Journal of Medicinal Chemistry
ARTICLE
(17) Inagaki, H.; Fujisawa, T.; Itoh, M.; Hayakawa, M.; Tsuda, T.;
Nagamochi, M.; Takahashi, H.; Takemura, M. Piperidine Derivatives.
PCT Int. Appl. WO 2009/125809, 2009.
(18) Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry,
D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.;
Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.;
Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Shillings, A.;
Theobald, A. F.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Type IIA
Topoisomerase Inhibition by a New Class of Antibacterial Agents.
Nature 2010, 466, 935–940.
(35) Subasinghe, N. L.; Travins, J. M.; Ali, F.; Huang, H.; Ballentine,
S. K.; Marugꢀan, J. J.; Khalil, E.; Hufnagel, H. R.; Bone, R. F.; DesJarlais,
R. L.; Crysler, C. S.; Ninan, N.; Cummings, M. D.; Molloy, C. J.;
Tomczuk, B. E. A Novel Series of Arylsulfonylthiophene-2-carboxami-
dine Inhibitors of the Complement Component C1s. Bioorg. Med. Chem.
Lett. 2006, 16, 2200–2204.
(36) Masson, S.; Saint-Clair, J.-F.; Saquet, M. Synthesis of New Mercap-
to-phosphono Substituted Heterocycles via a Thiophosphate-β-Mercapto-
phosphonate Rearrangement. Tetrahedron Lett. 1994, 35, 3083–3084.
(37) The diastereomeric ratio (dr) for each enriched mixture
(determined by 1H NMR spectroscopy) is listed in Table 1.
(38) The hydrolytic instability of the difluoromethyl group has been
noted previously. See, for example, the following: Shaitanova, E. N.;
Gerus, I. I.; Kukhar, V. P. A New Synthetic Route to 3-Polyfluoroalkyl-
Containing Pyrroles. Tetrahedron Lett. 2008, 49, 1184–1187.
(39) Analysis of the crude mixtures by LCꢀMS established the
following ratios of hydrolysis products: 15f/15i ≈ 1:1 and 15g/15j ≈
1.6:1. We were able to isolate 15f(S) and 15i(R) by PTLC but were
unable to separate 15f(R) and 15i(S). Diastereomers 15g(S) and
15g(R) were separated, but those of 15j were not (isolated as 15j(RS)).
We did not attempt to separate the diastereomers of 15h.
(40) Masson, S.; Saint-Clair, J.-F.; Saquet, M. Two Methods for the
Synthesis of (2-Mercaptophenyl)phosphonic Acid. Synthesis 1993
485–486.
(41) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal
Chemistry of hERG Optimizations: Highlights and Hang-Ups. J. Med.
Chem. 2006, 49, 5029–5046.
(42) Bird, C. W. A New Aromaticity Index and Its Application to
Five-Membered Ring Heterocycles. Tetrahedron 1985, 41, 1409–1414.
(43) Kerns, E. H; Di, L. Drug-like Properties: Concepts, Structure
Design and Methods: From ADME to Toxicity Optimization; Academic
Press: Amsterdam, 2008; Chapter 16.
(19) Hennessy, A. J.; Jones, G. E.; Markwell, R. E.; Miles, T.;
Pearson, N. D. Substituted (Aza)-1-methyl-1H-quinolin-2-ones as Anti-
bacterials. PCT Int. Appl. WO 2010/046388, 2010.
(20) Brickner, S. J.; Chen, J. M.; Li, Z. B.; Marfat, A.; Mitton-Fry,
M. J.; Reilly, U.; Plotkin, M. A.; Robinson, S.; Subramanyam, C.; Zhang,
Z. Substituted Heterocyclic Derivatives and Their Pharmaceutical Use
and Compositions. PCT Int. Appl. WO 2008/139288, 2008.
(21) Kiyoto, T.; Ando, J.; Tanaka, T.; Tsutsui, Y.; Yokotani, M.;
Noguchi, T.; Ushiyama, F.; Urabe, H.; Horikiri, H. Preparation of
Naphthyridones and Related Compounds as Antibacterial Agents. Jpn.
Kokai Tokkyo Koho JP 2009149618A, 2009.
(22) Jeong, L. S.; Tosh, D. K.; Choi, W. J.; Lee, S. K.; Kang, Y.-J.;
Choi, S.; Lee, J. H.; Lee, H.; Lee, H. W.; Kim, H. O. Discovery of a New
Template for Anticancer Agents: 20-Deoxy-20-fluoro-40-selenoarabino-
furanosyl-cytosine (20-F-40-Seleno-ara-C). J. Med. Chem. 2009, 52
5303–5306.
(23) Zhan, P.; Liu, X.; Fang, Z.; Pannecouque, C.; De Clercq,
E. 1,2,3-Selenadiazole Thioacetanilides: Synthesis and Anti-HIV Activity
Evaluation. Bioorg. Med. Chem. 2009, 17, 6374–6379.
(24) Grange, R. L.; Ziogas, J.; North, A. J.; Angus, J. A.; Schiesser,
C. H. Selenosartans: Novel Selenophene Analogues of Milfasartan and
Eprosartan. Bioorg. Med. Chem. Lett. 2008, 18, 1241–1244.
(25) Garud, D. R.; Koketsu, M. Synthesis of 3-Selena-1-dethiace-
phems and Selenazepines via Iodocyclization. Org. Lett. 2008,
10, 3319–3322.
(26) Bey, E.; Marchais-Oberwinkler, S.; Werth, R.; Negri, M.;
Al-Soud, Y. A.; Kruchten, P.; Oster, A.; Frotscher, M.; Birk, B.; Hartman,
R. W. Design, Synthesis, Biological Evaluation and Pharmacokinetics of
Bis(hydroxyphenyl) Substituted Azoles, Thiophenes, Benzenes, and
Aza-Benzenes as Potent and Selective Nonsteroidal Inhibitors of 17β-
Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1). J. Med. Chem.
2008, 51, 6725–6739.
(27) Dyck, B.; Markison, S.; Zhao, L.; Tamiya, J.; Grey, J.; Rowbot-
tom, M. W.; Zhang, M.; Vickers, T.; Sorensen, K.; Norton, C.; Wen, J.;
Heise, C. E.; Saunders, J.; Conlon, P.; Madan, A.; Schwarz, D.; Good-
fellow, V. S. A Thienopyridazinone-Based Melanin-Concentrating Hor-
mone Receptor 1 Antagonist with Potent in Vivo Anorectic Properties.
J. Med. Chem. 2006, 49, 3753–3756.
(28) Yanuka, Y.; Geryes, A.; Heller, M. Stereospecific Epimerization,
Oxidation and Toxine Rearrangement in Cinchona Alkaloids Catalyzed
by Acetic Acid. Tetrahedron 1987, 43, 911–922.
(29) Malleron, J.-L.; Tabart, M.; Carry, J.-C.; Evers, M.; El Ahmad,
Y.; Mignani, S.; Viviani, F.; Cheve, M. Quinolylpropylpiperidine Deri-
vatives, Their Preparation and the Compositions Which Comprise
Them. U.S. Patent 6,403,610, Jun 11, 2002.
(44) Carland, M.; Fenner, T. The Use of Selenium-Based Drugs in
Medicine. In Metallotherapeutic Drugs and Metal-Based Diagnostic Agents:
The Use of Metals in Medicine; Gielen, M., Tiekink, E. R. T., Eds.; Wiley:
Chichester, U.K., 2005; pp 313ꢀ332.
(45) Maruyama, I.; Abeyama, K.; Masayasu, H. Preventive or Ther-
apeutic Drug for Alzheimer’s Disease. U.S. Patent 5,948,800, Sep 7, 1999.
(46) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Organoselenium and
Organotellurium Compounds: Toxicology and Pharmacology. Chem.
Rev. 2004, 104, 6255–6285.
(47) Mugesh, G.; du Mont, W.-W.; Sies, H. Chemistry of Biologi-
cally Important Synthetic Organoselenium Compounds. Chem. Rev.
2001, 101, 2125–2179.
(48) Fischer, H.; Terlinden, R.; L€ohr, J. P.; Ro€mer, A. A Novel
Biologically Active Selenoorganic Compound. VIII. Biotransformation
of Ebselen. Xenobiotica 1988, 18, 1347–1359.
(49) Bourget, J.; Perrin, M. A.; Mignani, S.; Janocha, B.; Cheve, M.;
Neves, C.; Billot, P.; Tabart, M.; Lafont, S. Crystalline Form of (3R,4R)-
4-[3-(S)-Hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thie-
nylthio)ethyl]piperidine-3-carboxylic acid. U.S. Patent 6,982,334, Jan 3,
2006.
(50) Bourget, J.; Perrin, M. A.; Janocha, B.; Neves, C.; Billot, P.;
Lafont, S. Crystalline Form of (3R,4R)-4-[3-(S)-Hydroxy-3-(6-methox-
yquinolin-4-propyl]-1-[2-2-thienylthio)ethyl]piperidine-3-carboxylic
acid. U.S. Patent 6,939,970, Sep 6, 2005.
(51) Wang, Q.; Lucien, E.; Hashimoto, A.; Pais, G. C. G.; Nelson,
D. M.; Song, Y.; Thanassi, J. A.; Marlor, C. W.; Thoma, C. L.; Cheng, J.;
Podos, S. D.; Ou, Y.; Deshpande, M.; Pucci, M. J.; Buechter, D. D.;
Bradbury, B. J.; Wiles, J. A. Isothiazoloquinolones with Enhanced
Antistaphylococcal Activities against Multidrug-Resistant Strains: Ef-
fects of Structural Modifications at the 6-, 7-, and 8-Positions. J. Med.
Chem. 2007, 50, 199–210.
(30) Niwa, E.; Aoki, H.; Tanaka, H.; Munakata, K.; Namiki, M.
2-Furanthiol and 2-Furanselenol. Chem. Ber. 1966, 99, 3215–3217.
(31) Jones,E.;Moodie,I.M.2-Thiophenethiol.Org. Synth. 1970,50, 104.
(32) Yur’ev, Y. K; Mezentsova, N. N. Chemistry of Selenophene. V.
Selenophene-2-aldehyde, selenophene-2-carbinol, and selenophene-
2-acrylic acid. Zh. Obshch. Khim. 1957, 27, 179–182.
(33) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H.
Bis(2-methoxyethyl)aminosulfur Trifluoride: A New Broad-Spectrum
Deoxofluorinating Agent with Enhanced Thermal Stability. J. Org. Chem.
1999, 64, 7048–7054.
(34) Talukdar, S.; Hsu, J.-L.; Chou, T.-C.; Fang, J.-M. Direct
Transformation of Aldehydes to Nitriles Using Iodine in Ammonia
Water. Tetrahedron Lett. 2001, 42, 1103–1105.
3425
dx.doi.org/10.1021/jm2002124 |J. Med. Chem. 2011, 54, 3418–3425