U.S. patent application number 15/508609 was filed with the patent office on 2017-09-21 for 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.
The applicant listed for this patent is Pharmacyclics LLC. Invention is credited to Marina Gaillard, Philippe Letellier.
Application Number | 20170266151 15/508609 |
Document ID | / |
Family ID | 54186276 |
Filed Date | 2017-09-21 |
United States Patent
Application |
20170266151 |
Kind Code |
A1 |
Gaillard; Marina ; et
al. |
September 21, 2017 |
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
Abstract
Described herein are salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide, in particular that of formula (I):
##STR00001## 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 13C
CP/MAS NMR solid state spectrum. Also described are compositions,
methods of use and preparation thereof.
Inventors: |
Gaillard; Marina; (Orleans,
FR) ; Letellier; Philippe; (Orleans, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pharmacyclics LLC |
Sunnyvale |
CA |
US |
|
|
Family ID: |
54186276 |
Appl. No.: |
15/508609 |
Filed: |
September 3, 2015 |
PCT Filed: |
September 3, 2015 |
PCT NO: |
PCT/US2015/048243 |
371 Date: |
March 3, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/185 20130101;
A61P 35/00 20180101; A61P 35/02 20180101; G01V 3/14 20130101; C07D
307/85 20130101; A61P 21/00 20180101; G01N 23/20 20130101; A61P
25/00 20180101; A61P 17/00 20180101; A61K 31/135 20130101; A61K
31/343 20130101; A61K 31/166 20130101 |
International
Class: |
A61K 31/343 20060101
A61K031/343; A61K 31/166 20060101 A61K031/166; G01V 3/14 20060101
G01V003/14; A61K 31/185 20060101 A61K031/185; G01N 23/20 20060101
G01N023/20; C07D 307/85 20060101 C07D307/85; A61K 31/135 20060101
A61K031/135 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 3, 2014 |
FR |
1458215 |
Sep 3, 2014 |
FR |
1458224 |
Claims
1. A salt of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide of formula (I): ##STR00005## 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):
##STR00006## 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-benz-
ofuran-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.degree.): 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.degree.): 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.degree.) and interplanar spacing
d (expressed in .ANG.): TABLE-US-00029 Line no. Angle 2 theta
(degrees) Interplanar spacing (.ANG.) 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-benz-
ofuran-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 .sup.13C CP/MAS NMR spectrum exhibiting the
following peaks (expressed in ppm.+-.0.2 ppm): TABLE-US-00030 Peak
no. Chemical shift (ppm) .DELTA..delta. 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-benz-
ofuran-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.degree.): 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.degree.): 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.degree.) and interplanar spacing
d (expressed in .ANG.): TABLE-US-00031 Line no. Angle 2 theta
(degrees) Interplanar spacing (.ANG.) 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-benz-
ofuran-2-carboxamide according to claim 1 or 2, wherein HA is
naphthalene-2-sulfonic acid and wherein the crystalline form has a
solid state .sup.13C CP/MAS NMR spectrum exhibiting the following
peaks (expressed in ppm.+-.0.2 ppm): TABLE-US-00032 Peak no.
Chemical shift (ppm) .DELTA..delta. 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-benz-
ofuran-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.degree.): 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.degree.): 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.degree.) and interplanar spacing
d (expressed in .ANG.): TABLE-US-00033 Line no. Angle 2 theta
(degrees) Interplanar spacing (.ANG.) 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-benz-
ofuran-2-carboxamide according to claim 1 or 2, wherein HA is
oxalic acid and wherein the crystalline form has a solid state
.sup.13C CP/MAS NMR spectrum exhibiting the following peaks
(expressed in ppm.+-.0.2 ppm): TABLE-US-00034 Peak no. Chemical
shift (ppm) .DELTA..delta. 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-benz-
ofuran-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.degree.):
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.degree.): 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.degree.) and interplanar spacing
d (expressed in .ANG.): TABLE-US-00035 Line no. Angle 2 theta
(degrees) Interplanar spacing (.ANG.) 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-benz-
ofuran-2-carboxamide according to claim 1 or 2, wherein HA is
benzenesulfonic acid and wherein the crystalline form has a solid
state .sup.13C CP/MAS NMR spectrum exhibiting the following peaks
(expressed in ppm.+-.0.2 ppm): TABLE-US-00036 Peak no. Chemical
shift (ppm) .DELTA..delta. 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): ##STR00007##
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.degree.): 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.degree.): 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.degree.) and
interplanar spacing d (expressed in .ANG.): TABLE-US-00037 Line no.
Angle 2 theta (degrees) Interplanar spacing (.ANG.) 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 .sup.13C CP/MAS
NMR spectrum exhibiting the following peaks (expressed in
ppm.+-.0.2 ppm): TABLE-US-00038 Peak no. Chemical shift (ppm)
.DELTA..delta. 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-benz-
ofuran-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.degree.): 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.degree.): 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.degree.) and
interplanar spacing d (expressed in .ANG.): TABLE-US-00039 Line no.
Angle 2 theta (degrees) Interplanar spacing (.ANG.) 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-benz-
ofuran-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-b-
enzofuran-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-benz-
ofuran-2-carboxamide according to any one of claims 3 to 18,
wherein the
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-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-benz-
ofuran-2-carboxamide according to any one of claims 20 to 26, in
which the
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-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.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of French Patent
Application Nos. 1458215 and 1458224, both filed Sep. 3, 2014,
which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide or hydrates or polymorphs thereof, methods for
preparing the same as well as pharmaceutical compositions and uses
thereof.
BACKGROUND OF THE INVENTION
[0003]
3-[(Dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}--
1-benzofuran-2-carboxamide, also referred to as abexinostat, is a
histone deacetylase (HDAC) inhibitor which is described in the
patent application WO 2004/092116. It was shown to inhibit cell
growth and induce apoptosis in tumor cells cultured in vitro, and
inhibit tumor growth in viva in xenograft models (Buggy et al.,
Mol. Cancer Ther. 2006, 5 (5), 1309). Given its pharmacological
profile, abexinostat is intended to be used in the treatment of
cancer.
SUMMARY OF THE INVENTION
[0004] The present invention relates to novel salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide or hydrates or crystalline forms thereof,
methods for preparing or using the same as well as pharmaceutical
compositions containing the same.
[0005] More particularly, the invention relates to salts of
3-[(dimethylamino)
methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxami-
de of formula (I):
##STR00002##
in which HA is naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, oxalic acid, benzenesulfonic acid, or
sulfuric acid or hydrates thereof.
[0006] The present invention also relates to novel crystalline
forms of the salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide of formula (I), methods for preparing the same
as well as pharmaceutical compositions containing the same, and
uses thereof.
[0007] These and other aspects and embodiments are described in
following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0008] It should be understood that the detailed description and
the specific examples, while indicating specific embodiments, are
given by way of illustration only, since various changes and
modifications within the spirit and scope of the present disclosure
will become apparent to those skilled in the art from this detailed
description. The section headings used herein are for
organizational purposes only and are not to be construed as
limiting the subject matter described. All documents, or portions
of documents, cited in the application including, but not limited
to, patents, patent applications, articles, books, manuals, and
treatises are hereby expressly incorporated by reference in their
entirety for any purpose.
[0009] The patent application WO 2004/092115 describes two
different access routes for producing
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide. In both cases,
3-methylbenzofuran-2-carboxylic acid is used as the starting
material, but the functionalization of this central ring by the
dimethylamino group in position 3 is carried out at different
stages of the synthesis processes, before or after the coupling of
the derivative of benzofuran-2-carboxylic acid with methyl
4-(2-aminoethoxy)benzoate. The application WO 2004/092115
specifically describes the production of the hydrochloride of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide. However, the use of this salt on an
industrial scale is difficult because of its hygroscopic
properties.
[0010] From an industrial point of view, it is important to be able
to synthesize the compound with excellent purity, and in particular
in a highly reproducible form, exhibiting valuable properties of
dissolution, filtration, drying, ease of formulation and stability
enabling the prolonged storage thereof without specific
temperature, light, humidity or oxygen level conditions.
[0011] In one aspect, the present invention relates to
naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid oxalic
acid, benzenesulfonic acid, or sulfuric acid salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide or one of the hydrates thereof, a method for
preparing the same as well as pharmaceutical compositions
containing the same, and uses thereof.
[0012] In one aspect, the invention relates to salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide of formula (Ia):
##STR00003##
in which HA is naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, oxalic acid or benzenesulfonic
acid.
[0013] In another aspect, the subject matter of the invention
relates to the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide of formula (Ib):
##STR00004##
wherein HA is sulfuric acid, as well as hydrates thereof.
[0014] The present invention also describes methods for producing
salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide in well-defined and reproducible crystalline
forms or hydrated crystalline forms, inhibiting very good stability
compatible with the industrial constraints on preparation (in
particular, drying) and storage of pharmaceutical compositions.
[0015] In one aspect, provided is a crystalline form of the
naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to the
invention, which is characterized by a powder X-ray diffraction
diagram exhibiting the following diffraction lines (Bragg angle 2
theta, expressed in degrees.+-.0.2.degree.): 6.87; 10.71; 11.31;
13.97; 18.51; 21.49; 21.84; 24.56. More particularly, the
crystalline form of the naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide carboxamide is characterized by the following
diffraction lines: 6.87; 10.71; 11.31; 13.97; 18.51; 20.71; 21.18;
21.49; 21.84; 22.74; 24.56.
[0016] More specifically, the crystalline form of the
naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the powder X-ray
diffraction diagram below, 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.degree.) and interplanar spacing d (expressed in
.ANG.):
TABLE-US-00001 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0017] Finally, the crystalline form of the
naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide has also been characterized by solid state NMR
spectroscopy and the .sup.13C CP/MAS (cross polarization/magic
angle spinning) spectrum exhibits the following peaks (expressed in
ppm.+-.0.2 ppm):
TABLE-US-00002 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0018] In one aspect, provided is a crystalline form of the
naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to the
invention, which is characterized by a powder X-ray diffraction
diagram exhibiting the following diffraction lines (Bragg angle 2
theta, expressed m degrees.+-.0.2): 8.92; 9.33; 10.85; 17.89;
19.79; 21.79; 26.39.
[0019] More particularly, the crystalline form of the
naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the following diffraction
lines: 8.92; 9.33; 10.85; 11.78; 17.89; 19.79; 19.99; 21.79; 25.23;
26.39.
[0020] More specifically, the crystalline form of the
naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the powder X-ray
diffraction diagram below, 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 .ANG.):
TABLE-US-00003 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0021] Finally, the crystalline form of the naphthalene-2-sulfonate
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide has also been characterized by solid state NMR
spectroscopy and the .sup.13C CP/MAS spectrum exhibits the
following peaks (expressed in ppm.+-.0.2 ppm):
TABLE-US-00004 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0022] In one aspect, provided is a crystalline form of the oxalate
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to the
invention, which is characterized by 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. More
particularly, the crystalline form of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the following diffraction
lines: 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.
[0023] More specifically, the crystalline form of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the powder X-ray
diffraction diagram below, 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.degree.) and of interplanar spacing d (expressed in
.ANG.):
TABLE-US-00005 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0024] Finally, the crystalline form of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide has also been characterized by solid state NMR
spectroscopy and the .sup.13C CP/MAS spectrum exhibits the
following peaks (expressed in ppm.+-.0.2 ppm):
TABLE-US-00006 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0025] In one aspect provided is a novel crystalline form of the
benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to the
Invention, which is characterized by a powder X-ray diffraction
diagram exhibiting the following diffraction lines (Bragg angle 2
theta, expressed in degrees.+-.0.2.degree.): 8.08; 10.03; 10.36;
13.63; 15.00; 16.19; 17.73; 17.90; 18.77; 19.77; 21.98; 22.45. More
particularly, the crystalline form of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the following diffraction
lines: 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.
[0026] More specifically, the crystalline form of the
benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the powder X-ray
diffraction diagram below, 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.degree.) and of interplanar spacing d (expressed in
.ANG.):
TABLE-US-00007 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0027] Finally, the crystalline form of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide has also been characterized by solid state NMR
spectroscopy and the .sup.13C CP/MAS spectrum exhibits the
following peaks (expressed in ppm.+-.0.2 ppm):
TABLE-US-00008 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0028] In another aspect, provided is a crystalline form of the
hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide or a hydrate thereof. In one embodiment, the
hydrate is a hemipentahydrate. In another embodiment, the hydrate
is a hemiheptahydrate.
[0029] In one embodiment, the hemipentahydrate crystalline form of
the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to the
invention is characterized by a powder X-ray diffraction diagram
exhibiting the following diffraction lines (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.): 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. More particularly, the hemipentahydrate crystalline
form of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the following diffraction
lines: 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.
[0030] More specifically, the hemipentahydrate crystalline form of
the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the powder X-ray
diffraction diagram below, 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.degree.) and interplanar spacing d (expressed in
.ANG.):
TABLE-US-00009 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0031] Finally, the hemipentahydrate crystalline form of the
hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide has also been characterized by solid state NMR
spectroscopy and the .sup.13C CP/MAS (cross polarization/magic
angle spinning) spectrum exhibits the following peaks (expressed in
ppm.+-.0.2 ppm):
TABLE-US-00010 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0032] In one embodiment, the hemiheptahydrate crystalline form of
the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to the
invention is characterized by a powder X-ray diffraction diagram
exhibiting the following diffraction lines (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.): 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. More particularly, the hemiheptahydrate crystalline
form of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the following diffraction
lines: 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.
[0033] More specifically, the hemiheptahydrate crystalline form of
the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide is characterized by the powder X-ray
diffraction diagram below, 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.degree.) and interplanar spacing D (expressed in
.ANG.):
TABLE-US-00011 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0034] The invention also extends to the method for preparing salts
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide in a well-defined crystalline form,
characterized in that the
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethy-
l}-1-benzofuran-2-carboxamide is crystallised in a polar medium in
the presence of naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, oxalic acid or benzenesulfonic acid.
The polar medium preferably consists of one or more solvents chosen
from among water, alcohols, ketones, nitriles and esters. As used
herein: [0035] "alcohols" are understood to mean C.sub.1-C.sub.6
alcohols such as methanol, ethanol, propanol, isopropanol, butanol,
isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol;
[0036] "ketones" are understood to mean C.sub.3-C.sub.6 ketones
such as acetone, methylethyl ketone, 2-pentanone, 3-pentanone,
3-methyl-2-butanone, 2-hexanone, 3-hexanone, ethylisopropylketone,
methylisopropylketone, 2,2-dimethyl-3-butanone; [0037] "nitriles"
are understood to mean acetonitrile, acrylonitrile, propanenitrile
or benzonitrile; [0038] "esters" are understood to mean
C.sub.3-C.sub.8 esters such as ethyl formate, isopropyl formate,
ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate,
isobutyl acetate, tert-butyl acetate, pentyl acetate, isopentyl
acetate, hexyl acetate.
[0039] The preferred alcohols are ethanol and isopropanol. Among
the solvents, acetone and methylethylketone are the preferred
ketones, ethyl acetate is the preferred ester and acetonitrile is
the preferred nitrile.
[0040] Alternatively, the polar medium is a binary mixture, one of
the components of which is water. Even more preferably, the polar
medium is a binary mixture selected from among: acetone/water,
ethanol/water, isopropanol/water and methylethylketone/water.
[0041] In the crystallization method according to the invention, if
is possible to use
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) obtained by any method.
[0042] The invention also extends to another method for preparation
of the crystalline forms of the salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention, in which the
crystallization of the
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) is initiated by seeding of a very
small quantity of crystalline forms of the salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention, this reaction
being carried out in a polar medium and in the presence of the
corresponding acid. In this second crystallization method according
to the invention, it is also possible to use
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) obtained by any method.
[0043] Obtaining crystalline forms of the novel salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention has the advantage
of enabling the preparation of pharmaceutical formulations which
have a constant and reproducible composition and exhibit good
characteristics of dissolution and of stability, which is
particularly advantageous when the formulations are intended for
oral administration. More precisely, the use of crystalline forms
of the novel salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention is particularly
advantageous on an industrial scale taking account of their low
hydroscopicity.
[0044] Among the preferred solvents, use will be made of acetone
and methylethylketone for ketones and ethyl acetate for esters.
Water is a particularly preferred solvent.
[0045] Alternatively, the polar medium is a binary mixture of which
one of the components is water. Even more preferably, the polar
medium is a hydro-alcoholic mixture. Advantageously, the polar
medium is a binary mixture selected from among: acetone/water,
ethanol/water, isopropanol/water and methylethylketone/water.
[0046] In the crystallization process according to the invention,
it is possible to use
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) obtained by any method.
[0047] The invention likewise extends to another process for
preparation of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide in two well defined hydrated crystalline
forms, wherein the crystallization of the
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) is initiated by seeding of a very
small quantity of the hydrated crystalline form of the hydrogen
sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention, this reaction
being carried out in a polar medium and in the presence of sulfuric
acid. In this second crystallization process according to the
invention, it is also possible to use
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) obtained by any method.
[0048] Obtaining hydrated crystalline forms of the hydrogen sulfate
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention has the advantage
of being easily manipulated and enabling the preparation of
pharmaceutical formulations which have a constant and reproducible
composition whilst exhibiting good characteristics of dissolution
and of stability, which is particularly advantageous when the
formulations are intended for oral administration. More precisely,
the use of hydrated crystalline forms of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention is particularly
advantageous on an industrial scale.
[0049] The crystalline forms (including the hydrated crystalline
forms) of the novel salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention are intended for
the treatment of cancer and, more particularly, for the treatment
of a carcinoma, a tumor, a neoplasm, a lymphoma, a melanoma, a
glioma, a sarcoma or a blastoma.
[0050] The invention also extends to pharmaceutical compositions
including as active principle a salt of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the formula (I) and, even more
particularly, the crystalline forms (including the hydrated
crystalline forms) of salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention, with one or more
appropriate non-toxic inert carriers. Among the pharmaceutical
compositions according to the invention, mention may be made more
particularly of those which are suitable for oral, parenteral
(intravenous or subcutaneous) or nasal administration, plain or
coated tablets, granules, sublingual tablets, capsules, pills,
suppositories, creams, ointments, dermal gels, injectable
preparations, drinkable suspensions and chewing gums.
[0051] Orally administered pharmaceutical compositions are
preferred.
[0052] The useful dosage varies according to the sex, age and
weight of the patient, the administration route, the nature of the
cancer and any associated treatments, and the useful dosage ranges
between 20 mg and 480 mg of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}--
1-benzofuran-2-carboxamide expressed in free base per day.
[0053] The examples below illustrate the invention but do not limit
it in any way.
EXAMPLE 1
Method for Producing the Crystalline Form of the
naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0054] In a 50 mL flask, an equivalent of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) (1245.0 mg; 3.133 mmol) was added,
followed by a half-equivalent of naphthalene-1,5-disulfonic acid
tetrahydrate (564.5 mg; 1.566 mmol). Then 25 mL of isopropanol were
added and the reaction mixture was subjected to sustained magnetic
stirring at 60.degree. C. for 1 hour. Next the reaction mixture was
cooled under sustained magnetic stirring to 10.degree. C. at a
speed between 1 and 1.5.degree. C./min, then maintained for
approximately 1 day at 10.degree. C. After filtration on a porosity
3 glass frit, the solid was dried in a desiccator in vacuo (100
mbar) in order to give the compound of the title with an output of
96%. The solid was characterized by the powder X-ray diffraction
diagram and the NMR spectrum detailed in the following Examples 7
and 9.
EXAMPLE
Method for Producing the Crystalline Form of the
naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-b-
enzofuran-2-carboxamide
[0055] In a 50 mL flask, an equivalent of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) (1115.5 mg; 2.807 mmol) was added,
followed by an equivalent of naphthalene-2-sulfonic acid
monohydrate (635.9 mg; 2.806 mmol). Then 25 mL of acetonitrile were
added and the reaction mixture was subjected to sustained magnetic
stirring at 60.degree. C. for 1 hour. Next the reaction mixture was
cooled under sustained magnetic stirring to 10.degree. C. at a
speed between 1 and 1.5.degree. C./min, then maintained for
approximately 1 day at 10.degree. C. After filtration on a porosity
3 glass frit, the solid was dried in a desiccator in vacuo (100
mbar) in order to give the compound of the title with an output of
96 %. The solid was characterized by the powder X-ray diffraction
diagram and the NMR spectrum detailed in the following Examples 7
and 9.
EXAMPLE 3
Method for Producing the Crystalline Form of the Oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0056] In a 50 mL flask, an equivalent of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) (1382.8 mg; 3.479 mmol) was added,
followed by an equivalent of oxalic acid. (313.1 mg; 3.477 mmol).
Then 25 mL of ethanol were added and the reaction mixture was
subjected to sustained magnetic stirring at 60.degree. C. for 1
hour. Next the reaction mixture was cooled under sustained magnetic
stirring to 10.degree. C. at a speed between 1 and 1.5.degree.
C./min, then maintained for approximately 1 day at 10.degree. C.
After filtration on a porosity 3 glass frit, the solid was dried in
a desiccator in vacuo (100 mbar) in order to give the compound of
the title with an output of 95%. The solid was characterized by the
powder X-ray diffraction diagram and the NMR spectrum detailed in
the following Examples 7 and 9.
EXAMPLE 4
Method for Producing the Crystalline Form of the Benzenesulfonate
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0057] In a 100 mL flask, an equivalent of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) (1496 mg; 3.746 mmol) was added,
followed by 35 mL of isopropanol and 5 mL of water. The mixture was
brought to reflux. Then an equivalent of benzenesulfonic acid (599
mg; 3.787 mmol) were added and the reaction mixture was held at
reflux under sustained magnetic stirring for 1 hour. Next the
reaction mixture was cooled under sustained magnetic stirring to
ambient temperature then maintained for approximately 1 hour at
ambient temperature. After filtration on a disposable Chemrus 10
.mu.m frit and rinsing with 2.times.1 mL of isopropanol, the solid
was dried in an oven at 40.degree. C. in vacuo (10 mbar) for 24
hours in order to gives the compound of the title with a yield of
83%. The solid was characterized by the powder X-ray diffraction
diagram and the NMR spectrum detailed in the following Examples 7
and 9.
EXAMPLE 5
Method for Producing the Hemipentahydrate Crystalline Form of the
Hydrogen Sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0058] In a 50 mL flask, an equivalent of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide (free base) (1512.8 mg; 3.807 mmol) was added,
followed by a half-equivalent of sulfuric acid (5.302 mL of an
aqueous solution of 0.359 molL.sup.-1; 1.903 mmol). the mixture was
subjected to a magnetic stirring until a clear solution is
obtained. The water was then evaporated under a stream of air. The
white powder was then resuspended with 25 mL of n-heptane and the
reaction mixture was subjected to sustained magnetic stirring at
60.degree. C. for 1 hour. Next the reaction mixture was cooled
under sustained magnetic stirring to 10.degree. C. at a speed
between 1 and 1.5.degree. C./min, then maintained for approximately
1 day at 10.degree. C. After filtration on a porosity 3 glass frit,
the solid was dried in a desiccator in vacuo (100 mbar) in order to
give the compound of the title with an output of 96%. The solid was
characterized by the powder X-ray diffraction diagram and the NMR
spectrum detailed in the following Examples 7 and 9.
EXAMPLE 6
Method for Producing the Hemiheptahydrate Crystalline Form of the
Hydrogen Sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0059] A vial containing 100 mg of hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide, hemipentahydrate placed for 3 days in a bell
jar containing a saturated saline solution of KNO.sub.3 (90%
relative humidity) at ambient temperature led to the formation of
the compound of the title with a quantitative yield. The resulting
solid was characterized by the powder X-ray diffraction diagram
detailed in the following Example 7.
EXAMPLE 7
Powder X-ray Diffraction Diagrams of the Crystalline Forms of the
Salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide According to the Invention
[0060] The recording of the data was performed on a PANalytical
X'Pert Pro MPD diffractometer with an X'Celerator detector under
the following conditions: [0061] Voltage 45 kV, current 40 mA;
[0062] Mounting theta/theta; [0063] Anode copper; [0064] K alpha-1
wavelength: 1.54060 .ANG.; [0065] K alpha-2 wavelength: 1.54443
.ANG.; [0066] K alpha-2/K alpha-1 ratio: 0.5; [0067] Measurement
mode: continuous from 3.degree. to 55.degree. (Bragg angle 2 theta)
with incrementation by 0.017.degree.; [0068] Acquisition time: 15
min.
[0069] Crystalline form of the naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0070] The powder X-ray diffraction diagram of the crystalline form
of the naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
1 is expressed in terms of line position (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.) and of interplanar spacing d
(expressed in .ANG.). The significant lines are set out in the
following table:
TABLE-US-00012 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0071] Crystalline form of the naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0072] The powder X-ray diffraction diagram of the crystalline form
of the naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
2 is expressed in terms of line position (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.) and of interplanar spacing d
(expressed in .ANG.). The significant lines are set out in the
following table:
TABLE-US-00013 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0073] Crystalline form of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0074] The powder X-ray diffraction diagram of the crystalline form
of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
3 is expressed in terms of line position (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.) and of interplanar spacing d
(expressed in .ANG.). The significant lines are set out in the
following table:
TABLE-US-00014 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0075] Crystalline form of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0076] The powder X-ray diffraction diagram of the crystalline form
of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
4 is expressed in terms of line position (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.) and of interplanar spacing d
(expressed in .ANG.). The significant lines are set out in the
following table:
TABLE-US-00015 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0077] Hemipentahydrate crystalline form of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide:
[0078] The powder X-ray diffraction diagram of the hemipentahydrate
crystalline form of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
5 is expressed in terms of line position (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.) and of interplanar spacing d
(expressed in .ANG.). The significant lines are set out in the
following table:
TABLE-US-00016 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
[0079] Hemiheptahydrate crystalline form of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide:
[0080] The powder X-ray diffraction diagram of the hemiheptahydrate
crystalline form of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
6 is expressed in terms of line position (Bragg angle 2 theta,
expressed in degrees.+-.0.2.degree.) and of interplanar spacing d
(expressed in .ANG.). The significant lines are set out in the
following table:
TABLE-US-00017 Line no. Angle 2 theta (degrees) Interplanar spacing
(.ANG.) 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
EXAMPLE 8
Determination of the Lattices of the Crystalline Forms of the Salts
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0081] The crystalline structure was determined on the powders
obtained in the preceding examples using a PANalytical X'Pert Pro
MPD diffractometer with an X'Celerator detector. The following
parameters were established:
TABLE-US-00018 Salts Lattice parameters Space group
Naphthalene-1,5-disulfonate a = 10.586 .ANG. P -1 (produced using
the method b = 13.897 .ANG. according to Example 1) c = 9.879 .ANG.
.alpha. = 93.150.degree. .beta. = 102.358.degree. .gamma. =
110.806.degree. Oxalate a = 5.594 .ANG. P 1 2.sub.l/c 1 (produced
using the method b = 20.711 .ANG. according to Example 3) c =
20.285 .ANG. .beta. = 107.081 Benzenesulfonate a = 10.816 .ANG. P 1
2.sub.l/c 1 (produced using the method b = 13.965 .ANG. according
to Example 4) c = 19.784 .ANG. .beta. = 117.490.degree. Hydrogen
sulfate, hemipentahydrate a = 13.123 .ANG. P -1 (produced using the
method b = 14.696 .ANG. according to Example 5) c = 12.967 .ANG.
.alpha. = 99.965.degree. .beta. = 103.304.degree. .gamma. =
90.348.degree.
EXAMPLE 9
Solid State NMR Spectrum of the Crystalline Forms oft he Salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0082] The .sup.13C NMR spectra were recorded at ambient
temperature using a Bruker SB Avance III HD 400 spectrometer with a
probe of the 4 mm CP/MAS SB VTN type under the following
conditions: [0083] Frequency: 100.65 MHz; [0084] Spectral width: 40
kHz; [0085] Magic angle spinning rate of sample: 10 kHz; [0086]
Pulse sequence: CP (Cross Polarization) with SPINAL64 decoupling;
[0087] Repetition delay: 10s; [0088] Acquisition time: 46 ms;
[0089] Contact time: 4 ms; [0090] Number of scans: 4096.
[0091] An apodization function ("10 Hz line broadening") was
applied before the Fourier transform. The spectra thus obtained
were referenced relative to a sample of adamantane as external
sample (the highest-frequency peak of adamantane has a chemical
shift of 38.5 ppm). The peaks observed are expressed in ppm.+-.0.2
ppm.
[0092] .DELTA..delta. ppm: .DELTA..delta. corresponds to the
chemical shift difference between the indexed peak and the peak
with the lowest referenced chemical shift.
[0093] Crystalline form of the naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0094] The crystalline form of the naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
1 exhibits the following peaks:
TABLE-US-00019 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0095] Crystalline form of the naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0096] The crystalline form of the naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
2 exhibits the following peaks:
TABLE-US-00020 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0097] Crystalline form of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0098] The crystalline form of the oxalate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
3 exhibits the following peaks:
TABLE-US-00021 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0099] Crystalline form of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide
[0100] The crystalline form of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
4 exhibits the following peaks:
TABLE-US-00022 Peak no. Chemical shift (ppm) .DELTA..delta. 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
[0101] The hemipentahydrate crystalline form of the hydrogen
sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
5 exhibits the following peaks:
TABLE-US-00023 Peak no. Chemical shift (ppm) .DELTA..delta. 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
EXAMPLE 10
Hygroscopy
[0102] The hygroscopicity of the crystalline forms of the salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention was evaluated by
dynamic vapor sorption (DVS) using a DVS Intrinsic apparatus. A
sample of 5 to 10 mg of the substance, weighed accurately, was
disposed in a DVS sample pan operating at 25.degree. C. under
controlled humidity. The mass variation was recorded on the basis
of a balancing bearing at 50% relative humidity, followed by three
subsequent linear phases of increasing (from 50 to 90%), of
decreasing (from 90 to 0%) and of increasing (from 0 to 50%) the
relative humidity at a speed of 10% per hour. The relative humidity
was maintained constant when it reached either 0, or 50, or 90%
relative humidity, until the mass variation was less than 0.002%
per minute, with a time limit of 15 hours.
[0103] A mass variation of less than 1% was detected by DVS
analysis after exposure of a sample to between 0 and 90% relative
humidity at 25.degree. C. for the crystalline form of the
naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
1; the crystalline form of the naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
2; and the crystalline form of the benzenesulfonate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
4.
[0104] A mass variation of less than 0.2 % was detected by DVS
analysis after exposure of a sample to between 0 and 90% relative
humidity at 25.degree. C. for the crystalline form of the oxalate
of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
3.
[0105] Consequently, the crystalline forms of the salts of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the methods of Examples 1 to 4
have a low hygroscopicity enabling a particularly advantageous use
thereof on an industrial scale in the preparation of pharmaceutical
formulations.
[0106] The hygroscopicity of the hemipentahydrate crystalline form
of the hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide according to the invention was evaluated by
dynamic vapor sorption (DVS) using a DVS Intrinsic apparatus. A
sample of 5 to 10 mg of the substance, weighed accurately, was
disposed in a DVS sample pan operating at 25.degree. C. under
controlled humidity. The mass variation was recorded on the basis
of a balancing bearing at 50% relative humidity, followed by three
subsequent linear phases of increasing (from 50 to 90%), of
decreasing (from 90 to 0%) and of increasing (from 0 to 50%) the
relative humidity at a speed of 10% per hour. The relative humidity
was maintained constant when it reached either 0, or 50, or 90 %
relative humidity, until the mass variation is less than 0.002% per
minute, with a time limit of 15 hours.
[0107] The hemipentahydrate crystalline form of the hydrogen
sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
5 was stable between 15% relative humidity and 70% relative
humidity. Beyond 70% relative humidity, the hemipentahydrate
hydrogen sulfate was converted into hemiheptahydrate hydrogen
sulfate which was stable between 90% relative humidity and 20%
relative humidity. Below 20% relative humidity and to 0% relative
humidity, the hemiheptahydrate hydrogen sulfate dehydrated
completely and retransferred into hemipentahydrate hydrogen sulfate
from 15% relative humidity.
[0108] Consequently the hemipentahydrate crystalline form of the
hydrogen sulfate of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benz-
ofuran-2-carboxamide produced using the method according to Example
5 has properties which enable it to be easily manipulated--in
particular during the preparation of pharmaceutical
formulations--over wide ranges of relative humidity values.
EXAMPLE 11
Pharmaceutical Compositions
[0109] Formula for preparation of 1000 tablets each containing a
dose of 100 mg of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]eth-
yl}-1-benzofuran-2-carboxamide (expressed as equivalent to the
base):
TABLE-US-00024 Naphthalene-2-sulfonate of
3-[(dimethylamino)methyl]-N- 157.1 g
{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran- 2-carboxamide
Lactose monohydrate 216.1 g Magnesium stearate 2.5 g Corn starch 75
g Maltodextrin 50 g Anhydrous colloidal silica 1 g Sodium
carboxymethylcellulose 15 g
[0110] Formula for preparation of 1000 tablets each containing a
dose of 100 mg of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]eth-
yl}-1-benzofuran-2-carboxamide (expressed as equivalent to the
base):
TABLE-US-00025 Benzenesulfonate of 3-[(dimethylamino)methyl]-N-{2-
139.8 g [4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-
2-carboxamide Lactose monohydrate 207.8 g Magnesium stearate 2.5 g
Corn starch 75 g Maltodextrin 50 g Anhydrous colloidal silica 1 g
Sodium carboxymethylcellulose 15 g
[0111] Formula for preparation of 1000 tablets each containing a
dose of 100 mg of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]eth-
yl}-1-benzofuran-2-carboxamide (expressed as equivalent to the
base):
TABLE-US-00026 Oxalate of 3-[(dimethylamino)methyl]-N-{2- 122.7 g
[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran- 2-carboxamide
Lactose monohydrate 182.3 g Magnesium stearate 2.5 g Corn starch 75
g Maltodextrin 50 g Anhydrous colloidal silica 1 g Sodium
carboxymethylcellulose 15 g
[0112] Formula for preparation of 1000 tablets each containing a
dose of 100 mg of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]eth-
yl}-1-benzofuran-2-carboxamide (expressed as equivalent to the
base):
TABLE-US-00027 Naphthalene-1,5-disulfonate of
3-[(dimethylamino)methyl]- 145.4 g
N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-
2-carboxamide Lactose monohydrate 216.1 g Magnesium stearate 2.5 g
Corn starch 75 g Maltodextrin 50 g Anhydrous colloidal silica 1 g
Sodium carboxymethylcellulose 15 g
[0113] Formula tor preparation of 1000 tablets each containing a
dose of 100 mg of
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]eth-
yl}-1-benzofuran-2-carboxamide (expressed as equivalent to the
base):
TABLE-US-00028 Hydrogen sulfate of 3-[(dimethylamino)methyl]-N-{2-
153.9 g [4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-
2-carboxamide Lactose monohydrate 228.7 g Magnesium stearate 2.5 g
Corn starch 75 g Maltodextrin 50 g Anhydrous colloidal silica 1 g
Sodium carboxymethylcellulose 15 g
* * * * *