X-ray Crystallographic Structures of Two Lamotrigine Analogues: (I) 3,5-Diamino-6-(2-chlorophenyl)-1,2,4-triazine Water Solvate and (II) 3,5-Diamino-6-(3,6-dichlorophenyl)-1,2,4-triazine Methanol Solvate
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- Palmer, R.A., Potter, B.S., Leach, M.J. et al. J Chem Crystallogr (2008) 38: 387. doi:10.1007/s10870-008-9320-3
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The X-ray crystal structures of two lamotrigine derivatives (I) 3,5-diamino-6-(2-chlorophenyl)-1,2,4-triazine, C9H8ClN5, (465BL) as a hydrate, and (II) 3,5-diamino-6-(3,6-dichlorophenyl)-1,2,4-triazine, C9H7Cl2N5, (469BR) as a methanol solvate, have been carried out at liquid nitrogen temperature and room temperature, respectively. A detailed comparison of the two structures is given. Both are centrosymmetric with (I) in the orthorhombic space group Pbca, a = 12.2507(3), b = 15.7160(6), c = 21.71496(9) Å, Z = 16, and (II) in the monoclinic space group C2/c, a = 38.553(3), b = 4.9586(2), c = 14.546(2) Å, β = 111.59(1)°, Z = 8. Final R indices [I > 2sigma(I)] for (I) are R1 = 0.0670, wR2 = 0.1515 and for (II) R1 = 0.0434, wR2 = 0.1185. Structure (I) has water of crystallization in the lattice and (II) includes a solvated CH3OH. Structure (I) is characterized by having two crystallographically independent molecules, A and B, of 465BL, per asymmetric unit. Molecule B has a very unusual feature in that the 2-chlorophenyl ring is statistically disordered, occupying site (1) in 87.5% of the structure and site (2) in 12.5% of the structure. Sites (1) and (2) are related by an exact 180° pivot of the phenyl ring about the ring linkage bond. The presence of two independent molecules per asymmetric unit provides an ideal opportunity for the conformational flexibility of the molecule 465BL to be studied. Structure (I) also includes a further unusual feature in that the lattice contains one fully occupied water molecule and an additional solvated water which is only 33% occupied.
Rex A. Palmer, Brian S. Potter, Michael J Leach and Babur Z. Chowdhry
KeywordsCentral nervous system drugsTriazinesLamotriginesVoltage gated Na+ channel inhibitorsCrystal structures and drug design
5-Phenyl-2,4 diamino pyrimidine and 6-phenyl-1,2,4 triazine derivatives, which include lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) , have been investigated for some time for their effects on the central nervous system. Lamotrigine and structural analogues such as 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine (code name BW 1003C87) , sipatrigine (BW619C89) , and BW202W92  are all sodium channel blockers with a spectrum of in vivo actions particularly anticonvulsant (e.g. lamotrigine, 1003C87) neuroprotective (all) and also for lamotrigine-analgesic effects (neuropathic pain ). This paper is one of a series on the structures of lamotrigine analogues.
Crystals of (I) were grown by slow evaporation of a 50–50 ethanol/water solution at −20 °C. Crystals of (II) were grown by slow evaporation of a 50–50 ethanol/methanol solution at −20 °C. X-diffraction data were collected at low temperature for (I) and at room temperature for (II). For (I) a crystal 0.25 × 0.15 × 0.10 mm3 was selected, and for (II) a crystal 0.10 × 0.35 × 0.15 mm3 was selected. Intensity data were collected for (I) on an Enraf-Nonius CCD diffractometer controlled with the COLLECT software , using monochromated MoKα radiation, λ = 0.71073 Å. The diffractometer was equipped with an Oxford Cryosystems “Cryostreams” cooler , enabling the data to be collected at 100 K. Data were processed using DENZO , correcting for Lorentz and polarization effects, and absorption effects were applied using the program SORTAV [9, 10].
Intensity data for (II) were collected on an Enraf-Nonius CAD-4 automated 4-circle diffractometer equipped with a fine focus high intensity Cu source and a graphite monochromator, λ = 1.54178 Å, for room temperature recording of the diffraction pattern. CAD-4 Express Software  was used for cell determination and refinement and data reduction. The crystal showed no significant variations in the intensities of the three standard reflections during the course of data collection. Lorenz and polarization corrections were applied. An empirical absorption correction based on φ scans was also applied .
The crystals of (I) are orthorhombic, Pbca, with unit cell: a = 12.2507(3), b = 15.716(6), c = 21.7496(9) Å, and cell volume V = 4187.5(3) Å3. There are 16 molecules of C9 H8 Cl N5, 8 molecules of water and 8 partially occupied (32.49%) water molecule sites (per unit cell), giving a calculated density of 1.482 g/cm3, and a linear absorption coefficient of 0.357 mm−1. For (I) a total 25,562 integrated reflections were collected, of which 4,745 were unique (R(int) = 0.170). The high R(int) index is indicative of the relatively poor diffracting power of the crystal which may be due to the disordering in phenyl ring B. Nevertheless it is felt that the high quality of the resulting X-ray structure is sufficient for present purposes. Completeness of the data (to θ = 27.49°) was 98.9%. The resolution range was 10.89–0.77 Å.
The crystals of (II) are monoclinic, C2/c, with unit cell: a = 38.553(3), b = 4.9586(2), c = 14.546(2) Å, β = 111.59(1)°, and cell volume V = 2585.6(4) Å3. There are 8 molecules of C9H7Cl2N5, and 8 molecules of CH3OH per unit cell, giving a calculated density of 1.480 g/cm3 and a linear absorption coefficient of 4.504 mm−1. In total 3,548 integrated reflections were collected, of which 2,241 were unique (R(int) = 0.020), and completeness of data (to θ = 74.17°) was 85.1%. The resolution range was 17.89–0.80 Å. Neither crystal showed any significant variation in intensity during the course of data collection.
X-ray Structure Analyses
Both crystal structures were solved by Direct Methods in the program SHELXS-86  and refined using SHELXL-97  both implemented in the WinGX system of programs . Non-hydrogen atoms were refined anisotropically by full-matrix least square methods. Hydrogen atoms were added either using peaks in difference electron density maps or geometrically using the program, and refined, in riding mode if in geometrical locations, and with isotropic temperature factors. Geometrical calculations were made with the programs PARST and PLATON  as implemented in WinGX. The programs ORTEP  and Raster3D  also as implemented in WinGX were used to prepare Figs. 2a, b and 3a, b and the program MERCURY 1.4.1  was used to prepare Fig. 4a–c.
For (I), in the final refinement cycles there were 4,745 data to 311 parameters, resulting in a final Goodness-of-fit on F2 of 1.008 and final R indices [I > 2sigma(I)] of R1 = 0.067, wR2 = 0.1506. The largest and smallest difference electron density regions were 1.56 and −0.71 e Å−3 respectively.
Crystal data and structure refinement for I and II
Unit cell dimensions
a = 12.2507(3)Å α = 90°
a = 38.553(3)Å α = 90°
b = 15.7160(6)Å β = 90°
b = 4.9586(2)Å β = 111.59(1)°
c = 21.7496(9)Å γ = 90°
c = 14.546(2)Å γ = 90°
16 (2 per asymmetric unit)
Density (calculated) (Mg/m3)
Absorption coefficient (mm−1)
Crystal size (mm3)
0.25 × 0.15 × 0.10
0.10 × 0.35 × 0.15
θ Range for data collection
−15 ≤ h ≤ 15
−48 ≤ h ≤ 44
−20 ≤ k ≤ 19
−3 ≤ k ≤ 6
−23 ≤ l ≤ 28
−9 ≤ l ≤ 18
4,745 [R(int) = 0.1703]
2,241 [R(int) = 0.0200]
to θ 27.49° = 98.9%
to θ 74.17° = 85.1%
Full-matrix least-squares on F2
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R1 = 0.0670, wR2 = 0.1515
R1 = 0.0434, wR2 = 0.1185
R indices (all data)
R1 = 0.1548, wR2 = 0.1809
R1 = 0.0514, wR2 = 0.1228
Largest diff. peak/hole (e.Å−3)
Results and Discussion
Bond lengths are determined approximately to ±0.005 Å and bond angles to ±0.3° in (I), and to ±0.002 Å and ±0.2° in (II). Bond length and bond angle values in both structures are generally as expected and compare well with those found in organic compounds . Of special interest are the bond angles in the triazine rings of the lamotrigine analogues. As would be expected both the phenyl and triazine rings in these compounds are consistently highly planar. In structure (I) the triazine ring A atoms are planar with an rms deviation of 0.03 Å and the benzene ring A atoms are planar with an rms deviation of 0.005 Å. For the triazine ring A the attached nitrogen atom N(3′A) is −0.159(5) Å out of plane and N(5′A) is 0.121(5) Å out of plane. For the benzene ring A CLl(2A) is −0.108(5) Å out of plane and C(6′A) is 0.023(6) Å out of plane. In structure (I) the triazine ring B atoms are planar with an rms deviation of 0.004 Å and the benzene ring A atoms are planar with an rms deviation of 0.007 Å. For the triazine ring B the attached N atom N(3′B) is 0.045(5) Å out of plane and N(5′B) is −0.017(5) Å out of plane. For the benzene ring B CL(2B) is −0.110(6) Å out of plane, CL(6B) is −0.26(2) Å out of plane and C(6′B) is 0.076(6) Å out of plane. In structure (II) the triazine ring atoms are planar with an rms deviation of 0.007 Å and the benzene ring atoms are planar with an rms deviation of 0.001 Å. For the triazine ring the attached N atom N(3′) is −0.001(3) Å out of plane and N(5′) is 0.008(3) Å out of plane. For the benzene ring CL(3) is −0.009(3) Å out of plane, CL(6) is 0.020(3) Å out of plane and C(6′A) is 0.045(3) Å out of plane.
Torsion angle τ = C(2)–C(1)–C(6′)–C(5′): indicating the relative orientation of rings A and Ba
τ = C(2)–C(1)–C(6′)–C(5′)
Hydrogen Bonding in (I) and (II)
Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC-633700 and CCDC-633701. Copies of available material can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336033 or e-mail: email@example.com).
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.