Novel salts of 3-[(DIMETHYLAMINO)METHYL]-N--1-BENZOFURAN-2-CARBOXAMIDE, related crystalline forms, method for preparing the same and pharmaceutical compositions containing the same
Described herein are salts of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide, in particular that of formula (I): wherein HA is naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oxalic acid, benzenesulfonic acid, or sulfuric acid, or hydrates thereof, and crystalline forms thereof characterized by the powder X-ray diffraction diagram and the 13 C CP/MAS NMR solid state spectrum. Also described are compositions, methods of use and preparation thereof.
1 . A salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide of formula (I):
wherein HA is naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oxalic acid, benzenesulfonic acid, or sulfuric acid, or a hydrate thereof.
2 . The salt of claim 1 , which is a salt of formula (Ia):
wherein HA is naphthalene-1,5-disulfonic acid, naphthalene-sulfonic acid, oxalic acid or benzenesulfonic acid.
3 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is naphthalene-1,5-disulfonic acid and wherein the crystalline form has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 6.87; 10.71; 11.31; 13.97; 18.51; 21.49; 21.84; 24.56.
4 . The crystalline form according to claim 3 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 6.87; 10.71; 11.31; 13.97; 18.51; 20.71; 21.18; 21.49; 21.84; 22.74; 24.56.
5 . The crystalline form according to claim 3 or 4 characterized in that it has a powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg angle 2 theta, expressed in degrees±0.2°) and interplanar spacing d (expressed in Å):
Line no.
Angle 2 theta (degrees)
Interplanar spacing (Å)
1
6.87
12.861
2
10.71
8.262
3
11.31
7.821
4
13.97
6.341
5
18.51
4.794
6
20.71
4.288
7
21.18
4.194
8
21.49
4.134
9
21.84
4.069
10
22.74
3.910
11
24.56
3.625
6 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is naphthalene-1,5-disulfonic acid and wherein the crystalline form has a solid state 13 C CP/MAS NMR spectrum exhibiting the following peaks (expressed in ppm±0.2 ppm):
Peak no.
Chemical shift (ppm)
Δδ ppm (/37.8 ppm)
1
167.9
130.1
2
161.1
123.3
3
158.6
120.8
4
153.8
116.0
5
145.5
107.7
6
142.4
104.6
7
130.3
92.5
8
126.0
88.2
9
122.4
84.6
10
119.6
81.8
11
114.3
76.5
12
64.5
26.7
13
51.2
13.4
14
45.6
7.8
15
44.0
6.2
16
37.8
0.0
7 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is naphthalene-2-sulfonic acid and wherein the crystalline form has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 8.92; 9.33; 10.85; 17.89; 19.79; 21.79; 26.39.
8 . The crystalline form according to claim 7 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 8.92; 9.33; 10.85; 11.78; 17.89; 19.79; 19.99; 21.79; 25.23; 26.39.
9 . The crystalline form according to claim 7 or 8 characterized in that it has a powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg angle 2 theta, expressed in degrees±0.2°) and interplanar spacing d (expressed in Å):
Line no.
Angle 2 theta (degrees)
Interplanar spacing (Å)
1
8.92
9.917
2
9.33
9.476
3
10.85
8.153
4
11.78
7.515
5
17.89
4.957
6
19.79
4.484
7
19.99
4.440
8
21.79
4.078
9
25.23
3.529
10
26.39
3.376
10 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is naphthalene-2-sulfonic acid and wherein the crystalline form has a solid state 13 C CP/MAS NMR spectrum exhibiting the following peaks (expressed in ppm±0.2 ppm):
Peak no.
Chemical shift (ppm)
Δδ ppm (/41.7 ppm)
1
165.7
124.0
2
154.2
112.5
3
141.1
99.4
4
139.5
97.8
5
133.2
91.5
6
128.5
86.8
7
127.6
85.9
8
126.0
84.3
9
124.6
82.9
10
122.4
80.7
11
113.1
71.4
12
64.8
23.1
13
63.2
21.5
14
50.7
9.0
15
47.2
5.5
16
45.5
3.8
17
42.8
1.1
18
41.7
0.0
11 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is oxalic acid and wherein the crystalline form has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 9.11; 9.67; 16.39; 17.73; 18.49; 18.65; 18.79; 21.96; 22.39; 23.39; 26.76; 27.92; 30.72.
12 . The crystalline form according to claim 11 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 9.11; 9.67; 16.39; 16.56; 17.73; 18.49; 18.65; 18.79; 20.35; 20.85; 21.00; 21.96; 22.39; 23.39; 23.91; 26.22; 26.76; 27.92; 30.72.
13 . The crystalline form according to claim 11 or 12 characterized in that it has a powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg angle 2 theta, expressed in degrees±0.2°) and interplanar spacing d (expressed in Å):
Line no.
Angle 2 theta (degrees)
Interplanar spacing (Å)
1
9.11
9.704
2
9.67
9.142
3
16.39
5.408
4
16.56
5.354
5
17.73
5.004
6
18.49
4.798
7
18.65
4.758
8
18.79
4.721
9
20.35
4.364
10
20.85
4.260
11
21.00
4.229
12
21.96
4.048
13
22.39
3.971
14
23.39
3.804
15
23.91
3.722
16
26.22
3.399
17
26.76
3.332
18
27.92
3.196
19
30.72
2.911
14 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is oxalic acid and wherein the crystalline form has a solid state 13 C CP/MAS NMR spectrum exhibiting the following peaks (expressed in ppm±0.2 ppm):
Peak no.
Chemical shift (ppm)
Δδ ppm (/42.9 ppm)
1
168.9
126.0
2
162.6
119.7
3
153.7
110.8
4
146.1
103.2
5
130.0
87.1
6
128.7
85.8
7
127.4
84.5
8
125.8
82.9
9
124.3
81.4
10
123.2
80.3
11
119.8
76.9
12
118.5
75.6
13
114.2
71.3
14
113.5
70.6
15
111.8
68.9
16
65.8
22.9
17
50.9
8.0
18
47.3
4.4
19
42.9
0.0
15 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is benzenesulfonic acid and wherein the crystalline form has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 8.08; 10.03; 10.36; 13.63; 15.00; 16.19; 17.73; 17.90; 18.77; 19.77; 21.98; 22.45.
16 . The crystalline form according to claim 15 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 8.08; 10.03; 10.36; 11.86; 12.66; 13.63; 15.00; 16.19; 16.39; 16.52; 17.73; 17.90; 18.77; 19.77; 20.20; 20.86; 21.11; 21.98; 22.45; 23.84; 26.13; 26.74; 27.44.
17 . The crystalline form according to claim 15 or 16 characterized in that it has a powder X-ray diffraction diagram, measured on a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg angle 2 theta, expressed in degrees±0.2°) and interplanar spacing d (expressed in Å):
Line no.
Angle 2 theta (degrees)
Interplanar spacing (Å)
1
8.08
10.949
2
10.03
8.818
3
10.36
8.539
4
11.86
7.463
5
12.66
6.992
6
13.63
6.498
7
15.00
5.906
8
16.19
5.473
9
16.39
5.407
10
16.52
5.366
11
17.73
5.002
12
17.90
4.954
13
18.77
4.728
14
19.77
4.492
15
20.20
4.395
16
20.86
4.259
17
21.11
4.209
18
21.98
4.043
19
22.45
3.961
20
23.84
3.732
21
26.13
3.411
22
26.74
3.333
23
27.44
3.251
18 . A crystalline form of the salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 1 or 2 , wherein HA is benzenesulfonic acid and wherein the crystalline form has a solid state 13 C CP/MAS NMR spectrum exhibiting the following peaks (expressed in ppm±0.2 ppm):
Peak no.
Chemical shift (ppm)
Δδ ppm (/42.0 ppm)
1
165.5
123.5
2
161.7
119.7
3
152.6
110.6
4
145.9
103.9
5
128.2
86.2
6
126.5
84.5
7
121.6
79.6
8
114.3
72.3
9
111.2
69.2
10
68.4
26.4
11
51.2
9.2
12
44.5
2.5
13
42.0
0.0
The salt of claim 1 , which is a salt of formula (Ib):
wherein HA is sulfuric acid, or a hydrate thereof.
20 . A hemipentahydrate crystalline form of the salt according to claim 19 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 6.92; 9.01; 11.04; 13.87; 14.24; 14.89; 15.06; 17.34; 18.96; 20.05; 21.49; 24.34; 24.59; 25.19; 25.89.
21 . The hemipentahydrate crystalline form according to claim 20 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 6.92; 9.01; 11.04; 11.82; 13.87; 14.24; 14.89; 15.06; 17.34; 18.96; 20.05; 20.84; 21.23; 21.49; 22.68; 22.85; 24.34; 24.59; 25.19; 25.89; 28.28.
22 . The hemipentahydrate crystalline form according to claim 20 or 21 characterized in that it has a powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg angle 2 theta, expressed in degrees±0.2°) and interplanar spacing d (expressed in Å):
Line no.
Angle 2 theta (degrees)
Interplanar spacing (Å)
1
6.92
12.782
2
9.01
9.815
3
11.04
8.015
4
11.82
7.489
5
13.87
6.386
6
14.24
6.222
7
14.89
5.949
8
15.06
5.882
9
17.34
5.114
10
18.96
4.681
11
20.05
4.429
12
20.84
4.262
13
21.23
4.185
14
21.49
4.134
15
22.68
3.920
16
22.85
3.892
17
24.34
3.657
18
24.59
3.620
19
25.19
3.535
20
25.89
3.441
21
28.28
3.156
23 . A hemipentahydrate crystalline form of the salt according to claim 19 characterized in that it has a solid state 13 C CP/MAS NMR spectrum exhibiting the following peaks (expressed in ppm±0.2 ppm):
Peak no.
Chemical shift (ppm)
Δδ ppm (/38.4 ppm)
1
166.0
127.6
2
159.2
120.8
3
146.8
108.4
4
123.1
84.7
5
121.8
83.4
6
120.7
82.3
7
114.8
76.4
8
112.8
74.4
9
112.1
73.7
10
110.0
71.6
11
107.1
68.7
12
66.7
28.3
13
63.0
24.6
14
49.0
10.6
15
41.7
3.3
16
40.2
1.8
17
38.4
0.0
24 . A hemiheptahydrate crystalline form of the hydrogen sulfate or 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to claim 19 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 9.99; 10.67; 13.79; 13.92; 14.25; 14.67; 15.18; 16.21; 18.44; 18.82; 20.42; 21.71; 22.47; 23.30; 24.25.
25 . The hemiheptahydrate crystalline form according to claim 24 characterized in that it has a powder X-ray diffraction diagram exhibiting the following diffraction lines (Bragg angle 2 theta, expressed in degrees±0.2°): 9.99; 10.67; 12.65; 13.79; 13.92; 14.25; 14.67; 15.18; 16.21; 16.43; 18.44; 18.82; 20.42; 20.76; 21.09; 21.45; 21.71; 22.47; 22.92; 23.30; 23.89; 24.25; 26.02; 26.54.
26 . The hemiheptahydrate crystalline form according to claim 24 or 25 characterized in that it has a powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg angle 2 theta, expressed in degrees±0.2°) and interplanar spacing d (expressed in Å):
Line no.
Angle 2 theta (degrees)
Interplanar spacing (Å)
1
9.99
8.838
2
10.67
8.284
3
12.65
6.995
4
13.79
6.418
5
13.92
6.356
6
14.25
6.211
7
14.67
6.032
8
15.18
5.831
9
16.21
5.464
10
16.43
5.389
11
18.44
4.808
12
18.82
4.712
13
20.42
4.345
14
20.76
4.276
15
21.09
4.209
16
21.45
4.140
17
21.71
4.090
18
22.47
3.953
19
22.92
3.877
20
23.30
3.814
21
23.89
3.721
22
24.25
3.667
23
26.02
3.422
24
26.54
3.355
27 . A pharmaceutical composition comprising a salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to any one of claims 1 , 2 or 19 as an active ingredient and one or more pharmaceutically acceptable carriers.
28 . A pharmaceutical composition comprising a crystalline form of a salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to any one of claims 3 to 18 or 20 to 26 as an active ingredient and one or more pharmaceutically acceptable carriers.
29 . The pharmaceutical composition according to claim 27 or 28 for use in the treatment of cancer.
30 . The pharmaceutical composition according to any one of claims 27 to 29 wherein the cancer is a carcinoma, a tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma or a blastoma.
31 . A method for preparing a crystalline form of a salt of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to any one of claims 3 to 18 , wherein the 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide is crystallized in the presence of naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oxalic acid or benzenesulfonic acid in a polar medium.
32 . The method according to claim 31 , wherein the polar medium consists of one or more solvents chosen from among water, alcohols, ketones, nitriles and esters.
33 . The method according to claim 31 , wherein the polar medium is a binary mixture, one of the components of which is water.
34 . The method according to claim 31 , wherein the polar medium is a binary mixture chosen from among: acetone/water, ethanol/water, isopropanol/water and methylethylketone/water.
35 . A method for preparing a hydrated crystalline form of the hydrogen sulfate of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide according to any one of claims 20 to 26 , in which the 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide is crystallized in a polar medium in the presence of sulfuric acid.
36 . The method according to claim 35 , wherein the polar medium consists of one or more solvents chosen from among water, ketones, nitriles and esters.
37 . The method according to claim 35 , wherein the polar medium is a binary mixture, one of the components of which is water.