Journal of Chemical Crystallography

, Volume 38, Issue 4, pp 255–260 | Cite as

Low Temperature X-ray Crystallographic Structures of Two Lamotrigine Analogues: (I) 2-Methyl,3-amino, 5-imino-6-(2,3-dichlorophenyl)-1,2,4-triazine Water Solvate and (II) 2-Methyl,3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine Isethionate, Hemi-hydrate

  • Rex A. PalmerEmail author
  • Brian S. Potter
  • Michael J. Leach
  • Babur Z. ChowdhryEmail author
Original Paper


The X-ray crystal structures of two lamotrigine derivatives (I) 2-methyl, 3-amino, 5-imino-6-(2, 3-dichlorophenyl)-1,2,4-triazine, C10H9Cl2N5, as the hemi hydrate and (II) 2-methyl,3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, C10H10Cl2N5, as the isethionate-water solvate, have been carried out at liquid nitrogen temperature. A detailed comparison of the two structures is given. Both are monoclinic and centrosymmetric, with (I) in space group C2/c, and (II) in space group P21/n. For (I) the unit cell dimensions are a = 19.5466(10), b = 7.5483(4), c = 15.7861(8) Å, β = 91.458(3)°, volume = 2328.4(2) Å3, Z = 8, density = 1.590 Mg/m3; for (II). For (II) the unit cell dimensions are a = 6.0566(2), b = 11.0084(4) c = 23.9973(9) Å, β = 92.587(3)°, volume = 1598.35(10) Å3, Z = 4, density = 1.597 Mg/m3. For (I) final R indices [I > 2sigma(I)] are R1 = 0.0356, wR2 = 0.0782 and R indices (all data) are R1 = 0.0424, wR2 = 0.0817. For (II) final R indices [I > 2sigma(I)] are R1 = 0.0380, wR2 = 0.0871 and R indices (all data) R1 = 0.0558, wR2 = 0.0949. Both structures have a molecule of water of crystallization and (II) also includes a solvated CH3SO3. Comparisons are made between the two structures. Structure (I) is very unusual in having a = NH group at position C5′ on the triazine ring. No other examples of this particular substitution, which is usually −NH2, have been reported.

Index Abstract

Rex A. Palmer, Brian S. Potter, Michael J Leach and Babur Z. Chowdhry

The crystal structures of (I) 2-methyl,3-amino, 5-imino-6-(2, 3-dichlorophenyl)-1, 2, 4-triazine, water solvate and (II) 2-methyl,3, 5-diamino-6-(2, 3-dichlorophenyl)-1, 2, 4-triazine isethionate water solvate are presented. The relative orientation of the two rings is shown to vary. Lamotrigine and analogues have been investigated for some time for their effects on the central nervous system. For example both lamotrigine and 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine (code name BW 1003C87) are voltage-gated sodium channel blockers as well as blocking the release of the neurotransmitter glutamate [D. R. Riddall, M. J. Leach, J. Garthwaite, Mol. Pharmacol. 2006, 69 (1), 278.3], BW10003C87 (like lamotrigine) has been shown to exhibit excitatory amino acid antagonist activity similar to that of three conventional antiepileptic drugs phenytoin, carbamazepine and phenobarbital [R. Lingamaneni, H. C. Hemmings Jr., Epilepsy Res. 1993, 15, 101.]. BW 1003C87 has also been shown [B. S. Meldrum, J. H. Swan, M. J. Leach, M. H. Millan, R. Gwinn, K. Kadota, S. H Graham, J. Chen, R. P. Simon , Brain Res., 1992, 593, 1.] to reduce the release of glutamate evoked by veratrine in brain tissue, providing a therapeutic approach in both cerebral ischemia and epilepsy. This is one of a series of papers on the structures of lamotrigine analogues.


Central nervous system drugs Triazines Lamotrigines Voltage gated Na+ channel inhibitors Crystal structures and drug design 



We thank Dr P. Barraclough (University of Greenwich) for the synthesis and provision of samples of (I) and (II). Low temperature X-ray intensity data were collected on the EPSRC single crystal X-ray data facility at Southampton University.


  1. 1.
    Janes RW, Palmer RA (1989) Acta Cryst C45:129Google Scholar
  2. 2.
    Palmer RA, Potter BS, Leach MJ, Chowdhry BZ (2007) J Chem Crystallogr 37:771Google Scholar
  3. 3.
    Riddall DR, Leach MJ, Garthwaite J (2006) Mol Pharmacol 69(1):278Google Scholar
  4. 4.
    Lingamaneni R, Hemmings HC Jr (1993) Epilepsy Res 15:101CrossRefGoogle Scholar
  5. 5.
    Meldrum BS, Swan JH, Leach MJ, Millan MH, Gwinn R, Kadota K, Graham SH, Chen J, Simon RP (1992) Brain Res 593:1CrossRefGoogle Scholar
  6. 6.
    Barnes CL (1997) ORTEP-3 for Windows–a version of ORTEP-III with a Graphical User Interface (GUI). J Appl Cryst 30:568. [Based on ORTEP-III (v 1.0.3) by Johnson CK, Burnett MN]Google Scholar
  7. 7.
    Merrit EA, Bacon DJ (1997) Raster 3D Graphics version 2.7c. Meth Enzymol. 277:505 [Implemented in WinGX (qv) and generated by Ortep-3 for Windows]Google Scholar
  8. 8.
    Ladd MFC, Palmer RA (2003) Structure Determination by X-ray Crystallography, 4th edn. Klewer-Plenum, NY, p 503Google Scholar
  9. 9.
    Macrae CF, Edgington PR, McCabe P, Pidcock E, Shields GP, Taylor R, Towler M (2006) J van de Streek J Appl Cryst 39:453CrossRefGoogle Scholar
  10. 10.
    Hooft R, Nonius BV (1998) COLLECT: X-ray Data collection and processing software user interfaceGoogle Scholar
  11. 11.
    Cosier J, Glazer AM (1986) J Appl Cryst 19:105CrossRefGoogle Scholar
  12. 12.
    Otwinowski Z, Minor W (1997) Meth Enzymol 276:307; In: Carter CW Jr, Sweet RM (eds) Macromolecular crystallography. Academic Press, New YorkGoogle Scholar
  13. 13.
    Blessing RH (1995) Acta Cryst A51:33Google Scholar
  14. 14.
    R.H. Blessing (1997) J Appl Cryst 30:421CrossRefGoogle Scholar
  15. 15.
    Sheldrick GM (1996) SHELXS-86. Program for Crystal Structure Determination. University of Göttingen, GermanyGoogle Scholar
  16. 16.
    Sheldrick GM (1997) SHELXL97. Program for Crystal Structure Refinement. University of Göttingen, GermanyGoogle Scholar
  17. 17.
    Farrugia LJ, Win GX (1999) J Appl Cryst 32:837CrossRefGoogle Scholar
  18. 18.
    Spek AL (1990) Acta Crystallogr A46:C34Google Scholar
  19. 19.
    Palmer RA, Potter BS, Leach MJ, Chowdhry BZ (2007) J Chem Cryst (Accepted)Google Scholar
  20. 20.
    Potter BS, Palmer RA, Withnall R, Leach MJ, Chowdhry BZ (1999) J Chem Cryst 29(6):701CrossRefGoogle Scholar
  21. 21.
    Janes RW, Palmer RA (1989) Acta Cryst C45:129Google Scholar
  22. 22.
    Janes RW, Palmer RA (1995) Acta Cryst C51:440Google Scholar
  23. 23.
    Janes RW, Palmer RA (1995) Acta Cryst C51:685Google Scholar
  24. 24.
    Janes RW, Palmer RA (1996) Acta Cryst C52:2627Google Scholar
  25. 25.
    Janes RW (1999) J Chem Cryst 29(2):163CrossRefGoogle Scholar
  26. 26.
    Janes RW, Palmer RA (1995) J Mol Struct (Theochem) 339:95CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.School of Crystallography, Birkbeck CollegeUniversity of LondonLondonUK
  2. 2.Medway School of ScienceUniversity of Greenwich (Medway Campus)KentUK

Personalised recommendations