Synthesis, properties, and perspectives of gem-diphosphono substituted-thiazoles

Article abstract of DOI:10.1016/j.ejmech.2007.07.005

A series of substituted arylidene thiazoles were allowed to react with Wittig-Horner (WH) reagent, tetraethyl methyl-1,1-bisphosphonate, to produce via Michael addition reaction the corresponding heteroarylmethylenebisphosphonates (BPs) in different yields according to the experimental conditions. Acid hydrolysis of the new BPs was undertaken to obtain the corresponding bisphosphonic acids. Prediction and the in vivo activity of the products in the rat adjuvant model are also discussed in terms of structure-activity relationships (SAR).

Full text of DOI:10.1016/j.ejmech.2007.07.005

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1015e1024
http://www.elsevier.com/locate/ejmech
Original article
Synthesis, properties, and perspectives of gem-diphosphono
substituted-thiazoles
a
b
a
Wafaa M. Abdou a, , Neven A. Ganoub , Athina Geronikaki , Eman Sabry
*
a Pesticide Chemistry Department, National Research Centre, Elbohouth Street, D-12622 Dokki, Cairo, Egypt
b School of Pharmacy, Aristotle, Thessaloniki University, Thessaloniki, Greece
Received 28 April 2007; received in revised form 6 July 2007; accepted 9 July 2007
Available online 27 July 2007
Abstract
A series of substituted arylidene thiazoles were allowed to react with WittigeHorner (WH) reagent, tetraethyl methyl-1,1-bisphosphonate, to
produce via Michael addition reaction the corresponding heteroarylmethylenebisphosphonates (BPs) in different yields according to the exper-
imental conditions. Acid hydrolysis of the new BPs was undertaken to obtain the corresponding bisphosphonic acids. Prediction and the in vivo
activity of the products in the rat adjuvant model are also discussed in terms of structureeactivity relationships (SAR).
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Drug research; Chronic inflammation; Bone resorption; Heteroarylmethylene-1,1-bisphosphonates; a-Phosphonate carbanions
1. Introduction
This structural analogy and increased stability enabled
gem-diphosphonates and their related bisphosphonic acids to
have high affinity for bone minerals and to accumulate prefer-
entially under the osteoclast so that high concentration can be
reached [6,7]. Thus, they can be used in bone scintigraphy
[8,9] for the treatment of Paget’s disease [10,11] as well as
for the preventive treatment of osteoporosis [12] and hy-
percalcemia of malignant tumors [6,7]. Furthermore, the
anti-inflammatory potential of bisphosphonic acids is also
tested [13e15]. For example, studies in the rat adjuvant arthri-
tis model with these drugs, especially risedronate [15], demon-
strated significant suppression of bone erosion in the joint and
consistently revealed significant inhibition of inflammation.
In one of the preceding articles [1e3], we reported a simple
and efficient procedure for the synthesis of several examples
of N-heterocycle substituted-methylene-1,1-bisphosphonic
acids 3 derived from the reaction of the parent olefin of
different heterocyclic species with tetraethyl methylene-1,1-
bisphosphonate (1), followed by acid hydrolysis (Scheme 1) [3].
In this communication, our studies focused on thiazole het-
erocycles with different substituted arylidene species, taking
into account that the most active BPs were found in the series
in which thiazole (or imidazole) residues were linked via
In our research program on synthesis and antiresorptive po-
tency of a variety of bisphosphonates (BPs) and their related
bisphosphonic acids (BP acids) [1e3], it was of interest to
introduce another series of these compounds for investigating
the structureeactivity relationships (SAR). Bisphosphonic
acids I are synthetic stable analogs of naturally occurring
inorganic pyrophosphoric acid II, which are resistant to break-
down by enzymatic hydrolysis (Fig. 1) [4,5].
A
C
HO
HO
OH
OH
OH
OH
HO
HO
P
O
P
P
P
O
O
O
B
O
I
II
A = H, alkyl with a possible functional group,
OR, SR, NH ; heterocycle; B = H, OH, Cl, NH
2
2
Fig. 1.
* Corresponding author. Fax: þ20 2 7601877.
E-mail address: wabdou@intouch.com (W.M. Abdou).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.07.005

1016
W.M. Abdou et al. / European Journal of Medicinal Chemistry 43 (2008) 1015e1024
a single methylene to C(1)eP2. Extension of the links causes
a marked loss of activity [16]. Furthermore, the prospective
potency of our products as antiresorptive agents for treating
the inflammatory joint disease as well as other chronic inflam-
matory diseases was based on the results of the prediction that
had been carried out, in the earlier stage. The computer-
assisted molecular modeling (CAMM), PASS program, was
adopted for designing e in silico e the structures of poten-
tially active molecules for future synthesis. Later on, the in
vivo activity of the synthesized BP-acids in the rat adjuvant
model from previous [3] and present work was also studied
in terms of structureeactivity relationships (SAR).
3. Results and discussion
Only one isomer of the respective bisphosphonates 5aef
was isolated. The configuration of the exo-heterocyclic substit-
uents was examined by NMR analysis. The 1H NMR spectrum
of 5a, taken as an example revealed three types of methine
protons with different chemical shifts at d 2.98 (dd, JHH ¼ 9 Hz,
2JHP ¼ 12.8 Hz, 1H, HaC), 3.67 (ddd, JHH ¼ 9, 11 Hz, 3JPeH
¼
4 Hz, 1H, HbC), 4.54 (dd, JHH ¼ 11 Hz, JPeH ¼ 2.9 Hz, 1H,
CHc). This large coupling constant (JHH) of Hb with Ha as
well as with Hc clearly indicates that Hb is in a trans-configura-
tion to Ha and Hc [20]. The unique structure of 5aef was also
verified by careful inspection of a model in terms of the
Newman projection, which confirmed the staggered anti-
conform for the adducts 5aef [21,22].
4
2. Chemistry
On the other hand, the vinylbisphosphonates 7aef were iso-
lated exclusively in the Z-configuration, which was established
In our present systematic study [3], 2-arylidene-cyano-
methyl-1,3-benzothiazoles 4 were treated with a little excess
of molar amount of tetraethyl methyl-1,1-bisphosphonate (1)
in dimethylformamide (DMF) containing thrice the amount of
NaH at room temperature for the proper time (TLC), poured
intoice-water and acidified with conc. HCl. The product mixture
was easily separated by solvent extraction and purified by
column chromatography to give tetraethyl 2-arylidene-2-(10,
30-benzothiazol-20-yl)ethyl-1,1-bisphosphonates 7 as a major
products (71e76%) together with tetraethyl 3-cyano-2-aryl-
1
by NMR analysis. In the H NMR spectrum of 7a the vinyl
proton on C3 appeared as an ill-defined doublet of doublet
4
(4JHH ¼ 1.1 Hz, JPeH ¼ 3.2 Hz, Hb) at 7.31 ppm while
the CHaeP2 proton (dd, JHH ¼ 1.1 Hz, JHP ¼ 24 Hz) was
deshielded at 5.04 ppm. According to the small allylic (HeCe
C]CeHe) coupling constant (4JHH ¼ 0.9e1.3 Hz) of the allylic
moiety and the large PeH coupling constant of Hb (4JPeH ¼ 3.2e
3.8 Hz) as well as the result of the inspection of a model in terms
of the Newman projection [21,22], adducts 7 should be in the
syn-configuration of the H-3-proton to H-1-proton.
4
2
3(10,30-benzothiazol-20-yl)propanyl-1,1-bisphosphonates
5
In the case of 7d the configuration at the exocyclic double
bond was examined by selective NOE experiments, which
were also useful for the assignment of the 13C NMR signals.
The irradiation of CHb proton (7.35 ppm) resulted only in
the enhancement of the 1-C-triplet (40.03 ppm) and the
C-2-doublet (144.6 ppm). Irradiation of the CHa proton
(5.16 ppm) produced an NOE at the 3-C-doublet
(139.2 ppm) and at the 2-C-doublet (144.6 ppm), indicating
the syn-configuration of the Ha proton and the Hb proton.
Next, it was found that when the above reaction (4 þ 1) was
allowed to proceed in absolute ethanol containing sodium
ethanolate (EtONa), the reaction required less time to com-
plete, yielding 5 and 7 in almost equal yields (z38%).
Furthermore, the enormous growth in the use of microwave
irradiation [23] in synthetic organic chemistry inspired us to
perform the same reactions (4aef þ 1) to achieve, under
microwave conditions, significantly remarkable rate enhance-
ments and drastic reduction of reaction time. Thus, when the
arylidenes 4 and the phosphonyl carbanion 1 were mixed in
EtONa/EtOH/DMF solution and heated in a microwave
oven, the Michael products 5 were exclusively obtained
(ꢁ85%) in 2e5 min see Table 1.
(ꢀ7%). Obviously, Michael addition of 1 to 4 at the b-carbon
to the cyano group afforded compounds 5 whereas coupling of
4 with 1 with concomitant loss of HCN afforded vinylbi-
sphosphonates 7 [3,17e19].
O
O
P(OH)2
(EtO)2P
(I) NaH/DMF
Y`
CY`Y``
Hetero
CH
C
+
Hetero
(II) Conc HCl
(EtO)2P
2
Y``
O
2
1
3
Hetero-species
Hetero-species
2&3
Y`, Y``
2&3
Y`, Y``
H, Ph
N
O
C
H, Ph
HN
a
e
S
CN
S
NH
N
S
CN,
C
H, furyl
H, Ph
CO2Et
b
c
f
CN
CH
CH
S
S
O
In our earlier study, we reported that treatment of 5-aryli-
dene-2-thioxo-4-thiazolidinones 9a,b with the carbanion 1 af-
forded the bisphosphonates 11a,b as the major products
(z47%) along with the monophosphonates 10a,b in y25%
yield (Scheme 3) [3]. In this context, the reaction of 9a,b
with 1 was repeated, under the microwave conditions, to
achieve BPs in better yields. However, when 9a,b and 1
were mixed in 1:1.5 ratio in DMF containing EtONa solution
(CN)2
HN
g
S
S
S
O
H,
HN
d
p-C6H4NMe2
S
Scheme 1.

W.M. Abdou et al. / European Journal of Medicinal Chemistry 43 (2008) 1015e1024
1017
Table 1
Reactions of the substrates 4aef and 9aef with WittigeHorner reagent 1 under different conditions
Entry
Ar (PheR)
NMe2-p
Conditions/temp.
NaH/DMF/r.t.
Time (h)
2 days
Products
Yield (%)
MP (ꢂC)
1 þ 4a
5a
7a
5a
7a
5a
5b
7b
5b
7b
5b
5c
ꢀ5
71
33
42
88
7
205e207b
193e195c
e
1 þ 4a
NMe2-p
EtONa/EtOH/r.t.
30 h
1 þ 4a
1 þ 4b
NMe2-p
Me-p
EtONa/EtOH/DMF/microwave oven
NaH/DMF/r.t.
3 min
2 days
e
162e164c
147e149d
e
75
32
36
86
ꢀ5
74
35
38
92
8
1 þ 4b
Me-p
EtONa/EtOH/r.t.
30 h
1 þ 4b
1 þ 4c
Me-p
NO2-o
EtONa/EtOH/DMF/microwave oven
NaH/DMF/r.t.
3 min
3 days
e
217e218b
171e173d
e
7c
5c
1 þ 4c
NO2-o
EtONa/EtOH/r.t.
2 days
7c
5c
1 þ 4c
1 þ 4d
NO2-o
NO2-p
EtONa/EtOH/DMF/microwave oven
NaH/DMF/r.t.
5 min
3 days
e
5d
7d
5d
7d
5d
5e
247e249d
213e215b
e
74
35
40
92
8
1 þ 4d
NO2-p
EtONa/EtOH/r.t.
2 days
1 þ 4d
1 þ 4e
NO2-p
Cl-o
EtONa/EtOH/DMF/microwave oven
NaH/DMF/r.t.
5 min
2 days
e
156e158e
133e135f
e
7e
5e
74
34
36
90
7
1 þ 4e
Cl-o
EtONa/EtOH/r.t.
30 h
7e
5e
1 þ 4e
1 þ 4f
Cl-o
Cl-p
EtONa/EtOH/DMF/microwave oven
NaH/DMF/r.t.
2 min
2 days
e
5f
209e211d
188e190b
e
7f
76
34
48
90
85
87
84
84
90
82
1 þ 4f
Cl-p
EtONa/EtOH/r.t.
30 h
5f
7f
1 þ 4f
1 þ 9a
1 þ 9b
1 þ 9c
1 þ 9d
1 þ 9e
1 þ 9f
Cl-p
EtONa/EtOH/DMF/microwave oven
EtONa/EtOH/DMF/microwave oven
EtONa/EtOH/DMF/microwave oven
EtONa/EtOH/DMF/microwave oven
EtONa/EtOH/DMF/microwave oven
EtONa/EtOH/DMF/microwave oven
EtONa/EtOH/DMF/microwave oven
5 min
10 min
8 min
5f
e
H
11a
11b
11c
11d
11e
11f
112e114f
155e157e
163e165e
212e214d
141e143f
135e137e
NMe2-p
NO2-o
NO2-p
Cl-o
12 min
12 min
9 min
OH-o
12 min
aSee Section 7 for further details.
b
Solvent of crystallization: acetonitrile.
Solvent of crystallization: CHCl3.
c
d
Solvent of crystallization: EtOH.
Solvent of crystallization: CH2Cl2.
Solvent of crystallization: cyclohexane.
e
f
(5 mL) and heated in a microwave oven, the bisphosphonates
11a,b were exclusively obtained (ꢁ85% yield) in 8e12 min
(see Table 1) after the usual working up. Efforts for detecting
and/or separating the, previously obtained, monophosphonates
10 from the reaction mixtures of 9 and 1 were unsuccessful.
Similar sequence was applied to other arylidenes for the
synthesis of more derivatives of bisphosphonate analogs
11cef via applying the WittigeHorner reagent 1 on the parent
arylidenes 9cef under microwave conditions (Table 1). Ele-
mental analyses and spectral data substantiated the chemical
structure 11. The configuration of the exo-hetrocyclic substit-
uents was examined by careful NMR analysis of the three exo-
cyclic methine protons Ha, Hb and Hc (Table 5) as well as by
the inspection of a model in terms of the Newman projection
[21,22] and by analogy with structure 5 that confirmed the
staggered anti-conform for the adducts 11aef.
As structureeactivity studies in several pharma laboratories
have identified impressively distinct therapeutic characteristics
from 1,1-bisphosphonic acid to 1,1-bisphosphonate ester coun-
terparts [4,5], hydrolysis of the synthesized BPs 5aef, 7aef and
11aef was undertaken to give the corresponding BP acids (E )-
6aef, (Z )-8aef and (E )-12aef (Schemes 2 and 3).
The structures suggested for all new compounds are in good
agreement with their analytical and spectral data (Tables 4e6).
4. Prediction
Prediction of antiresorptive activity as well as anti-
inflammatory was made at the earlier stage of the designed se-
ries 6aef, 8aef and 12aef using PASS software [24,25]. The
prediction result is presented as a list of activities (Tables 2

1018
W.M. Abdou et al. / European Journal of Medicinal Chemistry 43 (2008) 1015e1024
O
N
Ar
Ha
Hc
N
P(OR1)2
Base
2`
+
1
C
CH
Ar
1
3
*
S
P(OR1)2
O
*
S
Hb
CN
NC
4a-f
5, R1 = Et,
6, R1 = H
O
O
Ha
(R1O)2P
P(OR1)2
Hb
1
N
Base
- HCN
C
C
Ar
2`
2
S
7, R1 = Et,
8, R1 = H
4-8a, Ar = PhNMe2-p; b, Ar = PhCH3-p
c, Ar = PhNO2-o; d, Ar = PhNO2-p
e, Ar = PhCl-o; f. Ar = PhCl-p
conc.-HCl
or
or
5
7
6
8
Scheme 2.
and 3) with appropriate Pa and Pi, which are the estimates of
probability to be active and inactive, respectively.
12b as their Pa values are from 47.7% to 53.8%. This suggests
that these compounds differ significantly from the classic anti-
inflammatory compounds and that they may be new chemical
entities (NCEs).
An important criterion for selecting the more prospective
compounds is their novelty. If the Pa value is high, e.g.
Pa > 0.7, one may often find close analogy of known pharma-
ceutical agents. For instance, in the case of standard antire-
sorptive agent pamidronate Pa ¼ 0.96. If Pa < 0.7 the chance
to find the activity in experiment is less, but for a compound
that is not so similar to known pharmaceutical agents, the
less of the Pa value the more chance for this compound to
be a new chemical entity (NCE) [26].
The data in Table 2 demonstrate that PASS program [25]
has proved 100% accuracy in its predictions of antiresorptive
activity of tested compounds. Nevertheless there is no correla-
tion between predicted values of probability and experimental
values (i.e., the calculated Pa value is not proportional to the
potency of the compound).
5. Pharmacological evaluation
The effects on bone resorption, the inflammatory joint dis-
ease and chronic inflammatory diseases of the newly synthe-
sized bisphosphonic acids (BP acids) are studied. Evaluation
of the antiresorptive activity of the new series 6aeb, 8aef,
and 12aef relied on assessing the potency in an in vivo
bone resorption model. Thus, compounds were tested in thyro-
parathyroidectomized (TPTX) rats with hypercalcemia in-
duced by 1,25-dihydroxy vitamin D3 [27] to stimulate bone
resorption in vivo. All tested compounds (Table 2) showed
good to moderate antiresorptive properties compared to avail-
able BP-drug pamidronate (13). In general, this data indicated
only marginal differences for the potency of the tested BP
Regarding anti-inflammatory activity, the prediction results
in Table 3 show that the most active compounds are 6a,f and
O
O
O
O
N
NH
(EtO)2P
Base
-H2S
+
P(OEt)2
S
HC
Ar
ArHC
S
S
(EtO)2P
10a, Ar = Ph
10b, Ar = PhNMe2-p
O
9a-f
1
O
O
O
O
NH
NH
S
(HO)2P
(EtO)2P
b
HCl (Conc)
H
5
5
b
c
S
a
S
S
(EtO)2P
O
(HO)2P
c
a
H
H
Ar
Ar
O
12a-f
11a-f
9,11,12a, Ar = Ph; b, Ar = Ph-NMe2-p
c, Ar = PhNO2-o; d, Ar = PhNO2-p
e, Ar = PhCl-o; f, Ar = PhOH-o
Scheme 3.

W.M. Abdou et al. / European Journal of Medicinal Chemistry 43 (2008) 1015e1024
1019
Table 2
Antiresorptive activity (ARA), effective dose (ED50) of the new BP acids and
predicted activity by PASS program
Table 3
Delayed type hypersensitivity granuloma,a and prediction results of new BP
acids
BP acid ortho
para
TPTX*-VitD3 Prediction Pa Coincidence
Compound Dose
no.
% Inhibition of granuloma Prediction Coincidence
(AIA) Pa P/E
ED50[mg/kg]
P/E
(mg/kg) scb
Wet wt.
Dry wt.
13
6a
e
e
e
85
80
0.964
0.688
0.748
0.672
0.689
0.735
0.731
0.580
0.690
0.682
0.698
0.685
0.679
0.794
0.746
0.741
0.741
0.778
0.767
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
14
6a
100
100
60
48***
53***
46***
36*
44***
58***
35*
e
ꢃ/þ
þ/þ
e
eN(Me)2
eMe
e
0.477
e
6b
6c
e
110
105
95
eNO2
e
eCl
e
6b
6c
6d
6e
6f
100
100
100
100
100
60
38*
51***
38*
0.540
0.385
0.438
0.479
0.538
e
þ/þ
þ/þ
þ/þ
þ/þ
þ/þ
e
6d
6e
eNO2
e
48***
50***
50***
52***
44**
14
90
90
6f
8a
eCl
eNMe2
eMe
e
41**
53***
40**
19
e
e
110
125
135
115
105
118
77
8b
8c
eNO2
e
eCl
8a
100
100
100
100
150
150
100
100
60
0.349
0.401
0.670
e
0.358
0.406
e
þ/þ
þ/þ
þ/ꢃ
ꢃ/ꢃ
þ/ꢃ
þ/þ
ꢃ/þ
ꢃ/þ
e
8d
8e
eNO2
e
eCl
eH
8b
8c
6
13
11
8
8f
8d
8e
8
18
10
21
12a
12b
12c
12d
12e
12f
eH
e
e(Me)2
e
eNO2
e
70
88
8f
20
20
eNO2
e
12a
12b
46***
52***
48***
42**
43**
38*
39**
55***
38**
46***
46***
44**
51***
40**
85
80
e
e
eCl
eOH
e
78
12c
12d
12e
12f
100
100
100
100
60
e
ꢃ/þ
ꢃ/þ
ꢃ/þ
ꢃ/þ
e
* e All data are generated in thyroparathyroidectomized (APTX) acute in vivo
rat model, P e prediction; E e experiment; P/E e accuracy of prediction, þ/þ
means that both prediction and experiment gives positive results.
e
e
e
54***
38*
e
P e prediction; E e experiment; P/E e accuracy of prediction; þ/þ means
that both prediction and experiment give positive results; ꢃ/ꢃ means that
both prediction and experiment give negative results; þ/ꢃ means that predic-
tion gives positive results but experiment gives negative results; ꢃ/þ means
that prediction gives negative results but experiment give positive results.
acids, due to different arylidene substituents. However, screen-
ing results showed that the most active BP acids were found in
the series 12aef.
O
P(OH)2
a
O
P(OH)2
***p < 0.001, **p < 0.01, *p < 0.05; p is the percentage of inhibition.
sc: subcutaneously.
b
H2N [CH2]2
HO
OH
HO
HO
P
P
ONa
N
12a,c,d all displayed inhibitory effect, which were equivalent
to that of risedronate at 100 mg/kg. BP acids 6b and 12e
showed moderate activity against the dry weight granuloma.
In contrast, vinylbisphosphonic acids 8aef showed only mar-
ginal activity at higher dose. These results also indicate that
the activity of BP acids on arthritic and chronic inflammation
is highly dependent on small modifications to the structure,
which is not the case for the inhibition of bone resorption.
In summary, the inhibition of bone resorption of the newly
synthesized BP acids is significantly high when compared to
available BP-drug, pamidronate (13, standard). However, we
developed an optimized pharmacophore hypothesis to explain
the complex structureeactivity relationships of the active ni-
trogen containing bisphosphonate. Nevertheless, investigation
of the structureeactivity relationship of BP acids, so far, has
come to no clear-cut conclusion. Thus, the results obtained
are encouraging for further optimization of the antiresorptive
properties of these compounds. Furthermore, some of the
produced BP acids, e.g., 6a and 12b,f showed a significant
anti-inflammatory activity and were capable of treating the
inflammatory joint disease and chronic inflammatory diseases
in animals, and could be used to treat Man in the future.
Finally, to summarize the correlation between the predic-
tion results and the pharmacological evaluation, it can be
deduced from the data in Tables 2 and 3 that the average
ONa
O
O
13 (Pamidronate)
14 (Risedronate)
Next, BP acids were evaluated in a mouse model of chronic
inflammation by adopting the delayed type hypersensitivity
granuloma assay as a model of chronic inflammation since bi-
sphosphonates have demonstrated an activity in this model
[28e30]. Respectively, mice were previously sensitized to
methylated bovine serum albumin (mBSA) and surgically im-
planted with hydroxyapatite disks (two per mouse), soaked in
mBSA, in order to generate granulomas. This model is unaf-
fected by traditional nonsteroidal anti-inflammatory drugs,
such as aspirin or ibuprofen [28,29]. Following the delayed
type hypersensitivity granuloma reaction (DTH-GRA) tech-
nique, previously reported by Nugent et al. [30], BP acids
6aef, 8aef and 12aef were administered subcutaneously in
a delayed type hypersensitivity granuloma model, on analogy
to the behavior of risedronate and the results are shown in
Table 3. BP-risedronate (14) was selected for its optimal
potency and safety in early screening assays [4e11].
The data in Table 3 show that 14 reproducibly inhibited
granuloma wet and dry weights and served as a positive con-
trol in other experiments. Compounds 6a, 12b [R ¼ N(Me2)],
6f (R ¼ Cl-p) and 12f (R ¼ OH-o) significantly inhibited the
granuloma in a dose-dependent manner, while 6c,d, and

1020
W.M. Abdou et al. / European Journal of Medicinal Chemistry 43 (2008) 1015e1024
accuracy of prediction (AAP) for antiresorptive activity is
w100% while the average accuracy of prediction (AAP) for
anti-inflammatory activity is 55.5%.
6. Conclusion
The studied reactions in the previous [3] and the present in-
vestigations are offered as an easy way for the transformation
of easily available starting materials to the title BPs and the
related BP acids in satisfactory yields. In addition, our proto-
col demonstrates an efficient site selective method for making
addition products in high yields from arylidenes and methyl-
1,1-bisphosphonate under microwave conditions.
In parallel, screening results are in agreement with the pre-
viously reported [13e15] of the affection of the substituent.
Small changes in the structure A or B moiety in the
bisphosphonic acid I (see Fig. 1, structure I) can lead to
extensive alterations in their physicochemical, biological and
therapeutic characteristics.
7. Experimental section
All melting points are uncorrected. IR spectra were
recorded on a PerkineElmer spectrophotometer model 297 us-
ing KBr disc. The 1H and 13C NMR spectra were recorded on
a JNM-GX-400 Fa Joel spectrometer using TMS as an internal
reference. 31P NMR spectra were taken with a Varian CFT-20
(vs. external 85% H3PO4). The mass spectra were performed
at 70 eV on an MS-50 Kratos (A.E.I.) spectrometer provided
with a data system. Elemental analyses were carried out at
the Microanalysis Laboratory, Cairo University, Cairo, Egypt.
The appropriate precautions in handing moisture-sensitive
compounds were observed. Materials and reagents were pur-
chased from Aldrich Company.
7.1. Reactions of arylidenes 4aef with tetraethyl methyl-
1,1-bisphosphonate (1)
7.1.1. In the presence of NaH as a base
General procedure: to a slurry of 4.8 mmol of sodium hy-
dride dispersion (80% in mineral oil) in 15 mL of anhydrous
DMF was added dropwise 1.6 mmol of 1 in 5 mL of dry
DMF at 0 ꢂC. The reaction mixture was further stirred at
room temperature for 1 h, and a solution of 1.1 mmol of
the appropriate substrates 4aef in DMF (10 mL) was intro-
duced all at once. After stirring for the appropriate time
(TLC, see Table 1), the reaction mixture was poured into
200 mL of distilled water and HCl (1 N) was added
(at ꢃ5 ꢂC) until the pH of the reaction mixture became
acidic, and extracted with AcOEt (3 ꢄ 50 mL). The combined
organic phase was dried over anhydrous sodium sulfate,
followed by removal of the solvent, under reduced pressure.
The resulting residue was chromatographed on silica gel
(n-hexane/ethyl acetate) to give BP-products 5aef and 7aef.
Percentage yields, physical and spectral data of the products
are listed in Tables 1, 4 and 5.

Table 5
IR, 1H, 31P and 13C NMR spectral data for 5aef, 7aef and 11cef
Compound no.
IR (KBr) nmax (cmꢃ1
)
1H and 31P NMR d (ppm)
13C NMR d (ppm)
4
3
5aa
2212 (CN), 1455 (N]CeS), 1281 (P]O),
1052, 1023 (PeOeC).
1.31 (dt, JHH ¼ 6.8 Hz, JPH ¼ 3.8 Hz, 12H, 4CH3), 2.98 (dd,
16.1 (t, JPC ¼ 2.9 Hz, 4CH3), 34.9 [N(CH3)2], 41.9 (t,
JHH ¼ 9 Hz, JPH ¼ 12.8 Hz, 1H, HaC), 3.13 [s, 6H, N(CH3)2],
1JPC ¼ 133 Hz, CeP2), 44.4 (d, JPC ¼ 7 Hz, CHb), 48.8
2
2
3.67 (ddd, JHH ¼ 9, 11 Hz, JPH ¼ 4 Hz, 1H, HbC), 3.99 (qt,
(d, JPC ¼ 4.5 Hz, CHeCN), 62.3 (t, JCP ¼ 6.7 Hz,
4CH2O), 113.9 (CN), 117.6, 118.7, 121.8, 122.6, 124.1,
127.4, 132.8, 151.9, 153.6, 157.1 (Het. and Ph-C ).
3
3
2
JPH ¼ 11.5 Hz, 8H, 4H2CO), 4.54 (dd, JHH ¼ 11 Hz,
4JPH ¼ 2.9 Hz, 1H, CHc), 7.46e8.13 (m, 8H, H-Ph); dP: (2s)
19.43, 21.82.
4
3
5bb
2208 (CN), 1441 (N]CeS), 1254 (P]O),
1128, 1041 (PeOeC).
1.32 (dt, JHH ¼ 7 Hz, JPH ¼ 4 Hz, 12H, 4CH3), 2.32 (s, 3H,
16.5 (t, JPC ¼ 3.4 Hz, 4CH3), 22.6 (s, CH3ePh), 40.3
H3CePh), 3.26 (dd, JHH ¼ 9 Hz, JPH ¼ 12 Hz, 1H, HaC), 3.77
(t, JPC ¼ 130 Hz, CeP2), 43.6 (d, JPC ¼ 7 Hz, CHb), 49.4
2
1
2
(ddd, JHH ¼ 9, 11 Hz, JPH ¼ 6 Hz, 1H, HbC), 4.13 (qt,
(d, JPC ¼ 4.5 Hz, CHeCN), 62.2 (t, JCP ¼ 7.3 Hz,
4CH2O), 112.8 (CN), 121.8, 122.6, 124.7, 133.1, 135.3,
136.2, 136.9, 144.3, 152.9, 158.4 (Het. and Ph-C ).
3
3
2
JPH ¼ 10.5 Hz, 8H, 4H2CO), 4.54 (dd, JHH ¼ 10.5 Hz,
4JPH ¼ 2.9, 1H, CHc), 7.43e8.16 (m, 8H, H-Ph); dP: (2s) 21.1,
22.6.
3
1
5ca
5da
5ea
5fa
2227 (CN), 1425 (N]CeS), 1258 (P]O),
1068, 1039 (PeOeC).
1.28 (dt, JHH ¼ 6.5 Hz, JPH ¼ 3.9 Hz, 12H, 4CH3), 3.37 (dd,
15.3 (t, JPC ¼ 3.4 Hz, 4CH3), 40.8 (t, JPC ¼ 140 Hz,
JHH ¼ 9 Hz, JPH ¼ 13.8 Hz, 1H, HaC), 3.73 (ddd, JHH ¼ 9,
CeP2), 44.3 (d, JPC ¼ 6 Hz, CHb), 49.6 (d, JPC ¼ 4 Hz,
2 3
2
11 Hz, JPH ¼ 6 Hz, 1H, HbC), 3.95 (qt, JPH ¼ 11.5 Hz, 8H,
CHeCN), 62.6 (t, JPC ¼ 6.7 Hz, 4 OCH2), 112.8 (CN),
3
2
4H2CO), 4.63 (dd, JHH ¼ 11 Hz, JPH ¼ 2.7 Hz, 1H, HcC),
121.2, 126.3, 129.8, 133.8, 134.7, 148.1, 154.2, 158.7 (Het
and Ph-C ).
4
7.49e8.14 (m, 8H, H-Ph); dP: (2s) 20.19, 21.88.
1.29 (dt, JHH ¼ 7 Hz, JPH ¼ 3.8 Hz, 12H, 4CH3), 2.98 (dd,
3
1
2223 (CN), 1443 (N]CeS), 1262 (P]O),
1130, 1063 (PeOeC).
16.3 (t, JPC ¼ 4.5 Hz, 4CH3), 40.5 (t, JCP ¼ 136 Hz,
JHH ¼ 9 Hz, JPH ¼ 12.8 Hz, 1H, HaC), 3.57 (ddd, JHH ¼ 9,
CeP2), 43.9 (d, JPC ¼ 6 Hz, CHb), 49.1 (d, JPC ¼ 4.5 Hz,
2 3
2
11 Hz, JPH ¼ 4.6 Hz, 1H, HbC), 3.88 (qt, JPH ¼ 10.8 Hz, 8H,
CHeCN), 61.8 (t, JPC ¼ 7.6 Hz, 4 OCH2), 112.6 (CN),
3
2
4H2CO), 4.39 (dd, JHH ¼ 10.5 Hz, JPH ¼ 3.1 Hz, 1H, HcC),
120.5, 122.5, 126.4, 129.3, 130.6, 133.8, 148.3, 152.1,
155.5 (Het. and Ph-C ).
4
7.42e8.05 (m, 8H, H-Ph); dP: (2s) 20.25, 21.92.
3
1
2208 (CN), 1441 (N]CeS), 1253 (P]O),
1133, 1041 (PeOeC).
1.32 (dt, JHH ¼ 6.5 Hz, JPH ¼ 4 Hz, 12H, 4CH3), 2.93 (dd,
16.2 (t, JPC ¼ 4.8 Hz, 4CH3), 41.6 (t, JPC ¼ 132 Hz,
JHH ¼ 9 Hz, JPH ¼ 11.5 Hz, 1H, HaC), 3.57 (ddd, JHH ¼ 9,
CeP2), 45.9 (d, JPC ¼ 7.5 Hz, CHb), 50.8 (d,
2
2
11 Hz, JPH ¼ 3.8 Hz, 1H, HbC), 4.09 (dd, JHH ¼ 10.2 Hz,
3JPC ¼ 4.5 Hz, CHeCN), 61.8 (t, JPC ¼ 6.5 Hz, 4 OCH2),
3
2
4JPH ¼ 2.8 Hz, 1H, CHc), 4.31 (qt, JPH ¼ 12 Hz, 8H, 4H2CO),
7.4e8.09 (m, 8H, H-Ph); dP: 23.02, 21.68.
113.4 (CN), 121.4, 126.2, 129.6, 134.7, 140.1, 152.5,
156.03 (Het. and Ph-C ).
3
1
2227 (CN), 1445 (N]CeS), 1255 (P]O),
1135, 1074 (PeOeC).
1.39 (dt, JHH ¼ 7 Hz, JPH ¼ 4 Hz, 12H, 4CH3), 3.20 (dd,
15.1 (t, JPC ¼ 3.7 Hz, 4CH3), 40.2 (t, JPC ¼ 133 Hz,
JHH ¼ 10.3 Hz, JPH ¼ 11.5 Hz, 1H, HaC), 3.35 (ddd, JHH ¼ 9,
CeP2), 45.9 (d, JPC ¼ 7.5 Hz, CHPh), 49.1 (d,
2
2
11 Hz, JPH ¼ 6 Hz, 1H, HbC), 4.07 (dd, JHH ¼ 11 Hz,
3JPC ¼ 4.5 Hz, CHb), 62.2 (t, 2JPC ¼ 6.7 Hz, 4CH2O), 113.4
(CN), 121.4, 126.6, 133.4, 140.1, 135.5, 143.4, 151.6, 157.5
(Het. and Ph-C ).
3
4JPH ¼ 3.2 Hz, 1H, HcC), 4.26 (qt, JPH ¼ 11.3 Hz, 8H, 4H2CO),
7.38 (m, 8H, H-Ph); dP: (2s) 23.2, 21.7.
3
7ab
7ba
7ca
1618 (C]CHPh), 1425 (N]CeS), 1268
(P]O), 1110, 1085 (PeOeC).
1.05, 1.23 (2dt, JHH ¼ 7 Hz, JPH ¼ 4.6 Hz, 12H, 4CH3), 3.1,
15.6 (t, JPC ¼ 4.2 Hz, 4CH3), 31.8, 32.6 [2s, N(CH3)2],
1
2
3.17 [2s, 6H, N(CH3)2], 3.98e4.14 (m, 8H, 4H2CO), 5.04 (dd,
42.8 (t, JPC ¼ 148 Hz, CeP2), 61.5 (t, JPC ¼ 6 Hz,
4JHH ¼ 1.1 Hz, JPH ¼ 24 Hz, 1H, HaC), 7.31 (dd,
4CH2O), 122.7, 124.7, 125.1, 126.4, 135.1, 152.6, 158.3
2
4JHH ¼ 1.1 Hz, JPH ¼ 3.2 Hz, HbC), 7.71e8.1 (m, 8H, H-Ph);
(Het. and Ph-C ), 133.4 (d, JPC ¼ 4.5 Hz, C3), 142.9
4
3
2
dP: (2s) 20.78, 22.13.
0.99, 1.27 (2dt, JHH ¼ 6.5 Hz, JPH ¼ 3.2 Hz, 12H, 4CH3), 2.29
(d, JPC ¼ 9.8 Hz, C2).
3
1616 (C]CHPh), 1459 (N]CeS), 1256
(P]O), 1121, 1072 (PeOeC).
15.9 (t, JCP ¼ 4.5 Hz, 4CH3), 21.9 (s, CH3ePh), 43.2
1
2
(s, 3H, H3CePh), 3.98e4.19 (m, 8H, 4H2CO), 5.21 (dd,
(t, JCP ¼ 145 Hz, CeP2), 61.9 (t, JCP ¼ 5.9 Hz, 4CH2O),
4JHH ¼ 0.9 Hz, JPH ¼ 18.6 Hz, 1H, HaC), 7.37 (dd,
119.7, 121.4, 122.5, 126.4, 130.1, 132.5, 141.3, 143.0
3
2
4JHH ¼ 0.9 Hz, 4JPH ¼ 3.8 Hz, HbC), 7.72e8.01 (m, 8H, H-Ph);
dP: (2s) 19.58, 21.41.
(Het. and Ph-C ), 136.6 (d, JCP ¼ 5.8 Hz, C3), 144.6
2
(d, JCP ¼ 8.7 Hz, C2).
3
1
1626 (C]CHPh), 1449 (N]CeS), 1258
(P]O), 1110, 1082 (PeOeC).
1.16, 1.28 (2dt, JHH ¼ 7 Hz, JPH ¼ 4.2 Hz, 12H, 4H3C), 4.01e
4.26 (m, 8H, 4H2CO), 5.08 (dd, 4JHH ¼ 1.3 Hz, 2JPH ¼ 20.6 Hz,
1H, HaC), 7.35 (dd, 4JHH ¼ 1.3 Hz, 4JPH ¼ 3.4 Hz, HbC), 7.76e
8.34 (m, 8H, H-Ph); dP: (2s) 20.22, 22.91.
15.3 (t, JPC ¼ 3.7 Hz, 4CH3), 44.98 (t, JPC ¼ 144 Hz,
CeP2), 62.8 (t, 2JPC ¼ 7.4 Hz, 4CH2O), 120.4, 122.6, 124.3,
126.7, 139.1, 139.7, 142.5, 156.1, 156.9 (Het. and Ph-C ),
3
2
137.2 (d, JPC ¼ 6.2 Hz, C3), 144.9 (d, JCP ¼ 9.4 Hz, C2).
(continued on next page)

Table 5 (continued)
Compound no.
7da
IR (KBr) nmax (cmꢃ1
)
1H and 31P NMR d (ppm)
13C NMR d (ppm)
3
1
1622 (C]CHPh), 1445 (N]CeS), 1258
(P]O), 1120, 1069 (PeOeC).
1.07, 1.2 (2dt, JHH ¼ 7 Hz, JPH ¼ 4.5 Hz, 12H, 4H3C), 4.01e
4.25 (m, 8H, 4H2CO), 5.16 (dd, 4JHH ¼ 1.1 Hz, 2JPH ¼ 23.6 Hz,
1H, HaC), 7.35 (dd, 4JHH ¼ 1.1 Hz, 4JPH ¼ 3.4 Hz, HbC), 7.76e
8.36 (m, 8H, H-Ph); dP: (2s) 20.19, 22.9.
15.2 (t, JPC ¼ 3.7 Hz, 4CH3), 40.03 (t, JPC ¼ 148 Hz,
CeP2), 62.4 (t, 2JPC ¼ 5.6 Hz, 4CH2O), 120.5, 124.3, 126.9,
139.1, 142.3, 156.3, 157.1 (Het. and Ph-C ), 139.2
3
2
(d, JPC ¼ 8 Hz, C3), 144.6 (d, JPC ¼ 8.9 Hz, C2).
7ea
1618 (C]CHPh), 1443 (N]CeS), 1281
(P]O), 1133, 1053 (PeOeC).
1.23, 1.36 (2dt, JHH ¼ 6.8 Hz, JPH ¼ 4.2 Hz, 12H, 4H3C),
15.4 (t, JPC ¼ 2.8 Hz, 4CH3), 46.1 (t, JPC ¼ 140 Hz,
3
4
4.02e4.35 (m, 8H, 4H2CO), 5.06 (dd, JHH ¼ 1.2 Hz,
CeP2), 61.4 (t, 2JPC ¼ 6.2 Hz, 4CH2O), 119.6, 121.9, 123.4,
JPH ¼ 24.6 Hz, 1H, HaC), 7.34 (dd, JHH ¼ 1.2 Hz,
126.1, 129.8, 130.8, 134.5, 141.2, 152.2 (Het. and Ph-C ),
3
4
4JPH ¼ 3.3 Hz, HbC), 7.74e8.08 (m, 8H, H-Ph); dP: (2s) 21.19,
23.14.
137.1 (d, JPC ¼ 3.8 Hz, C3), 145.4 (d, JPC ¼ 8.5 Hz, C2).
2
7fa
1618 (C]CePh), 1448 (N]CeS), 1268
(P]O), 1118, 1047 (PeOeC).
1.03, 1.41 (2dt, JHH ¼ 6.8 Hz, JPH ¼ 4.6 Hz, 12H, 4H3C),
15.7 (t, JPC ¼ 3.8 Hz, 4CH3), 42.9 (t, JPC ¼ 140 Hz,
CeP2), 62.3 (t, 2JPC ¼ 6.5 Hz, 4CH2O), 124.3, 126.3, 129.8,
130.7, 134.5, 141.3, 152.1 (Het. and Ph-C ), 137.7
3
1
4
4.01e4.37 (m, 8H, 4H2CO), 5.13 (dd, JHH ¼ 1.1 Hz,
JPH ¼ 26 Hz, 1H, HaC), 7.32 (dd, JHH ¼ 1.1 Hz,
4
4JPH ¼ 2.2 Hz, HbC), 7.77e8.10 (m, 8H, H-Ph); dP: (2s) 21.17,
(d, JPC ¼ 3.8 Hz, C3), 148.6 (d, JPC ¼ 9.8 Hz, C2).
3
2
23.19.
11ca
3415 (NH), 1686 (C]O), 1436 (C]S),
1252 (P]O), 1128, 1047 (PeOeC).
1.21, 1.36 (2dt, JHH ¼ 7 Hz, JPH ¼ 4.2 Hz, 4CH3), 2.78
16.4 (t, JCP ¼ 2.8 Hz, 4CH3), 38.2 (t, JCP ¼ 133 Hz,
4
3
1
2
2
(dd, JHH ¼ 9.5 Hz, JPH ¼ 10.5 Hz, 1H, CHa), 3.46 (ddd,
CHeP2), 44.7 (d, JCP ¼ 8 Hz, CHb), 48.1 (d,
3
2
JHH ¼ 9.5, 10.6 Hz, JPH ¼ 6 Hz, 1H, HbC), 3.89e4.02
3JCP ¼ 4.7 Hz, 5-CH ), 62.2 (t, JCP ¼ 6.8 Hz, 4CH2O),
3
(2qt, JPH ¼ 10.5 Hz, 8H, 4H2CO), 4.34 (dd, JHH ¼ 10.6 Hz,
124.8, 131.8, 136.2, 147.3, 153.1 (C-Ph), 176.5 (C]O),
202.5 (C]S).
3JPH ¼ 2.3 Hz, 1H, HcC), 7.47e8.07 (m, 4H, H-Ph), 9.45
(s, 1H, HNc); dP: (2s) 21.34, 23.89.
11db
11eb
11fb
a
3418 (NH), 1680 (C]O), 1435 (C]S),
1258 (P]O), 1122, 1049 (PeOeC).
1.03, 1.31 (2dt, JHH ¼ 6.5 Hz, JPH ¼ 4.5 Hz, 4CH3), 2.65 (dd,
16.1 (t, JPC ¼ 3.5 Hz, 4CH3), 37.6 (t, JPC ¼ 133 Hz,
4
3
1
2
2
JHH ¼ 9.6 Hz, JHP ¼ 11.2 Hz, 1H, CHa), 3.63 (ddd, JHH ¼ 9.6,
CHeP2), 40.3 (d, JPC ¼ 8 Hz, CHb), 48.2
11 Hz, 3JPH ¼ 6 Hz, 1H, CHb), 3.99e4.21 (2qt, 3JPH ¼ 10.8 Hz,
(d, JPC ¼ 4.2 Hz, 5-C ), 62.1 (t, JCP ¼ 7.3 Hz, 4CH2),
126.4, 132.1, 136.1, 144.3, 152.8 (C-Ph), 173.3 (C]O),
202.6 (C]S).
3
2
4
8H, 4H2CO), 4.62 (dd, JHH ¼ 11.2 Hz, JPH ¼ 3.3 Hz, 1H,
CHc), 7.43e8.11 (m, 4H, H-Ph), 9.42 (s, 1H, HNc); dP: (2s)
21.26, 23.12.
4
3
1
3410 (NH), 1683 (C]O), 1432 (C]S),
1262 (P]O), 1155, 1083 (PeOeC).
1.06, 1.23 (2dt (br), JHH ¼ 7.5 Hz, JPH ¼ 4.7 Hz, 4CH3), 3.02
16.4 (t, JPC ¼ 3.4 Hz, 4CH3), 38.5 (t, JPC ¼ 138 Hz,
(dd, JHH ¼ 9 Hz, 2JPH ¼ 12.8 Hz, 1H, CHa), 3.81 (ddd, JHH ¼ 9,
11 Hz, 3JPH ¼ 6 Hz, 1H, CHb), 4.13e4.28 (2qt, 3JPH ¼ 11.3 Hz,
CHeP2), 42.8 (d, JPC ¼ 8 Hz, CHb), 48.3
2
3
2
(d, JPC ¼ 4.2 Hz, 5-C ), 61.8 (t, JCP ¼ 7.3 Hz, 4CH2O),
126.2, 127.1, 133.3, 136.2, 144.9, 153.4 (C-Ph), 179.8
(C]O), 202.9 (C]S).
8H, 4H2CO), 4.46 (dd, JHH ¼ 11 Hz, JPH ¼ 3.3 Hz, 1H, HcC),
4
7.42e8.13 (m, 4H, H-Ph), 9.65 (s, 1H, HNc); dP: (2s) 22.31,
23.92.
4
3
1
3458e3364 (OH and NH), 1683 (C]O),
1436 (C]S), 1266 (P]O), 1144, 1085
(PeOeC).
0.98, 1.12 (2dt, JHH ¼ 6.8 Hz, JPH ¼ 3.8 Hz, 4CH3), 2.84 (dd,
16.2 (t, JPeC ¼ 4.6 Hz, 4CH3), 39.6 (t, JPeC ¼ 137 Hz,
2
2
JHH ¼ 9 Hz, JPH ¼ 12.4 Hz, 1H, CHa), 3.35 (ddd, JHH ¼ 10.2,
CHeP2), 41.8 (d, JPC ¼ 8 Hz, CHb), 48.9
3
3
2
11 Hz, JPH ¼ 6 Hz, 1H, CHb), 3.98e4.18 (2q, 3JPH ¼ 11.2 Hz,
(d, JPC ¼ 4.2 Hz, 5-C ), 62.3 (t, JPC ¼ 7.4 Hz, 4CH2),
126.4, 127.4, 136.3, 144.9, 153.4 (C-Ph), 178.4 (C]O),
202.3 (C]S).
8H, 4H2CO), 4.58 (dd, JHH ¼ 11 Hz, JPH ¼ 3.3 Hz, 1H, HcC),
4
7.46e8.01 (m, 4H, H-Ph), 9.82 (s, 1H, HNc), 10.47 (s, 1H,
HOePh); dP: (2s) 21.63, 23.1.
Solvents of NMR:DMSO-d6.
Solvents of NMR:CDCl3.
Proton exchangeable with D2O.
b
c

Table 6
Analytical data, physical properties, IR and NMR spectra for the products 6aef, 8aef and 12bef
Compound no.a,b,c
Yieldd (%)
Mp (ꢂC)/solvent
Mol. form. (M. wt.)
Anal. Found (Calcd.) %
C
H
Cl
N
P
S
6ae
6b
6c
82
78
87
84
83
85
88
84
86
92
88
81
91
92
92
88
92
>300/H2O/acetone
230e232/acetone
>300/H2O/acetone
>300/H2O/acetone
218e220/AcOEt
187e188/EtOH
>300/H2O/acetone
198e200/MeCN
262e264/MeOH
>300/H2O/acetone
178e180/EtOH
C19H21N3O6P2S (481.41)
C
47.49 (47.40)
47.89 (47.79)
42.28 (42.25)
42.31 (42.25)
43.31 (43.18)
43.24 (43.18)
47.72 (47.58)
48.13 (48.00)
42.21 (42.12)
42.01 (42.12)
43.19 (43.11)
43.18 (43.11)
35.54 (35.46)
29.94 (29.87)
29.96 (29.87)
30.56 (30.60)
32.22 (31.97)
4.46 (4.40)
4.12 (4.01)
3.02 (3.13)
3.04 (3.13)
3.26 (3.20)
3.28 (3.20)
4.53 (4.44)
4.10 (4.03)
3.00 (3.09)
2.96 (3.09)
3.07 (3.17)
3.08 (3.17)
4.05 (4.12)
2.69 (2.73)
2.77 (2.73)
2.73 (2.80)
3.25 (3.17)
e
8.82 (8.73)
6.05 (6.19)
8.55 (8.69)
8.53 (8.69)
5.99 (5.93)
5.96 (5.93)
6.11 (6.17)
3.35 (3.29)
6.04 (6.14)
6.18 (6.14)
3.25 (3.14)
3.21 (3.14)
6.46 (6.36)
6.30 (6.33)
6.21 (6.33)
3.34 (3.24)
3.47 (3.39)
12.97 (12.87)
13.72 (13.69)
12.88 (12.82)
12.92 (12.82)
13.17 (13.10)
13.19 (13.10)
13.79 (13.63)
14.52 (14.56)
13.51 (13.57)
13.48 (13.57)
13.84 (13.89)
14.08 (13.89)
14.16 (14.07)
14.07 (14.00)
14.13 (14.00)
14.48 (14.34)
14.85 (14.99)
6.73 (6.66)
18H18N2O6P2S (452.36)
C17H15N3O8P2S (483.34)
C17H15N3O8P2S (483.34)
e
7.01 (7.09)
6.67 (6.63)
6.71 (6.63)
6.89 (6.78)
6.86 (6.78)
7.17 (7.06)
7.66 (7.54)
7.13 (7.03)
7.13 (7.03)
7.23 (7.19)
7.16 (7.19)
14.61 (14.56)
14.57 (14.50)
14.42 (14.50)
14.99 (14.85)
15.57 (15.52)
e
6d
6e
e
7.56 (7.51)
C
C
17H15ClN2O6P2S (472.83)
17H15ClN2O6P2S (472.83)
6f
7.43 (7.51)
e
8a
C18H20N2O6P2S (454.38)
C17H17NO6P2S (425.34)
8bf
8c
e
C
16H14N2O8P2S (456.31)
e
8d
8e
C16H14N2O8P2S (456.31)
C16H14ClNO6P2S (445.8)
C16H14ClNO6P2S (445.8)
C13H18N2O7P2S2 (440.37)
C11H12N2O9P2S2 (442.30)
C11H12N2O9P2S2 (442.30)
C11H12ClNO7P2S2 (431.8)
C11H13NO8P2S2 (413.31)
e
8.11 (7.96)
8f
300e305/H2O/acetone
224e225/EtOH
8.01 (7.96)
e
12b
12c
12d
12eg
12f
a
241e243/MeOH
>300/H2O/acetone
200e202/MeOH
178e180/EtOH
e
e
8.27 (8.22)
e
Data of 12a were previously reported [3].
b
c
d
e
IR (KBr): nmax cmꢃ1 of all products showed stretching bands in the regions 3330e3250 (PeOH) and 1224e1235 (P]O, bonded).
31P NMR (D2O) of all products showed signals in the range dp 20e23 ppm.
Yields are based on the consumed corresponding bisphosphonate.
dH (D2O) (ppm): 2.93 (dd, JHH ¼ 7 Hz, JPH ¼ 12.6 Hz, 1H, HCeP2), 3.1 [s, 6H, N(CH3)2], 3.68 (ddd, JHH ¼ 9, 11 Hz, JPH ¼ 4 Hz, 1H, HbC), 4.31 (dd, JHH ¼ 11 Hz, JPeH ¼ 4.3 Hz, 1H, HcC), 7.44e8.09 (m,
8H, H-Ph).
f
dH (D2O): 2.34 (s, 3H, H3CePh), 5.17 (dd, JHH ¼ 1.2 Hz, JPH ¼ 13.6 Hz, 1H, HCeP2), 7.31 (dd, JHH ¼ 1.1 Hz, JPH ¼ 3.2 Hz, HbC), 7.39e8.12 (m, 8H, H-Ph).
4
4
g
2
3
3
dH (D2O): 3.08 (dd, JHH ¼ 10.6 Hz, JPH ¼ 11.8 Hz, 1H, HaC), 3.53 (ddd, JHH ¼ 9, 11 Hz, JPeH ¼ 3.5 Hz, 1H, HbC), 4.08 (d of d, JHH ¼ 10.5 Hz, JPH ¼ 3.3 Hz, 1H, HcC), 7.42e8.11 (m, 4H, H-C6H4).

1024
W.M. Abdou et al. / European Journal of Medicinal Chemistry 43 (2008) 1015e1024
7.1.2. In the presence of EtONa as a base
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raethyl methyl-1,1-bisphosphonate (1) and 3 mmol of Na in
10 mL dry EtOH was added dropwise a solution of
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15 mL EtOH at 0 ꢂC. The resulting mixture was allowed to
warm to r.t., and stirred for the proper time (TLC, Table 1).
HCl (1 N) was added (at ꢃ5 ꢂC) until the pH of the reaction
mixture became acidic. The mixture was extracted with
AcOEt (3 ꢄ 50 mL) and the combined organic phase was dried
over anhydrous Na2SO4. After removal of the solvent, under
vacuum, the resulting residue was chromatographed on silica
gel (n-hexane/ethyl acetate) to give BP-products 5aef and
7aef. Percentage yields, physical and spectral data of the
products are listed in Tables 1, 4 and 5.
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This research has been supported by the Egyptian Govern-
ment (National Research Centre).