPh), 4.33–4.37 (2H, m, CONHCHHPh+
(Hyd C-5), 126.2 (Ar C-2, C-6), 127.3 (Ar C-4), 128.4 (Ar C-3, CHCH2NHCH2Ph), 6.50 (1H, d, J=7.5Hz, ArNHCONHCH),
C-5), 132.2 (Ar C-1), 155.5 (Hyd C-2), 172.2 (Hyd C-4). The 7.20–7.31 (12H, m, Ar H), 7.40–7.42 (2H, m, Ar H),
hydrochloride of this compound was identical to an authentic 8.57 (1H, t, J=6.0Hz, ArNHCONHCH), 8.93 (1H, s,
sample.16)
CONHCH2Ph). 13C-NMR (DMSO-d6) δ: 42.0 (CONHCH2Ph),
5-((Benzylamino)methyl)-3-phenylimidazolidine-2,4-dione 50.9 (CHCH2NHCH2Ph), 52.6 (CHCH2NHCH2Ph), 52.8
(6): A white solid; mp 151–152°C. IR (KBr) cm−1: 1770, 1710. (CHCH2NHCH2Ph), 118.9 (Ar C-2, C-6 in 4-chlorophenyl),
FAB-MS (positive) m/z: 296 (M+H)+, 120 (CH2=NHCH2Ph)+. 124.5 (Ar C-4 in 4-chlorophenyl), 126.5, 126.6, 127.0, 127.0,
1H-NMR (DMSO-d6) δ: 2.29 (1H, br, NHCH2Ph), 2.84 (1H, 127.8, 127.8, 128.0, 128.0, 128.1, 128.1, 128.4, 128.4 (Ar C),
dd, J=12.5, 6.0Hz, Hyd-CHH-NH), 2.92 (1H, dd, J=12.5, 139.2 (Ar C-1 in 4-chlorophenyl), 139.3 (Ar C-1 in
4.0Hz, Hyd-CHH-NH), 3.73, 3.78 (each 1H, d, J=14.0Hz, CONHCH2Ph), 140.4 (Ar C-1 in CHCH2NHCH2Ph),
CH2Ph), 4.28–4.30 (1H, m Hyd H-5), 7.21–7.48 (10H, m, Ar 154.5 (NHCONH), 171.3 (CONHCH2). Anal. Calcd for
H), 8.37 (1H, brs, Hyd H-1). 13C-NMR (DMSO-d6) δ: 49.1 C24H25N4O2Cl: C, 65.97; H, 5.77; N, 12.82. Found: C, 65.96; H,
(Hyd-CH2-NH), 52.7 (CH2-Ph), 57.2 (Hyd C-5), 126.5, 126.5, 5.95; N, 12.79.
127.5, 127.8, 128.0, 128.6 (Ar C), 132.2 (Ar C-1 in Hyd-Ph),
3-(4-Methoxyphenyl)-5-(pyr rolidin-1-ylmethyl)-
140.5 (Ar C-1 in CH2-Ph), 155.8 (Hyd C-2), 172.5 (Hyd C-4). imidazolidine-2,4-dione (9): A white solid; mp 98.5–99.5°C.
Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23 Found: IR (KBr) cm−1: 1773, 1710. FAB-MS (positive) m/z: 290
1
C, 69.22; H, 5.86; N, 14.28.
(M+H)+, 84 (CH2=Pyr)+. H-NMR (DMSO-d6) δ: 1.67–1.69
3 - (4 - Ch lorophe nyl) -5 - ( py r rol id i n-1-yl met hyl) - (4H, brs, Pyr H-3, H-4), 2.49–2.60 (4H, m, Pyr H-2, H-5),
imidazolidine-2,4-dione (7): A white solid; mp 138–139°C. 2.76–2.80, 2.88–2.92 (each 1H, m, CH2-Pyr), 3.79 (3H, s,
IR (KBr) cm−1: 1779, 1719. FAB-MS (positive) m/z: 294 (M+ OMe), 4.27 (1H, dd, J=6.5, 3.5Hz, Hyd H-5), 7.00–7.02 (2H,
1
H)+, 84 (CH2=Pyr)+. H-NMR (DMSO-d6) δ: 1.68 (4H, brs, m, Ar H), 7.19–7.20 (2H, m, Ar H), 8.40 (1H, br, Hyd H-1).
Pyr H-3, H-4), 2.49–2.60 (4H, m, Pyr H-2, H-5), 2.76–2.80, 13C-NMR (DMSO-d6) δ: 23.3 (Pyr C-3, C-4), 54.3 (Pyr C-2,
2.91–2.95 (each 1H, m, CH2-Pyr), 4.30 (1H, dd, J=6.5, 3.5Hz, C-5), 56.3 (OMe), 56.5 (CH2-Pyr), 57.0 (Hyd C-5), 113.9
Hyd H-5), 7.37, 7.53 (each 2H, d, J=8.5Hz, Ar H), 8.53 (1H, (Ar C-3, C-5), 124.4 (Ar C-1), 127.8 (Ar C-2, C-6), 156.0
br, Hyd H-1). 13C-NMR (DMSO-d6) δ: 23.3 (Pyr C-3, C-4), (Hyd C-2), 158.4 (Ar C-4), 172.2 (Hyd C-4). Anal. Calcd for
54.3 (Pyr C-2, C-5), 56.4 (CH2-Pyr), 57.1 (Hyd C-5), 128.0, C15H19N3O3: C, 62.27; H, 6.62; N, 14.52. Found: C, 62.08; H,
128.0, 128.7, 128.7 (Ar C), 131.0 (Ar C-1 or C-4), 131.9 (Ar 6.62; N, 14.47.
C-4 or Ar C-1), 155.4 (Hyd C-2), 172.2 (Hyd C-4). Anal. Calcd
5-((Ben z ylamino)methyl)-3-(4 -methoxy phenyl)-
for C14H16N3O2Cl·0.3H2O: C, 56.21; H, 5.59; N, 14.05. Found: imidazolidine-2,4-dione (10): This compound was purified by
C, 56.08; H, 5.36; N, 14.17.
centrifugal silica gel chromatography with AcOEt as a sol-
5 - (( B e n z yl a m i no) me t hyl) -3 - (4 - ch lo r o phe nyl) - vent; a white solid; mp 153–154°C. IR (KBr) cm−1: 1771, 1707.
imidazolidine-2,4-dione (8) and N-Benzyl-3-(benzylamino)-2- FAB-MS (positive) m/z: 326 (M+H)+, 120 (CH2=NHCH2Ph)+.
(3-(4-chlorophenyl)ureido)propanamide (15).
1H-NMR (DMSO-d6) δ: 2.37–2.50 (1H, br, NHCH2Ph), 2.85
Compound 8 was obtained from the reaction of 4b and (1H, dd, J=12.5, 6.0Hz, NHCHH-Ph), 2.91 (1H, dd, J=12.5,
benzylamine by the above general procedure. The precipitated 4.0Hz, NHCHH-Ph), 3.74–3.79 (2H, m, Hyd-CH2-NH), 3.78
material formed in the filtrate (Et2O) of compound 8 was col- (3H, s, OMe), 4.25–4.27 (1H, m, Hyd H-5), 7.00–7.01 (2H, m,
lected by filtration and washed with AcOEt to give a ring- Ar H), 7.22–7.23 (3H, Ar H), 7.31–7.33 (4H, m Ar H), 8.31
opened urea derivative 15 in 39% yield. Data for compounds 8 (1H, brs, Hyd H-1). 13C-NMR (DMSO-d6) δ: 49.1 (NH-CH2-
and 15 are shown below.
Ph), 52.7 (Hyd-CH2-NH), 55.3 (OMe), 57.1 (Hyd C-5), 113.9
Compound (8): A white solid; mp 153–154°C. IR (KBr) (Ar C-3, C-5 in 4-methoxyphenyl), 124.8 (Ar C-1 in 4-me-
cm−1: 3249, 1772, 1710. FAB-MS (positive) m/z: 330 (M+H)+, thoxyphenyl), 126.5, 127.8, 127.8, 127.9, 127.9, 128.0, 128.0
120 (CH2=NHCH2Ph)+. 1H-NMR (DMSO-d6) δ: 2.30 (1H, (Ar C), 140.5 (Ar C-1 in CH2-Ph), 156.1 (Hyd C-2), 158.3 (Ar
br, NHCH2Ph), 2.85–2.93 (2H, m, Hyd-CH2-NH), 3.73, 3.77 C-4 in 4-methoxyphenyl), 172.4 (Hyd C-4). Anal. Calcd for
(each 1H, d, J=14.0Hz, CH2-Ph), 4.28–4.30 (1H, m, Hyd H-5), C18H19N3O3: C, 66.45; H, 5.89; N, 12.91 Found: C, 66.50; H,
7.21–7.22 (1H, m, Ar H-4 in NH-CH2-Ph), 7.29–7.32 (4H, Ar 6.00; N, 12.88.
H in NH-CH2-Ph), 7.39 (2H, d J=8.5Hz, Ar H in 4-chlorophe-
Typical Procedure for the Preparation of Products
nyl), 7.54 (2H, d, J=8.5Hz, Ar H in 4-chlorophenyl), 8.43 (1H, (11–14) from 5-Methylene Hydantoins (4a–c) 5-Methyl-3-
brs, Hyd H-1). 13C-NMR (DMSO-d6) δ: 49.0 (Hyd-CH2-NH), phenyl-5-(pyrrolidin-1-yl)imidazolidine-2,4-dione (11): A solu-
52.7 (NH-CH2-Ph), 57.2 (Hyd C-5), 126.5, 127.4, 127.4, 128.0, tion of a 5-methylene- hydantoin 4a (0.050g, 0.27mmol) and
128.0 (Ar C in NH-CH2-Ph), 128.0, 128.0, 128.6, 128.6 (Ar C pyrrolidine (0.019g, 0.27mmol) in CH2Cl2 was stirred for 5h
in 4-chlorophenyl), 131.1 (Ar C-1 or C-4 in 4-chlorophenyl), at room temperature. After concentration of the solvent, the
131.8 (Ar C-4 or C-1 in 4-chlorophenyl), 140.4 (Ar C-1 in NH- solid material was purified by centrifugal silica gel chroma-
CH2-Ph), 155.5 (Hyd C-2), 172.2 (Hyd C-4). Anal. Calcd for tography using AcOEt as a solvent to afford 11 (0.042g, 61%);
C17H16N3O2Cl·0.5H2O: C, 60.27; H, 5.06; N, 12.40. Found: C, a white solid; mp 142–143°C. IR (KBr) cm−1: 1778, 1726.
1
60.01; H, 4.79; N, 12.43.
Compound (15):
FAB-MS (positive) m/z: 260 (M+H)+, 72. H-NMR (DMSO-
A
white solid; mp 200–201°C. d6) δ: 1.57 (3H, s, Me), 1.70–1.73 (4H, m, Pyr H-3, H-4),
IR (KBr) cm−1: 1696, 1633. FAB-MS (positive) m/z: 2.56–2.58 (2H, m, Pyr H-2×1, H-5×1), 2.74–2.76 (2H, m, Pyr
437 (M+H)+. 1H-NMR (DMSO-d6) δ: 2.07 (1H, br, H-2×1, H-5×1), 7.32–7.34 (2H, m, Ar H-2, H-6), 7.39–7.40

May 2014
435
(1H, m, Ar H-4), 7.45–7.47 (2H, m Ar H-3, H-5), 8.62 (1H, 8.68 (1H, s, PhNHCONHCH). 13C-NMR (DMSO-d6) δ: 23.2
brs, Hyd H-1). 13C-NMR (DMSO-d6) δ: 23.0 (Me), 23.2 (Pyr (Pyr C-3, C-4 in CH2-Pyr), 23.6, 25.5 (Pyr C-3, C-4 in CO-
C-3, C-4), 45.2 (Pyr C-2, C-5), 75.0 (Hyd C-5), 126.7 (Ar C-2, Pyr), 45.5, 45.9 (Pyr C-2, C-5 in CO-Pyr), 50.4 (CHCH2Pyr),
C-6), 127.7 (Ar C-4), 128.7 (Ar C-3, C-5), 131.8 (Ar C-1), 53.9 (Pyr C-2, C-5 in CH2-Pyr), 57.6 (CH2-Pyr), 117.4 (Ar
154.2 (Hyd C-2), 173.0 (Hyd C-4). Anal. Calcd for C14H17N3O2: C-2, C-6), 121.0 (Ar C-4), 128.5 (Ar C-3, C-5), 140.2 (Ar
C, 64.85; H, 6.61; N, 16.20. Found: C, 64.78; H, 6.63; N, 16.11. C-1), 154.4 (NHCONH), 169.7 (CO-Pyr). Anal. Calcd for
5-(Benzylamino)-5-methyl-3-phenylimidazolidine-2,4-dione C18H26N4O2·0.25H2O: C, 64.55; H, 7.97; N, 16.73. Found: C,
(12): A white solid; mp 122–124°C. [The ratio of a mixture 64.55; H, 7.92; N, 16.65.
of three solvents (AcOEt–n-hexane–MeOH) changed stepwise
1-(4-Chlorophenyl)-3-(1-oxo-1,3-di(pyrrolidin-1-yl)propan-2-
(50:50:0→100:0:0→0:0:100%).] IR (KBr) cm−1: 1782, 1718. yl)urea (17): A mixture of a 5-methylene-hydantoin (4b)
1
FAB-MS (positive) m/z: 296 (M+H)+, 108. H-NMR (DMSO- (0.10g, 0.45mmol) and an excess amount of pyrrolidine (0.16g,
d6) δ: 1.53 (3H, s, Me), 3.40–3.42 (1H, m, NHCH2Ph), 3.58 2.25mmol) was allowed to stand for 1h at room tempera-
(1H, dd, J=13.0, 6.0Hz, NHCHHPh), 3.72 (1H, dd, J=13.0, ture. The solid material was filtered, washed with water, and
6.0Hz, NHCHHPh), 7.20–7.47 (10H, m, Ar H), 8.58 (1H, brs, dried. The obtained product was purified by centrifugal silica
Hyd H-1). 13C-NMR (DMSO-d6) δ: 24.0 (Me), 45.9 (NH-CH2- gel chromatography using MeOH as a solvent to give 17 as
Ph), 73.4 (Hyd C-5), 126.5, 126.6, 127.6, 127.9, 127.9, 128.5 a white solid (0.05g, 31%); mp 193–195°C. IR (KBr) cm−1:
1
(Ar H), 132.0 (Ar C-1 in Hyd-Ph), 140.0 (Ar C-1 in CH2-Ph), 1701, 1614. FAB-MS (positive) m/z: 365 (M+H)+. H-NMR
154.0 (Hyd C-2), 174.3 (Hyd C-4). Anal. Calcd for C17H17N3O2: (DMSO-d6) δ: 1.65–1.67 (4H, m, Pyr H-3, H-4 in CH2-Pyr),
C, 69.14; H, 5.80; N, 14.23 Found: C, 69.08; H, 5.76; N, 14.14.
1.78 (2H, dd, J=14.0, 6.5Hz, Pyr H-3, H-4 in CO-Pyr),
3-(4-Chlorophenyl)-5-methyl-5-(pyrrolidin-1-yl)- 1.87–1.92 (2H, m, Pyr H-3, H-4 in CO-Pyr), 2.47–2.51 (4H,
imidazolidine-2,4-dione (13): A white solid; mp 138–140°C m, Pyr H-2, H-5 in CH2-Pyr), 2.58–2.66 (2H, m, CH2-Pyr),
(AcOEt–n-hexane=7:3). IR (KBr) cm−1: 1781, 1723. FAB- 3.23–3.27 (2H, m, Pyr H-2, H-5 in CO-Pyr), 3.48–3.53 (1H,
1
MS (positive) m/z: 294 (M+H)+, 72. H-NMR (DMSO-d6) δ: m, Pyr H-2 or H-5 in CO-Pyr), 3.61–3.65 (1H, m, Pyr H-5 or
1.57 (3H, s, Me), 1.70–1.72 (4H, m, Pyr H-3, H-4), 2.50–2.58, H-2 in CO-Pyr), 4.55 (1H, dd, J=13.5, 7.5 H=14.0, 6.5Hz,
2.72–2.77 (each 2H, m, Pyr H-2, H-5), 7.40 (2H, d, J=9.0Hz, CHCH2Pyr), 6.41 (1H, d, J=7.5Hz, PhNHCONHCH), 7.25
Ar H-2, H-6 or H-3, H-5), 7.54 (2H, d, J=9.0Hz, Ar H-3, H-5 (2H, d, J=9.0Hz, Ar H-3, H-5), 7.39 (2H, d, J=9.0Hz, Ar H-2,
or H-2, H-6), 8.79 (1H, brs, Hyd H-1). 13C-NMR (DMSO- H-6), 8.84 (1H, brs, PhNHCONHCH). 13C-NMR (DMSO-
d6) δ: 22.9 (Me), 23.2 (Pyr C-3, C-4), 45.3 (Pyr C-2, C-5), d6) δ: 23.2 (Pyr C-3, C-4 in CH2-Pyr), 23.6, 25.5 (Pyr C-3,
75.1 (Hyd C-5), 128.3 (Ar C-2, C-6 or C-3, C-5), 128.7 (Ar C-4 in CO-Pyr), 45.5, 45.9 (Pyr C-2, C-5 in CO-Pyr), 50.4
C-3, C-5 or C-2, C-6), 130.7 (Ar C-1 or C-4), 130.7 (C-4 or (CHCH2Pyr), 53.9 (Pyr C-2, C-5 in CH2-Pyr), 57.5 (CH2-Pyr),
Ar C-1), 153.9 (Hyd C-2), 172.8 (Hyd C-4). Anal. Calcd for 118.9 (Ar C-2, C-6), 124.5 (Ar C-4), 128.4 (Ar C-3, C-5), 139.2
C14H16N3O2Cl·0.2H2O: C, 56.55; H, 5.56; N, 14.13 Found: C, (Ar C-1), 154.3 (NHCONH), 169.6 (CO-Pyr). Anal. Calcd for
56.55; H, 5.32; N, 14.13.
C18H25N4O2Cl·0.2H2O: C, 58.67; H, 6.95; N, 15.21. Found: C,
3-(4-Methoxyphenyl)-5-methyl-5-(pyrrolidin-1-yl)- 58.68; H, 6.71; N, 15.21.
imidazolidine-2,4-dione (14): A white solid; mp 128–130°C
N-Benzyl-N-((2,5-dioxo-1-phenylimidazolidin-4-yl)methyl)-
(AcOEt–n-hexane=7:3). IR (KBr) cm−1: 1776, 1727. FAB- ethanamide (18):
A solution of compound 6 (0.95g,
MS (positive) m/z: 290 (M+H)+, 72. 1H-NMR (DMSO-d6) 3.22mmol) in pyridine (19mL) was cooled to 0°C and then
δ: 1.55 (3H, s, Me), 1.71 (4H, br, Pyr H-3, H-4), 2.50–2.57, acetic anhydride (6.5mL) was added portionwise. The mixture
2.75–2.97 (each 2H, m, Pyr H-2, H-5), 3.78 (3H, s, OMe), was allowed to stand at rt with stirring for 2.5h and then con-
7.00–7.01, 7.21–7.23 (each 2H, d, J=8.5Hz, Ar H), 8.66 (1H, centrated under reduced pressure. The residue was dissolved
br, Hyd H-1). 13C-NMR (DMSO-d6) δ: 23.0 (Me), 23.2 (Pyr in 10% MeOH–AcOEt and the resulting mixture was again
C-3, C-4), 45.2 (Pyr C-2, C-5), 55.3 (OMe), 74.9 (Hyd C-5), concentrated in vacuo. The residue was purified by centrifugal
114.0 (Ar C-3, C-5), 124.4 (Ar C-1), 128.1 (C-2, C-6), 154.6 chromatography (silica gel) with an n-hexane–AcOEt gradi-
(Hyd C-2), 158.6 (Ar C-4), 173.2 (Hyd C-4). Anal. Calcd for ent (30→0% n-hexane) as a solvent to give an adhesiveness
C15H19N3O3·0.5H2O: C, 60.39; H, 6.76; N, 14.08. Found: C, product (0.98g, 90%) as a mixture of stereoisomers. IR (KBr)
60.29; H, 6.54; N, 14.13.
cm−1: 3424, 1719. FAB-MS (positive) m/z: 338 (M+H)+.
1-(1-Oxo-1,3-di(pyrrolidin-1-yl)propan-2-yl)-3-phenylurea 1H-NMR (DMSO-d6) δ: 2.07 (3H×0.6, s, Me), 2.18 (3H×0.4,
(16): A mixture of a 5-methylene-hydantoin (4a) (0.10g, s, Me), 3.60–3.78 (2H, m, Hyd-CH2-N=), 4.51–4.74 (3H, m,
0.53mmol) and pyrrolidine (0.19g, 2.68mmol) was allowed CH2-Ph+Hyd H-5), 7.22–7.49 (10H, m, Ar H), 8.51 (1H×0.6,
to stand for 2h at room temperature. The resulting solid brs, Hyd H-1), 8.70 (1H×0.4, brs, Hyd H-1). 13C-NMR
material was filtered, washed with Et2O, and dried to give (DMSO-d6) δ: 21.5, 21.6 (Me), 47.2, 52.5 (CH2-Ph), 47.2, 48.4
16 as a white solid (0.10g, 57%): mp 193°C. IR (KBr) cm−1: (Hyd-CH2-N=), 54.6, 55.4 (Hyd C-5), 126.3 (×3), 126.5 (×2),
1698, 1615. FAB-MS (positive) m/z: 331 (M+H)+. H-NMR 126.6 (×3), 127.1, 127.3 (×2), 128.3 (×2), 128.5 (×3), 128.6
1
(DMSO-d6) δ: 1.65–1.68 (4H, m, Pyr H-3, H-4 in CH2-Pyr), (×2), 128.7 (×2), 131.9, 132.1 (Ar C-1 in =N-Ph), 137.4, 137.5
1.77–1.80, 1.87–1.93 (each 2H, m, Pyr H-3, H-4 in CO-Pyr), (Ar C-1, in CH2-Ph), 155.58, 155.63 (Hyd C-2), 171.57, 171.64
2.48–2.52 (4H, m, Pyr H-2, H-5 in CH2-Pyr), 2.61–2.63 (2H, (Hyd C-4). Anal. Calcd for C19H19N3O3·0.3H2O: C, 66.57; H,
m, CH2-Pyr), 3.23–3.36 (2H, m, Pyr H-2, H-5 in CO-Pyr), 5.76; N, 12.26. Found: C, 66.59; H, 5.80; N, 12.05.
3.48–3.53, 3.62–3.66 (each 1H, m, Pyr H-2, H-5 in CO-
Preparation of Twin-Drug Type Molecules (19–24)
Pyr), 4.54–4.59 (1H, m, CHCH2Pyr), 6.38 (1H, d, J=8.0Hz, 3,3′-(Butane-1,4-diyl)bis(5-(pyrrolidin-1-ylmethyl)-
PhNHCONHCH), 6.88 (1H, t, J=7.5Hz, Ar H-4), 7.18–7.22 imidazolidine-2,4-dione) Dihydrochloride (19a): A solution
(2H, m, Ar H-3, H-5), 7.35 (2H, d, J=7.5Hz, Ar H-2, H-6), of 1,4-diisocyanatobutane (0.25g, 1.79mmol) in CH2Cl2 was

436
Vol. 62, No. 5
added to a solution of β-aminoalanine methyl ester dihydro- IR (KBr) cm−1: 1782, 1709. FAB-MS (positive) m/z: 477 (M+
1
chloride 1a (1.00g, 4.08mmol) and TEA (0.41g, 4.06mmol) H)+. H-NMR (DMSO-d6) δ: 1.23–1.26 (4H, m, hexane H-3,
in CH2Cl2 (20mL). The mixture was stirred for 3h at rt and H-4), 1.38–1.40 (2H, m, Pip HA-4), 1.49–1.51 (4H, m, hexane
concentrated in vacuo. Concentrated HCl (7mL) was added to H-2, H-5), 1.7–1.72 (2H, m, Pip HB-4), 1.80–1.90 (8H, m,
the residue and the mixture was allowed to stand for 6d at rt. Pip H-3, H-5), 2.93–3.01 (4H, m, Pip HA-2, HA-6), 3.33–3.62
After removal of the solvent under reduced pressure, the resi- (12H, m, Pip HB-2, HB-6+ CH2-Pip+hexane H-1, H-6), 4.78
due was washed with EtOH and collected by filtration to give (2H, d, J=9.0Hz, Hyd H-5), 8.53 (2H, brs, Hyd H-1), 10.73
19a (0.59g, 67%). An analytical sample was obtained by wash- (2H, brs, NH+). 13C-NMR (DMSO-d6) δ: 20.9 (Pip C-4), 21.9
ing with MeOH–EtOH as a white solid; mp >260°C (dec). IR (Pip C-3 or C-5), 22.0 (Pip C-5 or C-3), 25.3 (hexane C-3,
(KBr) cm−1: 1769, 1716. FAB-MS (positive) m/z: 421 (M+ C-4), 27.0 (hexane C-2, C-5), 37.8 (hexane C-1, C-6), 51.7
1
H)+. H-NMR (DMSO-d6) δ: 1.51 (4H, s, butane H-2, H-3), (Pip C-2 or C-6), 51.9 (Hyd C-5), 53.4 (Pip C-6 or C-2), 57.9
1.90–2.01 (8H, m, Pyr H-3, H-4), 3.06–3.09 (8H, m, Pyr H-2, (CH2-Pip), 156.0 (Hyd C-2), 170.9 (Hyd C-4). Anal. Calcd for
H-5), 3.42–3.54 (4H, m, CH2-Pyr), 3.64 (4H, br, butane H-1, C24H42Cl2N6O4·1.0H2O: C, 50.79; H, 7.81; N, 14.81. Found: C,
H-4), 4.62–4.63 (2H, m, Hyd H-5), 8.37 (2H, brs, Hyd H-1), 50.49; H, 7.69; N, 14.74.
10.73 (2H, br, NH+).13C-NMR (DMSO-d6) δ: 22.5 (Pyr C-3,
3,3′-(Octane-1,8-diyl)bis(5-(pyrrolidin-1-ylmethyl)-
C-4), 24.3 (btane C-2, C-3), 37.4 (butane C-1, C-4), 52.9, 54.0 imidazolidine-2,4-dione) Dihydrochloride (21a): This com-
(Pyr C-2, C-5), 53.5 (Hyd C-5), 55.0 (CH2-Pyr), 156.3 (Hyd pound was obtained from the reaction of 1a and 1,8-diiso-
C-2), 170.9 (Hyd C-4). Anal. Calcd for C20H34Cl2N6O4·1.0H2O: cyanatooctane by a method similar to that for 19a as a white
C, 46.97; H, 7.09; N, 16.43. Found: C, 46.99; H, 6.82; N, 16.58. solid. An analytical sample was obtained by recrystallization
3,3′-(Butane-1,4-diyl)bis(5-(piperidin-1-ylmethyl)- from MeCN–MeOH; a white solid; mp 177–182°C (with dec).
imidazolidine-2,4-dione) Dihydrochloride (19b): This com- IR (KBr) cm−1: 1766, 1706. FAB-MS (positive) m/z: 477 (M+
1
pound was obtained from the reaction of 1b and 1,4-diiso- H)+. H-NMR (DMSO-d6) δ: 1.24 (8H, brs, octane H-3–H-6),
cyanatobutane by a method similar to that for 19a as a white 1.50 (4H, ddd, J=14.0, 7.0, 7.0Hz, octane H-2, H-7), 1.88–1.91
solid. An analytical sample was obtained by washing with (4H, m, Pyr HA-3, HA-4), 2.02–2.04 (4H, m, Pyr HB-3, HB-4),
EtOH; mp >200°C (dec). IR (KBr) cm−1: 1770, 1718. FAB- 2.93–3.07 (4H, m, Pyr HA-2, HA-5), 3.34 (4H, t, J=7.0Hz,
1
MS (positive) m/z: 449 (M+H)+. H-NMR (DMSO-d6+D2O) octane H-1, H-8), 3.37–3.66 (8H, Pyr HB-2, HB-5+CH2-Pyr),
δ: 1.4–1.9 (12H, m, Pip H-3, H-4, H-5), 1.51 (4H, s, butane 4.66–4.68 (2H, m, Hyd H-5), 8.45 (2H, br, Hyd H-1), 11.07
H-2, H-3), 2.9–3.5 (8H, m, Pip H-2, H-6), 3.30–3.35 (2H, m, (2H, brs, NH+). 13C-NMR (DMSO-d6) δ: 22.4 (Pyr C-3 or
CHH-Pip), 3.41 (4H, brs, butane H-1, H-4), 3.43–3.47 (2H, m, C-4), 22.6 (Pyr C-4 or C-3), 25.8 (octane C-3, C-6), 27.2 (oc-
CHH-Pip), 4.64 (2H, dd, J=8.0, 3.5Hz, Hyd H-5). 13C-NMR tane C-2, C-7), 28.2 (octane C-4, C-5), 38.0 (octane C-1, C-8),
(DMSO-d6+D2O) δ: 21.5 (Pip C-4), 23.2 (Pip C-3, C-5), 25.2 53.1 (Pyr C-2 or C-5), 53.5 (Hyd C-5), 53.9 (Pyr C-5 or C-2),
(butane C-2, C-3), 38.6 (butane C-1, C-4), 52.9, (Hyd C-5), 55.2 (CH2-Pyr), 156.2 (Hyd C-2), 170.8 (Hyd C-4). Anal. Calcd
54.1 (CH2-Pyr), 57.9 (Pip C-2, C-6), 158.0 (Hyd C-2), 172.4 for C24H42Cl2N6O4·0.8H2O: C, 51.11; H, 7.79; N, 14.90. Found:
(Hyd C-4). Anal. Calcd for C22H38Cl2N6O4·0.8H2O: C, 49.31; C, 51.15; H, 7.66; N, 15.00.
H, 7.45; N, 15.68. Found: C, 49.39; H, 7.38; N, 15.80.
3,3′-(Octane-1,8-diyl)bis(5-(piperidin-1-ylmethyl)-
3,3′-(Hexane-1,6-diyl)bis(5-(pyrrolidin-1-ylmethyl)- imidazolidine-2,4-dione) Dihydrochloride (21b): This com-
imidazolidine-2,4-dione) Dihydrochloride (20a): This com- pound was obtained from the reaction of 1b and 1,8-diiso-
pound was obtained from the reaction of 1a and 1,6-diiso- cyanatooctane by a method similar to that for 19a as a white
cyanatohexane by a method similar to that for 19a as a white solid. An analytical sample was obtained by washing with
solid. An analytical sample was obtained by recrystallization EtOH; a white solid; mp 188–195°C (with dec). IR (KBr) cm−1:
1
from MeCN–H2O (20:1); a white solid; mp >240°C (dec). 1786, 1712. FAB-MS (positive) m/z: 505 (M+H)+. H-NMR
IR (KBr) cm−1: 1782, 1709. FAB-MS (positive) m/z: 449 (M+ (DMSO-d6) δ: 1.17–1.24 (8H, m, octane H-3–H-6), 1.33–1.41
1
H)+. H-NMR (DMSO-d6) δ: 1.24–1.25 (4H, m, hexane H-3, (2H, m, Pip HA-4), 1.49 (4H, ddd, J=14.0, 7.0, 7.0Hz, oc-
H-4), 1.49 (4H, t, J=6.5Hz, hexane H-2, H-5), 1.89–1.90 (4H, tane H-2, H-7), 1.70 (2H, d, J=13.5Hz, Pip HB-4), 1.78–1.87
m, Pyr HA-3, HA-4), 2.03 (4H, brs, Pyr HB-3, HB-4), 3.04–3.06 (8H, m, Pip H-3, H-5), 2.90–3.09 (4H, m, Pip HA-2, HA-6),
(4H, m, Pyr HA-2, HA-5), 3.33–3.35 (4H, m, hexane H-1, H-6), 3.30–3.38 (6H, m, octane H-1, H-8+CHH-Pip), 3.40–3.43 (4H,
3.43–3.48 (2H, m, CHH-Pyr), 3.54–3.66 (6H, m, Pyr HB-2, m, CHH-Pip+Pip HB-2 or HB-6), 3.61 (2H, d J=11.5Hz, Pip
HB-5+ CHH-Pyr), 4.66 (2H, dd, J=6.5, 1.5Hz, Hyd H-5), 8.45 HB-6 or HB-2), 4.78 (2H, d, J=9.5Hz, Hyd H-5), 8.57 (2H,
(2H, s, Hyd H-1), 11.01 (2H, br NH+). 13C-NMR (DMSO-d6) brs, Hyd H-1), 10.73 (2H, brs, NH+).13C-NMR (DMSO-d6) δ:
δ: 22.4 (Pyr C-3 or C-4), 22.6 (Pyr C-4 or C-3), 25.4 (hexane 21.0 (Pip C-4), 22.0 (Pip C-3 or C-5), 22.2 (Pip C-5 or C-3),
C-3, C-4), 27.1 (hexane C-2, C-5), 37.9 (hexane C-1, C-6), 53.2 25.8 (octane C-3, C-6), 27.2 (octane C-2, C-7), 28.2 (octane
(Pyr C-2 or C-5), 53.5 (Hyd C-5), 53.9 (Pyr C-5 or C-2), 55.2 C-4, C-5), 38.0 (octane C-1, C-8), 51.7 (Pip C-2 or C-6), 52.0,
(CH2-Pyr), 156.3 (Hyd C-2), 170.9 (Hyd C-4). Anal. Calcd for (Hyd C-5), 53.4 (Pip C-6 or C-2), 58.0 (CH2-Pip), 156.1 (Hyd
C22H38Cl2N6O4·0.5H2O: C, 49.81; H, 7.41; N, 15.84. Found: C, C-2), 171.0 (Hyd C-4). Anal. Calcd for C26H46Cl2N6O4·1.0H2O:
49.99; H, 7.34; N, 16.00.
C, 52.43; H, 8.12; N, 14.11. Found: C, 52.38; H, 7.96; N, 14.13.
3,3′-(Hexane-1,6-diyl)bis(5-(piperidin-1-ylmethyl)-
3,3′-(Dodecane-1,12-diyl)bis(5-(pyrrolidin-1-ylmethyl)-
imidazolidine-2,4-dione) Dihydrochloride (20b): This com- imidazolidine-2,4-dione) Dihydrochloride (22a): This com-
pound was obtained from the reaction of 1b and 1,6-diiso- pound was obtained from the reaction of 1a and 1,12-diisocya-
cyanatohexane by a method similar to that for 19a as a white natododecane by a method similar to that for 19a as a white
solid. An analytical sample was obtained by recrystallization solid. An analytical sample was obtained by recrystallization
from EtOH–MeOH (1:1); a white solid; mp >210°C (dec). from EtOH; a white solid; mp >200°C (dec). IR (KBr) cm−1:

May 2014
437
1767, 1707. FAB-MS (positive) m/z: 533 (M+H)+. 1H-NMR s, Hyd H-1), 11.13 (2H, brs, NH+). 13C-NMR (DMSO-d6) δ:
(DMSO-d6) δ: 1.20–1.23 (16H, brs, dodecane H-3–H-10), 22.4 (Pyr C-3 or C-4), 22.7 (Pyr C-4 or C-3), 40.1 (Ph-CH2-
1.46–1.52 (4H, m, dodecane H-2, H-11), 1.87–2.02 (8H, m, Ph), 53.3 (Pyr C-2 or C-5), 53.7 (Hyd C-5), 54.0 (Pyr C-5 or
Pyr H-3, H-4), 3.04 (4H, brs, Pyr HA-2, HA-5), 3.25–3.36 C-2), 55.1 (CH2-Pyr), 126.7 (Ar C-2, C-2′, C-6, C-6′), 128.9
(4H, m, dodecane H-1, H-12), 3.42–3.46 (4H, m, CH2-Pyr), (Ar C-3, C-3′, C-5, C-5′), 129.8 (Ar C-, C-1′), 140.8 (Ar C-4,
3.51–3.65 (4H, m, Pyr HB-2, HB-5), 4.66 (2H, d, J=9.0Hz, Hyd C-4′), 155.2 (Hyd C-2), 170.0 (Hyd C-4). Anal. Calcd for
H-5), 8.44 (2H, s, Hyd H-1), 11.0 (2H, brs, NH+). 13C-NMR C29H36Cl2N6O4·0.3H2O: C, 57.20; H, 6.06; N, 13.80. Found: C,
(DMSO-d6) δ: 22.4 (Pyr C-3 or C-4), 22.6 (Pyr C-4 or C-3), 57.19; H, 6.12; N, 13.81.
25.9 (dodecane C-3, C-10), 27.2 (dodecane C-2, C-11), 28.4,
28.7, 28.8 (dodecane C-4–C-9), 38.0 (dodecane C-1, C-12),
53.1 (Pyr C-2 or C-5), 53.5 (Hyd C-5), 53.9 (Pyr C-5 or C-2),
55.2 (CH2-Pyr), 156.2 (Hyd C-2), 170.8 (Hyd C-4). Anal. Calcd
for C28H50Cl2N6O4·0.3H2O: C, 55.04; H, 8.35; N, 13.75. Found:
C, 55.03; H, 8.35; N, 13.80.
References and Notes
1) Brickner S. J., Barbachyn M. R., Hutchinson D. K., Manninen P. R.,
J. Med. Chem., 51, 1981–1990 (2008) and related references cited
therein.
2) Lawrence L., Danese P., DeVito J., Franceschi F., Sutcliffe J., Anti-
microb. Agents Chemother., 52, 1653–1662 (2008) and related refer-
ences cited therein.
3) Locke J. B., Finn J., Hilgers M., Morales G., Rahawi S., Kedar G.
C., Picazo J. J., Im W., Shaw K. J., Stein J. L., Antimicrob. Agents
Chemother., 54, 5337–5343 (2010) and related references cited
therein.
4) Gibson S. E., Castaldi M. P., Angew. Chem. Int. Ed., 45, 4718–4720
(2006).
5) Trouche N., Wieckowski S., Sun W., Chaloin O., Hoebeke J., Four-
nel S., Guichard G., J. Am. Chem. Soc., 129, 13480–13492 (2007).
6) Balzarini J., Antiviral Res., 71, 237–247 (2006) and related refer-
ences cited therein.
7) Camille G. W., “The Practice of Medicinal Chemistry,” 3nd ed., Ac-
ademic Press, San Diego, 2008 and related references cited therein.
8) Humblet V., Misra P., Bhushan K. R., Nasr K., Ko Y., Tsukamoto T.,
Pannier N., Frangioni J. V., Maison W., J. Med. Chem., 52, 544–550
(2009).
9) Oshovsky G. V., Reinhoudt D. N., Verboom W., Angew. Chem. Int.
Ed., 46, 2366–2393 (2007).
10) Fujisaki F., Usami H., Nakashima S., Iwashita S., Kurose Y.,
Kashige N., Miake F., Sumoto K., HETEROCYCLES, 83, 1843–1851
(2011).
11) Fujisaki F., Usami H., Nakashima S., Nishida S., Fujioka T.,
Kashige N., Miake F., Sumoto K., HETEROCYCLES, 87, 665–675
(2013).
12) Fujisaki F., Hiromatsu S., Matsumura Y., Fukami A., Kashige N.,
Miake F., Sumoto K., J. Heterocyclic Chem., 50, 417–424 (2013).
13) Mibu N., Yokomizo K., Saisho M., Oishi M., Aki H., Miyata T.,
Sumoto K., HETEROCYCLES, 83, 385–393 (2011).
14) Mibu N., Yokomizo K., Oishi M., Miyata T., Sumoto K., Chem.
Pharm. Bull., 56, 1052–1058 (2008).
15) Mibu N., Yokomizo K., Miyata T., Sumoto K., Chem. Pharm. Bull.,
55, 1406–1411 (2007).
16) Fujisaki F., Shoji K., Sumoto K., HETEROCYCLES, 78, 213–220
(2009).
17) Fujisaki F., Shoji K., Sumoto K., Chem. Pharm. Bull., 57, 1415–1420
(2009).
18) Fujisaki F., Shoji K., Shimodouzono M., Kashige N., Miake F., Su-
moto K., Chem. Pharm. Bull., 58, 1123–1126 (2010).
19) Fujisaki F., Egami M., Toyofuku K., Sumoto K., HETEROCYCLES,
87, 133–145 (2013).
20) Fujisaki F., Toyofuku K., Egami M., Ishida S., Nakamoto N.,
Kashige N., Miake F., Sumoto K., Chem. Pharm. Bull., 61, 1090–
1093 (2013).
21) In our previous paper (refs. 19, 20), we showed the preparation of
this symmetrical bivalent compound 24b and its antibacterial activ-
ity (MIC) values against S. aureus and E. coli strains (MIC=0.024
and 0.095mM, respectively).
3,3′-(Dodecane-1,12-diyl)bis(5-(piperidin-1-ylmethyl)-
imidazolidine-2,4-dione) Dihydrochloride (22b): This com-
pound was obtained from the reaction of 1b and 1,12-diisocy-
anatododecane by a method similar to that for 19a as a white
solid. An analytical sample was obtained by recrystallization
from EtOH; a white solid; mp 160–163°C. IR (KBr) cm−1:
1
1780, 1709. FAB-MS (positive) m/z: 561 (M+H)+. H-NMR
(DMSO-d6) δ: 1.23 (16H, brs, dodecane H-3–H-10), 1.36–1.38
(2H, m, Pip HA-4), 1.49 (4H, t, J=7.0Hz, dodecane H-2, H-11),
1.62–1.72 (2H, m, Pip HB-4), 1.80–1.87 (8H, m, Pip H-3,
H-5), 2.91–3.01 (4H, m, Pip HA-2, HA-6), 3.31–3.38 (8H, m,
dodecane H-1, H-12+CH2-Pyr), 3.40–3.43 (2H, m, Pip HB-2
or HB-6), 3.61–3.63 (2H, m, Pip HB-6 or HB-2), 4.79 (2H, d,
J=9.5Hz, Hyd H-5), 8.56 (2H, s, Hyd H-1), 10.73 (2H, brs,
NH+). 13C-NMR (DMSO-d6) δ: 21.1 (Pip C-4), 22.0 (Pip C-3
or C-5), 22.2 (Pip C-5 or C-3), 25.9 (dodecane C-3, C-10), 27.2
(dodecane C-2, C-11), 28.4, 28.7, 28.8 (dodecane C-4–C-9),
38.0 (dodecane C-1, C-12), 51.7 (Pip C-2 or C-6), 52.0 (Hyd
C-5), 53.4 (Pip C-6 or C-2), 58.0 (CH2-Pyr), 156.1 (Hyd C-2),
171.0 (Hyd C-4). Anal. Calcd for C30H54Cl2N6O4·0.7H2O: C,
55.75; H, 8.64; N, 13.00. Found: C, 55.76; H, 8.52; N, 13.03.
3,3′-(1,4-Phenylene)bis(5-(piperidin-1-ylmethyl)-
imidazolidine-2,4-dione) Dihydrochloride (23b): This com-
pound was obtained from the reaction of 1b and 1,4-phen-
ylene diisocyanate by a method similar to that for 19a as a
white solid. An analytical sample was obtained by washing
with EtOH; a white solid; mp >200°C (dec). IR (KBr) cm−1:
1
1783, 1722. FAB-MS (positive) m/z: 469 (M+H)+. H-NMR
(DMSO-d6+D2O) δ: 1.50–1.73 (12H, m, Pip H-3, H-4, H-5),
2.99–3.13 (8H, m, Pip H-2, H-6), 3.41–3.53 (4H, m, CH2-Pip),
4.74–4.76 (2H, m, Hyd H-5), 7.46 (4H, s, Ar H). 13C-NMR
(DMSO-d6+D2O) δ: 21.4 (Pip C-4), 23.2 (Pip C-3, C-5), 49.2
(Pip C-2, C-6), 53.1, (Hyd C-5), 57.9 (CH2-Pip), 128.0 (Ar C-2,
C-3, C-5, C-6), 131.9 (Ar C-1, C-4), 156.4 (Hyd C-2), 171.1
(Hyd C-4). Anal. Calcd for C24H32Cl2N6O4·0.5H2O: C, 52.36;
H, 6.41; N, 15.27. Found: C, 52.32; H, 6.18; N, 15.45.
3,3′-(4,4′-Methylenebis(4,1-phenylene))bis(5-(pyrrolidin-1-
ylmethyl)imidazolidine-2,4-dione) Dihydrochloride (24a): This
compound was obtained from the reaction of 1a and 4,4′-di-
phenylmethane diisocyanate by a method similar to that for
19a as a white solid. An analytical sample was obtained by
recrystallization from MeCN; a white solid; mp >245°C
(dec). IR (KBr) cm−1: 1776, 1715. FAB-MS (positive) m/z:
1
531 (M+H)+. H-NMR (DMSO-d6) δ: 1.92–2.06 (8H, m, Pyr
22) Krishnamurthy V. M., Estroff L. A., Whitesides G. M., “Methods
and Principles in Medicinal Chemistry: Fragment-based Approach-
es in Drug Discovery,” Vol. 34, ed. by Mannhold R., Kubinyi H.,
H-3, H-4), 3.08 (4H, brs, Pyr HA-2, HA-5), 3.63–3.69 (8H, m,
CH2-Pyr+Pyr HB-2, HB-5), 4.04 (2H, s, Ph-CH2-Ph), 4.81 (2H,
t, J=5.5Hz, Hyd H-5), 7.29–7.36 (8H, m, Ar H), 8.70 (2H,

438
Vol. 62, No. 5
Folkers G., WILEY-VCH Verlag GmbH & Co., KGaA, Weinheim,
2006, pp. 11–53 and related references cited therein.
Zhou J., Miyata T., Sumoto K., J. Therm. Anal. Calorim., 113,
1015–1018 (2013).
23) From a stereochemical viewpoint, these products 19–24 can be con- 26) Mibu N., Yokomizo K., Kashige N., Miake F., Miyata T., Uyeda M.,
sidered to be a mixture of three twin-drug type molecules, i.e., two
C2-symmetrical molecules that have the same absolute configuration
(R,R or S,S) regarding two chiral hydantoin rings in the molecules
and a Cs-symmetrical meso compound having different absolute
configurations (R,S). We distinguished the presence of three pre-
dominant stereoisomers in the free base of product 24b by an HPLC
method (CHIRALPAK IA®).20) We used stereoisomeric mixtures
for calorimetric experiments and for the biological evaluation (anti-
bacterial activity).
Sumoto K., Chem. Pharm. Bull., 55, 111–114 (2007).
27) Regarding small molecule antagonists of glycosaminoglycan sul-
fates, it has been demonstrated that the identification of small
molecule antagonists against such glycosaminoglycans may lead to
the development of new pharmacological agents to treat infectious
diseases that involve a glycosaminoglycan sulfate binding stage
(for example, see following reference). Schuksz M., Fuster M. M.,
Brown J. R., Crawford B. E., Ditto D. P., Lawrence R., Glass C.
A., Wang L., Tor Y., Esko J. D., Proc. Natl. Acad. Sci. U.S.A., 105,
13075–13080 (2008).
24) Varki A., Cummings R. D., Esko J. D., Freeze H. H., Stanley P.,
Bertozzi C. R., Hart G. W., Etzler M. E., “Essentials of Glycobiol- 28) The Japanese Society of Chemotherapy, Chemotherapy, 38, 102–105
ogy,” 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring
Harbor, N. Y., 2009, p. 719.
(1990).
29) The Japanese Society of Chemotherapy, Chemotherapy, 41, 184–189
25) Mibu N., Aki H., Ikeda H., Saito A., Uchida W., Yokomizo K.,
(1993).