Thiol derivatives of arylnaphthylmethane as novel anti-osteoporotic agents

Article abstract of DOI:10.1007/s00706-007-0848-2

(Mercaptophenyl)naphthylmethane derivatives were synthesized as novel estrogen receptor binding ligands. [4-(Methylsulfonyl)phenyl](naphth-1-yl)ketone shows a very promising activity towards osteoporosis.

Full text of DOI:10.1007/s00706-007-0848-2

Monatsh Chem 139, 1269–1277 (2008)
DOI 10.1007/s00706-007-0848-2
Printed in The Netherlands
Thiol derivatives of arylnaphthylmethane as novel anti-osteoporotic agents
Sangita1;ꢀ, Atul Kumar1, Shikha Sharma2, Surojeet Sengupta2, Man Mohan Singh2,
Suprabhat Ray1
1
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India
2
Endocrinology Division, Central Drug Research Institute, Lucknow, India
Received 3 October 2007; Accepted 5 November 2007; Published online 24 July 2008
# Springer-Verlag 2008
of Centchroman (A), as the first non-steroidal
oral contraceptive. This compound also possessed
potent anti-osteoporotic as well as antiinflamma-
tory activities. It has been observed in our labo-
ratory that compounds showing antiinflammatory
property might also show contraceptive activity and
vice versa. However, the two activities do not run
parallel [3–7].
Abstract (Mercaptophenyl)naphthylmethane deriva-
tives were synthesized as novel estrogen receptor
binding ligands. [4-(Methylsulfonyl)phenyl](naphth-
1-yl)ketone shows a very promising activity towards
osteoporosis.
Keywords Osteoporosis; (Mercaptophenyl)naphthylmethane;
Sulfide; Thiophenol; Sulfones.
On the other hand prostaglandins and several Cy-
clo-Oxygenase (COX) inhibitors, such as indometh-
acin, having antiinflammatory property, have been
found to inhibit osteoclastic bone resorption induced
by certain cytokines and growth factors in vitro ac-
tivity [8]. The sulfur containing SERM Raloxifene
(B) with structural similarity to Centchroman is the
only drug for osteoporosis.
Based on the above observations, it was con-
sidered worthwhile to design compounds having
similarity to Raloxifene, the potent SERM, with sub-
stituents responsible for COX inhibitory activity as
present in the potent COX-2 inhibitors [9–11] such
as Rofecoxib (C), for enhanced anti-bone resorption
activity.
Introduction
Type II osteoporosis is a common disease associated
with old age. In females, it has been linked to post-
menopausal decrease of estrogen level [1]. In an
approach towards development of anti-osteoporotic
agents, a large number of non-steroidal estrogens=
anti-estrogens have been studied for estrogen re-
placement therapy. This study has led to the devel-
opment of Selective Estrogen Receptor Modulators
(SERMs) [2]. Their effectiveness towards treatment
of bone formation=maintenance lies in their selec-
tive estrogenic action on bone with overall estrogen
antagonistic activity in other tissues such as uterus
and breast.
Our efforts towards the development of SERMs
for fertility regulation had led to the introduction
Results and discussion
ꢀ
CDRI communication no. 7155.
Chemistry
Correspondence: Sangita, Medicinal and Process Chemistry
Division, Central Drug Research Institute, Lucknow 226001,
India. Email: sangitap123@hotmail.com
In the present study molecular modification of some
of the reported antiimplantation agents, such as dia-

1270
Sangita et al.
Scheme 1
Scheme 2

Thiol derivatives of arylnaphthylmethane
1271
Scheme 3
ryl naphthyl methane derivatives, was carried out.
Molecular residues such as methyl sulfone and
methyl sulfide groups, responsible for antiinflam-
matory activity [12–15] were introduced at an ap-
propriate positions.
Thus, synthesis of methylthio substituted aryl-
naphthylmethane derivatives, has been carried out
by Friedel Crafts reaction using thioanisol or
thiophenol with 1-naphthoic acid (Scheme 1)
or 2-naphthoic acid (Scheme 2). The methylsulfone
group was generated by oxidation of the S-methyl
group. In the first step a Friedel Crafts reaction on
naphthoic acid using PPA generated the carbonyl
group which was reduced by sodium borohydride
to a secondary alcohol.
methoxy products were formed with the para iso-
mer as major product.
In order to introduce an antiestrogenic subunit in the
molecule,thephenolicdiarylnaphthylcompoundswere
treated with appropriate tertiary amino alkyl halide in
the presence of base. These tertiary amino alkoxy deri-
vatives produced were finally converted into sulfones
bytreating it withH2O2 and acetic acid (Scheme 3). For
introduction of a secondary amino alkoxy group as an
antiestrogenic subunit, the phenolic compound was
first reacted with epichlorohydrin at an elevated tem-
perature in the presence of a base. 2,3-Epoxypropyloxy
compounds thus formed were subsequently treated
with different amines to give the desired secondary
amino alkoxy derivatives (Scheme 3) (Table 1).
Since promising anti-osteoporotic activity was ob-
served with (4-methylthiophenyl)(naphth-1-yl)ketone,
its alkylated derivatives (Scheme 4) were prepared
[16–17].
Friedel Crafts condensation of phenol=anisole
with the carbinol in the presence of SnCl4 and
AlCl3 led to the formation of substituted aryl-
naphthylmethane. Both ortho and para hydroxy=
Table 1 Residues R1 and R2 in 11–31
Compound nos.
R1
R2
11 and 24
12 and 25
13 and 26
14 and 27
15 and 28
16 and 29
17 and 30
18 and 31
H
H
H
H
CH3
CH3
CH3
CH3
(CH2)2N(CH3)2
(CH2)2N(CH2CH3)2
(CH2)2N(CH2)4
(CH2)2N(CH2)5
(CH2)2N(CH3)2
(CH2)2N(CH2CH3)2
(CH2)2N(CH2)4
(CH2)2N(CH2)5
Scheme 4
19
20
H
H
CH2–HC
Compound no.
R
32
33
34
35
H
C2H5
CH(CH3)2
(CH2)2N(CH2)5
21
22
23
H
H
H
CH2CHOHCH2N(CH2)4
CH2CHOHCH2N(CH2)5
CH2CHOHCH2N(C2H5)2

1272
Sangita et al.
heated for 10–12h on a water bath at 80ꢂC. The reaction
mixture was poured onto ice-water and extracted with ethyla-
cetate. The organic layer was washed with water, dried over
anhydrous sodium sulfate and concentrated to give an oil,
which was crystallized from methanol to give the desired
compound. Yield 11.5g (71.2%); mp 65ꢂC; IR (KBr):
ꢂꢀ¼ 1647 (C¼O), 1585, 1550, 1506 (ArH), 1025, 650 (C–S)
cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 2.5 (s, 3H, MeS), 7.23–7.25 (dd,
2H, ArH), 7.27 (dd, 2H, ArH), 7.47–8.01 (m, 7H, naphth)
ppm; MS: m=z ¼ 278.
Biological activity
Inhibition in parathyroid hormone-induced resorp-
tion of 45Ca from chick fetal bones in culture
Table 2 Biological activity of 1, 2, 4–6, 10, 13, 14, 19, 20,
23, 33
Compound no.
Concentration ꢀM
T=C ratio
1
25
50
100
0.77
0.66
0.44
(4-Methylthiophenyl)(naphth-1-yl)carbinol (2, C18H16OS)
(4-Methylthiophenyl)(naphth-1-yl)ketone (10 g, 35.9 mmol)
was dissolved in 100 cm3 methanol, then 4.5 g sodium boro-
hydride (118.9mmol) were added slowly and the reaction
mixture was stirred for 5–6 h. Then methanol was distilled
off and the reaction mixture was extracted with ethyl acetate.
The organic layer extract was washed with water, dried over
anhydrous sodium sulfate, and concentrated to give an oil,
which was crystallized from benzene–n-hexane to give the
desired compound. Yield 9.0g (89.4%); mp 80ꢂC; IR (KBr):
ꢂꢀ¼ 3400 (OH), 2927 (CH), 1600, 1595, 1560 (ArH), 1180,
2
4
5
6
10
13
14
19
20
23
33
50
100
100
100
100
100
100
100
100
100
100
1.41
0.93
0.97
0.71
1.15
1.05
0.87
1.31
1.02
0.78
0.77
1
1062, 669 (C–S) cmꢁ1; H NMR (CDCl3): ꢁ ¼ 2.45 (s, 3H,
MeS), 3.8 (s, 1H, OH), 6.5 (s, 1H, CH), 7.18–7.22 (dd, 2H,
ArH), 7.30–7.34 (dd, 2H, ArH), 7.41–7.98 (m, 7H, naphth)
ppm; MS: m=z ¼ 280.
Conclusion
(4-Methylthiophenyl)(4-hydroxyphenyl)(naphth-1-yl)-
methane (3, C24H20OS)
On the basis of biological activity data it has been
observed that only compound 1 shows promising
antiresorptive activity in vitro using chick foetal bone
culture assay with T=C ratio of 0.4–0.8 at 25 ꢀM to
100 ꢀM concentrations in comparisons to Raloxifene
having T=C of 0.6 [18]. It was devoid of any estro-
genic or post-coital antifertility activities in rats.
Compound nos. 6, 14, 23, and 33 also showed
moderately antiresorptive activity. Thus, 4-(methyl-
sulfonylphenyl)(naphth-1-yl)ketone will be a very
useful antiresorptive agent in the treatment of post-
menopausal osteoporosis.
A mixture of 2.0 g (4-methylthiophenyl)(naphth-1-yl)carbi-
nol (7.14 mmol) and 1.5 g phenol (15.9 mmol) was taken in a
mixture of dry benzene and dry n-pentane (30 cm3, 1:2) and
was stirred. To this stirred solution, 0.6 g aluminium chloride
(4.49 mmol) were added at 0–4ꢂC under nitrogen atmosphere.
After 15 min 10 cm3 tin chloride (85.4 mmol) were added and
stirring was continued for 4–6 h. The reaction mixture was
poured onto ice–cold water and extracted with ethyl acetate.
The organic extract was washed with water and dried over
anhydrous sodium sulfate and concentrated to give an oil,
which was purified by column chromatography on silica gel
by using 5% ethyl acetate in n-hexane as eluent. Yield 1.7 g
(66.9%); IR (Neat): ꢂꢀ¼ 3149 (OH), 2923 (CH), 1602, 1548,
1504, 1494 (ArH), 1145, 669 (C–S) cmꢁ1; 1H NMR (CDCl3):
ꢁ ¼ 7.18–8.03 (m, 15H, ArH), 4.93 (s, 1H, CHOH), 2.4 (s, 3H,
MeS), 6.49 (s, 1H, CH) ppm; MS: m=z ¼ 356.
Experimental
Chemicals were procured from Merck, Aldrich, and Fluka
chemical companies. FT IR spectra (4000–200 cmꢁ1) were
recorded on Beckmann Perkin-Elmer 881 and FTIR 8201
(4-Methylsulfonylphenyl)(naphth-1-yl)ketone (4, C18H14O3S)
A mixture of 1 g (4-methylthiophenyl)(naphth-1-yl)ketone
(3.59 mmol) and 23cm3 hydrogen peroxide (30%, 223mmol)
in 5 cm3 acetic acid was stirred for 14 h. The reaction mixture
was poured onto water and extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous
sodium sulfate, and concentrated to give an oil, which was
crystallized from methanol. Yield 0.7 g (62.8%); mp 150ꢂC;
IR (KBr): ꢂꢀ¼ 1664 (C¼O), 1583, 1508, (ArH), 1396, 1149,
1
PC, Shimadzu spectrometers whereas H NMR spectra were
recorded on Bruker 400 FT NMR and Bruker advance DRX-
300 NMR spectrometers. All spectra were obtained in CDCl3
by using TMS as internal standard (chemical shift in ꢁ=ppm).
Microanalysis were done on Carlo erba model EA-11108 and
Heraeus CHN rapid instrument and agreed favorably with
calculated values.
678 (sulfone) cmꢁ1
MeSO2), 7.2 (dd, 2H, ArH), 7.4 (dd, 2H, ArH), 7.5–8.1 (m,
7H, naphth) ppm; MS: m=z ¼ 310.
;
1H NMR (CDCl3): ꢁ ¼ 3.06 (s, 3H,
(4-Methylthiophenyl)(naphth-1-yl)ketone (1, C18H14OS)
A mixture of 10 g 1-naphthoic acid (58.08mmol), 8.19cm3
thioanisol (69.7 mmol), and 100 g polyphosphoric acid was

Thiol derivatives of arylnaphthylmethane
1273
(4-Methylsulfonylphenyl)(naphth-1-yl)carbinol
(4-Methylsulfonylphenyl)(naphth-2-yl)ketone (9, C18H14O3S)
A mixture of 1 g (4-methylthiophenyl)(naphth-2-yl)ketone
(3.59 mmol), 23cm3 hydrogen peroxide (30%, 223mmol) in
5 cm3 acetic acid was stirred for 14h. The reaction mixture
was poured onto water and extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous
sodium sulfate, and concentrated to give an oil, which was
crystallized from methanol. Yield 0.5 g (44.8%); mp 160ꢂC;
IR (KBr): ꢂꢀ¼ 1684 (C¼O), 1598, 1466 (ArH), 1396, 1298,
(5, C18H16O3S)
A mixture of 1 g (4-methylthiophenyl)(naphth-1-yl)carbinol
(3.57 mmol) and 20 cm3 hydrogen peroxide (30%, 194 mmol)
in 5 cm3 acetic acid was stirred for 15 h. Then solvent was
distilled off and the reaction mixture was extracted with ethyl
acetate. The organic layer was washed with water, dried over
anhydrous sodium sulfate and concentrated togive anoil, which
was crystallized from benzene–n-hexane to give the desired
compound. Yield 0.6g (53.9%); mp 160ꢂC; IR (KBr):
ꢂꢀ¼ 3475 (OH), 2927 (CH), 1598, 1514, 1481 (ArH), 1311,
1149, 673 (sulfone) cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 3.01 (s, 3H,
MeSO2), 3.5 (s, 1H, OH), 6.47 (s, 1H, CH), 7.25 (dd, 2H,
ArH), 7.35 (dd, 2H, ArH), 7.45–8.05 (m, 7H, naphth) ppm;
MS: m=z ¼ 312.
1149 (sulfone) cmꢁ1
;
1H NMR (CDCl3): ꢁ ¼ 3.14 (s, 3H,
MeSO2), 7.25–8.72 (m, 11H, ArH) ppm; MS: m=z ¼ 310.
(4-Methylsulfonylphenyl)(naphth-2-yl)carbinol
(10, C18H16O3S)
A mixture of 1 g (4-methylthiophenyl)(naphth-2-yl)carbinol
(3.57 mmol) 20cm3 hydrogen peroxide (30%, 194 mmol) in
5 cm3 acetic acid was stirred for 15h. The solvent was distilled
off and the reaction mixture was extracted with ethyl acetate.
The organic layer was washed with water, dried over anhy-
drous sodium sulfate, and concentrated to give an oil, which
was crystallized from benzene–n-hexane to give the desired
compound. Yield 0.7 g (62.8%); mp 140ꢂC; IR (KBr):
ꢂꢀ¼ 3413 (OH), 1608, 1574, 1403 (ArH), 1298, 1146 (sulfone)
cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 3.02 (s, 3H, MeSO2), 3.7 (s, 1H,
OH), 6.08 (s, 1H, CH), 7.26–7.93 (m, 11H, ArH) ppm; MS:
m=z ¼ 312.
(4-Methylsulfonylphenyl)(4-hydroxyphenyl)(naphth-1-yl)-
methane (6, C24H20O3S)
A mixture of 1.0 g (4-methylthiophenyl)(4-hydroxyphenyl)
(naphth-1-yl)methane (2.80 mmol) and 25 cm3 hydrogen per-
oxide (30%, 243 mmol) in 5 cm3 acetic acid was stirred for
12h. Solvent was distilled off and reaction mixture was
extracted with ethyl acetate, washed with water, dried over
anhydrous sodium sulfate, and concentrated to give an oil,
which was crystallized from benzene–n-hexane to give the
desired compound. Yield 0.7 g (64.2%); mp 150–152ꢂC; IR
(KBr): ꢂꢀ¼ 3394 (OH), 2927 (CH), 1602, 1598, 1514, 1498
(ArH), 1313, 1151, 1022, 669 (sulfone) cmꢁ1 1H NMR
;
General experimental procedure for the synthesis
of compounds 11–18
(CDCl3): ꢁ ¼ 3.06 (s, 3H, MeSO2), 4.93 (m, 1H, OH), 6.13
(s, 1H, CH), 6.8–7.8 (m, 15H, ArH) ppm; MS: m=z ¼ 388.
A mixture of 1.0mmol (4-methylthiophenyl)(4-hydroxyphe-
nyl)(naphth-1-yl)-methane=(4-methylthiophenyl)(2-methyl-
4-hydroxy phenyl)(naphth-1-yl)methane, 1.5 mmol tertiary
alkylhalide, and 3.0mmol anhydrous potassium carbonate in
dry acetone was refluxed for 14–18h. Potassium carbonate
was filtered off. Acetone was distilled off. Reaction mixture
was extracted with ethyl acetate, washed with water, dried
over anhydrous sodium sulfate, and concentrated to give an
oil. The reaction mixture was passed through a basic alumina
column using n-hexane–benzene as eluent. The oil thus
obtained was treated with ethanolic HCl and crystallized
with absolute alcohol and dry ether. It was filtered under
anhydrous condition (hygroscopic) and dried in Abderhalden
drying apparatus.
(4-Methylthiophenyl)(naphth-2-yl)ketone (7, C18H14OS)
A mixture of 6 g 2-naphthoic acid (34.84 mmol), 4.5 cm3
thioanisol (38.33 mmol), and 60 g polyphosphoric acid was
heated for 10–12h on a water bath at 80ꢂC. The reaction
mixture was poured onto ice-water and extracted with ethyl
acetate. The organic layer was washed with water, dried over
anhydrous sodium sulfate, and concentrated to give an oil,
which was crystallized from methanol to give the desired
compound. Yield 5 g (51.5%); mp 130ꢂC; IR (KBr):
ꢂꢀ¼ 1684 (C¼O), 1610, 1466 (ArH), 650 (C–S) cmꢁ1
;
1H
NMR (CDCl3): ꢁ ¼ 2.55 (s, 3H, MeS), 7.30–8.72 (m, 11H,
ArH) ppm; MS: m=z ¼ 278.
(4-Methylthiophenyl)(naphth-2-yl)carbinol (8, C18H16OS)
(4-Methylthiophenyl)(naphth-2-yl)ketone (1g, 3.59 mmol)
was dissolved in 10 cm3 methanol, then 0.5g sodium borohy-
dride (13.21mmol) were added slowly and the reaction mix-
ture was stirred for 5–6 h. Then methanol was distilled off and
the reaction mixture was extracted with ethyl acetate. The
organic layer extract was washed with water, dried over an-
hydrous sodium sulfate, and concentrated to give an oil, which
was crystallized from benzene–n-hexane to give the desired
compound. Yield 0.65 g (64.5%); mp 58ꢂC; IR (KBr):
ꢂꢀ¼ 3306 (OH), 2927 (CH), 1596, 1491 (ArH), 1022, 627
(4-Methylthiophenyl)(4-dimethylaminoethoxyphenyl)-
(naphth-1-yl)methane hydrochloride (11, C28H29NOS ꢃ HCl)
Yield 69.1%; mp 170ꢂC; IR (KBr): ꢂꢀ¼ 3759 (amine), 2977
1
(CH), 1610, 1504 (ArH), 1158, 1040, 667 (C–S) cmꢁ1; H
NMR (CDCl3): ꢁ ¼ 1.26 (s, 6H, N(CH3)2), 2.42 (s, 3H, MeS),
2.74–2.80 (t, 2H, CH2N), 4.03–4.08 (t, 2H, OCH2), 6.1 (s, 1H,
CH), 6.8–7.8 (m, 15H, ArH) ppm; MS: m=z ¼ 427 [Mþ ꢁ 37].
(4-Methylthiophenyl)(4-diethylaminoethoxyphenyl)(naphth-
1-yl)methane hydrochloride (12, C30H33NOS ꢃ HCl)
1
(C–S) cmꢁ1; H NMR (CDCl3): ꢁ ¼ 2.44 (s, 3H, MeS), 3.9
Yield 71.6%; mp 90ꢂC; IR (KBr): ꢂꢀ¼ 3352 (amine), 2970
1
(s, 1H, OH), 5.94 (s, 1H, CH), 7.19–7.86 (m, 11H, ArH) ppm;
MS: m=z ¼ 280.
(CH), 1598, 1504, 1467 (ArH), 1046, 667 (C–S) cmꢁ1; H
NMR (CDCl3): ꢁ ¼ 0.8–0.9 (t, 6H, 2CH3), 2.46 (s, 3H, MeS),

1274
Sangita et al.
(4-Methylthiophenyl)[4-(2,3-epoxypropyloxy)phenyl]-
3.46 (t, 2H, CH2N), 3.86 (q, 4H, 2CH2 of N (CH2CH3)2), 4.5
(t, 2H, OCH2), 6.16 (s, 1H, CH), 6.79–7.9 (m, 15H, ArH)
ppm; MS: m=z ¼ 455 [Mþ ꢁ 37].
(naphth-1-yl)methane (19, C27H24O2S)
A mixture of 2 g (4-methylthiophenyl)(4-hydroxyphenyl)-
(naphth-1-yl)methane (5.62 mmol), 6 g anhydrous potassium
carbonate (43.4 mmol), and 20 cm3 epichlorohydrin
(255 mmol) was refluxed for 10 h at 120ꢂC. The reaction
mixture was filtered and solvent was distilled off. It was
extracted with ethyl acetate, washed with water, dried over
anhydrous sodium sulfate, and concentrated to give an oil.
This oil was purified by column chromatography on silica-
gel using n-hexane–benzene as eluent to give the desired
product. Yield 2.2 g; (95.05%), mp 160–162ꢂC; IR (KBr):
ꢂꢀ¼ 2950 (CH), 1610, 1514, 1483 (ArH), 1373, 1022, 671
(4-Methylthiophenyl)(4-pyrrolidinoethoxyphenyl)(naphth-1-
yl)methane hydrochloride (13, C30H31NOS ꢃ HCl)
Yield 75.2%; mp 140ꢂC; IR (KBr): ꢂꢀ¼ 3425 (amine), 2968
1
(CH), 1610, 1504, 1463 (ArH), 1053, 663 (C–S) cmꢁ1; H
NMR (CDCl3): ꢁ ¼ 1.78–1.83 (m, 4H, 2CH2 of pyrrolidine),
2.45 (s, 3H, MeS), 2.55–2.65 (m, 4H, 2NCH2), 2.88–2.9 (t,
2H, CH2N), 4.06–4.1 (t, 2H, OCH2), 6.16 (s, 1H, CH), 6.80–
7.82 (m, 15H, ArH) ppm; MS: m=z ¼ 453 [Mþ ꢁ 37].
(C–S), 761 (C–O) cmꢁ1
;
1H NMR (CDCl3): ꢁ ¼ 2.45 (s,
(4-Methylthiophenyl)(4-piperidinoethoxyphenyl)(naphth-1-
yl)methane hydrochloride (14, C31H33NOS ꢃ HCl)
3H, MeS), 2.75–2.87 (d, 2H, oxinane), 3.46–3.49 (m, 1H,
oxinane), 4.12–4.19 (d, 2H, OCH2), 6.16 (S, 1H, CH), 6.8–
7.82 (m, 15H, ArH) ppm; MS: m=z ¼ 412.
Yield 70.7%; mp 125ꢂC; IR (KBr): ꢂꢀ¼ 3436 (amine), 2977
1
(CH), 1617, 1506 (ArH), 1045, 667 (C–S) cmꢁ1; H NMR
(CDCl3): ꢁ ¼ 1.57–1.65 (m, 6H, 3CH2 of piperidine), 2.42 (s,
3H, MeS), 2.43–2.5 (m, 4H, 2NCH2), 2.72–2.78 (t, 2H,
CH2N), 4.04–4.10 (t, 2H, OCH2), 6.79–8.07 (m, 15H, ArH),
6.17 (s, 1H, CH) ppm; MS: m=z ¼ 467 [Mþ ꢁ 37].
General experimental procedure for the synthesis of
compounds 20–23
A mixture of 412 mg (4-methylthiophenyl)[4-(2,3-epo-
xypropyloxy)phenyl](naphth-1-yl)methane (1.0 mmol) and
1.5 mmol secondary amine in 15cm3 absolute alcohol was
refluxed for 4–5 h. The alcohol was distilled off, and the
reaction mixture was passed through a basic alumina column
using n-hexane–benzene as eluent. The solvent was distilled
off to give the product as oil. The oil thus obtained was treated
with ethanolic HCl. The solvent was distilled off and the
compound was crystallized from absolute alcohol and dry
ether, filtered off under anhydrous condition (hygroscopic),
and dried in Abderhalden drying apparatus.
(4-Methylthiophenyl)(2-methyl-4-dimethylaminoethoxy-
phenyl)(naphth-1-yl)methane (15, C29H31NOS)
Yield 68.8%; IR (Neat): ꢂꢀ¼ 3400 (amine), 2934 (CH), 1608,
1495 (ArH), 1188, 1041, 622 (C–S) cmꢁ1; 1H NMR (CDCl3):
ꢁ ¼ 1.25 (s, 6H, N(CH3)2), 2.17 (s, 3H, Me), 2.5 (s, 3H, MeS),
2.67–2.73 (t, 2H, CH2N), 3.99–4.04 (t, 2H, OCH2), 6.17 (s,
1H, CH), 6.59–7.86 (m, 14H, ArH) ppm; MS: m=z ¼ 441.
(4-Methylthiophenyl)(2-methyl-4-diethylaminoethoxy-
phenyl)(naphth-1-yl)methane (16, C31H35NOS)
(4-Methylthiophenyl)[4-(2-hydroxy-3-piperazinylpropyloxy)-
phenyl](naphth-1-yl)methane hydrochloride
Yield 78.89%; IR (Neat): ꢂꢀ¼ 3756 (amine), 2969 (CH), 1607,
1495, 1450 (ArH), 1046, 665 (C–S) cmꢁ1; 1H NMR (CDCl3):
ꢁ ¼ 0.96–1.05 (t, 6H, 2CH2CH3), 2.17 (s, 3H, Me), 2.45 (s,
3H, MeS), 2.54–2.63 (q, 4H, 2CH2CH3), 2.84 (t, 2H, CH2N),
3.96–3.99 (t, 2H, OCH2), 6.17 (s, 1H, CH), 6.59–7.82 (m,
14H, ArH) ppm; MS: m=z ¼ 469.
(20, C31H34N2O2S ꢃ HCl)
Yield 80.7%; mp 95ꢂC; IR (KBr): ꢂꢀ¼ 3772 (amine), 3425
(OH), 2927 (CH), 1602, 1569, 1510, 1481 (ArH), 1388,
1
1097, 661 (C–S) cmꢁ1; H NMR (CDCl3): ꢁ ¼ 2.46 (s, 3H,
MeS), 2.78 (m, 8H, 4CH2 piperazine), 2.83 (d, 2H, CH2N),
3.56 (s, 1H, NH), 3.86 (d, 2H, OCH2), 4.03 (m, 1H, CHOH),
6.09 (s, 1H, CH), 6.73–7.86 (m, 15H, ArH) ppm; MS:
m=z ¼ 498 [Mþ ꢁ 37].
(4-Methylthiophenyl)(2-methyl-4-pyrrolidinylethoxyphenyl)-
(naphth-1-yl)methane (17, C31H33NOS)
Yield 59.4%; IR (Neat): ꢂꢀ¼ 3417 (amine), 2928 (CH), 1601,
1
1491, 1454 (ArH), 1192, 1089, 688 (C–S) cmꢁ1; H NMR
(4-Methylthiophenyl)[4-(2-hydroxy-3-n-pyrrolidinyl-
propyloxy)phenyl](naphth-1-yl)methane (21, C31H33NO2S)
Yield 59.7%; IR (Neat): ꢂꢀ¼ 3363 (OH), 3759 (amine), 2929
(CDCl3): ꢁ ¼ 1.77–1.79 (m, 4H, 2CH2 of pyrrolidine), 2.17 (s,
3H, Me), 2.45 (s, 3H, MeS), 2.46–2.63 (m, 4H, 2NCH2), 2.87
(t, 2H, CH2N), 4.06 (t, 2H, OCH2), 6.17 (s, 1H, CH), 6.59–
7.87 (m, 14H, ArH) ppm; MS: m=z ¼ 467.
1
(CH), 1614, 1506 (ArH), 1053, 667 (C–S) cmꢁ1; H NMR
(CDCl3): ꢁ ¼ 1.06–1.58 (m, 4H, 2CH2 of pyrrolidine), 2.35–
2.4 (m, 4H, 2NCH2 of pyrrolidine), 2.45 (s, 3H, MeS), 2.86 (d,
2H, CH2N), 3.94 (d, 2H, OCH2), 4.0 (m, 1H, CHOH), 6.16 (s,
1H, CH), 6.45–7.83 (m, 15H, ArH) ppm; MS: m=z ¼ 483.
(4-Methylthiophenyl)(2-methyl-4-piperidinylethoxyphenyl)-
(naphth-1-yl)methane hydrochloride (18, C32H35NOS ꢃ HCl)
Yield 69.2%; mp 240–242ꢂC; IR (KBr): ꢂꢀ¼ 3404 (amine),
2935 (CH), 1607, 1495, 1448 (ArH), 1125, 1046, 664 (C–S)
(4-Methylthiophenyl)[4-(2-hydroxy-3-piperidinylpropyloxy)-
phenyl](naphth-1-yl)methane hydrochloride
(22, C32H35NO2S ꢃ HCl)
cmꢁ1
;
1H NMR (CDCl3): ꢁ ¼ 1.25–1.59 (m, 6H, 3CH2 of
piperidine), 2.17 (s, 3H, Me), 2.45 (s, 3H, MeS), 2.48–2.53
(m, 4H, 2NCH2), 2.74 (t, 2H, CH2N), 4.02–2.08 (t, 2H,
OCH2), 6.17 (s, 1H, CH), 6.57–7.86 (m, 14H, ArH) ppm;
MS: m=z ¼ 481 [Mþ ꢁ 37].
Yield 82.9%; mp 195ꢂC; IR (KBr): ꢂꢀ¼ 3749 (amine), 3392
(OH), 2937(CH), 1606, 1510, 1390 (ArH), 669 (C–S) cmꢁ1
;
1H NMR (CDCl3): ꢁ ¼ 1.45–1.65 (m, 6H, 3CH2 of piperidine

Thiol derivatives of arylnaphthylmethane
1275
ring), 2.45 (s, 3H, MeS), 2.48–2.58 (m, 4H, 2NCH2), 2.8 (d, 2H,
CH2N), 3.92 (d, 2H, OCH2), 4.1 (m, 1H, CHOH), 6.16 (s, 1H,
CH), 6.8–7.8 (m, 15H, ArH) ppm; MS: m=z ¼ 497 [Mþ ꢁ 37].
(4-Methylsulfonylphenyl)(2-methyl-4-dimethylaminoethoxy-
phenyl)(naphth-1-yl)methane (28, C29H31NO3S)
Yield 74.6%; IR (Neat): ꢂꢀ¼ 3398 (amine), 2989 (CH),
1608, 1569 (ArH), 1307, 1145, 668 (sulfone) cmꢁ1 1H
;
(4-Methylthiophenyl)[4-(2-hydroxy-3-diethylamino-
propyloxy)phenyl](naphth-1-yl)methane hydrochloride
(23, C31H35NO2S ꢃ HCl)
NMR (CDCl3): ꢁ ¼ 1.25 (s, 6H, N(CH3)2), 2.17 (s, 3H,
CH3), 3.06 (s, 3H, MeSO2), 3.4 (t, 2H, CH2N), 4.54 (t,
2H, OCH2), 6.29 (s, 1H, CH), 6.81–7.87 (m, 14H, ArH)
ppm; MS: m=z ¼ 473.
Yield 71.9%; mp 95ꢂC; IR (KBr): ꢂꢀ¼ 3745 (amine), 3389
(OH), 2940 (CH), 1608, 1510, 1460 (ArH), 1045, 669 (C–S)
cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 0.99 (t, 6H, 2CH3), 2.45 (s, 3H,
MeS), 2.52 (q, 4H, 2CH2), 2.55 (d, 2H, CH2N), 3.94 (d, 2H,
OCH2), 4.0 (m, 1H, CHOH), 6.16 (s, 1H, CH), 6.8 (m, 15H,
ArH) ppm; MS: m=z ¼ 485 [Mþ ꢁ 37].
(4-Methylsulfonylphenyl)(2-methyl-4-diethylaminoethoxy-
phenyl)(naphth-1-yl)methane (29, C31H35NO3S)
Yield 56.2%; IR (Neat): ꢂꢀ¼ 3396 (amine), 2985 (CH), 1600,
1568 (ArH), 1307, 1148, 666 (sulfone) cmꢁ1 1H NMR
;
(CDCl3): ꢁ ¼ 0.9–1.07 (t, 6H, 2CH2CH3), 2.17 (s, 3H, Me),
2.5–2.6 (q, 4H, 2CH2CH3), 3.4 (t, 2H, CH2N), 4.54 (t, 2H,
OCH2), 3.06 (s, 3H, MeSO2), 6.29 (s, 1H, CH), 6.80–7.82 (m,
14H, ArH) ppm; MS: m=z ¼ 501.
General experimental procedure for the synthesis
of compounds 24–31
A mixture of 1.0 mmol (4-methylthiophenyl)(4-alkoxyamino-
phenyl)(naphth-1-yl)methane and 2 cm3 hydrogen peroxide
(30%, 20.0mmol) in acetic acid was stirred for 10–12h. The
solvent was distilled off. The reaction mixture was extracted
with ethyl acetate, washed with water, dried over anhydrous
sodium sulfate, and concentrated to give an oil.
(4-Methylsulfonylphenyl)(2-methyl-4-pyrrolidinylethoxy-
phenyl)(naphth-1-yl)methane (30, C31H33NO3S)
Yield 51.5%; IR (Neat): ꢂꢀ¼ 3754 (amine), 2924 (CH), 1598,
1499, 1454, 1399 (ArH), 1307, 1149, 668 (sulfone) cmꢁ1; 1H
NMR (CDCl3): ꢁ ¼ 6.60–7.87 (m, 14H, ArH), 3.07 (s, 3H,
MeSO2), 6.29 (s, 1H, CH), 2.18 (s, 3H, Me), 2.96 (t, 2H,
CH2N), 3.92 (t, 2H, OCH2), 1.79–1.95 (m, 4H, 2CH2 of pyr-
rolidine), 2.46–2.69 (m, 4H, 2NCH2 of pyrrolidine) ppm; MS:
m=z ¼ 499.
(4-Methylsulfonylphenyl)(4-dimethylaminoethoxyphenyl)-
(naphth-1-yl)methane (24, C28H29NO3S)
Yield 77.5%; IR (Neat): ꢂꢀ¼ 3419 (amine), 2970 (CH), 1600,
1504 (ArH), 1373, 1155, 1028, 667 (sulfone) cmꢁ1; 1H NMR
(CDCl3): ꢁ ¼ 1.25 (s, 6H, N(CH3)2), 3.06 (s, 3H, MeSO2),
3.84 (t, 2H, CH2N), 4.54 (t, 2H, OCH2), 6.29 (s, 1H, CH),
6.82–7.89 (m, 15H, ArH) ppm; MS: m=z ¼ 459.
(4-Methylsulfonylphenyl)(2-methyl-4-piperidinylethoxy-
phenyl)(naphth-1-yl)methane hydrochloride
(31, C32H35NO3S ꢃ HCl)
Yield 56.3%; mp 170ꢂC; IR (Neat): ꢂꢀ¼ 3410 (amine), 2999
(CH), 1608, 1566 (ArH), 1307, 1147, 667 (sulfone) cmꢁ1; 1H
NMR (CDCl3): ꢁ ¼ 1.25–1.6 (m, 6H, 3CH2 of piperidine),
2.17 (s, 3H, Me), 2.4–2.53 (m, 4H, 2NCH2), 3.06 (s, 3H,
MeSO2), 3.4 (t, 2H, CH2N), 4.54 (t, 2H, OCH2), 6.29 (s,
1H, CH), 6.60–7.8 (m, 14H, ArH) ppm; MS: m=z ¼ 513
[Mþ ꢁ 37].
(4-Methylsulfonylphenyl)(4-diethylaminoethoxyphenyl)-
(naphth-1-yl)methane (25, C30H33NO3S)
Yield 50.5%; IR (Neat): ꢂꢀ¼ 3402 (amine), 2929 (CH), 1606,
1510 (ArH), 1384, 1150, 1025, 670 (sulfone) cmꢁ1; 1H NMR
(CDCl3): ꢁ ¼ 0.88–0.91 (t, 6H, 2CH3), 3.06 (s, 3H, MeSO2),
3.46–3.53 (t, 2H, CH2N), 3.82 (q, 4H, 2CH2), 4.54 (t, 2H,
OCH2), 6.29 (s, 1H, CH), 6.81–7.87 (m, 15H, ArH) ppm; MS:
m=z ¼ 487.
(4-Mercaptophenyl)(naphth-1-yl)ketone (32, C17H12OS)
A mixture of 8 g 1-naphthoic acid (46.46 mmol), 8 cm3 thio-
phenol (78.05 mmol), and 80g polyphosphoric acid was heat-
ed for 10–12 h on a water bath at 80ꢂC. The reaction mixture
was poured onto ice-water and extracted with ethyl acetate.
The organic layer was washed with water, dried over anhy-
drous sodium sulfate, and concentrated to give an oil, which
was crystallized from methanol to give the desired compound.
Yield 6.5 g (52.9%); mp 65ꢂC; IR (KBr): ꢂꢀ¼ 2360 (SH), 1683
(4-Methylsulfonylphenyl)(4-pyrrolidinylethoxyphenyl)-
(naphth-1-yl)methane (26, C30H31NO3S)
Yield 42.0%; IR (Neat): ꢂꢀ¼ 3735 (amine), 2934 (CH), 1598,
1454 (ArH), 1310, 1149, 1054, 667 (sulfone) cmꢁ1; 1H NMR
(CDCl3): ꢁ ¼ 1.78–1.82 (m, 4H, 2CH2 of pyrrolidine), 2.56–
2.7 (m, 4H, 2NCH2), 2.88 (t, 2H, CH2N), 3.06 (s, 3H,
MeSO2), 4.1 (t, 2H, OCH2), 6.1 (s, 1H, CH), 6.8–7.9 (m,
15H, ArH) ppm; MS: m=z ¼ 485.
1
(C¼O), 1592, 1507, 1475 (ArH) cmꢁ1; H NMR (CDCl3):
ꢁ ¼ 3.3 (s, 1H, SH), 7.18–8.48 (m, 11H, ArH) ppm; MS:
m=z ¼ 264.
(4-Methylsulfonylphenyl)(4-piperidinylethoxyphenyl)-
(naphth-1-yl)methane (27, C31H33NO3S)
Yield 46.8%; IR (Neat): ꢂꢀ¼ 3430 (OH), 3649 (amine), 2999
(CH), 1610, 1565 (ArH), 1307, 1145, 667 (sulfone) cmꢁ1; 1H
NMR (CDCl3): ꢁ ¼ 1.52–1.64 (m, 6H, 3CH2 of piperidine),
2.4–2.52 (m, 4H, 2NCH2), 2.8 (t, 2H, CH2N), 3.06 (s, 3H,
MeSO2), 4.0–4.1 (t, 2H, OCH2), 6.1 (s, 1H, CH), 6.81–8.07
(m, 15H, ArH) ppm; MS: m=z ¼ 499.
General experimental procedure for the synthesis of (4-alkyl
substituted thiophenyl)(naphth-1-yl)ketones 33–34
A mixture of 212 mg (4-mercaptophenyl)(naphth-1-yl)ketone
(0.76 mmol) and 8.0mmol haloalkane in 5 cm3 10% NaOH
was stirred for 12–14h. The reaction mixture was extracted

1276
Sangita et al.
with ethyl acetate. The organic layer was washed with water,
dried over anhydrous sodium sulfate, and concentrated to give
the desired compound as oil.
mur was placed in a drop of phosphate buffered saline (PBS)
before culturing in 300 mm3 of BGJb medium (pH 7.3) supple-
mented with penicillin (0.075mg=mm), streptomycin
(0.05 mg=mm), HEPES (2.382mg=mm), and bovine serum al-
bumin (1 mg=mm) in sterile 48-=96-well plates at 37ꢂC under
an atmosphere of 5% CO2 in air for 24h. Bones were trans-
ferred to BGJb culture medium containing 45CaCl2 (0.5ꢀCi=
300 mm3 medium) and incubated for 3 h at 37ꢂC under 5%
CO2 in air. Bones were then washed three times with BGJb
medium for 3 h at 37ꢂC under 5% CO2 in air. Labeled bones
were transferred to BGJb medium containing PTH (0.4ꢀM)
and chase cultured for 96h in presence or absence of test
agents or vehicle (ethanol=DMSO; final concentration 0.1%)
in 300 mm3 of BGJb medium. Contralateral femur of each
fetus served as corresponding control. Culture medium with
respective treatment in each well was changed after 48h. On
termination of culture, bones were transferred to 0.1N HCl
for 24h. Radioactivity due to 45Ca in spent medium collected
at 48 and 96 h of culture and HCl extract was quantified by
Liquid Scintillation Spectrophotometer (LKB Wallac 1282
Gamma Counter, Finland) in 10cm3 of scintillation fluid
(PPO: 2.00g, POPOP: 0.05 g, toluene: 500 cm3, methoxyetha-
nol: 500 cm3). One set of bones was heat killed by keeping
in PBS in sterile tubes in boiling water for 15 min and cultured
in parallel to assess viability of bones in culture system.
Bone resorbing activity was expressed as percentage of 45Ca
released into culture medium and the effect of test agents
as percent of corresponding contralateral control or T=C
(Treatment=Control) ratio as shown below. T=C ratio close
to unity shows lack of antiresorbing activity of the test agent.
(4-Ethylthiophenyl)(naphth-1-yl)ketone (33, C19H16OS)
Yield 67.8%; IR (Neat): ꢂꢀ¼ 1677 (C¼O), 1595, 1415 (ArH),
1
773, 665 (C–S) cmꢁ1; H NMR (CDCl3): ꢁ ¼ 1.25 (t, 3H,
CH2CH3), 3.3 (q, 2H, CH2CH3), 7.25–9.10 (m, 11H, ArH)
ppm; MS: m=z ¼ 292.
(4-Isopropylthiophenyl)(naphth-1-yl)ketone (34, C20H18OS)
Yield 60.4%; IR (Neat): ꢂꢀ¼ 1668 (C¼O), 1582, 1441, (ArH),
1
668, 759 (C–S) cmꢁ1; H NMR (CDCl3): ꢁ ¼ 1.25 (d, 6H,
CH(CH3)2), 3.5 (m, 1H, CH(CH3)2), 7.26–9.10 (m, 11H, ArH)
ppm; MS: m=z ¼ 306.
(4-Piperidinylethylthiophenyl)(naphth-1-yl)ketone
(35, C24H25NOS)
A mixture of 212 mg (4-mercaptophenyl)(naphth-1-yl)ketone
(0.76 mmol), 253 mg 1-(2-chloroethyl)piperidine hydrochlo-
ride (1.38 mmol), and 553 mg anhydrous potassium carbonate
(4.0mmol) in 15 cm3 dry acetone was refluxed for 15–18h.
Potassium carbonate was filtered off and acetone was distilled
off. The reaction mixture was extracted with ethyl acetate,
washed with water, dried over anhydrous sodium sulfate,
and concentrated to give an oil. This was passed through a
basic alumina column using n-hexane–benzene as eluent to
yield the desired product as oil. Yield 44.2%; IR (Neat):
ꢂꢀ¼ 3429 (amine), 1704 (C¼O), 1610, 1509 (ArH), 757, 661
(C–S)cmꢁ1; 1HNMR(CDCl3):ꢁ ¼ 1.18–1.32 (m, 6H, 3CH2 of
piperidine), 2.17 (m, 4H, 2NCH2), 4.28–4.33 (t, 2H, CH2N),
4.53–4.59 (t, 2H, SCH2), 7.27–8.94 (m, 11H, ArH) ppm; MS:
m=z ¼ 375.
45Ca resorptionð%Þ
45Ca released into the medium
45
¼
ꢄ100
ð Ca released into the medium
þ
45Ca remaining inthe bone ðHCl extractÞÞ
Animals and chemicals
Fertilized chicken eggs purchased from Government Poultry
Farm, Lucknow on the day of ovulation (day 1) were incubat-
ed at 37ꢂC in humidified air. Each egg was observed for
embryonic growth on egg kindler and manually rotated at
least once every 24h. BGJb bone culture medium, parathyroid
hormone (PTH, aa 1–34, and molecular weight 4117.7), bo-
vine serum albumin (fraction V), HEPES, streptomycin, peni-
cillin, DMSO, PPO, POPOP, and methoxyethanol were
purchased from Sigma Chemical Company, USA. Toluene
was purchased from Qualigen Fine Chemicals, Mumbai,
45CaCl2 (specific activity: 0.185–1.85 g Bq=mg Ca) from
Amersham Pharmacia Biotech, England and kits for biochem-
ical markers of bone turnover from Boehringer Mannheim,
Germany. All other chemicals were of analytical grade.
45Ca resorption in presence of PTH þ test agent
45Ca resorption in presence of PTH þ vehicle
T=C ratio ¼
Acknowledgements
The authors thank the Ministry of Health and Family Welfare,
Government of India for financial support. One of us (MMS)
thanks the Indian Council of Medical Research, New Delhi for
appointment as Emeritus Medical Scientist.
References
1. Rosen CJ (2005) N Engl J Med 353:595
2. Ray S, Sangita (2004) Drugs of the Future 29:185
3. Reese J, Zhao X, Ma W-G, Brown N, Maziasz TJ (2001)
Endocrinol 142:3198
Experimental design
Antiresorptive activity in vitro
The antiresorbing activity of test agents was assessed as de-
tailed earlier [18]. Briefly, femur bones isolated from chick
embryos on day 11 post-ovulation were cleared of adhering
connective tissue by carefully rotating each bone on dry
Whatman (I) filter paper under a stereomicroscope. Each fe-
4. Rankin JC, Ledford BE, Baggett B (1979) Biol Reprod
20:399
5. Mehrotra PK (1982) Ind J Exp Boil 20:719
6. Verma P, Arora PK, Salman M, Ray S, Srimal RC (1989)
Indian J Pharm Sci 51:48

Thiol derivatives of arylnaphthylmethane
1277
7. Ray S, Dwivedi I (1997) Adv Drug Res 29:172
8. Kawaguchi H, Pilbeam CC, Harrison JR, Raisz LG
(1995) Clin Orthop 313:36
9. Habeeb AG, Rao PNP, Knaus EE (2001) J Med Chem
44:2921
Ouimet N, Riendeau D, Visco D, Wang Z, Xu L, Prasit
P (1999) J Med Chem 42:1274
14. Li C-S, Black WC, Brideau C, Chan CC, Charleson S,
Cromlish WA, Claveau D, Gauthier JY, Gordon R, Greig
´
G, Grimm E, Guay J, Lau CK, Riendeau D, Therien M,
´
´
10. Therien M, Gauthier J-Y, Leblanc Y, Leger S, Perrier H,
Prasit P, Wang Z (2001) Synthesis 12:1778
11. Graul AI (1999) Drugs Today 35:409
Visco DM, Wong E, Xu L, Prasit P (1999) Bioorg Med
Chem Lett 9:3181
15. Dannhardt G, Kiefer W (2001) Eur J Med Chem 36:109
16. Sangita, Kumar A, Singh MM, Jain GK, Murthy PSR,
Ray S (2004) US 0229869:A1
17. Sangita, Kumar A, Singh MM, Jain GK, Murthy PSR,
Ray S (2006) EP:1692101
18. Arshad M, Sengupta S, Sharma S, Ghosh R, Savlani V,
Singh MM (2004) J Steroid Biochem Mol Biol 91:67
12. Chauret N, Yergey JA, Brideau C, Friesen RW, Mancini J,
Riendeau D, Silva J, Styhler A, Trimble LA, Nicoll-
Griffith DA (2001) Bioorg Med Chem Lett 11:1059
13. Black WC, Brideau C, Chan C-C, Charleson S, Chauret
N, Claveau D, Ethier D, Gordon R, Greig G, Guay J,
Hughes G, Jolicoeur P, Leblanc Y, Nicoll-Griffith D,
¨
Verleger: Springer-Verlag GmbH, Sachsenplatz 4–6, 1201 Wien, Austria. – Herausgeber: Osterreichische Akademie der Wissenschaften, Dr.-Ignaz-Seipel-Platz 2,
¨
1010 Wien, und Gesellschaft Osterreichischer Chemiker, Eschenbachgasse 9, 1010 Wien, Austria. – Redaktion: Getreidemarkt 9=163-OC, 1060 Wien, Austria. –
Satz und Umbruch: Thomson Press Ltd., Chennai, India. – Offsetdruck: Krips bv, Kaapweg 6, 7944 HV Meppel, The Netherlands. – Verlagsort: Wien. –
Herstellungsort: Meppel. – Printed in The Netherlands.