U.S. patent application number 13/946000 was filed with the patent office on 2014-02-20 for salt forms of 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-- 2-ylamino)phenyl]-benzamide.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Hans Michael Burger, Paul William Manley, Michael Mutz. Invention is credited to Hans Michael Burger, Paul William Manley, Michael Mutz.
Application Number | 20140051853 13/946000 |
Document ID | / |
Family ID | 34837520 |
Filed Date | 2014-02-20 |
United States Patent
Application |
20140051853 |
Kind Code |
A1 |
Burger; Hans Michael ; et
al. |
February 20, 2014 |
Salt forms of
4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin--
2-ylamino)phenyl]-benzamide
Abstract
The present invention relates to acid addition salts of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, which are selected from the group
consisting of a tartrate salt, such as a (D)(-) tartrate salt or a
(L)(+) tartrate salt, a hydrochloride salt, a citrate salt, a
malate salt, a fumarate salt, a succinate salt, a benzoate salt, a
benzenesulfonate salt, a pamoate salt, a formate salt, a malonate
salt, a 1,5-naphthalenedisulfonate salt, a salicylate salt, a
cyclohexanesulfamate salt, a lactate salt, a mandelate salt, aq
glutarate salt, an adipate salt, a squarate salt, a vanillate salt,
an oxaloacetate salt, an ascorbate salt and a sulfate salt.
Inventors: |
Burger; Hans Michael;
(Allschwil, CH) ; Manley; Paul William;
(Arlesheim, CH) ; Mutz; Michael; (Freiburg i. Br.,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Burger; Hans Michael
Manley; Paul William
Mutz; Michael |
Allschwil
Arlesheim
Freiburg i. Br. |
|
CH
CH
DE |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
34837520 |
Appl. No.: |
13/946000 |
Filed: |
July 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13368811 |
Feb 8, 2012 |
8513256 |
|
|
13946000 |
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|
10597287 |
Jun 19, 2008 |
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PCT/EP05/01077 |
Feb 3, 2005 |
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13368811 |
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60541817 |
Feb 4, 2004 |
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Current U.S.
Class: |
544/295 |
Current CPC
Class: |
A61P 35/04 20180101;
A61P 35/02 20180101; C07D 401/04 20130101; A61P 35/00 20180101 |
Class at
Publication: |
544/295 |
International
Class: |
C07D 401/04 20060101
C07D401/04 |
Claims
1: An acid addition salt selected from the group consisting of
imatinib ascorbate, imatinib formate, imatinib malonate, imatinib
oxaloacetate, imatinib squarate and imatinib vanillate.
Description
[0001] The present invention relates to salts forms of the
pharmaceutically active compound
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide.
[0002] The pharmaceutically active compound
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide is commonly known by its INN name
Imatinib. Imatinib and its preparation are described in U.S. Pat.
No. 5,521,184.
[0003] Basic pharmaceutically active compounds are commonly
formulated into pharmaceutical preparations as an acid addition
salt form, particularly as a crystalline acid addition salt. For
example, imatinib is marketed in many countries as its
monomethanesulfonate salt (imatinib mesylate) under the brandname
GLIVEC or GLEEVEC. Two crystal forms of imatinib mesylate are
described in WO 99/03854. The crystal form designated as the beta
form is described as having physical properties that make it
advantageous for the manufacture of solid oral pharmaceutical
dosage forms, such as tablet and capsule dosage forms.
[0004] Although it is known that the preparation of salt forms may
improve the physical or pharmaceutical properties of a basic
pharmaceutically active compound, it is not possible to predict
which salt forms may possess advantages for a particular purpose
prior to the actual preparation and characterization of the salt
form. The present invention relates to salt forms of imatinib,
other than imatinib mesylate, that are useful for the manufacture
of solid or liquid pharmaceutical dosage forms, particularly solid
oral dosage forms, such as tablets and capsules, and liquid oral
dosage forms, such as orally administered solutions and
suspensions, as well as suppositories and other pharmaceutical
dosage forms. Each of these salt forms possesses one or more
properties that provides advantages when used as a pharmaceutical
active ingredient, such as physical properties that make it easier
to manufacture one or more dosage forms, improved stability,
improved bioavailability and other such properties that are known
to one of skill in the art.
[0005] The salt forms of imatinib are prepared by methods known in
the art for making acid addition salts of amines, e.g., by
treatment of imatinib with an acid or a suitable anion exchange
reagent. Typically, imatinib or a solution of imatinib is combined
with a solution of an organic or mineral acid in, e.g., a lower
alcohol, such as methanol or ethanol, with or without heating. The
salt is isolated by crystallization or by evaporation of the
solvent and, if desired, purified by re-crystallization from an
appropriate re-crystallization solvent by methods known to one of
skill in the art.
[0006] For the purpose of administering a salt of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide by means of an oral solution, in
general those salts are preferred having an increased water
solubility compared to the free base. Salts having a lower water
solubility compared to the free base, render them in general more
suitable for the manufacture of sustained release formulations
compared to the free base.
[0007] Important embodiments of this invention include salts of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide selected from the group consisting
of a tartrate salt, such as a (D)(-) tartrate salt or a (L)(+)
tartrate salt, a hydrochloride salt, a citrate salt, a malate salt,
particularly a D-malate salt, a fumarate salt, a succinate salt, a
benzoate salt, a benzenesulfonate salt, a pamoate salt, a formate
salt, a malonate salt, a 1,5-naphthalenedisulfonate salt, a
salicylate salt, a cyclohexanesulfamate salt, a lactate salt,
particularly a (S)-lactate salt, a mandelate salt, particularly an
(R)(-) mandelate salt, a glutarate salt, an adipate salt, a
squarate salt, a vanillate salt, an oxaloacetate salt, an ascorbate
salt, particularly an (L)-ascorbate salt and a sulfate salt.
[0008] Further important embodiments of this invention include
imatinib ascorbate, imatinib formate, imatinib malonate, imatinib
oxaloacetate, imatinib squarate and imatinib vanillate.
[0009] In a preferred embodiment of the present invention, the acid
addition salt is selected from the group consisting of a tartrate
salt, such as a (D)(-) tartrate salt or a (L)(+) tartrate salt, a
hydrochloride salt, a citrate salt, a malate salt, particularly a
D-malate salt, a fumarate salt, a succinate salt, a benzoate salt,
a benzenesulfonate salt, a pamoate salt, a hemiformate salt, a
malonate salt, a salicylate salt, a cyclohexanesulfamate salt, a
mandelate salt, particularly an (R)(-) mandelate salt, a
hemiglutarate salt, an adipate salt, a vanillate salt and a sulfate
salt.
[0010] In a further preferred embodiment of the present invention,
the acid addition salt is selected from the group consisting of
imatinib D-tartrate, imatinib D-malate, imatinib hemiformate,
imatinib malonate, imatinib salicylate, imatinib hemiglutamate,
imatinib cyclohexanesulfamate, imatinib mandelate, particularly
imatinib (R)(-) mandelate, imatinib adipate, imatinib vanillate and
imatinib sulfate.
[0011] The present invention further relates to a pharmaceutical
composition comprising one of the above mentioned salts of imatinib
and a pharmaceutically acceptable carrier.
[0012] In one embodiment, the invention relates to a pharmaceutical
composition which comprises a pharmaceutically acceptable carrier
and an acid addition salt of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide selected from the group consisting
of a tartrate salt, such as a (D)(-) tartrate salt or a (L)(+)
tartrate salt, a hydrochloride salt, a citrate salt, a malate salt,
particularly a D-malate salt, a fumarate salt, a succinate salt, a
benzoate salt, a benzenesulfonate salt, a pamoate salt, a formate
salt, a malonate salt, a 1,5-naphthalenedisulfonate salt, a
salicylate salt, a cyclohexanesulfamate salt, a lactate salt,
particularly a (S)-lactate salt, a mandelate salt, particularly an
(R)(-) mandelate salt, aq glutarate salt, an adipate salt, a
squarate salt, a vanillate salt, an oxaloacetate salt, an ascorbate
salt, particularly an (L)-ascorbate salt and a sulfate salt.
[0013] In an important embodiment, the acid addition salt is
selected from the group consisting of imatinib ascorbate, imatinib
formate, imatinib malonate, imatinib oxaloacetate, imatinib
squarate and imatinib vanillate.
[0014] The invention relates also to a process for the treatment of
warm-blooded animals suffering from a tumour disease, wherein a
quantity of one of acid addition salt of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-[[4-(3-pyridinyl)-2-pyridi-
nyl]amino]phenyl]-benzamide disclosed herein which is effective
against the disease concerned, especially a quantity with
antiproliferative and especially tumour-inhibiting efficacy, is
administered to warm-blooded animals in need of such treatment,
especially the treatment of gliomas, ovarian tumours, prostate
tumours, gastro-intestinal stromal tumors, colon tumours, and
tumours of the lung, such as especially small cell lung carcinoma,
and tumours of the breast or other gynaecological tumours and, in
particular leukemia. Depending on species, age, individual
condition, mode of administration, and the clinical picture in
question, effective doses, for example daily doses of about 10-2000
mg, preferably 25-1000 mg, especially 50-800 mg, are administered
to warm-blooded animals of about 70 kg bodyweight.
[0015] In a further aspect, the present invention relates to the
use of an acid addition salt of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide according to any one claims 1 to 4
for the manufacture of a pharmaceutical composition for the
treatment of a tumour disease, especially the treatment of gliomas,
ovarian tumours, prostate tumours, gastro-intestinal stromal
tumors, colon tumours, and tumours of the lung, such as especially
small cell lung carcinoma, and tumours of the breast or other
gynaecological tumours and, in particular leukemia.
[0016] The following Examples illustrate the invention without
limiting the scope thereof.
EXAMPLE 1
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, tartrate
[0017]
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)--
2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to
a solution of (2R,3R)-2,3-dihydroxybutanedioic acid (L-(+)-tartaric
acid; Fluka, Buchs, Switzerland; 1.50 g, 10 mmol) in hot ethanol
(40 mL). The solution is evaporated to dryness under reduced
pressure and the resulting residue is re-crystallized from methanol
to afford, after filtering and drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, tartrate as a pale-yellow
crystalline solid, having the following analytical properties:
Analysis found: C, 60.18; H, 5.96; N, 14.86%; H.sub.2O, 2.25%.
Calculated for C.sub.33H.sub.37N.sub.7O.sub.7.about.0.82 H.sub.2O:
C, 60.19; H, 5.91; N, 14.89%; H.sub.2O, 2.24%.
EXAMPLE 2
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, hydrochloride
[0018] Aqueous hydrochloric acid (0.99 g of 37%) is added to a
solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) in ethanol (20
mL). The solution is evaporated to dryness under reduced pressure
and the resulting residue is re-crystallized from
ethanol-ethylacetate. The product is filtered-off and
re-crystallized from isopropanol to afford, after filtering and
drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, hydrochloride as a pale-yellow
crystalline solid, having the following analytical properties:
Analysis found: C, 65.27; H, 6.07; N, 18.19; Cl, 6.55%; H.sub.2O,
0.56%. Calculated for C.sub.20H.sub.32N.sub.7OCl--0.17 H.sub.2O: C,
65.33; H, 6.11; N, 18.39; Cl, 6.65%; H.sub.2O, 0.57%.
EXAMPLE 3
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, citrate
[0019]
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)--
2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to
a solution of anhydrous 2-hydroxy-1,2,3-propanetricarboxylic acid
(citric acid; Merck, Darmstadt, BRD; 1.92 g, 10 mmol) in methanol
(30 mL) at room temperature. Upon cooling,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, citrate crystallizes and is
filtered and dried to afford a pale-yellow crystalline solid,
having the following analytical properties: Analysis found: C,
59.24; H, 5.71; N, 13.60%, H.sub.2O, 2.14%. Calculated for
C.sub.35H.sub.39N.sub.7O.sub.8.about.0.83 H.sub.2O: C, 60.00; H,
5.85; N, 13.99%; H.sub.2O, 2.13%.
EXAMPLE 4
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl]-N-[4-ml-3-[[4-(3-pyridinyl-
)-2-pyrimidinyl]amino]phenyl]-benzamide, malate
[0020]
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)--
2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to
a solution of (2S)-(-)-hydroxybutanedioic acid (L-(-)-malic acid;
Fluka, Buchs, Switzerland; 1.34 g, 10 mmol) in water (40 mL). The
mixture is heated and the resulting hot solution is filtered and
evaporated to dryness under reduced pressure to give a residue
which is re-crystallized from ethanol, filtered and dried to give
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, malate as a pale-yellow
crystalline solid, having the following analytical properties:
Analysis found: C, 62.88; H, 6.04; N, 15.60%; H.sub.2O, 0.45%.
Calculated for CH.sub.33H.sub.37N.sub.7O.sub.6.about.0.16 H.sub.2O:
C, 62.86; H, 5.97; N, 15.55%; H.sub.2O, 0.46%.
EXAMPLE 5
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2pyrimi-
dinyl]amino]phenyl]-benzamide, fumarate
[0021] (Trans)-butenedioic acid (fumaric acid; Fluka, Buchs,
Switzerland; 1.16 g, 10 mmol) is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) in ethanol (25
mL). The mixture is heated to 90.degree. C., treated with water (18
g) and filtered. Upon cooling, the product crystallizes and is
filtered and dried to afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, fumarate a pale-yellow crystalline
solid, having the following analytical properties: Analysis found:
C, 63.91; H, 5.9.5; N, 15.74%; H.sub.2O, 1.27%. Calculated for
C.sub.33H.sub.35N.sub.7O.sub.5.about.0.44 H.sub.2O: C, 64.18; H,
5.86; N, 15.88%; H.sub.2O, 1.28%.
EXAMPLE 6
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, succinate
[0022]
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)--
2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to
a solution of butanedioic acid (succinic acid; Fluka, Buchs,
Switzerland; 1.18 g, 10 mmol) is added to a solution of in ethanol
(25 mL). The mixture is heated to 90.degree. C., treated with water
(0.2 g) and filtered. Upon cooling, the product crystallizes and is
filtered and dried to afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, succinate as a pale-yellow
crystalline solid, having the following analytical properties:
Analysis found: C, 64.19; H, 6.11: N, 15.82%; H.sub.2O, 0.87%.
Calculated for C.sub.33H.sub.37N.sub.7O.sub.5.about.0.30 H.sub.2O:
C, 64.23; H, 6.14; N, 15.89%; H.sub.2O, 0.88%.
EXAMPLE 7
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, benzoate
[0023]
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)--
2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to
a solution of benzoic acid (Fluka, Buchs, Switzerland; 1.22 g, 10
mmol) in xylene (50 mL). The mixture is heated and the resulting
hot solution is filtered. Upon cooling, the product crystallizes
and is filtered and dried to afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, benzoate as a pale-brown
crystalline solid, having the following analytical properties:
Analysis found: C, 70.13; H, 6.12; N, 16.24%. Calculated for
C.sub.36H.sub.37N.sub.7O.sub.3: C, 70.22; H, 6.06; N, 15.92%.
EXAMPLE 9
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, benzenesulphonate
[0024]
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)--
2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to
a solution of benzenesulphonic acid (Fluka, Buchs, Switzerland;
1.61 g, 10 mmol) in hot toluene (40 mL). The solution is evaporated
to dryness under reduced pressure and the resulting residue is
re-crystallized from ethanol-ethylacetate. The product is
filtered-off and dried to afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, benzenesulphonate as a pale-yellow
crystalline solid, having the following analytical properties:
Analysis found: C, 64.19; H, 5.68; N, 14.93; S, 4.87%; H.sub.2O,
0.34%. Calculated for C.sub.35H.sub.37N.sub.7O.sub.4S.about.0.12
H.sub.2O: C, 64.28; H, 5.74; N, 14.99; 5, 4.90%; H.sub.2O,
0.33%.
EXAMPLE 10
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, pamoate
[0025] A mixture of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[(4-(3-pyridinyl)-2-pyr-
imidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) and
4,4'-methyienebis[3-hydroxy-2-naphthoic acid (Fluka, Buchs,
Switzerland; 3.88 g, 10 mmol) in ethanol (50 mL) is heated. Water
(25 mL) is then added. Upon cooling, the product crystallises and
is filtered-off and dried to afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, pamoate as a pale-yellow solid,
having the following analytical properties: Analysis found: C,
69.12; H, 5.62; N, 10.88%; H.sub.2O, 2.50%. Calculated for
C.sub.52H.sub.47N.sub.7O.sub.7--1.26 H.sub.2O: C, 69.04; H, 5.52;
N, 10.84%; H.sub.2O, 2.51%.
EXAMPLE 11
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, salicylate
[0026] A solution of 2-hydroxybenzoic acid (salicylic acid; Fluka,
Buchs, Switzerland; 558 mg, 4 mmol) in ethanol (50 mL) is added to
a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyradinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is reduced in volume to
80 mL by rotary evaporation at 90.degree. C. and 400 mbar and then
slowly cooled to 20.degree. C. to afford, after filtering and
drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, salicylate as a crystalline solid,
having the following analytical properties: Analysis found: C,
68.18; H, 5.93; N, 15.52; O, 10.42%; H.sub.2O, 0.31%. Calculated
for C.sub.36H.sub.37N.sub.7O.sub.4--0.11 H.sub.2O: C, 68.23; H,
5.92; N, 15.47; O, 10.38%; H.sub.2O, 0.31%.
EXAMPLE 12
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide vanillate
[0027] A solution of 4-hydroxy-3-methoxybenzoic acid (vanillic
acid; Fluka, Buchs, Switzerland; 694 mg, 4 mmol) in ethanol (50 mL)
is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The solution is evaporated to dryness
under reduced pressure and the resulting residue is re-crystallized
from ethanol-acetone. The product is filtered-off and dried to
afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, vanillate as a crystalline solid,
having the following analytical properties: Analysis found: C,
66.61; H, 6.18; N, 14.74; O, 12.86%; H.sub.2O, 0.84%. Calculated
for C.sub.37H.sub.39N.sub.7O.sub.5--0.31 H.sub.2O: C, 66.59; H,
5.98; N, 14.69: O, 12.73%, H.sub.2O, 0.84%.
EXAMPLE 13
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, cyclohexanesulphamate
[0028] A solution of N-cyclohexylsulphamic acid (Fluka, Buchs,
Switzerland; 732 mg, 4 mmol) in ethanol (100 mL) is added to a
solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-p-
yrimidinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The solution is evaporated to dryness
under reduced pressure and the resulting residue is re-crystallized
from ethanol-isopropanol. The product is filtered-off and dried to
afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, sulphamate as a crystalline solid,
having the following analytical properties: Analysis found: C,
61.13; H, 6.75; N, 15.87; O, 11.80; S, 4.57%; H.sub.2O, 1.69%.
Calculated for C.sub.35H.sub.44N.sub.5O.sub.4S--0.40 i-PrOH-0.70
H.sub.2O: C, 61.28; H, 6.90; N, 15.79; O, 11.50; S, 4.52%,
H.sub.2O, 1.78%.
EXAMPLE 14
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, hemiglutarate
[0029] A solution of 1,5-pentanedioic acid (glutaric acid; Fluka,
Buchs, Switzerland; 539 mg, 4 mmol) in ethanol (60 mL) is added to
a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is reduced in volume to
80 mL by rotary evaporation at 90.degree. C. and 400 mbar and then
slowly cooled to 20.degree. C. to afford, after filtering and
drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, hemiglutarate as a crystalline
solid, having the following analytical properties: Analysis found:
C, 64.62; H, 5.81; N, 16.81; O, 11.96%; H.sub.2O, 4.14%. Calculated
for C.sub.32H.sub.36N.sub.7O.sub.3.about.1.5 H.sub.2O: C, 64.74; H,
6.62; N, 16.51; O, 12.13%. H.sub.2O, 4.55%.
EXAMPLE 15
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]benzamide, malonate
[0030] A solution of 1,3-propanedioic acid (malonic acid; Fluka,
Buchs, Switzerland; 420.5 mg, 4 mmol) in ethanol (60 mL) is added
to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-p-
yrimidinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is slowly cooled to
20.degree. C. to afford, after filtering and drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, malonate as a crystalline solid,
having the following analytical properties: Analysis found: C,
64.0; H, 6.1; N, 16.3; O, 13.6%; H.sub.2O, <0.3%. Calculated for
C.sub.32H.sub.35N.sub.7O.sub.5: C, 64.31; H, 5.90; N, 16.40; O,
13.38%.
EXAMPLE 16
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, sulphate
[0031] A solution of sulphuric acid (Fluka, Buchs, Switzerland; 4.0
mL of 1M) in ethanol (50 mL) is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-pyridinyl)-2-pyrimid-
inyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol (350
mL at 90.degree. C.). The hot solution is slowly cooled to
20.degree. C. to afford, after filtering and drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, sulphate as a crystalline solid,
having the following analytical properties: Analysis found: C,
55.17; H, 5.82; N, 15.57; O, 18.29; S, 5.26%. H.sub.2O, 5.89%.
Calculated for C.sub.29H.sub.33N.sub.7O.sub.5S--2.06 H.sub.2O: C,
55.34; H, 5.95; N, 15.59; O, 17.96; S, 5.10%; H.sub.2O, 5.90%.
EXAMPLE 17
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, adipate
[0032] A solution of 1,6-hexanedioic acid (adipic acid; Fluka,
Buchs, Switzerland; 1081 mg, 4 mmol) in ethanol (80 mL) is added to
a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-p-
yrimidinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is reduced in volume to
80 mL by rotary evaporation at 90.degree. C. and 400 mbar and then
slowly cooled to 20.degree. C. to afford, after filtering and
drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, adipate as a crystalline solid,
having the following analytical properties: Analysis found: C,
64.97; H, 6.33; N, 15.44; O, 12.77%; H.sub.2O, 1.43%. Calculated
for C.sub.35H.sub.41N.sub.7O.sub.5--0.5 H.sub.2O: C, 64.76; H,
6.53; N, 15.10; O, 13.61%, H.sub.2O, 1.44%.
EXAMPLE 18
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, (R)-(-)-mandelate
[0033] A solution of (R)-(-)-alpha-hydroxybenzeneaceticlic acid
((D)-(-)-mandelic acid; Fluke, Buchs, Switzerland; 553 mg, 3.13
mmol) in ethanol (60 mL) is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is reduced in volume to
80 mL by rotary evaporation at 90.degree. C. and 400 mbar and then
slowly cooled to 20.degree. C. to afford, after filtering and
drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, mandelate as a crystalline solid,
having the following analytical properties: Analysis found: C,
68.60; H, 6.27; N, 15.19; O, 9.91%; H.sub.2O, 0.22%. Calculated for
C.sub.37H.sub.39N.sub.7O.sub.4--0.08 H.sub.2O: C, 68.67; H, 6.10;
N, 15.15; O, 10.09%; H.sub.2O, 0.22%.
EXAMPLE 19
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, malate
[0034] A solution of (2R)-(-)-hydroxybutanedioic acid ((D)-malic
acid; Fluka, Buchs, Switzerland; 553 mg, 2.83 mmol) in ethanol (60
mL) is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is reduced in volume to
80 mL by rotary evaporation at 90.degree. C. and 400 mbar and then
slowly cooled to 20.degree. C. to afford, after filtering and
drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, malate as a crystalline solid,
having the following analytical properties: Analysis found: C,
62.14; H, 6.33; N, 15.48; O, 16.18%; H.sub.2O, 1.99%. Calculated
for C.sub.33H.sub.37N.sub.7O.sub.6--0.71 H.sub.2O: C, 61.88; H,
6.05; N, 15.31; O, 16.76%; H.sub.2O, 2.00%.
EXAMPLE 20
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, (D)-(-)-tartrate
[0035] A solution of (2S,3S)-2,3-dihydroxy-butanedioic acid
(tartaric acid; Fluka, Buchs, Switzerland; 606.5 mg, 1.97 mmol) in
ethanol (90 mL) is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The hot solution is slowly cooled to
20.degree. C. to afford, after filtering and drying,
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, tartrate as a crystalline solid,
having the following analytical properties: Analysis found: C,
60.54; H, 6.08; N, 14.37; O, 18.89%; H.sub.2O, 1.32%. Calculated
for C.sub.33H.sub.37N.sub.7O.sub.7--0.50 EtOH--0.50 H.sub.2O: C,
60.43; H, 6.12; N, 14.51; O, 18.94%. H.sub.2O, 1.33%.
EXAMPLE 21
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrim-
idinyl]amino]phenyl]-benzamide, hemiformate
[0036] A solution of formic acid (Fluka, Buchs, Switzerland; 368
mg, 8 mmol) in ethanol (20 mL) is added to a solution of
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol
(150 mL at 90.degree. C.). The solution is evaporated to dryness
under reduced pressure and the resulting residue is re-crystallized
from acetone. The product is filtered-off and dried to afford
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide, hemiformate as a crystalline
solid, having the following analytical properties: Analysis found:
C, 68.50; H, 6.24; N, 18.93; O, 6.43%. H.sub.2O, 1.69%. Calculated
for C.sub.59H.sub.84N.sub.14O.sub.4--1.80 H.sub.2O: C, 88.46; H,
6.25; N, 18.95; O, 6.34%; H.sub.2O, 0.17%.
EXAMPLE 22
Capsules
[0037] Capsules containing 100 mg of a
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide salt (Salt) are usually prepared in
the following composition:
TABLE-US-00001 Composition Salt 100 mg Avicel 200 mg PVPPXL 15 mg
Aerosil 2 mg Magnesium stearate 1.5 mg 318.5 mg
[0038] The capsules are prepared by mixing the components and
filling the mixture into hard gelatin capsules, size 1.
EXAMPLE 23
Water Solubility
[0039] Solubility in water at room temperature of the
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-benzamide salts is as listed in Table 1
below. For comparison, the solubility of the free base in water at
room temperature is 0.44 mg/ml.
TABLE-US-00002 TABLE 1 Solubility in water at room Salt of Example
temperature in mg/ml 1 >51 2 32.5 3 38.2 4 >49 5 9.71 6 50.1
7 47.9 8 47 9 >44 10 0.32 15 >53
* * * * *