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Synthesis 2009(6): 913-920  
DOI: 10.1055/s-0028-1087970
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Parallel Synthesis of Drug-like 5-Amino-Substituted 1,2,4-Thiadiazole Libraries Using Cyclization Reactions of a Carboxamidine Dithiocarbamate Linker

Joo Yeon Parka,b, In Ae Ryua,b, Ji Hoon Parka, Duck Chan Hab, Young-Dae Gong*a
a Center for High Throughput Synthesis Platform Technology, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Daejon 305-600, Korea
b Department of Chemistry, Korea University, Sungbuk-gu, Seoul 136-701, Korea
Fax: +82(42)8607698; e-Mail: ydgong@krict.re.kr;
Further Information

Publication History

Received 14 October 2008
Publication Date:
24 February 2009 (online)

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Abstract

A general method has been developed for the solution-phase parallel synthesis of various drug-like 5-amino-substituted 1,2,4-thiadiazole derivatives, which employs initial cyclization reaction of carboxamidine dithiocarbamate 2 with p-toluenesulfonyl chloride. The carboxamidine dithiocarbamate 2 was produced by a three-component nucleophilic substitution reaction between carbon disulfide, benzamidine 1, and benzyl chloride. The key intermediate in this sequence, 5-(benzylsulfanyl)-3-phenyl-1,2,4-thiadiazole (3), is then transformed to the desired 5-amino-substituted 3-phenyl-1,2,4-thiadiazoles 6 in good yields and purities via oxidation of the sulfide group to form the corresponding sulfone followed by substitution reactions with various amines.

Key words

parallel synthesis - drug-like properties - 5-amino-1,2,4-thiadiazole - dithiocarbamate linker

    References and Notes

  • 1a Krchňák V. Holladay MW. Chem. Rev.  2002,  102:  61 
    Google Scholar
  • 1b Thompson LA. Ellman JA. Chem. Rev.  1996,  96:  555 
    Google Scholar
  • 1c Terrett NK. Gardner M. Gordon DW. Kobylecki RJ. Steele J. Tetrahedron  1995,  51:  8135 
    Google Scholar
  • 2a Pal M. Batchu VR. Parasuraman K. Yeleswarapu KR. J. Org. Chem.  2003,  68:  6806 
    Google Scholar
  • 2b Watanabe N. Kabasawa Y. Takase Y. Matsukura M. Miyazaki K. Ishihara H. Kodama K. Adachi H. J. Med. Chem.  1998,  41:  3367 
    Google Scholar
  • 2c Napoletano M. Norcini G. Pellacini F. Marchini F. Morazzoni G. Fattori F. Ferlenga P. Pradella L. Bioorg. Med. Chem. Lett.  2002,  12:  5 
    Google Scholar
  • 2d Van der Mey M. Hatzelmann A. Van der Laan IJ. Sterk GJ. Thibaut U. Timmerman H. J. Med. Chem.  2001,  44:  2511 
    Google Scholar
  • 3a Mullican MD. Wilson MW. Connor DT. Kostlan CR. Schrier DJ. Dyer RD. J. Med. Chem.  1993,  36:  1090 
    Google Scholar
  • 3b Song Y. Connor DT. Sercel AD. Sorenson RJ. Doubleday R. Unangst PC. Roth BD. Beylin VG. Beylin VG. Gilbertsen RB. Chan K. Schrier DJ. Guglietta A. Bornemeier DA. Dyer RD. J. Med. Chem.  1999,  42:  1161 
    Google Scholar
  • 3c Labanauskas L. Kalcas V. Udrenaite E. Gaidelis P. Brukstus A. Dauksas A. Pharmazie  2001,  56:  617 
    Google Scholar
  • 3d Boschelli DH. Connor DT. Bornemeier DA. Dyer RD. Kennedy JA. Kuipers PJ. Okonkwo GC. Schrier DJ. Wright CD. J. Med. Chem.  1993,  36:  1802 
    Google Scholar
  • 4a El-Emam AA. Al-Deeb OA. Al-Omar M. Lehmann J. Bioorg. Med. Chem.  2004,  12:  5107 
    Google Scholar
  • 4b Dogan HN. Duran A. Rollas S. Sener G. Uysal MK. Gülen D. Bioorg. Med. Chem.  2002,  10:  2893 
    Google Scholar
  • 4c Hollar BS. Gonsalves R. Shenoy S. Eur. J. Med. Chem.  2000,  35:  267 
    Google Scholar
  • 5a Chapleo CB. Myers M. Myers PL. Saville JF. Smith ACB. Stillings MR. Tulloch IF. Walter DS. Welbourn AP. J. Med. Chem.  1986,  29:  2273 
    Google Scholar
  • 5b Chapleo CB. Myers PL. Smith AC. Stillings MR. Tulloch IF. Walter DS. J. Med. Chem.  1988,  31:  7 
    Google Scholar
  • 5c Akbarzadeh T. Tabatabai SA. Khoshnoud MJ. Shafaghi D. Shafiee A. Bioorg. Med. Chem.  2003,  11:  769 
    Google Scholar
  • 5d Foroumadi A. Tabatabai SA. Gitinezhad G. Zarrindast MR. Shafiee A. Pharm. Pharmacol. Commun.  2000,  6:  1 
    Google Scholar
  • 6a Turner S. Myers M. Gadie B. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  902 
    Google Scholar
  • 6b Turner S. Myers M. Gadie B. Hale SA. Horsley A. Nelson AJ. Pape R. Saville JF. Doxey JC. Berridge TL. J. Med. Chem.  1988,  31:  907 
    Google Scholar
  • 6c Tyagi M. Kumar A. Oriental J. Chem.  2002,  18:  125 
    Google Scholar
  • 7a Yoo S.-e. Seo J.-s. Yi KY. Gong Y.-D. Tetrahedron Lett.  1997,  38:  1203 
    Google Scholar
  • 7b Yoo S.-e. Gong Y.-D. Seo J.-s. Sung M.-M. Lee S. Kim Y. J. Comb. Chem.  1999,  1:  177 
    Google Scholar
  • 7c Gong Y.-D. Yoo S.-e. Bull. Korean Chem. Soc.  2001,  21:  941 
    Google Scholar
  • 7d Gong Y.-D. Seo J.-s. Chon Y.-S. Hwang J.-Y. Park J.-Y. Yoo S.-e. J. Comb. Chem.  2003,  5:  577 
    Google Scholar
  • 7e Lee IY. Kim SY. Lee JY. Yu C.-M. Lee DH. Gong Y.-D. Tetrahedron Lett.  2004,  45:  9319 
    Google Scholar
  • 8a Fawzi AB. Macdonald D. Bendow LL. Smith Torhan A. Zhang HT. Weig BC. Ho G. Tulshian D. Linder ME. Graziano MP. Mol. Pharmacol.  2001,  59:  30 
    Google Scholar
  • 8b Lanzafame A. Christopoulos A. J. Pharmacol. Exp. Ther.  2004,  308:  830 
    Google Scholar
  • 8c Castro A. Castano T. Encinas A. Porcal W. Gil C. Bioorg. Med. Chem.  2006,  14:  1644 
    Google Scholar
  • 9a Mamaeva EA. Bakibaev AA. Tetrahedron  2003,  59:  7521 
    Google Scholar
  • 9b Kihara Y. Kabashima S. Uno K. Furukawa M. Synthesis  1990,  1020 
    Google Scholar
  • 9c Smith RF. Feltz TP. J. Heterocycl. Chem.  1981,  18:  201 
    Google Scholar
  • 10a Kurzer F. Adv. Heterocycl. Chem.  1965,  5:  119 
    Google Scholar
  • 10b Taliani L. Perronnet J. J. Heterocycl. Chem.  1979,  16:  961 
    Google Scholar
  • 11 Edward HK. Li D. Drug-like Properties: Concepts, Structure Design and Methods   Academic Press; London: 2007.  p.6-253  
    Google Scholar
  • 12a Hwang JY. Choi H.-S. Lee D.-H. Yoo S.-e. Gong Y.-D. J. Comb. Chem.  2005,  7:  136 
    Google Scholar
  • 12b Hwang JY. Choi H.-S. Lee D.-H. Yoo S.-e. Gong Y.-D. J. Comb. Chem.  2005,  7:  816 
    Google Scholar
  • 12c Hwang JY. Gong Y.-D. J. Comb. Chem.  2006,  8:  297 
    Google Scholar
  • 14a Oprea TI. J. Comput. Aided Mol. Des.  2000,  14:  251 
    Google Scholar
  • 14b Veber DF. Johnson SR. Cheng H.-J. Smith BR. Ward KW. Kopple KD. J. Med. Chem.  2002,  45:  2615 
    Google Scholar
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