Journal of Chemical Crystallography

, Volume 38, Issue 5, pp 387–392

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

Authors

    • School of Crystallography, Birkbeck CollegeUniversity of London
  • Brian S. Potter
    • School of Crystallography, Birkbeck CollegeUniversity of London
  • Michael J. Leach
    • Medway School of ScienceUniversity of Greenwich (Medway Campus)
    • Medway School of ScienceUniversity of Greenwich (Medway Campus)
Original Paper

DOI: 10.1007/s10870-008-9320-3

Cite this article as:
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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Abstract

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.

Index Abstract

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

The crystal 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 are presented. Structure (I) includes two molecules per asymmetric unit labeled A and B where molecule B is unusually disordered having Cl in either position 2 (87.5% occupied) or position 6 of the phenyl ring (12.5% occupied), the two sites being related by 180deg rotation about the ring linkage bond. Molecule I(A) on the other hand shows no disorder. The relative orientations of the two rings in I(A and B) and in II is shown to be different. 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. BW 1003C87 has also been shown to reduce the release of glutamate evoked by veratrine in brain tissue, providing a therapeutic approach in both cerebral ischemia and epilepsy [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.]. This is one of a series of papers on the structures of lamotrigine analogues.
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Keywords

Central nervous system drugsTriazinesLamotriginesVoltage gated Na+ channel inhibitorsCrystal structures and drug design

Introduction

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) [1], 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) [2], sipatrigine (BW619C89) [3], and BW202W92 [4] 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 [5]). This paper is one of a series on the structures of lamotrigine analogues.

Experimental

Data Collection

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 [6], using monochromated MoKα radiation, λ = 0.71073 Å. The diffractometer was equipped with an Oxford Cryosystems “Cryostreams” cooler [7], enabling the data to be collected at 100 K. Data were processed using DENZO [8], 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 [11] 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 [12].

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 [13] and refined using SHELXL-97 [14] both implemented in the WinGX system of programs [15]. 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 [16] as implemented in WinGX. The programs ORTEP [17] and Raster3D [18] also as implemented in WinGX were used to prepare Figs. 2a, b and 3a, b and the program MERCURY 1.4.1 [19] 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.

For (II), in the final refinement cycles there were 2,241 data to 196 parameters, resulting in a final Goodness-of-fit on F2 of 1.073 and final R indices [I > 2sigma(I)] of R1 = 0.0434, wR2 = 0.1185. The largest and smallest difference electron density regions were 0.180 and −0.484 e Å−3 respectively. Crystal data for I and II are summarized in Table 1.
Table 1

Crystal data and structure refinement for I and II

 

I

II

Identification code

465BL

469BR

CCDC entry

CCDC-633700

CCDC-633701

Empirical formula

C18H18.66Cl2N10O1.33

C10H11Cl2N5O

Formula weight

467.26

288.14

Temperature (K)

123(2)

293(2)

Wavelength (Å)

0.71073

1.54180

Crystal system

Orthorhombic

Monoclinic

Space group

Pbca

C2/c

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°

Volume (Å3)

4187.5(3)

2585.6(4)

Z

16 (2 per asymmetric unit)

8

Density (calculated) (Mg/m3)

1.482

1.480

Absorption coefficient (mm−1)

0.353

4.504

F(000)

1,978

1,184

Crystal size (mm3)

0.25 × 0.15 × 0.10

0.10 × 0.35 × 0.15

θ Range for data collection

1.87–27.49°

2.47–74.17°

Index ranges

−15 ≤ h ≤ 15

−48 ≤ h  ≤ 44

−20 ≤ k ≤ 19

−3 ≤ k ≤ 6

−23 ≤ l ≤ 28

−9 ≤ l ≤ 18

Reflections collected

25,565

3,548

Independent reflections

4,745 [R(int) = 0.1703]

2,241 [R(int) = 0.0200]

Completeness

to θ 27.49° = 98.9%

to θ 74.17° = 85.1%

Refinement method

Full-matrix least-squares on F2

Data/restraints/parameters

4745/1/311

2241/0/196

Goodness-of-fit on F2

1.005

1.073

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

Extinction coefficient

0.0

0.0012(1)

Largest diff. peak/hole (e.Å−3)

1.559a/−0.706

0.180/−0.484

a The large +ve density is associated with the minor Cl site on the 2-chlorophenyl ring which is disordered by an exact 180° rotation from the major site at position 2 and labeled as Cl(6). A more detailed model may remove this peak but this has not been attempted successfully

Results and Discussion

Crystallographic Studies

Figure 1a and b shows the chemical formulae for lamotrigine analogues (I) and (II) and their atom numbering schemes. Ortep/RASTER3D [17, 18] views of molecules (I A), (I B1), (I B2) and (II) in the crystal structures are shown in Fig. 2a–c. To aid comparison, the view direction in these diagrams is perpendicular to the triazine ring. For clarity the solvated water has been omitted in Fig. 2a and b.
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Fig. 1

Chemical scheme and standard atom numbering for (a) (I) and (b) (II)

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Fig. 2

Ortep/Raster3d views of: (a) molecule (I A); (b) molecule (I B) with CL in position 2; (c) molecule (II). To aid comparison, the view direction in these diagrams is perpendicular to the triazine ring. For clarity the solvated water has been omitted in Fig. 2a, b. Thermal motion ellipsoids are 50% probability

Molecular Geometry

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 [20]. 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.

The inter ring-plane dihedral angles are as follows: (I A) 63.9(1)°; (I B) 79.3(1)°; (II) 78.13(5)°. The torsion angle τ = C(2)–C(1)–C(6′)–C(5′) is also a measure of the relative orientation of the two rings and has values of 67.2(5)° in (I A), 101.6(5)° in (I B) and 100.0(2)° in (II) (see Table 2). It is worth noting that, in view of their occurrence in centrosymmetric space groups, all three molecules exist in two alternative versions where τ has values related to those quoted above by transformation through 180°. It may be that one of the two enantiomers in each case may exhibit preferred drug activity over the other. Further information on this important aspect will hopefully be forthcoming from future studies. To enable conformational features of the three molecules to be compared Fig. 3a–c shows views of molecules (I A), (I B) and (II) looking along C(6′)–C(1), i.e., from the triazine ring side.
Table 2

Torsion angle τ = C(2)–C(1)–C(6′)–C(5′): indicating the relative orientation of rings A and Ba

Molecule

τ = C(2)–C(1)–C(6′)–C(5′)

I(A)

67.2(5)°

I(B)

101.6(5)°

II

100.0(2)°

a See also Fig. 3

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Fig. 3

(a) Molecule (I A); (b) molecule (I B) showing only the major chlorine site CL(1) and (c) molecule (II) viewed along C(5′)–C(1). The ring planes are seen edge-on and the torsion angle τ = C(2)–C(1)–C(5′)–C(4′) governs the opening of the rings seen in this view (see text). Thermal motion ellipsoids are 50% probability

Hydrogen Bonding in (I) and (II)

Both crystal structures are characterized by distinct hydrogen bonding. In (I) all hydrogen bond donors and acceptors in both molecules A and B participate in hydrogen bonding, whereas in (II) all but one donor (H5A) participate. Figure 4a shows part of the hydrogen bonding pattern in (I) including molecule A and a centrosymmetrically related molecule A′. Figure 4b shows hydrogen bonding involving both molecules I(A) and I(B) [for the sake of clarity the partially occupied CL(6B) and H(2B) are not shown here]. Figure 4c shows part of the hydrogen bonding scheme in molecule II involving a centrosymmetric pair of molecules and their solvated methanols. Figure 4a–c were produced by MERCURY [19].
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Fig. 4

(a) Part of the hydrogen bond scheme in structure (I) showing molecule A and a centosymmetrically related molecule A (A′). (b) Part of the hydrogen bond scheme in structure (I) showing molecules A and B. (c) Part of the hydrogen bond scheme in structure (II) showing a pair of centrosymmetrically related molecules

Supplementary Material

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: teched@chemcrys.cam.ac.uk).

Acknowledgments

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.

Copyright information

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