HK1028031B - Crystal modification of 1-(2,6-difluorobenzyl)-ih-1,2,3-triazole-4-carboxamide and its use as antiepileptic - Google Patents

Description

Crystal modification of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide and its use as antiepileptic

Background

A compound 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide represented by the formula:

has been described in European patent application publication No. 0199262A 2(EP 199262), for example, example 4. The compounds exhibit valuable pharmacological properties; it can be used, for example, as an antiepileptic drug. The compound 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide is prepared according to the method of EP199262 starting from 2, 6-difluorobenzyl azide and by forming 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxylic acid, analogously to example 2.

EP199262 does not describe any information on the possibility of obtaining crystalline modifications. If the procedure of example 4 is followed in combination with example 2, the crude 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide is finally recrystallized from ethanol. However, it is not clear from EP199262 that such recrystallization is to be particularly useful or to be carried out under specific conditions. It has now surprisingly been found that by selecting specifically selected reaction conditions, for example by selecting suitable recrystallization solvents and recrystallization times, different crystal modifications (polymorphs) can be prepared which are characterized as follows.

Detailed Description

The resulting 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide is available as a new crystalline modification-A, A', B and C. These crystal modifications are distinguished from: their thermodynamic stability, physical parameters such as IR and raman spectral absorption spectra, X-ray structural analysis and methods for their preparation.

The present invention relates to novel crystalline modifications of B and C, processes for their preparation and their use in pharmaceutical formulations containing them.

Compared to a, modifier a' has a defect in its lattice. This can be determined by methods such as X-ray analysis, for example by analysis of a reduction in the line spacing and other substantially identical lines or bands.

The novel crystal modification A of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide melts at 242 deg.C (239-.

In the FT infrared (FT-IR) spectrum (KBr pellet-transmission), modification A or A was significantly different from modifications B and C in the shape and relative intensity of many bands. The features that were not present in the FT-IR spectra of modifications B and C are: 3412cm^-1And 3092cm^-1Band of (c) [ see: FIG. 1 of the drawings]. At 4000-^-1The following characteristic bands were determined from modification A: 3412. 3189, 3092, 1634, 1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125, 1053, 1036, 1014, 885, 840, 799, 781, 723, 688 and 640cm^-1. FT-IR spectra of each modification can be recorded using, for example, an IFS 88(Bruker) instrument.

In the FT raman spectrum (powder-reflectance method 180 °), modified form a or a' is significantly different from modified forms B and C in the shape and relative intensity of many bands.The characteristic features of the modified B and C which do not exist in the Raman spectrum are: 1080cm^-1Band of (c) [ see: FIG. 2 of the drawings]. At 3400 and 300cm^-1The following characteristic bands were determined from modification A: 3093. 2972, 1628, 1614, 1558, 1465, 1446, 1393, 1279, 1245, 1147, 1080, 1061, 1036, 1014, 840, 724, 691, 667, 550, 499, 437 and 368cm^-1. FT raman spectra of each modification can be recorded using, for example, RFS100(Bruker) instruments.

The novel modification A has an interplanar spacing (d value) in its X-ray powder spectrum of: characteristic spectral lines of 10.5 *, 5.14 *, 4.84 *, 4.55 *, 4.34 *, 4.07 *, 3.51 *, 3.48 *, 3.25 *, 3.19 *, 3.15 *, 3.07 * and 2.81 * [ see attached Table 1]. The measurement can be carried out, for example, in transmission geometry using a FR 552 Tenebrio camera produced by Enraf-Nonius, Delft (the Netherlands) and using copper Ka₁Radiation (wavelength 1.54060 *). The spectra recorded on the X-ray films were measured with an LS-18 linear scanner produced by Johannsson, Taby (Sweden) and calculated with Scanpi software (university of Stockholm, P.E. Werner).

The novel modification A is characterized by its thermogram measured by differential scanning calorimetry. An endothermic peak is shown in the graph between the 230-260 ℃ range. The peak temperature was 239-. The measurements were performed using a Perkin Elmer DSC 7 in a closed pan with a heating rate of 20K/min. The standard sample amount was about 4 mg. Typical distinguishing features that are different from modifications B and C are: there were no other thermal signals in the thermogram of modified form a.

The crystal of modification A' has the same crystal structure as modification A. However, it differs from modification A in the X-ray powder spectrum: the line spacing between its characteristic spectral line pairs is slightly reduced. They are pairs of lines with the following interplanar spacings: 3.68 * and 3.64 *, 3.51 * and 3.48 *, 3.19 * and 3.15 *.

Modification of B in FT-IR (KBr pellet-Transmission) Spectroscopy in many bandsIs significantly different from the modified bodies A, A' and C in shape and relative strength, and is characterized by 1678cm^{- 1}Band of (c) [ see: FIG. 1 of the drawings]This was not found in the corresponding maps for modifications a and C. At 4000-^-1The following characteristic bands were obtained from modification B: 3404, 3199, 3125, 1678, 1635, 1560, 1475, 1393, 1357, 1322, 1286, 1237, 1051, 1036, 1028, 889, 837, 800, 719, 667, and 645cm^-1. FT-IR spectra of each modification can be recorded using, for example, an IFS 85(Bruker) instrument.

In the FT-Raman spectrum (powder-reflectance 180 ℃ C.), modification B is clearly different from modification A, A' and modification C in the shape and relative intensity of many bands and is characterized by 3166cm^-1And 1086cm^-1Band of (c) [ see: FIG. 2 of the drawings]This is not present in the raman spectra of modifications a and C. At 3400 and 300cm^-1The following characteristic bands were obtained from modification B: 3166, 3089, 2970, 1678, 1628, 1614, 1559, 1464, 1441, 1391, 1275, 1244, 1147, 1086, 1062, 1036, 1014, 839, 773, 724, 690, 668, 595, 549, 500, 493, 430 and 365cm^-1.

FT-Raman spectra of each modification can be recorded using, for example, an RFS100(Bruker) instrument.

Modification B has an interplanar spacing (d value) in its X-ray powder pattern of: characteristic lines of 11.0 *, 8.3 *, 5.18 *, 4.88 *, 4.80 *, 4.42 *, 4.33 *, 4.19 *, 4.12 *, 3.81 *, 3.50 *, 3.41 *, 3.36 *, 3.32 *, 3.28 *, 3.24 *, 3.05 *, 2.83 * [ see: attached Table 1 ].

In the thermogram measured by differential scanning calorimetry, modification B had a weak thermal signal at 205 ℃ (180-.

In the FT-IR (KBr pellet-Transmission) spectrum, modification C is significantly less in shape and relative intensity of many bands than modifications A, A' and BThe same is true. It is characterized by 3137cm^-1Band of (c) [ see: FIG. 1 of the drawings]This was not found in the corresponding maps for modifications a and B.

At 4000-^-1The following characteristic bands were obtained from modification C: c: 3396, 3287, 3137, 1657, 1631, 1602, 1559, 1475, 1392, 1323, 1287, 1237, 1122, 1104, 1047, 1035, 1012, 876, 839, 797, 773, 729 and 653cm^-1FT-IR spectra of each modification can be recorded using, for example, IFS 85(Bruker) instruments.

In the FT-raman spectrum (powder-reflectance method 180 °), modified bulk C is significantly different from modified bulk a or a' and B in the shape and relative intensity of many bands. The characteristics which do not exist in the Raman spectra of the modified forms A and B are as follows: 3137 and 1602cm^-1Band of (c) [ see: FIG. 2 of the drawings]. At 3400 and 300cm^-1The following characteristic bands were obtained from modification C: 3137, 3080, 3012, 2971, 1673, 1629, 1602, 1561, 1436, 1271, 1248, 1105, 1065, 1035, 1013, 839, 800, 767, 726, 690, 672, 593, 549, 500, 492, 435 and 370cm^-1. FT raman spectra of each modification can be recorded using, for example, an RFS100(Bruker) instrument.

Modified form C has an interplanar spacing (d value) in its X-ray powder spectrum of: characteristic lines of 9.0 *, 4.73 *, 4.65 *, 3.75 *, 3.54 *, 3.42 * and 3.25 * [ see attached table 1 ]. In the thermogram measured by differential scanning calorimetry, the improved body C has an endothermic signal (peak temperature 239-245 ℃) in the range of 230-260 ℃ and a non-endothermic signal in the region of 180 DEG C

Similar to the broad and weak heat release signals of modified forms A or A' and B.

Table 1: characterization of modified A, B and C (X-ray powder pattern)

Improvement A:		improvement B:		improvement body C:
						d[*]	strength of	d[*]	Strength of	d[*]	Strength of
10.9	Weak (weak)	11.0	Medium and high grade	9.0	Medium and high grade
						10.5	Medium and high grade	8.3	Medium and high grade	7.0	Weak (weak)
6.6	Weak (weak)	8.1	Is very weak	5.49	Weak (weak)
						5.63	Weak (weak)	5.68	Is very weak	5.11	Is very weak
5.25	Weak (weak)	5.18	Is very strong	4.80	Weak (weak)
						5.14	Medium and high grade	5.11	Weak (weak)	4.73	High strength
4.94	Weak (weak)	4.88	Medium and high grade	4.65	Is very strong
						4.84	Is very strong	4.80	High strength	4.47	Is very weak
4.55	High strength	4.71	Is very weak	4.19	Is very weak
						4.42	Is very weak	4.61	Weak (weak)	4.11	Is very weak
4.34	Medium and high grade	4.45	Weak (weak)	3.98	Is very weak
						4.23	Is very weak	4.42	High strength	3.83	Is very weak
4.16	Weak (weak)	4.33	Is very strong	3.75	High strength
						4.07	Medium and high grade	4.19	Medium and high grade	3.73	Weak (weak)
4.01	Weak (weak)	4.12	High strength	3.54	Medium and high grade
						3.68	Is very weak	4.09	Weak (weak)	3.50	Weak (weak)
3.64	Is very weak	3.99	Is very weak	3.42	High strength
						3.60	Weak (weak)	3.95	Is very weak	3.25	Medium and high grade
3.56	Weak (weak)	3.84	Weak (weak)	2.88	Is very weak
						3.51	Medium and high grade	3.81	Medium and high grade	2.80	Is very weak
3.48	Medium and high grade	3.65	Weak (weak)	2.74	Is very weak
						3.38	Is very weak	3.61	Is very weak	2.67	Is very weak
3.25	High strength	3.58	Is very weak	2.64	Weak (weak)
						3.19	Medium and high grade	3.54	Weak (weak)

3.15	Medium and high grade	3.50	Medium and high grade
						3.11	Weak (weak)	3.47	Is very weak
3.07	Medium and high grade	3.41	Medium and high grade
						2.93	Is very weak	3.36	Is very strong
2.87	Is very weak	3.32	High strength
						2.81	Medium and high grade	3.28	Medium and high grade
2.76	Weak (weak)	3.24	Medium and high grade
						2.73	Is very weak	3.10	Weak (weak)
2.68	Weak (weak)	3.07	Weak (weak)
						2.62	Is very weak	3.05	Medium and high grade
2.53	Weak (weak)	2.93	Weak (weak)
						2.43	Weak (weak)	2.88	Weak (weak)
2.40	Is very weak	2.87	Is very weak
								2.83	Medium and high grade
		2.66	Weak (weak)
								2.63	Is very weak
		2.55	Weak (weak)
								2.50	Weak (weak)
		2.46	Weak (weak)
								2.44	Weak (weak)
		2.37	Weak (weak)
								2.35	Weak (weak)

Single crystal X-ray analysis:

the crystal mass and unit cell of modifications A, B and C will be identified by wesenberg and loiter photographs. The intensity was measured with a four-axis Nonius CAD-4 diffractometer. The crystal structure was resolved using SHELXS-97 and refined using SHELXL-97 software.

Improved body A

Space group: pan2₁Of orthorhombic crystals

Unit cell size:

a＝24.756(5)* b＝23.069(4)* c＝5.386(1)*

v＝3075.9*³ Z＝12 D_x＝1.543gcm^-3

v/molecular formula: v_z＝256.3*³

9011 characteristic reflections; of these 2479 reflections had significance of I > 2 σ (I). 557 parameters were accurate.

The positions of all H atoms were determined by differential fourier mapping and refined isotropically.

Reliability index R₁: 3.65% (wR of all 9011 reflections₂：11.34％)。

Improved body B

Space group: p^-Of 1-triclinic crystals

Unit cell size:

a＝5.326(1)* b＝11.976(2)* c＝17.355(3)*

α＝107.22(3)° β＝92.17(3)° γ＝102.11(3)°

v＝1027.9*³ Z＝4 D_x＝1.539gcm^-3

v/formula V_z＝257.0*³

4934 characteristic reflections; of these 834 had significance with I > 2 σ (I). 232 parameters are accurate.

The positions of all H atoms were determined by differential fourier mapping and refined isotropically.

Reliability index R₁: 4.20% (wR of all 4934 reflections₂：7.93％)

Improved body C

Space group: p2₁of/C-monoclinic crystals

Unit cell size:

a＝10.982(2)* b＝5.350(1)* c＝17.945(3)*

β＝91.59(1)°

v＝1053.9*³ Z＝4 D_x＝1.501gcm^-3

v/molecular formula: v_z＝263.5*³3073 characteristic reflections; of these 1071 had significance with I > 2 σ (I). 187 parameters were accurate.

All H atom positions were determined by differential fourier mapping and refined isotropically. Reliability index R₁: 5.02% (wR of all 3073 reflections₂：14.55％)

Modifications B and C have valuable pharmacological properties compared to modifications a or a'; they are particularly useful in the treatment of epilepsy.

Modifications B and C are particularly advantageous over modification A or A'.

We found, for example, that modification B dissolved faster in water and gastric fluid than modification a or a'. Thus, the rapid onset of action of modification B when used in therapy is particularly advantageous, for example, in the case of acute epileptic seizures.

The invention relates to a modified form B of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide, characterized in that it has the following absorptions in the infrared spectrum (KBr pellet-transmission method): 1678cm^-1Band(s).

The present invention relates to an improved form B of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide, characterized in that: measured by X-ray powder spectrometry, has

Characteristic lines of the interplanar spacings (d values) of 11.0 *, 8.3 *, 5.18 *, 4.88 *, 4.80 *, 4.42 *, 4.33 *, 4.19 *, 4.12 *, 3.81 *, 3.50 *, 3.41 *, 3.36 *, 3.32 *, 3.28 *, 3.24 *, 3.05 * and 2.83 *.

The invention relates to modifications B of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide, which are characterized by the characteristic spectral lines with the interplanar spacings (d values) shown in Table 1.

The invention relates to a modified form B of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide which, in a differential scanning calorimetry thermogram, in addition to an endothermic signal (peak temperature 239 ℃) at 260 ℃ and a weak thermal signal at 205 ℃ (180 ℃) 220 ℃.

The invention relates to a modified form C of 1- (2, 6-difluorobenzyl) -1H, -1, 2, 3-triazole-4-carboxamide, which exhibits an infrared spectrum (KB)₁Tablet-transmission method) had the following absorption: 3137cm^-1Band(s).

The invention relates to a modification C of 1- (2, 6-difluorobenzyl) -1H, -1, 2, 3-triazole-4-carboxamide, characterized in that it has an interplanar spacing (d-value) in the X-ray powder diagram: 9.0 *, 4.73 *, 4.65 *, 3.75 *, 3.54 *, 3.42 * and 3.25 *.

The invention relates to a modification C of 1- (2, 6-difluorobenzyl) -1H, -1, 2, 3-triazole-4-carboxamide, which is characterized by the characteristic lines with the interplanar spacings (values of d) shown in Table 1.

The invention relates to a modified form C of 1- (2, 6-difluorobenzyl) -1H, -1, 2, 3-triazole-4-carboxamide which, in a differential scanning calorimetry thermogram, in addition to an endothermic signal (peak temperature 239-.

The present invention relates to substantially pure modifications B and C of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide. The term "substantially pure" means a purity of > 95%, preferably > 98%, most preferably > 99%, based on modifications B and C.

The invention relates to pharmaceutical preparations containing 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modifications B and C. The invention relates in particular to pharmaceutical preparations suitable for the treatment of epilepsy and its secondary disorders. The invention also relates to the application of the 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-formamide modifications B and C in preparing medicinal preparations, in particular to the application in preparing medicinal preparations for treating epilepsy and secondary symptoms thereof.

The novel 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modifications B and C can be employed, for example, in the form of pharmaceutical preparations which contain an effective therapeutic amount of the active ingredient, if desired in combination with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers suitable for enteral, intragastric, e.g. oral, or parenteral administration. In addition, the novel 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modifications B and C can be administered in the form of preparations which are administered parenterally or as infusion solutions. The above-mentioned pharmaceutical preparations may be sterilized and/or contain excipients such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for osmotic pressure regulation and/or buffers. The pharmaceutical formulations of the present invention contain from about 0.1 to 100%, preferably from about 1 to 50%, of the lyophilizate to about 100% of the active ingredient.

The invention also relates to the use of the 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modifications B and C, in particular in pharmaceutical preparations. The dosage used will depend on a variety of factors, such as mode of administration, species, age of the patient and/or individual condition. The daily dose in the case of oral administration is between about 0.25 and 10mg/Kg, and preferably in the range of about 20 to 50mg for a warm-blooded species weighing about 70 Kg.

The preparation of modifications B and C can be accomplished, for example, by the following embodiments.

Example 1: improved body B

1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide (18.29kg) was dissolved in formic acid (89.3kg) with stirring and at 58-63 ℃. The above solution was added to stirred methanol (105.5 liters) at 20 ℃ to 0 ℃ for 30 minutes and then washed with formic acid (6.1kg) to form a suspension. The product was isolated immediately by filtration and washed with cold methanol (150 l, ca. 4 ℃). Vacuum drying at about 60 ℃ gave the product, polymorph B, in about 94% yield.

Example 2: improved body C

1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide (15.0g) was dissolved in acetic acid (120ml) with stirring and at about 90 ℃. The solution was cooled to 20 ℃ over a period of about 8 minutes to form a suspension. The product was isolated immediately by filtration, washed with toluene (120ml) and dried under vacuum at about 60 ℃. The product modified form C is obtained. The yield was 67.3%.

Formulation example 1:

film-coated tablets containing 100, 200 or 400mg of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modification B or C, respectively, per dosage unit and the following components:

core material mg mg mg

Active ingredient 100.00200.00400.00

Anhydrous, colloidal silica 0.881.753.5

Microcrystalline cellulose 36.6273.25146.50

Hydroxypropyl methylcellulose 5.0010.0020.00

Lactose 20.0040.0080.00

Magnesium stearate 2.004.008.00

Corn starch 10.0020.0040.00

Sodium carboxymethyl cellulose 5.0010.0020.00

Sodium dodecyl sulfate 0.501.002.00

Coating film mg mg mg

Hydroxypropyl methylcellulose 3.226.4312.87

Red iron oxide 0.040.090.18

Polyethylene glycol 80000.581.162.32

Flocculus body

Talc 2.334.669.31

Titanium dioxide 0.831.663.32

The active ingredient is granulated with deionized water. The ground lactose, corn starch, Avicel PH102, cellulose-HP-M-603, and sodium lauryl sulfate were then added to the above mixture and further granulated with deionized water.

The resulting wet wood was dried and ground. The homogeneous mixture is compressed after the addition of the remaining ingredients to produce a tablet core having the above active ingredient content.

The tablet cores are coated with a coating consisting of suitable ingredients, dissolved or suspended in water or a small amount of ethanol containing 5% isopropanol.

Drawings

FIG. 1 is a graphical representation of FT-IR spectra of KBr pellets of crystal modification A, B and C.

FIG. 2 is a graphical representation of FT-Raman spectra of powders of modified A, B and C.

In both figures, modification a is indicated by symbol, modification B is indicated by symbol and modification C is indicated by symbol.

Claims (5)

1. Modified form B of 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide represented by the following formula:

the method is characterized in that:

interplanar spacings (d-values) determined by X-ray powder mapping

Characteristic lines of 11.0 *, 8.3 *, 5.18 *, 4.88 *, 4.80 *, 4.42 *, 4.33 *, 4.19 *, 4.12 *, 3.81 *, 3.50 *, 3.41 *, 3.36 *, 3.32 *, 3.28 *, 3.24 *, 3.05 * and 2.83 *;

its FT-IR spectrum (KBr tablet-transmission method) has the following absorptions: 3404, 3199, 3125, 1678, 1635, 1560, 1475, 1393, 1357, 1322, 1286, 1237, 1051, 1036, 1028, 889, 837, 800, 719, 667, and 645cm^-1；

Its FT-raman spectrum (powder-reflectance 180 °) has the following absorptions: 3166, 3089, 2970, 1678, 1628, 1614, 1559, 1464, 1441, 1391, 1275, 1244, 1147, 1086, 1062, 1036, 1014, 839, 773, 724, 690, 668, 595, 549, 500, 493, 430 and 365cm^-1；

It has a weak thermal signal at 205 ℃ (180-.

2. The improvement of claim 1, characterized by an X-ray powder pattern having the following interplanar spacing (d value) characteristic lines: 11.0 (medium), 8.3 (medium), 8.1 (weak), 5.68 (weak), 5.18 (weak), 5.11 (weak), 4.88 (medium), 4.80 (strong), 4.71 (weak), 4.61 (weak), 4.45 (weak), 4.42 (strong), 4.33 (strong), 4.19 (medium), 4.12 (strong), 4.09 (weak), 3.99 (weak), 3.95 (weak), 3.84 (weak), 3.81 (medium), 3.65 (weak), 3.61 (weak), 3.58 (weak), 3.54 (weak), 3.50 (medium), 3.47 (weak), 3.41 (medium), 3.36 (strong), 3.32 (strong), 3.28 (medium), 3.24 (medium), 3.10 (weak), 3.07 (weak), 3.05 (medium), 2.93 (weak), 2.88 (weak), 2.83 (weak), 2.87 (weak), 2.63 * (very weak), 2.55 * (weak), 2.50 * (weak), 2.46 * (weak), 2.44 * (weak), 2.37 * (weak), 2.35 * (weak).

3. Modification B according to claim 1 or 2, which is more than 95% pure.

4. A pharmaceutical formulation comprising 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modification B according to claim 1 or 2, together with pharmaceutically acceptable excipients and additives.

5. Use of the 1- (2, 6-difluorobenzyl) -1H-1, 2, 3-triazole-4-carboxamide modifier B according to claim 1 or 2 for the preparation of a pharmaceutical preparation for the treatment of epilepsy and its secondary disorders.