U.S. patent application number 14/798412 was filed with the patent office on 2015-11-05 for new salt of abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them.
The applicant listed for this patent is PHARMACYCLICS, INC.. Invention is credited to Philippe LETELLIER, Anne PIMONT-GARRO.
Application Number | 20150315167 14/798412 |
Document ID | / |
Family ID | 48521256 |
Filed Date | 2015-11-05 |
United States Patent
Application |
20150315167 |
Kind Code |
A1 |
PIMONT-GARRO; Anne ; et
al. |
November 5, 2015 |
NEW SALT OF ABEXINOSTAT, ASSOCIATED CRYSTALLINE FORM, A PROCESS FOR
THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING
THEM
Abstract
Abexinostat tosylate of formula (II): ##STR00001## and its
crystalline form I characterised by its X-ray powder diffraction
diagram, its Raman spectrum and its solid-state .sup.13C CP/MAS NMR
spectrum. Medicinal products containing the same which are useful
in the treatment of cancer.
Inventors: |
PIMONT-GARRO; Anne;
(Versailles, FR) ; LETELLIER; Philippe; (ORLEANS,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PHARMACYCLICS, INC. |
Sunnyvale |
CA |
US |
|
|
Family ID: |
48521256 |
Appl. No.: |
14/798412 |
Filed: |
July 13, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
14195186 |
Mar 3, 2014 |
9115108 |
|
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14798412 |
|
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61772191 |
Mar 4, 2013 |
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Current U.S.
Class: |
514/469 ;
549/467 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 29/00 20180101; A61P 35/02 20180101; C07D 307/85 20130101;
C07C 309/30 20130101 |
International
Class: |
C07D 307/85 20060101
C07D307/85 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 4, 2013 |
FR |
13/51898 |
Claims
1.
N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2ylcarbonylamino-
]-ethoxy}benzamide tosylate, or a solvate thereof.
2. A tosylate salt of abexinostat of formula (I): ##STR00004##
3. A pharmaceutical composition comprising, as active ingredient
abexinostat tosylate according to claim 1, in combination with one
or more pharmaceutically acceptable excipients.
4. A method of treating cancer in a subject in need thereof,
comprising administration of an effective amount of the
pharmaceutical composition according to claim 3.
5. The method according to claim 4, wherein the cancer is a
carcinoma, a tumour, a neoplasm, a lymphoma, a melanoma, a glioma,
a sarcoma or a blastoma.
6. A process for the preparation of crystalline form I of
abexinostat tosylate, having an X-ray powder diffraction diagram
having the following diffraction lines (Bragg's angle 2 theta,
expressed in degrees .+-.0.2.degree.): 6.50; 9.94; 11.35; 12.33;
14.08; 18.95; 21.08; 27.05, wherein the abexinostat is crystallised
in the presence of para-toluenesulphonic acid in a polar medium and
wherein the crystallisation is seeded using a very small amount of
crystalline form I of abexinostat tosylate.
Description
[0001] The present invention relates to
N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)-benzofuran-2-ylcarbonylamino]-
ethoxy}benzamide tosylate, or a solvate thereof.
[0002] Alternatively, the subject-matter of the invention relates
to a tosylate salt of abexinostat of formula (I):
##STR00002##
[0003] More especially, the invention is directed to the salt of
formula (II):
##STR00003##
[0004] The present invention relates also to crystalline form I of
N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]e-
thoxy}benzamide tosylate, to a process for its preparation and also
to pharmaceutical compositions comprising it.
[0005]
N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonyla-
mino]ethoxy}-benzamide, also known as abexinostat, is a historic
deacetylase (HDAC) inhibitor described in patent application
WO2004/092115. it allows inhibition of cell growth and induces
apoptosis in cultured tumour cells in vitro, and it inhibits tumour
growth in vivo in xenograft models (Buggy et al., Mol. Cancer Ther
2006 5(5) 1309). In view of its pharmacological profile,
abexinostat is intended for use in the treatment of cancer.
[0006] From the industrial point of view it is imperative to be
able to synthesise the compound with excellent purity, especially
in a perfectly reproducible form, having valuable characteristics
of dissolution, filtration, drying, ease of formulation and
stability allowing its prolonged storage without particular
requirements for temperature, light, humidity or oxygen levels.
[0007] Patent application WO2004/092115 describes two different
routes for obtaining abexinostat. In both cases,
3-methyl-benzofuran-2-carboxylic acid is used as starting material,
but functionalisation of this central nucleus by the
dimethylaminomethyl group in the 3-position is carried out at
different stages in the synthesis process, namely before or after
coupling of the benzofuran-2-carboxylic acid compound with methyl
4-(2aminoethoxy)benzoate. Obtaining abexinostat hydrochloride is
specifically described in the WO2004/092115 application. However,
using this salt on an industrial scale is problematic because of
its hygroscopic properties.
[0008] The present invention describes a process for obtaining
abexinostat tosylate (abexinostat 4-methylbenzenesulfonate) in a
well-defined, perfectly reproducible crystalline form having very
good stability that is compatible with the industrial constraints
of preparation (especially drying) and storage of pharmaceutical
compositions.
[0009] Crystalline form I of abexinostat tosylate is characterised
by an X-ray powder diffraction diagram having the following
diffraction lines (Bragg's angle 2 theta, expressed in degrees)
.+-.0.2.degree.); 6.50; 9.94; 11.35; 12.33; 14.08; 18.95; 21.08;
27.05. Even more especially, crystalline form I of abexinostat
tosylate is characterised by the following diffraction lines: 6.50;
9.94; 11.35; 12.33; 14.08; 18.95; 19.61; 19.96; 21.08; 22.82;
23.61; 27.05.
[0010] More specifically, crystalline form I of abexinostat
tosylate is characterised by the X-ray powder diffraction diagram
hereinbelow, measured using a PANalytical X'Pert Pro MPD
diffractometer with an X'Celerator detector and expressed in terms
of line position (Bragg's angle 2 theta, expressed in degrees
.+-.0.2.degree.) and interplanar distance d (expressed in
.ANG.):
TABLE-US-00001 Angle 2-theta Interplanar Line no. (degrees)
distance (.ANG.) 1 6.50 13.581 2 9.94 8.894 3 11.35 7.789 4 12.33
7.173 5 14.08 6.285 6 18.95 4.683 7 19.61 4.526 8 19.96 4.449 9
21.08 4.215 10 22.82 3.897 11 23.61 3.768 12 27.05 3.296
[0011] Besides that, crystalline form I of abexinostat tosylate has
been characterised by Raman spectroscopy. Significant peaks were
observed at the following positions: 940 cm.sup.-1, 1088 cm.sup.-1,
1132 cm.sup.-1, 1242 cm.sup.-1, 1360 cm.sup.-1, 1608 cm.sup.-1.
[0012] Alternatively, crystalline form 1 of abexinostat tosylate
may be characterised by the X-ray powder diffraction diagram which
includes the 12 significant lines given hereinabove and also by a
Raman spectrum having a significant peak at the position 1608
cm.sup.-1.
[0013] Finally, crystalline form I of abexinostat tosylate has also
been characterised by solid-state NMR spectroscopy, Significant
peaks were observed at 121.2 ppm, 122.1 ppm, 123.5 ppm, 126.0 ppm,
126.8 ppm, 128.2 ppm, 128.9 ppm, 143.4 ppm, 144.6 ppm, 153.8 ppm,
159 ppm, 161.2 ppm and 162.1 ppm.
[0014] More specifically, the .sup.13C CP/MAS (Cross Polarization
Magic Angle Spinning) spectra have the following peaks (expressed
in ppm.+-.0.2 ppm):
TABLE-US-00002 Chemical shift Peak no. (ppm) 1 162.1 2 161.2 3
159.0 4 153.8 5 144.6 6 143.4 7 128.9 8 128.2 9 126.8 10 126.0 11
123.5 12 122.1 13 121.3 14 65.9 15 50.6 16 46.9 17 45.0 18 21.9
[0015] The invention relates also to a process for the preparation
of crystalline form I of abexinostat tosylate, which process is
characterised in that abexinostat is crystallised from a polar
medium in the presence of paro-toluenesulphonic acid. Preferably,
the polar medium is composed of one or more solvents selected from
water, alcohols ketones and esters, it being understood that:
[0016] "alcohols" means C.sub.1-C.sub.6 alcohols such as methanol,
ethanol, propanol, isopropanol, butanol, isobutanol, pentanol,
2-pentanol, 3-pentanol, isopentanol, hexanol, [0017] "ketones"
means a C.sub.3-C.sub.6 ketone such as acetone, methyl ethyl
ketone, 2-pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone,
3-hexanone, ethyl isopropyl ketone, methyl isopropyl ketone,
2,2-dimethyl-3-butanone, [0018] "esters" means C.sub.3-C.sub.8
ester 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.
[0019] Preferred alcohols are ethanol and isopropanol. Among the
preferred solvents preference will also be given to acetone and
methyl ethyl ketone among the ketones and to ethyl acetate among
the esters.
[0020] Alternatively, the polar medium is a binary mixture, one of
the constituents of which is water. Even more preferably, the polar
medium is a binary mixture selected from: acetone/water,
ethanol/water, isopropanol/water and methyl ethyl ketone/water.
[0021] In the crystallisation process according to the invention,
abexinostat (free base) obtained by any process may be used.
[0022] The invention relates also to another process for the
preparation of crystalline form I of abexinostat tosylate, in which
process the crystallisation is seeded using a very small amount of
crystalline form I of abexinostat tosylate.
[0023] In this second crystallisation process according to the
invention, abexinostat (free base) obtained by any process may also
be used.
[0024] Obtaining crystalline form I of abexinostat tosylate has the
advantage of making it possible to prepare pharmaceutical
formulations having a consistent and reproducible composition and
having good characteristics of dissolution and stability, which is
especially advantageous when the formulations are intended for oral
administration. More specifically, use of crystalline form I of
abexinostat tosylate is especially valuable in an industrial
context in view of its low hygroscopicity.
[0025] Crystalline form I of abexinostat tosylate is intended for
the treatment of cancer, more especially the treatment of a
carcinoma, a tumour, a neoplasm, a lymphoma, a melanoma, a glioma,
a sarcoma or a blastoma.
[0026] The invention relates also to pharmaceutical compositions
comprising, as active ingredient, tosylate salt of abexinostat,
even more especially crystalline form I of abexinostat tosylate,
together with one or more appropriate, non-toxic, inert excipients.
Among the pharmaceutical compositions according to the invention
there may be more especially mentioned those that are suitable for
oral, parenteral (intravenous or subcutaneous) or nasal
administration, tablets or dragees, granules, sublingual tablets,
capsules, lozenges, suppositories, creams, ointments, dermal gels,
injectable preparations, drinkable suspensions and chewing
gums.
[0027] Preference is given to pharmaceutical compositions
administered via the oral route.
[0028] 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; the useful dosage ranges from
20 mg to 480 mg of
N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)-benzofuran-2-ylcarbonylamino]-
ethoxy}benzamide per day expressed in terms of the free base.
[0029] The Examples hereinbelow illustrate the invention but do not
limit it in any way.
EXAMPLE 1
Process for obtaining crystalline form of abexinostat tosylate
[0030] 1.66 kg of abexinostat (free base) are placed in 9.48 kg of
a mixture of isopropanol/water (50/50 weight/weight) at ambient
temperature, para-Toluenesulphonic acid monohydrate (0.83 kg) in
2.36 kg of water is added at ambient temperature. The mixture is
then heated at 75.degree. C. for 30 minutes before being cooled to
0.degree. C. When crystallisation is complete, the suspension is
filtered at 20.degree. C. After drying, crystalline form I of
abexinostat tosylate is obtained in a yield of about 85% and with a
purity greater than 99%. The solid was characterised by the X-ray
powder diffraction diagram, Raman spectrum and NMR spectrum as set
out in Examples 3-5 and 6 hereinbelow.
EXAMPLE 2
Process for obtaining crystalline form I of abexinostat tosylate
(seeding)
[0031] 33.9 kg of abexinostat (free base) are placed in 170 kg of a
mixture of isopropanol/water (45.6/54.4 weight/weight) at ambient
temperature. A solution composed of para-toluenesulphonic acid
monohydrate (17.06 kg) in water (24.1 kg) is added. The mixture is
then heated at 70-75.degree. C., cooled and seeded with 1.935 kg of
crystalline form I of abexinostat tosylate. The suspension is then
filtered at 20.degree. C. After drying, crystalline form I of
abexinostat tosylate is obtained in a yield of about 86% and with a
purity greater than 99%. The solid was characterised by the X-ray
powder diffraction diagram. Raman spectrum and NMR spectrum as set
out in Examples 3-5 and 6 hereinbelow.
EXAMPLE 3
Crystalline form I of aboxinostat tosylate (X-ray powder
diffraction diagram)
[0032] Recording of the data was carried out using a PANalytical
X'Pert Pro MPD diffractometer with an X'Celerator detector under
the following conditions: [0033] Voltage 45 kV, current 40 mA,
[0034] Mounting: theta/theta, [0035] Anode: copper, [0036] K
alpha-1 wavelength: 1.54060 .ANG., [0037] K alpha-2 wavelength:
1.54443 .ANG., [0038] K alpha-2/K alpha-1 ratio: 0.5, [0039]
Measurement mode: continuous from 3.degree. to 55.degree. (Bragg's
angle 2 theta) in increments of 0.017.degree., [0040] Measurement
time per step: 35.53 s.
[0041] The X-ray powder diffraction diagram of form I of
abexinostat tosylate obtained according to the process of Example 1
or 2 is expressed in terms of line position (Bragg's angle 2 theta,
expressed in degrees .+-.0.2.degree.), interplanar distance
(expressed in .ANG.) and relative intensity (expressed as a
percentage relative to the most intense line). The significant
lines have been collated in the following table:
TABLE-US-00003 Angle 2-theta Interplanar Relative Line no.
(degrees) distance (.ANG.) intensity (%) 1 6.50 13.581 75.6 2 9.94
8.894 58.4 3 11.35 7.789 19.1 4 12.33 7.173 23.7 5 14.08 6.285 33.1
6 18.95 4.683 100 7 19.61 4.526 53.9 8 19.96 4.449 50.9 9 21.08
4.215 93.5 10 22.82 3.897 28.5 11 23.61 3.768 32.6 12 27.05 3.296
16.0
EXAMPLE 4
Crystalline form I of abexinostat tosylate (crystal unit cell)
[0042] A saturated solution of abexinostat tosylate in
2,2,2-trifluoroethanol is prepared by stirring a suspension for 24
hours at ambient temperature, followed by filtration. 1 mL of the
resulting solution is then poured into a 1.8-mL HPLC vial, to which
0.25 mL of water is added. The solution is maintained at ambient
temperature for 75 minutes. After centrifuging and then drying, the
solid is isolated for analysis. From among the crystals obtained a
crystal of sufficient quality is taken for single-crystal X-ray
diffraction analysis. The crystalline structure of the above single
crystal was determined using a Bruker Kappa CCD diffractometer
equipped with an FR590 generator having a molybdenum anticathode
(.lamda.MoK.alpha.1=0.7093 .ANG.) with an angular range from
2.degree. to 27.5.degree. in terms of .theta.. The following
parameters were established: [0043] crystal unit cell: triclinic
[0044] unit cell parameters: a=10.467 .ANG., b=14.631 .ANG.,
c=20.159 .ANG., .alpha.=73.971.degree., .beta.=79.040.degree.,
.gamma.=72.683.degree. [0045] space group: P-1 [0046] number of
molecules in the unit cell: 4 [0047] volume of the unit cell:
V.sub.unit cell=2813.0 .ANG..sup.3 [0048] density: d=1.345
g/cm.sup.3.
EXAMPLE 5
Crystalline form I of abexinostat tosylate (Raman spectrum)
[0049] Form I of abexinostat tosylate was characterised by Raman
spectroscopy. The spectra were recorded in diffuse reflectance mode
(Raman Station 400, PerkinElmer) using a 785 nm laser. The signal
was recorded by a CCD detector. The wavelength shift depends on the
material and is characteristic of that material, which allows
analysis of the chemical composition and of the molecular
arrangement of the sample studied. The spectra were acquired with
maximum power (100% laser capacity), a spot size of 100 .mu.m,
twenty exposures of 2 seconds and a spectral resolution of 2
cm.sup.-1. The spectral range explored ranges from 0 to 3278
cm.sup.-1.
[0050] Significant peaks were observed at the following positions:
940 cm.sup.-1, 1088 cm.sup.-1, 1132 cm.sup.-1, 1242 cm.sup.-1, 1360
cm.sup.-1, 1608 cm.sup.-1,
EXAMPLE 6
Crystalline form I of abexinostat tosylate (solid NMR spectrum)
[0051] Form I of abexinostat tosylate was also characterised by
solid-state NMR spectroscopy. The .sup.13C NMR spectra were
recorded at ambient temperature using a Bruker SB Avance
spectrometer with a 4-mm CP/MAS SB VTN type probe under the
following conditions: [0052] Frequency: 125.76 MHz, [0053] Spectral
width: 40 kHz, [0054] Magic angle spinning rate of sample: 10 kHz,
[0055] Pulse sequence: CP (Cross Polarization) with SPINAL64
decoupling (decoupling power: 80 kHz), [0056] Repetition delay: 10
s. [0057] Acquisition time: 35 ms, [0058] Contact time: 4 ms,
[0059] Number of scans: 4096.
[0060] An apodisation function ("5 Hz line broadening" is applied
to the collected signal before the Fourier transform. The spectra
thereby obtained were referenced relative to a sample of adamantane
(the highest-frequency peak of adamantane has a chemical shift of
38:48 ppm).
[0061] The peaks observed have been collated in the following table
(expressed in ppm.+-.0.2 ppm):
TABLE-US-00004 Chemical shift Peak no. (ppm) 1 162.1 2 161.2 3
159.0 4 153.8 5 144.6 6 143.4 7 128.9 8 128.2 9 126.8 10 126.0 11
123.5 12 122.1 13 121.3 14 65.9 15 50.6 16 46.9 17 45.0 18 21.9
EXAMPLE 8
Pharmaceutical composition
[0062] Formula for the preparation of 1000 tablets each containing
100 mg of abexinostat (expressed in terms of the base
equivalent):
TABLE-US-00005 Abexinostat tosylate 143.4 g Lactose monohydrate
213.1 g Magnesium stearate 2.5 g Maize starch 75 g Maltodextrin 50
g Anhydrous colloidal silica 1 g Sodium carboxymethylcellulose 15
g
EXAMPLE 8
Hygroscopicity
[0063] Hygroscopicity of form I of abexinostat tosylate was
assessed using dynamic vapor sorption (DVS) technique. 5 to 10 mg
of the drug substance test sample were accurately weighed into a
DVS sample pan working at 25.degree. C. under controlled humidity.
The mass variation was recorded whilst drying under 0 per cent RH
(relative humidity) and during two subsequent cycles of increasing
and decreasing linear variations of relative humidity in the range
0-90 per cent RH at a rate of 10 per cent per hour. The relative
humidity was maintained constant when it reached either 0 or 90 per
cent RH until the mass variation was less than 0.002 per cent per
minute within a limit of time of 15 h.
[0064] An increase in weight lower than 0.5% was detected by DVS
analysis when a sample was exposed to relative humidities from 0%
to 90% at 25.degree. C.
* * * * *