Novel Synthesis Approach and Antiplatelet Activity Evaluation of 6-Arylmethyleneamino-2-Alkylsulfonylpyrimidin-4(3H)-one Derivatives and Its Nucleosides

DOI: 10.4236/ijoc.2013.33A004   PDF   HTML     3,045 Downloads   5,096 Views  


A new and efficient procedure has been designed for the preparation of 6-arylmethylene-amino-2-alkyl sulfonyl-pyrimidine. The first alkylthio group was introduced into the pyrimidine ring by S-alkylation. The introduction of the second one was successfully achieved using the phosphorous oxychloride method to afford 4-chloro-2-alkylthio-pyrimidines. Subsequent nucleophilic displacement by the corresponding alkylamines followed by glycoside bromide addition conveniently gave a series of the target compounds. Thus, the two same or different alkylamino groups were easily introduced into the pyrimidine ring through the two different approaches. The human anti-platelet aggregation activity of the newly synthesized compounds was also described.

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A. Alshammari and A. El-Gazzar, "Novel Synthesis Approach and Antiplatelet Activity Evaluation of 6-Arylmethyleneamino-2-Alkylsulfonylpyrimidin-4(3H)-one Derivatives and Its Nucleosides," International Journal of Organic Chemistry, Vol. 3 No. 3A, 2013, pp. 28-40. doi: 10.4236/ijoc.2013.33A004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. Clark, M. S. Shahhet, D. Korakas and G. Varvounis, “Synthesis of Thieno[2,3-d] Pyrimidines from 4,6-Dichloropyrimidine-5-Carbaldehydes” Journal of Heterocyclic Chemistry, Vol. 30, No. 4, 1993, pp. 1065-1072.
[2] B. Tozkoparan, M. Ertan, P. Kelicen and R. Demirdamar, “Synthesis and Anti-Inflammatory Activities of Some Thiazolo[3,2-a]pyrimidine Derivatives” Farmaco, Vol. 54, No. 9, 1999, pp. 588-593.
[3] K. Ogowva, I. Y. Yamawaki, Y. I. Matsusita, N. Nomura, P. F. Kador and J. H. Kinoshita, “Syntheses of Substituted 2,4-Dioxo-Thienopyrimidin-1-Acetic Acids and Their Evaluation as Aldose Reductase Inhibitors,” European Journal of Medicinal Chemistry, Vol. 28, No. 10, 1993, pp. 769-781.
[4] M. Santagati, M. Modica, A. Santagati, F. Russo, S. Spampinato, “Synthesis of Aminothienopyrimidine and Thienotriazolopyrimidine Derivatives as Potential Anticonvulsant, Agents” Pharmazie, Vol. 51, No. 1, 1996, pp. 7-11.
[5] A. B. A. El-Gazzar and H. N. Hafez, “Synthesis of 4-Substituted Pyrido[2,3-d]pyrimidin-4(1H)-one as Analgesic and Anti-Inflammatory Agents,” Bioorganic & Medicinal Chemistry Letters, Vol. 19, No. 13, 2009, pp. 3392-3397.
[6] V. K. Ahluwalia, M. Chopra and R. Chandra, “Convenient Synthesis of Novel Pyrimidine Analogues of O-Hy-droxy Chalcones and Pyrano[2,3-d]pyrimidines and Their Biological Activities,” Journal of Chemical Research, No. 4, 2000, pp. 162-163.
[7] L. V. G. Nargund, V. V. Badiger and S. M. Yarnal, “Synthesis and Antibacterial Activity of Substituted 4-Aryloxypyrimido[5,4-c]cinnolines,” European Journal of Medicinal Chemistry, Vol. 29, No. 3, 1994, pp. 245-247.
[8] M. van Laar, E. Volerts and M. Verbaten, “Subchronic Effect of the GABA-Agonist Lorazepam and the 5-HTsub(2A/2C) Antagonist Ritanserin on Driving Performance, Slow Wave Sleep and Daytime Sleepiness in the Healthy Volunteers,” Psychopharmacology, Vol. 154, No. 2, 2001, pp. 189-197.
[9] K. Danel, E. B. Pedersen and C. Nielsen, “Synthesis and Anti-HIV-1 Activity of Novel 2,3-Dihydro-7H-Thiazolo[3, 2-a]pyrimidin-7-ones,” Journal of Medicinal Chemistry, Vol. 41, No. 2, 1998, pp. 191-198.
[10] H. C. Zhang, B. E. Maryanoff, H. Ye and C. Chen, “PCT International Applied WO2008054795, 2008,” Chemical Abstracts, 2008, Vol. 148, Article ID: 517743.
[11] S. W. Kortum, R. M. Lachance, B. A. Schweitzer, G. Yalamanchili, H. Rahman, M. D. Ennis, R. M. Huff and R. E. Tenbrink, “Thienopyrimidine-Based P2Y12 Platelet Aggregation Inhibitors,” Bioorganic & Medicinal Chemistry Letters, Vol. 19, No. 20, 2009, pp. 5919-5923.
[12] H. S. Kim, D. Barak, T. K. Harden, J. Boyer and K. A. Jacobson, “Acyclic and Cyclopropyl Analogues of Adenosine Bisphosphate Antagonists of the P2Y1 Receptor: Structure-Activity Relationships and Receptor Docking,” Journal of Medicinal Chemistry, Vol. 44, No. 19, 2001, pp. 3092-3108.
[13] B. Xu, A. Stephens, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S. A. Kim, H. S. Kim, N. Bischofberger, G. Cook and K. A. Jacobson, “Acyclic Analogues of Adenosine Bisphosphates as P2Y Receptor Antagonists: Phosphate Substitution Leads to Multiple Pathways of Inhibition of Platelet Aggregation,” Journal of Medicinal Chemistry, Vol. 45, No. 26, 2002, pp. 5694-5709.
[14] P. Crepaldi, B. Crepaldi, B. Cacciari, M. C. Bonache, G. Spalluto, K. Varani, P. A. Borea, I. von Kuegelgen, K. Hoffmann, M. Pugliano, C. Razzari and M. Cattaneo, “6-Amino-2-Mercapto-3H-pyrimidin-4-one Derivatives as New Candidates for the Antagonism at the P2Y12 Receptors,” Bioorganic & Medicinal Chemistry, Vol. 17, No. 13, 2009, pp. 4612-4621.
[15] A. H. Ingall, J. Dixon, A. Bailey, M. E. Coombs, D. Cox, J. I. McInally, S. F. Hunt, N. D. Kindon, B. J. Teobald, P. A. Willis, R. G. Humphries, P. Leff, J. A. Clegg, J. A. Smith and W. Tomlinson, “Antagonists of the Platelet P2T Receptor: A Novel Approach to Anti-Thrombotic Therapy,” Journal of Medicinal Chemistry, Vol. 42, No. 2, 1999, pp. 213-220.
[16] H. N. Hafez, H. A. R. Hussein and A. B. A. El-Gazzar, “Synthesis of Substituted Thieno[2,3-d]pyrimidine-2,4-dithiones and Their S-Glycoside Analogues as Potential Antiviral and Antibacterial Agents,” European Journal of Medicinal Chemistry, Vol. 45, No. 9, 2010, pp. 4026-4034.
[17] A. S. Abbas, H. N. Hafez and A. B. A. El-Gazzar, “Synthesis, in Vitro Antimicrobial and in Vivo Antitumor Evaluation of Novel Pyrimidoquinolines and Its Nucleoside Derivatives,” European Journal of Medicinal Chemistry, Vol. 46, No. 1, 2011, pp. 21-30.
[18] D. Gravier, J. P. Dupin, F. Casadebaig, G. Hou, M. Boisseau and H. Bernard, “Synthesis and in Vitro Study of Platelet Antiaggregant Activity of Some 4-Quinazolinone Derivatives,” Pharmazie, Vol. 47, 1992, pp. 91-94.
[19] J. P. Dupin, R. J. Gryglewski, D. Gravier, G. Hou, F. Casadebaig, J. Swies and S. Chlopicki, “Synthesis and Thrombolytic Activity of New Thienopyrimidinone Derivatives,” Journal of Physiology and Pharmacology, Vo. 53, No. 4, 2002, pp. 625-634.
[20] A. Vema, S. K. Panigrahi, G. Rambabu, B. Gopalakrishnan, J. A. Sarma and G. R. Desiraju, “Design of EGFR Kinase Inhibitors: A Ligand-Based Approach and Its Confirmation with Structure-Based Studies,” Bioorganic & Medicinal Chemistry, Vol. 11, No. 21, 2003, pp. 4643-4653.
[21] Y. M. Zhang, S. Cockerill, S. B. Guntrip, D. Rusnak, K. Smith, D. Vanderwall, E. Wood and K. Lackey, “Synthesis and SAR of Potent EGFR/erbB2 Dual Inhibitors,” Bioorganic & Medicinal Chemistry Letters, Vol. 14, No. 1, 2004, pp. 111-114.
[22] I. A. da Silveira, L. G. Paulo, A. L. da Miranda, S. O. Rocha, A. C. Freitas and E. J. Barreiro, “New Pyrazolylhydrazone Derivatives as Inhibitors of Platelet Aggregation,” Journal of Pharmacy and Pharmacology, Vol. 45, No. 7, 1993, pp. 646-649.
[23] C. Bertez, M. Miquel, C. Coquelet, D. Sincholle and C. Bonne, “Dual Inhibition of Cyclo-Oxygenase and Lipoxygenase by 2-Acetylthiophene 2-Thiazolye Hydrazone (CBS-1108) and Effect on Leukocyte Migration in Vivo,” Biochemical Pharmacology, Vol. 33, No. 11, 1984, pp. 1757-1762.

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