Synthesis of 1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents: Cyclopropane-based conformationally restricted analogs of haloperidol

Article abstract of DOI:10.1016/j.bmc.2008.08.061

A series of the cyclopropane-based conformationally restricted analogs of haloperidol were designed as potential antidopaminergic agents and were effectively synthesized using highly stereoselective Grignard reaction with tert-butanesulfinyl imines as the key step. Pharmacological evaluation of the compounds showed that the conformational restriction method can effectively work for improving the pharmacological selectivity of a parent compound and also for investigating the bioactive conformation.

Full text of DOI:10.1016/j.bmc.2008.08.061

Bioorganic & Medicinal Chemistry 16 (2008) 8875–8881
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of 1-arylpiperazyl-2-phenylcyclopropanes designed
as antidopaminergic agents: Cyclopropane-based conformationally
restricted analogs of haloperidol
Kazuya Yamaguchi a, Yuji Kazuta a, Kazufumi Hirano b, Shizuo Yamada b, Akira Matsuda a, Satoshi Shuto a,
*
a Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
b Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of the cyclopropane-based conformationally restricted analogs of haloperidol were designed as
potential antidopaminergic agents and were effectively synthesized using highly stereoselective Grignard
reaction with tert-butanesulfinyl imines as the key step. Pharmacological evaluation of the compounds
showed that the conformational restriction method can effectively work for improving the pharmacolog-
ical selectivity of a parent compound and also for investigating the bioactive conformation.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 July 2008
Revised 25 August 2008
Accepted 26 August 2008
Available online 29 August 2008
Keywords:
Dopamine receptor
Conformational restriction
Cyclopropane
1. Introduction
Adjacent cis-oriented substituents on a cyclopropane ring exert
significant mutual steric repulsion, because they are fixed in the
Conformational restriction of a biologically active compound
with conformational flexibility often results in improving the po-
tency, and, consequently, intensive effort has been made on
designing and synthesizing the conformationally restricted analogs
of biologically active compounds.1 In conformationally restricted
analogs, the spatial orientation of the functional groups, that are
essential for the compound–target biomolecule interaction, should
correspond to that in the bioactive conformation of the parent
compound.2 By such effective conformational restriction, binding
affinity can be enhanced as a result of reducing the entropic loss
upon binding to the target molecule.
eclipsed orientation, which is ‘cyclopropylic strain’.2 Consequently,
conformation of the substituents on a cyclopropane ring can be re-
stricted to the conformation B by steric effect of the adjacent sub-
stituent, especially when it is bulky, as indicated in Figure 1a.
This method has been successfully applied to the design of the
conformationally restriction analogs of milnacipran, which is a
clinically effective antidepressant due to competitive inhibition
of the re-uptake of serotonin (5-HT) and noradrenaline in the
CNS, is also recognized as a weak noncompetitive NMDA receptor
antagonist. As a result, a new class of NMDA receptor antagonist
In design of conformationally restricted analogs, it should be
considered that the analogs are as similar as possible to the parent
compound in size, shape, and molecular weight.1a Because of its
characteristic small and rigid carbocyclic structural feature, a
cyclopropane ring is effective in restricting the conformation of a
molecule without significantly changing the chemical and physical
properties of the parent compounds.2,3 Thus, cyclopropanes have
already been successfully used to restrict the bioactive conforma-
tions of a variety of pharmacologically active compounds.4–6
We devised a new method for restricting the conformation of
cyclopropane derivatives based on the ‘cyclopropylic strain’.2,6c,6d
a
S
L
M
M
R
S
R
L
R
L
M
S
A
B
C
bulkiness: L > M > S
b
Ph
Ph
Ph
H
Et
NH2
H N
R
R
H
2
Et
R
Et
NH2
H
A
B
C
(endo)
(anti)
(syn)
R = CONEt2
* Corresponding author. Tel./fax: +81 11 706 3769.
E-mail address: shu@pharm.hokudai.ac.jp (S. Shuto).
Figure 1. Conformational restriction due to the ‘cyclopropylic strain’.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.08.061

8876
K. Yamaguchi et al. / Bioorg. Med. Chem. 16 (2008) 8875–8881
Ph
1
Ph
Ph
Ph
Ph
2
H
H
X
X
H
Et
1'
NH2
NH2
O
O
H
Me
H
X
Me
Me
H
H
X
X
H
H
Et2N
H
Et2N
4 (anti)
4 (syn)
4 (endo)
PPDC (1S,2R,1'S)
milnacipran (racemic)
Ph
Ph
Me
5 (syn)
Figure 2. Milnacipran and its ‘cyclopropylic strain’-based conformationally
Me
H
Me
restricted analog PPDC.
Me
Me
N
X =
5 (anti)
N
Me
PPDC (Fig. 2), which strongly antagonizes NMDA receptor without
affecting the 5-HT and noradrenaline re-uptake.6d The conforma-
tion of PPDC was investigated in detail by X-ray crystallographic,
1H NMR, and computational calculation analyses to show that
the aminomethyl moiety, which is essential for the biological activ-
ity,7 actually restricted to the conformation as B (anti) in Figure 1b
due to the ‘cyclopropylic strain’.6a,6j
Ph
Me
6 (anti)
Ph
Me Me
Me
X
H
X
H
6 (syn)
Figure 4. The ‘cyclopropylic-strain’-based conformational restriction of 4, 5, and 6.
With these encouraging results in mind, we applied the above
descried method for designing conformationally restricted analogs
of the well-known antipsychotic drug haloperidol (1, Fig. 3).
are conformationally restricted differently from that in the corre-
sponding trans-congener 2b.
We designed conformationally restricted analogs 4, 5, and 6,
based on the ‘cyclopropylic strain’. In analog 4, a methyl group
was introduced at the position cis to the piperazylmehyl moiety
on the cyclopropane ring of 2b. Accordingly, the positioning of
the arylpiperazyl moiety would be restricted due to steric repul-
sion for the methyl group; as shown in Figure 4, the syn and
anti-forms would be more stable than the endo-form in 4. In ana-
logs 5 and 6, the methyl group additionally introduced at the inter-
jacent carbon between the cyclopropane and piperazine rings
would further restrict the three-dimensional positioning of aro-
matic and arylpiperazine rings differently depending on the config-
uration of the piperazylmethyl moiety, as shown in Figure 4. Thus,
analogs 5 and 6 would prefer the anti-form and the syn-form,
respectively.
We expected that some of these analogs might be selectively
bind to the D2 receptor or the D4 receptor, and therefore, pharma-
cological evaluation of these analogs might clarify the bioactive
conformation of haloperidol for these receptors. In addition, li-
gands highly selective to the D2 or D4 receptor may be useful as
a drug lead and/or a pharmacological tool.
1.1. Design of the conformationally restricted analogs
Haloperidol (1) is a clinically effective antipsychotic drug, and
its pharmacological effect is considered to be mainly due to the
antagonism of dopaminergic receptors.8 A drawback of haloperidol
in clinical therapy is the side effects derived from its affinity for
other receptors, such as adrenergic receptors.8,9 Recently, Thurkauf
and co-workers designed and synthesized arylpiperazine deriva-
tives 2a and 2b, having a trans-cyclopropane structure, and identi-
fied them as dopamine receptor antagonists with reduced
adrenergic a1 receptor affinity.9 These compounds can be consid-
ered conformationally restricted analogs of haloperidol, in which
the three-dimensional positioning of the aromatic ring and the
arylpiperazine moiety is restricted by the trans-cyclopropane
structure. These results suggest that binding of haloperidol to the
receptors other than the desired dopaminergic receptors may be
attributed to its conformationally flexible structure, at least to
some extent. The 2,4-disubstituent phenylpirerazine structure
may also be important for the dopaminergic selective activity of
the compounds. Thus, we planned to apply the ‘cyclopropylic
strain’-based conformational restriction method described above
to the Thurkauf’s compound 2b.
1.2. Synthesis
Considerable effort has been devoted to developing efficient
methods for preparing cyclopropane derivatives.3–6,10,11 In recent
years, we have developed methods for synthesizing a variety of
We also were interested in the pharmacological effect of the cis-
cyclopropane stereoisomer 3 of 2b and its enantiomer ent-3
(Fig. 3), in which the aromatic ring and the arylpiperazyl moiety
O
Me
R
N
Cl
1
N
N
Me
2
OH
N
N
R
F
3 (1S,2R)
haloperidol (1)
2a (1S,2S): R = Cl
2b (1S,2S): R = Me
Me
N
1'
Me
Me
H
Me
Me
N
1'
N
N
Me
N
N
Me
Me
N
N
Me
Me
H
Me
Me
Me
ent-3 (1R,2S)
4 (1S,2S)
5 (1S,2S, 1'R)
6 (1S,2S, 1'S)
Figure 3. Haloperidol (1) and its conformationally restricted analogs.

K. Yamaguchi et al. / Bioorg. Med. Chem. 16 (2008) 8875–8881
8877
chiral cyclopropane derivatives from easily available chiral (R)- and
(S)-epichlorohydrins,5,6,11,12 which were also applied to the synthe-
sis of the target compounds in this study (Scheme 1).
The cis-cyclopropane compound 3 was synthesized from Wein-
reb amide 9, which was prepared from (S)-epichlorohydrin [(S)-7]
via lactone 8, by the procedure reported previously.12 The corre-
sponding enantiomer ent-3 was synthesized similarly starting
from (R)-epichlorohydrin.
The methylcyclopropane-type target compound 4 was also syn-
thesized from the Weinreb amide 9. The amide 9 was treated with
DIBAL-H in CH2Cl2 and then with NaBH4 in THF/MeOH to give alco-
hol product 10, which was converted into the corresponding bro-
t-BuSONH2, are used as the substrates, the stereochemical outcome
of the Grignard reaction can be dependent on the stereochemistry at
the sulfinyl moiety. Recently, we have successfully developed a gen-
eral synthetic procedure for systematically providing chiral 2,3- and
3,4-methanoamino acids with stereochemical diversity using the
tert-butanesulfinyl imine method as the key step.14 Thus, we ex-
pected that both of the targets 5 and 6 would be provided via the
Grignard reaction of the (R)- and (S)-tert-butanesulfinyl imines de-
rived from the cyclopropanecarbaldeyde 13.
Treatment of 13 with (R)- or (S)-t-BuSONH2 formed the corre-
sponding (E)-sulfinyl imine 16 or 19, respectively. When (R)-sulfi-
nyl imine 16 was treated with MeMgBr in CH2Cl2 at room
temperature, it stereoselectively gave the 10S-product 17
(10R:10S = 1:12). The mixture was easily separated by silica gel col-
umn chromatography and the diastereomerically pure 17 was ob-
tained in 93% yield. The 10R-product 20 was exclusively obtained in
quantitative yield, when the (S)-sulfinyl imine 19 was treated with
MeMgBr in CH2Cl2 at room temperature. Thus, both of the 10-dia-
stereomers 17 and 20 were successfully obtained (Scheme 2).
The sulfinyl group of 17 or 20 was removed by acidic hydrolysis
with HCl in aqueous dioxane to give amine 18 or 21, respectively.
The 10-stereochemistry was confirmed based on the modified
Mosher’s method by the conversion of 21 into the corresponding
mide 11 with
a CBr4/Ph3P/CH2Cl2 system. After reductive
debromination of the 11 by treating it with LiAlH4 in THF, the si-
lyl-protecting group of the product was removed with TBAF/THF
to afford the cyclopropanemethanol derivative 12, of which two-
steps oxidation gave the carboxylic acid 14. Condensation between
14 and 2,4-dimethylphenylpiperazine effectively proceeded by
treating them with EDC in CH2Cl2 to form the corresponding amide
product 15. Reduction of 15 was carried out with LiAlH4 in THF to
furnish the desired conformationally restricted analog 4.
Forthesynthesisofthe10S-and10R-methyl-substitutedconform-
ationally restricted analogs 5 and 6, stereoselective construction of
the 10-carbon moieties was the key step. Ellman has reported that
tert-butanesulfinyl imines are extremely effective substrates for
the stereoselective 1,2-additionof Grignard reagents.13 In thismeth-
od, when tert-butanesulfinyl imines, prepared from chiral (R)- or (S)-
MTPA amides,
D
d values of which are shown in Scheme 2.15
Reaction of 18 with N,N-di-(2-chloroethyl)aniline derivative 22,
which was prepared from 2,4-dimethylaniline (Scheme 3), pro-
duced the conformationally restricted analog 6 with 10S-configura-
tion. Similarly, the 10R-analog 5 was prepared from 21.
1.3. Biological activity
Ph
Ph
O
Me
ref. 12
a
Cl
N
OTBDPS
O
O
8
Thurkauf and co-workers identified compound 2 as a mixed
dopamine D2/D4 receptor antagonist based on the working hypoth-
esis that dopamine receptor antagonists with a ratio of D2/D4
receptor affinity of approximately 4–7 may be effective as antipsy-
chotic drugs.9 Therefore, we also evaluated binding affinities of the
compounds for dopamine D2 and D4 receptors using membrane
expressing human D2s and D4.2 receptors using [3H]YM-09151-2
as a radioligand. Binding affinities for adrenaline a1 receptor,
which is related to cardiovascular side-effects,9 were also evalu-
ated. These results are summarized in Table 1.
In our evaluation systems, the binding affinities of Thurkauf’s
compound 2b, synthesized by the procedure previously developed
by us,12 for dopamine receptors were moderate. The Ki values were
540 nM for D2 and 130 nM for D4, respectively, which were clearly
weaker than haloperidol. The D2/D4 ratio of 2b was about 4, which
was similar to that reported by Thurkauf and co-workers.9 The cor-
responding cis-cyclopropane congener 3 showed lower binding
affinity than 2b both for the D2 and D4 receptors and the D2/D4 ra-
tio was about 1. Its enantiomer ent-3 was active to D2 receptor
(Ki = 515 nM) similarly to the parent compound 2b (Ki = 540 nM),
MeO
9
O
(S)-7
ref. 12
Ph
X
OTBDPS
3
10: X = OH
b
11: X = Br
c
Ph
Me
Ph
Me
Ph
e
d
CO2H
OH
Me
CHO
Me
14
13
12
g
f
4
N
N
Me
Me
O
15
Scheme 1. Reagents and yields: (a) 1—DIBAL-H, CH2Cl2; 2—NaBH4, THF/MeOH,
88%; (b) CBr4, PPh3, CH2Cl2, 93%; (c) 1—LiAlH4, THF; 2—TBAF, THF, 96%; (d) Dess–
Martin ox., 94%; (e) NaClO2, NaH2PO4, 2-methyl-2-butene, aq acetone, 96%; (f) 2,4-
dimethylphenylpiperazine, EDC, CH2Cl2, 96%; (g) LiAlH4, THF, 77%.
Me
Ph
Me
17
Ph
Me
18
Ph
Me
Cl
Cl
1'
d
b
c
Me
N
6
5
NH
S
NH2
NH2
N
But
But
Me
Me
Me
Me
a
e
S
But
But
16
22
O
O
—0.039
—0.104
13
Ph
Ph
Ph
Me
19
Ph
—0.017
(R)NH
c
1'
d
b
Me
Me
N
Me
NH
S
—0.140
Me
+0.036
S
MTPA
21
O
O
20
Δδ = δS — δR (ppm)
Scheme 2. Reagents and yields: (a) (R)-t-BuSONH2, MS4A, benzene, 70%; (b) MeMgBr, CH2Cl2, 93% (17), quant. (20); (c) HCl, MeOH, quant. (18), 92% (21); (d) 22, i-Pr2NEt,
MeCN, 55% (6), 41% (5); (e) (S)-t-BuSONH2, CuSO4, CH2Cl2, 72%.

8878
K. Yamaguchi et al. / Bioorg. Med. Chem. 16 (2008) 8875–8881
2.1.1. (2R,1S)-1-(tert-Butyldiphenylsiloxy)methyl-2-
hydroxymethyl-2-phenylcyclopropane (10)
OH
NaHCO3
Me
NH2
Me
Br
X
X
A mixture of 9 (3.22 g,6.8 mmol) and DIBAL-H (1.0 M in hexane,
10.2 mL, 10.2 mmol) in CH2Cl2 (70 mL) was stirred at ꢀ78 °C for
4 h. After addition of MeOH, the solvent was evaporated, and the
residue was partitioned between CHCl3 and 1 M HCl. The organic
layer was washed with brine, dried (Na2SO4), and evaporated. A
mixture of the residue and NaBH4 (270 mg, 6.8 mmol) in THF/
MeOH (4:1, 70 mL) was stirred at room temperature for 4 h. After
the solvent was evaporated, the residue was partitioned between
AcOEt and 1 M HCl. The organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by column
Me
Me
N
82%
23
SOCl2
CH2Cl2
88%
24: X = OH
22: X = Cl
Scheme 3.
chromatography (silica gel, hexane/AcOEt, 10:1) to give 10
while its affinity for D4 receptor was significantly reduced
(Ki = 2050 nM).
ꢀ52.6 (c 1.26, CHCl3); 1H NMR
25
(2.50 g, 88%) as an oil: [
a]
D
(400 MHz, CDCl3) d 0.71 (1H, dd, J = 5.3, 5.3 Hz), 1.03 (1H, dd,
J = 5.3, 9.7 Hz), 1.10 (9H, s), 1.54 (1H, m), 3.50 (1H, t, J = 11.1 Hz),
3.54 (1H, t, J = 11.1 Hz), 3.71 (1H, d, J = 11.1 Hz), 4.15 (1H, t,
J = 11.8 Hz), 4.19 (1H, dd, J = 5.5, 11.8 Hz), 7.23 (1H, m), 7.30–
7.48 (10H, m), 7.72 (4H, m); 13C NMR (100 MHz, CDCl3) d 16.75,
19.04, 25.79, 26.74, 32.76, 65.17, 67.62, 126.09, 127.51, 127.55,
127.94, 128.58, 129.59, 129.62, 132.44, 135.17, 135.24, 143.93;
LR-MS (FAB) m/z 417 (MH+). Anal. Calcd for C27H32O2Si: C, 77.84;
H, 7.74. Found: C, 77.81; H, 7.53.
When a methyl substituent was introduced into the cyclopro-
pane ring at the position cis to the arylpiperazine moiety of 2b, that
is, compound 4, the affinity for the D2 receptor was lost, while it
preserved the affinity for the D4 receptor. The conformationally re-
stricted analogs 5 and 6 based on the ‘cyclopropylic strain’ showed
only insignificant binding affinity.
All of these compounds synthesized showed similar moderate
binding affinities for the a1 receptor, irrespective of the structure
(Ki = 250–906 nM).
As described above, the cis-methyl substituted analog 4 of 2b
was highly selectively active to the D4 receptor (D2/D4 > 42). The
selective affinity of 4 for the D4 receptor suggested that the bioac-
tive conformation of parent compound 2b in its binding to the D4
receptor seems not to be the endo-form, but to be the syn- or the
anti-form, as indicated in Figure 4.
As described, we stereoselectively synthesized a series of the
cyclopropane-based conformational restriction analogs of haloper-
idol, using highly stereoselective Grignard reaction with tert-
butanesulfinyl imines as the key step. We showed that the confor-
mational restriction method can effectively work for improving the
selectivity of a parent compound to the receptors and for investi-
gating the bioactive conformation, as indicated in the case of com-
pound 4 selectively active to the D4 receptor.
2.1.2. (1S,2R)-1-(tert-Butylsiloxy)methyl-2-bromomethyl-2-
phenylcyclopropane (11)
A mixture of 10 (414 mg, 1.0 mmol), CBr4 (525 mg, 2.0 mmol)
and PPh3 (995 mg, 3.0 mmol) in CH2Cl2 (10 mL) was stirred at
0 °C for 5 min. After addition of aqueous saturated NaHCO3, the
mixture was partitioned between CHCl3 and H2O, and the organic
layer was washed with brine, dried (Na2SO4), and evaporated.
The residue was purified by column chromatography (silica gel,
hexane/AcOEt, 15:1) to give 11 (448 mg, 93%) as an oil: 1H NMR
(400 MHz, CDCl3) d 0.88 (1H, dd, J = 5.3, 5.9 Hz), 1.09 (9H, s), 1.28
(1H, dd, J = 5.2, 8.7 Hz), 1.71 (1H, m), 3.70 (1H, d, J = 10.5 Hz),
3.75 (1H, dd, J = 8.3, 11.5 Hz), 3.85 (1H, d, J = 10.5 Hz), 4.07 (1H,
dd, J = 5.5, 10.5 Hz), 7.23–7.47 (11H, m), 7.68–7.72 (4H, m); HRMS
(FAB) calcd for C27H31BrOSi: 479.1406 (MH+), found 479.1413.
2. Experimental
2.1.3 (1S,2S)-1-Hydroxymethyl-2-methyl-2-
phenylcyclopropane (12)
2.1. General methods
A
mixture of 11 (2.91 g, 6.1 mmol) and LiAlH4 (920 mg,
24 mmol) in THF (60 mL) was heated under reflux for 1 h. After
addition of MeOH, the resulting mixture was evaporated, and the
residue was partitioned AcOEt and 1 M HCl. The organic layer
was washed with brine, dried (Na2SO4), and evaporated. A mixture
of the residue and TBAF (1.0 M in THF, 9.1 mL, 9.1 mmol) in THF
(60 mL) was stirred at room temperature for 12 h and then evapo-
NMR spectra were recorded at 400 MHz (1H) and at 100 MHz
(
13C), and are reported in ppm downfield from Me4Si. The 1H
NMR assignments indicated were in agreement with COSY spectra.
Thin-layer chromatography was performed on Merck coated plate
60 F254. Silica gel chromatography was performed with Merck sil-
ica gel 5715 or 9385 (neutral). Reactions were carried out under
an argon atmosphere.
rated. The residue was purified by column chromatography (silica
23
gel, hexane/AcOEt, 9:1) to give 12 (987 mg, 96%) as an oil: [a]
D
+41.4 (c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.60 (1H, dd,
J = 4.9, 5.6 Hz), 1.14 (1H, dd, J = 4.9, 8.8 Hz), 1.39 (1H, m), 1.46
(3H, s), 3.70 (1H, dd, J = 8.3, 11.9 Hz), 3.90 (1H, dd, J = 6.6,
11.9 Hz), 7.21–7.34 (5H, m); 13C NMR (100 MHz, CDCl3) d 18.83,
20.62, 24.96, 27.88, 63.56, 125.66, 127.06, 128.15, 147.34; LRMS
(EI) m/z 162 (M+). HRMS (EI) calcd for C11H14O: 162.1045 (M+),
found 162.1052.
Table 1
Binding affinities (Ki) of the compounds for dopaminergic and adrenergic receptors
a
a
b
Compound
D2s
D4.2
D2s/D4.2
a1
2b
3
ent-3
4
5
6
540 60
935 109
515 60
>10,000
>10,000
>10,000
130 33
4.2
1.0
432 67
521 105
537 102
906 204
401 64
250 15
897 145
2050 60
236 53
4660 2060
4190 1320
9.32 0.61
0.25
>42
>2.1
>2.4
0.22
2.1.4. (1S,2S)-2-Formyl-1-methyl-2-phenylcyclopropane (13)
A mixture of 12 (30 mg, 0.19 mmol) and Dess–Martin periodi-
nate (119 mg, 0.28 mmol) in CH2Cl2 (2 mL) was stirred at room
temperature for 30 min. After addition of aqueous saturated
Na2S2O4, the resulting mixture was partitioned between CHCl3
and aqueous saturated NaHCO3, and the organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was puri-
fied by column chromatography (silica gel, hexane/AcOEt, 4:1) to
Haloperidol
5.09 0.36
a
Assay was carried out with membrane expressing human D2s or D4.2 dopamine
receptors, using [3H]YM-09151 (n = 3).
b
Assay was carried out with mouse brain homogenate, using [3H]prazosin
(n = 3).

K. Yamaguchi et al. / Bioorg. Med. Chem. 16 (2008) 8875–8881
8879
+206.0 (c 0.97, CHCl3); 1H
132.68, 133.68, 135.06, 147.18, 148.18; LRMS (FAB) m/z 335
(MH+). Anal. Calcd for C23H31N2Br: C, 66.50; H, 7.52; N, 6.74; Br
19.23. Found: C, 66.24; H, 7.52; N, 6.74; Br, 19.40.
22
give 13 (29 mg, 94%) as an oil: [
a]
D
NMR (400 MHz, CDCl3) d 1.59 (3H, s), 1.65 (1H, dd, J = 4.9,
8.5 Hz), 1.70 (1H, dd, J = 4.9, 5.7 Hz), 2.17 (1H, m), 7.21–7.34 (5H,
m), 9.59 (1H, d, J = 4.9 Hz); 13C NMR (100 MHz, CDCl3) d 21.01,
22.17, 34.12, 36.90, 126.69, 127.08, 128.45, 144.82, 200.35.
2.1.8. (R)-tert-Butanesulfinyl imine (16)
A mixture of 13 (425 mg, 2.65 mmol), (R)-(+)-2-methyl-2-pro-
panesulfinamide (353 mg, 2.91 mmol), and MS4A (powder,
70 mg) in benzene (30 mL) was heated under reflux for 6 h. The
resulting mixture was filtered thorough Celite, and the filtrated
was evaporated. The residue was purified by column chromatogra-
phy (silica gel, hexane/AcOEt, 19:1) to give 16 (490 mg, 70%) as an
oil: 1H NMR (400 MHz, CDCl3) d 1.23 (9H, s), 1.50 (1H, dd, J = 5.1,
5.6 Hz), 1.56 (3H, s), 1.71 (1H, dd, J = 5.1, 8.5 Hz), 2.29 (1H, m),
7.21–7.40 (5H, m), 7.88 (1H, d, J = 8.1 Hz); HRMS calcd for
2.1.5. (1S,2S)-2-Carboxy-1-methyl-2-phenylcyclopropane (14)
A
mixture of 13 (214 mg, 1.33 mmol), NaClO2 (422 mg,
4.66 mmol), NaH2PO4ꢁ2H2O (208 mg. 1.33 mmol) and 2-methyl-
2-butene (503 L, 5.99 mmol) in acetone/H2O (4:1, 10 mL) was
l
stirred at room temperature for 12 h and then evaporated. The res-
idue was partitioned between AcOEt and 1 M HCl, and the organic
layer was washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (silica gel, hex-
C
15H22NOS: 264.1422 (MH+), found 264.1436.
22
ane/AcOEt, 15:1) to give 14 (225 mg, 96%) as an oil: [
a
]
D
+199.3 (c 0.86, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.51 (2H, m),
1.59 (3H, s), 1.99 (1H, dd, J = 6.0, 8.1 Hz), 7.28 (5H, m); 13C NMR
(100 MHz, CDCl3) d 20.28, 21.60, 27.59, 32.25, 126.52, 127.27,
128.38, 145.38, 178.33; HRMS (EI) calcd for C11H12O2: 176.0837
(M+), found 176.0835.
2.1.9. Grignard reaction product (17)
A mixture of 16 (28 mg, 0.11 mmol) and MeMgBr (1.4 M in tol-
uene/THF, 3:1, 91 lL, 0.13 mmol) in CH2Cl2 (1.1 mL) was stirred at
room temperature for 6 h, and then aqueous saturated NH4Cl was
added. The resulting mixture was partitioned between AcOEt and
H2O, and the organic layer was washed with brine, dried (Na2SO4),
and evaporated. The residue, the 10R/10S ratio of which was 1:12
based on the 1H NMR spectrum, was purified by column chroma-
tography (silica gel, hexane/AcOEt, 4:1–1:1) to give 17 (32 mg,
93%) as an oil: 1H NMR (400 MHz, CDCl3) d 0.75 (1H, m), 1.04
(1H, m), 1.18–1.29 (10H, m), 1.42 (3H, s), 3.03–3.22 (2H, m),
7.15–7.39 (5H, m); HRMS calcd for C16H26NOS: 280.1735 (MH+),
found 280.1712.
2.1.6. (1S,2S)-1-[4-(2,4-Dimethylphenyl)piperazyl]carbonyl-2-
methyl-2-phenylcyclopropane (15)
A mixture of 14 (192 mg, 1.11 mmol), 2,4-dimethylphenylpip-
erazine (463 mmol, 2.44 mmol), and EDC (468 mg, 2.44 mmol) in
CH2Cl2 (10 mL) was stirred at 0 °C for 30 min and then at room
temperature for 12 h. The resulting mixture was partitioned be-
tween CHCl3 and H2O, and the organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was purified
by column chromatography (silica gel, hexane/AcOEt, 30:1–15:1)
22
to give 15 (225 mg, 96%) as an oil: [
a
]
D
+111.0 (c 0.93, CHCl3);
2.1.10. (1S,2S)-1-[(S)-1-Aminoethyl]-2-methyl-2-
1H NMR (400 MHz, CDCl3) d 1.44 (1H, m), 1.45 (3H, s), 1.63 (1H,
t, J = 5.4 Hz), 1.99 (1H, dd, J = 5.9, 8.5 Hz), 2.23 (3H, s), 2.29 (3H,
s), 2.82 (2H, m), 2.91 (2H, m), 3.71 (3H, m), 3.96 (1H, m), 6.88–
7.02 (3H, m), 7.12–7.35 (5H, m); 13C NMR (100 MHz, CDCl3) d
17.80, 19.25, 19.43, 20.84, 27.42, 30.00, 42.78, 46.34, 52.15,
52.75, 118.92, 125.78, 126.05, 126.96, 128.46, 131.75, 132.44,
133.07, 145.27, 148.25, 168.51; HRMS (EI) calcd for C23H28N2O:
348.2202 (M+), found 348.2201.
phenylcyclopropane hydrochloride (18)
A solution of 17 (22 mg, 80
L, 240 mol) in MeOH (1 mL) was stirred at room temperature
for 20 min. The resulting solution was evaporated to give 18
lmol) and HCl (4 M in dioxane,
80
l
l
22
(17 mg, quant.) as a white solid: [
a]
+18.1 (c 0.92, CH3OH); 1H
D
NMR (400 MHz, CDCl3) d 0.92 (1H, dd, J = 5.6, 5.6 Hz), 1.22 (1H,
dd, J = 5.3, 8.5 Hz), 1.36 (1H, m), 1.39 (3H, s), 1.63 (3H, d,
J = 6.6 Hz), 3.13 (1H, m), 7.16–7.28 (5H, m), 8.56 (3H, br s); 13C
NMR (100 MHz, CDCl3) d 19.38, 20.40, 21.22, 26.41, 28.84, 50.45,
126.16, 127.35, 128.29, 146.03; HRMS (FAB) calcd for C12H18N:
176.1436 (MH+ꢀHCl), found 176.1443 (MH+ꢀHCl).
2.1.7. (1S,2S)-1-[4-(2,4-Dimethylphenyl)piperazyl]methyl-2-
methyl-2-phenylcyclopropane (4)
A mixture of 15 (236 mg, 0.68 mmol) and LiAlH4 (1.0 M in THF,
1.4 mL, 1.4 mmol) in THF (6 mL) was stirred at 0 °C for 30 min and
then at room temperature for 3 h. The resulting mixture was par-
titioned between AcOEt and aqueous NaOH (10%), and the organic
layer was washed with brine, dried (Na2SO4), and evaporated. The
2.1.11. (1S,2S)-1-[(S)-2-[4-(2,4-Dimethylphenyl)piperazyl]-
ethyl]-2-methyl-2-phenylcyclopropane hydrobromide (6)
A mixture of 18 (free amine, 14 mg, 82
l
mol), prepared by the
ꢀ
treatment of hydrochloride of 18 with Diaion PA312 ( HCO3
form), diisopropylethylamine (72
residue was purified by column chromatography (silica gel, hex-
l
L, 0.41 mmol), and 22 (41 mg,
21
ane/AcOEt, 5:1) to give 4 (176 mg, 77%) as an oil: [
a]
+49.9 (c
0.16 mmol) in MeCN (2 mL) was heated under reflux for 2 days.
The resulting mixture was partitioned between AcOEt and H2O,
and the organic layer was washed with brine, dried (Na2SO4),
and evaporated. The residue was purified by column chromatogra-
D
1.03, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.52 (1H, dd, J = 4.6,
6.0 Hz), 1.18 (1H, dd, J = 4.6, 9.0 Hz), 1.28 (1H, m), 1.43 (3H, s),
2.27 (3H, s), 2.28 (3H, s), 2.54 (1H, dd, J = 6.6, 12.6 Hz), 2.72 (4H,
br s), 2.76 (1H, dd, J = 6.0, 12.6 Hz), 2.94 (4H, t, J = 4.9 Hz), 6.94–
7.00 (3H, m), 7.13–7.30 (5H, m); 13C NMR (100 MHz, CDCl3) d
17.66, 20.36, 20.45, 20.63, 13.57, 23.65, 51.82, 53.62, 58.55,
118.62, 125.22, 126.44, 126.67, 127.89, 131.41, 132.12, 132.15,
phy (silica gel, hexane/AcOEt, 15:1) to give 6 (16 mg, 55%) as an oil:
20
[a
]
D
ꢀ14.0 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.70 (1H,
dd, J = 5.9, 6.0 Hz), 1.10 (1H, m), 1.26 (2H, m), 1.35 (3H, d,
J = 6.4 Hz), 1.41 (3H, s), 2.27–2.28 (7H, m) 2.76–3.00 (8 H), 6.93–
6.99 (3H, m), 7.15 (1H, m), 7.25–7.28 (4H, m); 13C NMR
(100 MHz, CDCl3) d 17.68, 18.83, 20.63, 20.87, 21.67, 22.71,
28.42, 50.39, 52.16, 60.69, 118.60, 125.31, 126.67, 126.89, 127.94,
131.40, 132.07, 132.15, 147.93, 148.80. The hydrobromide of 6
147.58, 148.73. To a solution of 4 (free amine, 17 mg, 48
lmol)
in i-PrOH (0.5 mL) was added aqueous HBr (48%, 17 L) where
l
the pH was ca. 3. To the resulting mixture was added i-Pr2O to give
white precipitates of 4 (24 mg, 96%) as a dihydrobromide: mp 215–
22
217 °C (i-PrOH–i-Pr2O); [
a]
+30.5 (c 0.87, CH3OH); 1H NMR
was prepared as described above for 4: mp (i-PrOH–i-Pr2O) 192–
D
ꢀ7.27 (c 0.63, MeOH); 1H NMR (400 MHz, CD3OD)
21
(400 MHz, CDCl3) d 0.79 (1H, m), 1.32 (2H, m, H-1), 1.39 (3H, s),
2.15 (3H, s), 2.20 (3H, s), 3.21 (7H, m), 3.62 (3H, m), 6.96 (3H, d,
J = 15.7 Hz), 7.07–7.11 (1H, m), 7.18–7.25 (4H, m); 13C NMR
(100 MHz, CD3OD) d 17.82, 17.85, 20.54, 20.89, 20.92, 21.06,
21.16, 50.46, 53.77, 58.64, 120.04, 127.22, 127.90, 128.11, 129.39,
194 °C; [
a]
D
d 0.99 (1H, dd, J = 5.4, 5.8 Hz), 1.21 (1H, m), 1.38–1.41 (4H, m),
1.60 (3H, d, J = 6.8 Hz), 2.16 (3H, s), 2.21 (3H, s), 3.05–3.38 (7H,
m), 3.66 (1H, m), 3.77 (1H, m), 6.89–6.93 (3H, m), 7.08–7.12 (1H,
m), 7.19–7.24 (4H, m); 13C NMR (100 MHz, CD3OD) d 17.42,

8880
K. Yamaguchi et al. / Bioorg. Med. Chem. 16 (2008) 8875–8881
17.85, 20.88, 21.31, 21.60, 26.22, 27.14, 50.64, 50.68, 51.23, 51.48,
65.58, 120.00, 127.30, 128.16, 128.19, 129.42, 132.74, 133.63,
with brine, dried (Na2SO4), and evaporated. The residue was puri-
fied by column chromatography (silica gel, hexane/AcOEt 4:1–1:1)
to give 24 (1.71 g, 82%) as an oil: 1H NMR (400 MHz, CDCl3) d 2.29
(3H, s), 2.32 (3H, s), 3.16 (4H, m), 3.60 (4H, m), 7.00–7.26 (3H, m);
13C NMR (100 MHz, CDCl3) d 18.28, 20.93, 57.06, 60.05, 123.87,
127.37, 131.89, 134.61, 135.20, 146.14; HR-MS (EI) calcd for
135.28, 147.32, 147.13; HRMS (FAB) calcd for
C24H33N2:
349.2644, found 349.2649. Anal. Calcd for C23H31N2: C, 55.50; H,
6.79; N, 5.39. Found: C, 55.26; H, 6.88; N, 5.30.
2.1.12. (S)-tert-Butanesulfinyl imine (19)
C
12H19NO2: 209.1416 (M+), found 209.1420.
A mixture of 13 (29 mg, 0.18 mmol), (S)-(ꢀ)-2-methyl-2-pro-
panesulfinamide (24 mg, 2.0 mmol), and CuSO4 (70 mg,
0.44 mmol) in CH2Cl2 (1.8 mL) was heated under reflux for 6 h.
The resulting mixture was filtered through Celite, and the filtrated
was evaporated. The residue was purified by column chromatogra-
2.1.17. N,N-Bis-(2-chloroethyl)-2,4-dimethylaniline (22)
mixture of 24 (37 mg, 0.18 mmol) and SOCl2 (29 lL,
A
0.40 mmol) in CH2Cl2 (2 mL) was heated under reflux for 1 h. The
resulting mixture was partitioned between AcOEt and H2O, and
the organic layer was washed with brine, dried (Na2SO4), and evap-
orated. The residue was purified by column chromatography (silica
gel, hexane/AcOEt 40:1) to give 22 (39 mg, 88%) as an oil: 1H NMR
(400 MHz, CDCl3) d 2.28 (6H, s), 3.37 (4 H), 3.44 (4 H) 6.96–7.05
(3H, m); 13C NMR (100 MHz, CDCl3) d 18.05, 20.95, 41.77, 56.79,
123.82, 127.13, 131.90, 134.50, 135.73, 144.32; LRMS (EI) m/z
245 (M+). Anal. Calcd for C12H17Cl2N: C, 58.55; H, 6.96; N, 5.69.
Found: C, 58.87; H, 6.92; N, 5.54.
phy (silica gel, hexane/AcOEt, 19:1) to give 19 (34 mg, 72%) as an
21
oil: [a]
+417.09 (c 0.81, CHCl3); 1H NMR (400 MHz, CDCl3) d
D
1.22 (9H, s), 1.45 (1H, dd, J = 5.3, 5.3 Hz), 1.59 (3H, s), 1.76 (1H,
dd, J = 5.1, 8.7 Hz), 2.29 (1H, m), 7.20–7.33 (5H, m), 7.88 (1H, d,
J = 8.3 Hz); HRMS calcd for C15H22NOS: 264.1422. (MH+), found
264.1414.
2.1.13. Grignard reaction product (20)
Compound 20 (110 mg, quant.) was obtained from 19 (100 mg,
0.38 mmol) as an oil, as described for the synthesis of 17: 1H NMR
(400 MHz, CDCl3) d 0.45 (1H, dd, J = 5.6, 5.7 Hz), 1.06 (1H, m, H-1),
1.14 (1H, dd, J = 4.5, 9.2 Hz,), 1.24 (s, 9H), 1.42 (3H, d, J = 6.5 Hz),
1.48 (3H, s), 3.17 (2H, m) 7.14–7.28 (5H, m); 13C NMR (100 MHz,
CDCl3) d 18.49, 2.72, 22.66, 22.80, 23.60, 25.99, 53.35, 55.49,
125.61, 127.10, 128.09, 147.38; HR-MS calcd for C15H22NOS:
280.1735. (MH+), found 280.1740.
2.2. Binding assay of human D2s and D4.2 dopamine receptors
Membrane suspensions expressing human D2s or D4.2 dopamine
receptors were purchased from PerkinElmer Life Sciences (Boston,
MA), and radioreceptor binding assay was performed using
[3H]YM-09151-2 (3.15 TBq/mmol, DuPont-NEN, Boston, MA) as
previously described.9 Briefly, the membrane suspensions (3.3
and 43 lg protein for D2 and D4 receptor assays, respectively) were
2.1.14. (1S,2S)-1-[(R)-1-Aminoethyl]-2-methyl-2-
phenylcyclopropane hydrochloride (21)
Compound 21 (10 mg, quant.) was obtained from 20 (13 mg,
0.046 mmol) as an oil, as described for the synthesis of 18: [a]
incubated with [3H]YM-09151-2 (0.05–2.0 nM) for 2 h at 20 °C in
50 mM Tris–HCl buffer (pH 7.4) containing 120 mM NaCl, 5 mM
KCl, 5 mM MgCl2, and 1 mM EDTA. The reaction was terminated
by rapid filtration (Cell Harvester, Brandel Co., Gaithersburg, MD,
USA) through Whatman GF/B glass fiber filters, and the filters were
rinsed three times with 2 mL of ice-cold buffer. Tissue-bound
radioactivity was extracted from filters overnight in scintillation
fluid (2 L of toluene, 1 L of Triton X-100, 15 g of 2,5-diphenyloxa-
zole, and 0.3 g of 1,4-bis[2-(5-phenyloxazolyl)]benzene), and it
was determined in a liquid scintillation counter. Specific binding
of [3H]YM-09151-2 was determined experimentally from the dif-
22
D
+37.5 (c 0.92, CH3OH); 1H NMR (400 MHz, CDCl3) d 0.49 (1H, dd,
J = 5.2, 5.3 Hz), 1.26 (1H, dd, J = 5.1, 9.4 Hz), 1.38 (1H, m), 1.54
(3H, d, J = 6.6 Hz), 1.61 (3H, s), 3.07 (1H, m), 7.07–7.42 (5H, m),
8.72 (3H, br s); 13C NMR (100 MHz, CDCl3) d 18.41, 19.27, 20.93,
26.23, 29.22, 49.52, 125.69, 127.29, 127.86, 145.42; HRMS (FAB)
calcd for C12H18N: 176.1436 (MH+ꢀHCl), found 176.1441.
2.1.15. (1S,2S)-1-[(R)-2-[4-(2,4-Dimethylphenyl)piperazyl]-
ethyl]-2-methyl-2-phenylcyclopropane dihydrobromide (5)
Compound 5 (free amine, 24 mg, 41%) was obtained from 21
ference between counts in the absence and presence of 2.0
haloperidol.
lM
(51 mg, 0.21 mmol) as an oil, as described for the synthesis of 6:
2.3. Binding assay of mouse brain a1-adrenoceptor
+87.6 (c 1.26, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.38
21
[a
]
D
(1H, dd, J = 4.5, 5.5 Hz), 1.12–1.22 (2H, m), 1.25 (3H, d, J = 6.6 Hz),
1.47 (3H, s), 2.26 (3H, s), 2.28 (3H, s), 2.33 (1H, m), 2.79–2.93 (8
H), 6.92–6.99 (3H, m), 7.13–7.18 (1H, m), 7.24–7.28 (4H, m); 13C
NMR (100 MHz, CDCl3) d 117.63, 17.89, 19.12, 20.81, 21.44,
25.86, 31.06, 50.28, 52.48, 59.87, 118.75, 125.35, 126.33, 126.83,
Male ICR strain mice at 6–8 weeks of age (Japan SLC Inc., Shi-
zuoka, Japan) were exsanguinated by taking the blood from
descending aorta under light anesthesia with Et2O, and the whole
brain tissue was removed. The brain tissue was homogenized in 19
vol. of 50 mM Tris–HCl buffer (pH 7.5) with a Polytron homoge-
nizer, and the homogenate was centrifuged at 40,000g for
15 min. The pellet was resuspended in the buffer and centrifuged
again. The resulting pellet was suspended in 24 vol. of the buffer
128.10, 131.58, 132.18, 132.27, 147.58, 148.98. The hydrobromide
23
of 5 was prepared as described above for 4: mp 191–193 °C; [a]
D
+68.0 (c 0.85, CH3OH); 1H NMR (400 MHz, CD3OD) d 0.59 (1H, m),
1.32–1.39 (2H, m), 1.48 (3H, s), 1.54 (6H, d, J = 6.5 Hz), 2.15 (3H, s),
2.20 (3H, s), 3.06–3.38 (7H, m), 3.63–3.69 (2H, m), 6.88–6.93 (3H,
m), 7.08–7.13 (1H, m), 7.20–7.25 (3H, m); 13C NMR (100 MHz,
CD3OD) d 17.51, 17.83, 19.31, 20.87, 21.31, 27.97, 29.67, 50.43,
50.71, 50.81, 52.60, 120.10, 126.84, 127.22, 128.17, 129.56,
132.73, 133.65, 135.36, 146.10, 147.68; Anal. Calcd for C23H31N2:
C, 67.12; H, 7.75; N, 6.52; Found: C, 66.94; H, 7.83; N, 6.46.
and utilized for binding assay. The binding assay for a1-adrenocep-
tor was performed according to the previous method16 using
[3H]prazosin (2.98 TBq/mmol, DuPont-NEN, Boston, MA). Briefly,
the brain homogenate (approximately 400 lg protein) was incu-
bated with [3H]prazosin (0.05–1 nM) for 1 h at 20 °C. The reaction
was terminated as described above. Specific binding of [3H]prazo-
sin was determined experimentally from the difference between
counts in the absence and presence of 10 lM phentolamine.
2.1.16. N,N-Bis-(2-hydroxyethyl)-2,4-dimethylaniline (24)
A mixture of 2,4-dimethylaniline (23, 1.24 mL, 10 mmol), 2-bro-
moethanol (3.52 mL, 50 mmol) and NaHCO3 (1.68 g, 20 mmol) was
stirred at 57 °C for 2 days. The resulting reaction mixture was par-
titioned between CHCl3 and H2O, and the organic layer was washed
2.4. Data analysis
Analysis of binding data was performed as described
previously.17,18

K. Yamaguchi et al. / Bioorg. Med. Chem. 16 (2008) 8875–8881
8881
Nakamura, T.; Shuto, S.; Kazuta, Y.; Matsuda, A.; Nakajima-Iijima, S.;
Kohsaka, S.; Kudo, Y.; Mishina, M. FEBS Lett. 2001, 69, 2007; (h) Kazuta,
Y.; Tsujita, R.; Ogawa, K.; Hokonohara, T.; Yamashita, K.; Morino, K.;
Matsuda, A.; Shuto, S. Bioorg. Med. Chem. 2002, 10, 1777; (i) Kazuta, Y.;
Tsujita, R.; Uchino, S.; Kamiyama, N.; Mochizuki, D.; Yamashita, K.; Ohmori,
Y.; Yamashita, A.; Yamamoto, T.; Uchino, S.; Kohsaka, S.; Matsuda, A.; Shuto,
Acknowledgments
This investigation was supported by a Grant-in-Aid for Scien-
tific Research (S.S.) from the Japan Society for the Promotion of Sci-
ence. We are grateful to Daiso Co., Ltd for gift of chiral
epichlorohydrins and to Ms. S. Oka (Center for Instrumental Anal-
ysis, Hokkaido University) for technical assistance with NMR, MS,
and elemental analyses.
S. J. Chem. Soc., Perkin Trans.
1 2002, 1199; (j) Ono, S.; Ogawa, K.;
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Pharm. Bull. 2002, 50, 966; (k) Kazuta, Y.; Tsujita, R.; Yamashita, K.; Uchino,
S.; Kohsaka, S.; Matsuda, A.; Shuto, S. Bioorg. Med. Chem. 2002, 10, 3829.
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Matsuda, A. J. Med. Chem. 1995, 38, 2964.
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Totowa, 1997; (b) Sibley, D. R.; Monsma, F. J., Jr. Trends Pharmacol. Sci.
1992, 13, 61.
9. Zhang, X.; Hodgetts, K.; Rachwal, S.; Zhao, H.; Wasley, J. W. F.; Craven, K.;
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Thurkauf, A. J. Med. Chem. 2000, 43, 3923.
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Protopopova, M. N. Tetrahedron 1998, 54, 7919; (c) Cossy, J.; Blanchard, N.;
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Charette, A. B. Chem. Rev. 2003, 103, 977; (e) Muller, P.; Allenbach, Y. F.;
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and references therein.
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