Brief Articles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2345
zolo[4,3-d]sulfonamides 3 except that they generally
appear to give better CT-luci values. Aryl sulfonamides
(40/1 to 20/1), gave 346 mg (1.01 mmol, a 76% yield) of 20 as
1
a white solid; mp 103-104 °C. H NMR (CDCl
3
): δ 8.53 (s,
1
3
7
H), 4.05 (t, J ) 7.4 Hz, 2H), 3.98 (t, J ) 7.4 Hz, 2H), 3.42 (s,
H), 1.78-1.67 (m, 2H), 1.63-1.54 (m, 2H), 1.39 (sept, J )
2
2-26 again appear to have the optimal in vitro profile
with CT-luci values ranging from 2 to 3.6 and CTS
values ranging from 2.9 to 4.8. The o-CN analogue 23
gives a particularly strong CT-luci TAR (CT-luci, 3.6).
Thiophene analogue 25 has a particularly good in vitro
profile as it shows notable CT-luci/CTS activity with
very little PDE4 inhibition (CT-luci, 3.2; CTS, 3.0; PDE4
-
1
.4 Hz, 4H), 0.99-0.91 (m, 6H). IR (cm ): 1724, 1668, 1608.
+
MS (ES): 343 (MH) . Anal. (C14
22 4 4
H N O S) C, H, N.
Ack n ow led gm en t. We thank OSI pharmaceuticals
for the development of the calcitonin/luciferase reporter
gene expression assay, the calcitonin secretion assay,
and a fruitful collaboration on this work.
3
0, 16). Homologation of an aryl group to a benzyl,
compound 24, results in a slight loss of CT-luci activity
as compared to the other aryl sulfonamides in Table 2.
The same effect was seen for the benzyl sulfonamide
Su p p or tin g In for m a tion Ava ila ble: Full experimentals
and spectral data for compounds 5-10, 12-18, and 21-26 and
pharmacological methods describing the CT-luci, CTS, and
PDE4 30 assays. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
6 in Table 1. The 8-quinoline 26 analogue has sub-
stantial PDE4 inhibitory activity (similar to the activity
of rolipram), which is not seen with the isomeric
pyrazolo[4,3-d]pyrimidine analogue 18.
Refer en ces
(
1) (a) Bilezikian, J . P. Current and Future Nonhormonal Ap-
proaches to the Treatment of Osteoporosis. Int. J . Fertil.
Menopausal Stud. 1996, 41, 148-155. (b) Revilla, M.; Hernan-
dez, E. R.; Villa, L. F.; Alvarez de Buergo, M. Total and Regional
Bone Mineral Content and Fracture Rate in Postmenopausal
Osteoporosis Treated with Salmon Calcitonin: A Prospective
Study. Calcif. Tissue Int. 1995, 56, 181-185. (c) Munoz, B. Y.;
Domingo, A. R.; Minguella, J . F. Calcitonin: Osteoporosis
Treatment and Prevention. Drugs Today 2000, 36 (Suppl. D),
Con clu sion
In summary, we have discovered two new series of
pyrazolopyrmidine sulfonamides, 3 and 4, which in-
crease CT-luci transcription as well as cellular CT
production and secretion. Moreover, these series of
compounds do not possess the same potent PDE4
inhibitory activity as the related xanthines such as
denbufyllene 2. These series of compounds are examples
of interesting new chemical entities that may be useful
as a new class of antiresorptive agents for the treatment
of bone loss diseases.
1
3-25.
(
2) Deftos, L. J .; Nolan, J . J .; Seely, B. L.; Clopton, P. L.; Cote, G.
J .; Whitham, C. L.; Florek, L. J .; Christensen, T. A.; Hill, M. R.
Intrapulmonary Drug Delivery of Salmon Calcitonin. Calcif.
Tissue Int. 1997, 61, 345-347.
(
3) Plosker, G. L.; McTavish, D. M. Intranasal Salcatonin (Salmon
Calcitonin). Drugs Aging 1996, 8, 378-400.
(4) Baudys, M.; Kim, S. W. Stabilization and Oral Delivery of
Calcitonin. WO 9800155.
(
5) Sakuma, S.; Suzuki, N.; Kikuchi, H.; Hiwatari, K.-i.; Arikawa,
K.; Kishida, A.; Akashi, M. Absorption Enhancement of Orally
Administered Salmon Calcitonin by Polystyrene Nanoparticles
Having Poly(N-isopropylacrylamide) Branches on Their Sur-
faces. Int. J . Pharm. 1997, 158, 69-78.
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover Mel-
temp apparatus and are uncorrected. The proton ( H) NMR
1
spectra were recorded at 300 MHz on a Bruker DPX-300
spectrometer using tetramethylsilane (δ 0.0) as an internal
standard. Infrared (IR) spectra were obtained as KBr pellets.
Combustion analyses were obtained using a Perkin-Elmer
Series II 2400 CHNS/O analyzer. Mass spectra were obtained
using a Micromass Platform Electrospray Ionization Quadra-
pole mass spectrometer. Flash chromatography was performed
using EM Science 230-400 mess silica gel. Thin-layer chro-
matography (TLC) was performed in Analtech silica gel GHLF
(6) (a) Labroo, V. M.; Beigel, S. Synthetic Calcitonin Mimetics. U.S.
698672. (b) Milstein, S. J .; Barantsevitch, E. N.; Sarubbi, D.
5
J .; Leone-Bay, A.; Paton, D. R. Oral Drug Delivery Compositions
and Methods. U.S. 5766633.
(
7) There have been reports in the literature of molecules that act
as calcitonin mimetics. (a) Baindur, N.; Labroo, V.; Stroop, S.;
Beigel, S.; Martinez, T.; Petrie, C.; Orme, M. W.; McKernan, P.
A.; Moore, E. E. Calcitonin Mimetics. WO 9837077. (b) Baindur,
N.; Labroo, V.; Martinez, T.; Carollo, S.; Lum, K.; Strachan, M.;
Liu, C.; Moore, B.; Stroop, S.; McKernan, P. Discovery, Synthesis
and SAR of Substituted Piperazines as the First Non-Peptide
Calcitonin Receptor Agonists for Potential Treatment of Os-
teoporosis and Related Bone Deficit Conditions. Book of Ab-
stracts, 217th ACS National Meeting, Anaheim, California,
March 21-25, 1999. (c) Katayama, T.; Furuya, M.; Yamaichi,
K.; Konishi, K.; Sugiura, N.; Murafuji, H.; Magota, K.; Saito,
M.; Tanaka, S.; Oikawa, S. Discovery of a Non-Peptide Small
Molecule that Selectively Mimics the Biological Actions of
Calcitonin. Biochem. Biophys. Acta 2001, 1526, 183-190.
2
50 µm prescored plates.
,6-Dibu t yl-2-m et h a n esu lfon yl-2,4-d ih yd r o-p yr a zolo-
4,3-d ]p yr im id in e-5,7-d ion e (11). To 281 mg (1.06 mmol) of
in 10 mL of CH Cl were added 0.28 mL (206 mg, 1.60 mmol)
of i-Pr NEt and 90 µL (134 mg, 1.17 mmol) of MeSO Cl. After
4
[
7
2
2
2
2
this mixture was stirred at 23 °C for 2 h, the mixture was
poured into 50 mL of brine and extracted with 2 × 25 mL of
EtOAc. The combined organics were washed with 1 × 25 mL
(8) Gilbert, A. M.; Caltabiano, S.; Roberts, D.; Sum, S. F. W.;
Francisco, G. D.; Lim, K.; Asselin, M.; Ellingboe, J . W.; Kharode,
Y.; Cannistraci, A.; Francis, R.; TrailSmith, M.; Gralnick, D.
Novel and Selective Calcitonin Inducing Agents. J . Med. Chem.
of H
2
O and 1 × 25 mL of brine, dried over MgSO
4
, filtered,
and evaporated to a yellow solid. Flash chromatography on
SiO , eluting with CH Cl /EtOAc (40/1 to 20/1), gave 259 mg
0.76 mmol, a 71% yield) of 11 as a white solid; mp 183-184
2
2
2
2
000, 43, 1223-1233.
(
°
(9) Xanthine PDE4 inhibitors have emetic properties due to their
affinity to a hypothesized high affinity rolipram binding site.
See Duplantier, A. J .; Biggers, M. S.; Chambers, R. J .; Cheng,
J . B.; Cooper, K.; Damon, D. B.; Eggler, J . F.; Kraus, K. G.;
Marfat, A.; Masamune, H.; Pillar, J . S.; Shirley, J . T.; Umland,
J . P.; Watson, J . W. J . Med. Chem. 1996, 39, 120-125.
(10) Papesch, V.; Dodson, R. M. Isomeric pyrazolo[4,3-d]pyrim-
idinediones. J . Org. Chem. 1965, 30, 199-203.
11) Hirota, K.; Maruhashi, K.; Asao, T.; Kitamura, N.; Maki, Y.;
Senda, S. Pyrimidine derivatives and related compounds. XLVI.
Thermal and photochemical transformation of 5-substituted
1
C. H NMR (CDCl
3
): δ 7.87 (s, 1H), 4.05 (t, J ) 7.4 Hz, 2H),
3
0
1
.85 (t, J ) 7.5 Hz, 2H), 1.72-1.57 (m, 4H), 1.45-1.31 (m, 4H),
-
1
.98 (t, J ) 7.5 Hz, 3H), 0.96 (t, J ) 7.5 Hz, 3H). IR (cm ):
+
714, 1675, 1624. MS (ES): 343 (MH) . Anal. (C14
22 4 4
H N O S)
C, H, N.
,7-Dibu t yl-2-m et h a n esu lfon yl-2,7-d ih yd r o-p yr a zolo-
3,4-d ]p yr im id in e-4,6-d ion e (20). To a 23 °C solution of 350
mg (1.32 mmol) of 10 and 10 mL of CH Cl were added 0.35
mL (257 mg, 1.99 mmol) of i-Pr NEt and 110 µL (167 mg, 1.46
mmol) of MeSO Cl. After the mixture was stirred at 23 °C for
h, the reaction mixture was poured into 50 mL of brine and
extracted with 2 × 25 mL of EtOAc, and the combined organics
were washed with 1 × 50 mL of H O and 1 × 50 mL of brine,
dried over MgSO , filtered, and evaporated to a yellow oil.
Flash chromatography on SiO , eluting with CH Cl /EtOAc
5
(
[
2
2
2
6
-azido-1,3-dimethyluracils into fused pyrimidines such as isox-
2
azolo[3,4-d]pyrimidines, pyrazolo[3,4-d]pyrimidines, and pyr-
imido[4,5-d][1,2,3]triazine. Chem. Pharm. Bull. 1983, 31, 3959-
3
2
966.
(
12) Chen, B. C.; von Philipsborn, W. Helv. Chim. Acta 1983, 66,
537-1555.
2
1
4
2
2
2
J M010554S