1226
Z. J. Jia et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1221–1227
(c) Rai, R.; Spengeler, P. A.; Elrod, K. C.; Young, W. B.
Curr. Med. Chem. 2001, 8, 101. (d) Sanderson, P. E. J.
Annu. Rep. Med. Chem. 2001, 36, 79. (e) Walenga, J. M.;
Jeske, W. P.; Hoppensteadt, D.; Fareed, J. Curr. Opin.
Invest. Drugs 2003, 4, 272.
3. For precedent work, see: Jia, Z. J.; Wu, Y.; Huang, W.;
Goldman, E.; Zhang, P.; Woolfrey, J.; Wong, P.; Huang,
B.; Sinha, U.; Park, G.; Reed, A.; Scarborough, R. M.;
Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2002, 12, 1651.
4. Part of the work described in this communication has
been previously presented at the 223rd ACSNational
Meeting in April 2002 in Orlando, Florida (MEDI-27 and
MEDI-126) and at the 226th ACSNational Meeting in
September 2003 in New York, New York (MEDI-32).
5. (a) Pinto, D. J.; Orwat, M. J.; Wang, S.; Amparo, E.;
Pruitt, J. R.; Rossi, K. A.; Alexander, R. S.; Fevig, J. M.;
Cacciola, J.; Lam, P. Y. S.; Knabb, R. M.; Wong, P. C.;
Wexler, R. R. Abstracts of Papers, 217th ACSNational
Meeting, Anaheim, CA, 1999, MEDI-006. (b) Pinto, D. J.;
Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.;
Amparo, E. C.; Cacciola, J.; Rossi, K. A.; Alexander,
R. S.; Smallwood, A. S.; Luettgen, J. M.; Liang, L.;
Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.;
Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2001, 44, 566.
6. Thrombin generation (TG) assay in human plasma:
Potential fXa inhibitors are dissolved in DMSO, and
serial dilutions are made in wells of 96-well plates. Repti-
lase-treated human plasma is added to the inhibitors, fol-
lowed by substrate (H-b-Ala-Gly-Arg-p-nitroanilide) and
CaCl2. The thrombin generation reaction is started by
addition of 640 pmol/L of recombinant tissue factor. The
absorbance is monitored at 405 nm at 37 ꢁC for 22 min.
The results are expressed as 2ÂTG, the concentration of
an inhibitor required to double the time of maximum
thrombin generation. Aꢀ1 mM 2ÂTG value is usually
required for positively efficacious response in our rabbit
DVT model. The 2ÂTG results for DuPont’s SN429 and
DPC4235 are 0.16 mM and 1.2 mM, respectively.
7. Sinha, U.; Lin, P. H.; Edwards, S. T.; Wong, P. W.; Zhu,
B.-Y.; Scarborough, R. M.; Su, T.; Jia, Z. J.; Song, Y.;
Zhang, P.; Clizbe, L. A.; Park, G.; Reed, A.; Hollenbach,
S. J.; Malinowski, J.; Arfsten, A. E. Arterios. Thromb.
Vasc. Biology 2003, 23, 1098.
8. (a) Hemker, H. C.; Giesen, P. L. A.; Ramjee, M.;
Wagenvoord, R.; Beguin, S. Thromb. Haemost. 2000, 83,
589. (b) Prasa, D.; Svendsen, L.; Sturzebecher, J. Thromb.
Haemost. 1997, 78, 1215. (c) Hemker, H. C.; Wielders, S.;
Kessels, H.; Behuin, S. Thromb. Haemost. 1993, 70, 617.
9. (a) Quan, M. L.; Liauw, A. Y.; Ellis, C. D.; Pruitt, J. R.;
Carini, D. J.; Bostrom, L. L.; Huang, P. P.; Harrison, K.;
Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler,
R. R. J. Med. Chem. 1999, 42, 2752. (b) Quan, M. L.;
Ellis, C. D.; Liauw, A. Y.; Alexander, R. S.; Knabb,
R. M.; Lam, G.; Wright, M. R.; Wong, P. C.; Wexler,
R. R. J. Med. Chem. 1999, 42, 2760.
Scheme 4. (a) (1) NaNO2 (1.05 equiv), concd HCl, 0 ꢁC, 30 m; (2) KI
(1.5 equiv, solution in water), 0 ꢁC–rt, overnight; (b) (1) DPPA (1.5
equiv), Et3N (1.5 equiv), DMF, rt, 3ꢁh; (2) water, reflux, 1 h; (c) (1)
.
NaNO2 (1.05 equiv), concd HCl, 0 C, 30 m; (2) SnCl2 2H2O (2.5
equiv), concd HCl, 0 ꢁC, 1.5 h; (d) HOAc, dioxane, reflux, 2.5 h;
(e) MeSO2Na (3 equiv), MeNHCH2CH2NHMe (0.1 equiv),
ꢁ
.
(CuOTf)2 PhH (0.1 equiv), DMSO, 115 C, overnight.
common precursor for compounds 28 and 29. Reduc-
tion of the nitrile yielded the aminomethyl analogue 28.
Treatment of the nitrile using commercial lithium
bis(trimethylsilyl)amide and lithium dimethylamide
afforded the amidine analogues 29 and 30, respectively.
Compounds 31 and 32 were similarly prepared. The
biphenylamine building block 61 for targets 34, 41 and
48 was produced through Suzuki coupling,18 while the
imidazolylaniline building block 62 for fXa inhibitors
36, 42 and 49 was prepared using Buchwald-type Cu(I)-
promoted C–N cross coupling. Analogues 33 and 35
were prepared using the same chemistry approach for
compounds 34 and 36.
The synthesis of building block ethyl 1-(3-aminosulfo-
nyl-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxylate (64)
has been improved from what we reported previously.3
As shown in Scheme 4, commercial 3-amino-2-naph-
thoic acid was first converted to 3-iodo-2-naphthoic
acid. The one-pot diphenylphosphoryl azide (DPPA)
reaction19 produced 3-iodo-2-naphthylamine, which
was then used to build pyrazole 63. Employing Wang’s
20
Cu(I)-promoted C–Scross coupling methodology,
compound 64 was smoothly produced in high yield
from the iodonaphthyl precursor 63.
Acknowledgements
We would like to thank Jaya Kothule, Sherin Halfon,
Paul Wong, Brian Huang, Bridget May and Shannon
Poole for performing the biological assays.
10. The relative hydrophilicity (water solubility) comparison
was experimentally made using the fXa inhibitors reten-
tion time on reverse-phase analytical HPLC with solvents
of water and acetonitrile containing 0.1% TFA. The
cLogP is calculated using ChemDraw Ultra 7.0.1.
References and notes
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M.; Herbert, J.-M.; van Boeckel, C. A. A.; Meuleman,
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