U.S. patent application number 12/598743 was filed with the patent office on 2010-05-27 for mono-hydrochloric salts of an inhibitor of histone deacetylase.
Invention is credited to Julius W.J. Dickens, Ioannes Nicolaos Houpis, Yolande Lydia Lang, Carina Leys, Sigrid Carl Maria Stokbroekx, Johan Erwin Edmond Weerts.
Application Number | 20100130523 12/598743 |
Document ID | / |
Family ID | 38659779 |
Filed Date | 2010-05-27 |
United States Patent
Application |
20100130523 |
Kind Code |
A1 |
Dickens; Julius W.J. ; et
al. |
May 27, 2010 |
MONO-HYDROCHLORIC SALTS OF AN INHIBITOR OF HISTONE DEACETYLASE
Abstract
This invention provides novel crystalline forms of mono-HCl
salts and a mono-HCl salt hydrate of JNJ-26481585, an inhibitor of
histone deacetylases. The invention also relates to processes for
production of these forms, to intermediates used in these
processes, to pharmaceutical compositions comprising these forms,
and to the use of these forms in medical treatment for instance as
a medicine to inhibit proliferative conditions, such as cancer and
leukemia.
Inventors: |
Dickens; Julius W.J.;
(Beerse, BE) ; Houpis; Ioannes Nicolaos;
(Antwerpen, BE) ; Lang; Yolande Lydia; (Vosselaar,
BE) ; Leys; Carina; (Stabroek, BE) ;
Stokbroekx; Sigrid Carl Maria; (Beerse, BE) ; Weerts;
Johan Erwin Edmond; (Beerse, BE) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
38659779 |
Appl. No.: |
12/598743 |
Filed: |
May 13, 2008 |
PCT Filed: |
May 13, 2008 |
PCT NO: |
PCT/EP08/55804 |
371 Date: |
November 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60917821 |
May 14, 2007 |
|
|
|
Current U.S.
Class: |
514/275 ;
544/331; 546/232 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 35/02 20180101; C07D 211/26 20130101; A61P 35/00 20180101;
C07D 401/14 20130101 |
Class at
Publication: |
514/275 ;
546/232; 544/331 |
International
Class: |
A61K 31/506 20060101
A61K031/506; C07D 211/28 20060101 C07D211/28; C07D 401/14 20060101
C07D401/14; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 14, 2007 |
EP |
07108176.4 |
Claims
1. A mono-hydrochloric salt of formula (XIX) ##STR00024##
2. The mono-hydrochloric salt of claim 1 wherein said salt is in
crystalline Form I, Form II or in a hydrate form.
3. The mono-hydrochloric salt of claim 1 in crystalline Form I
wherein said crystalline form has an X-ray powder diffraction
pattern comprising peaks at 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., 23.4.degree..+-.0.2.degree.,
24.4.degree..+-.0.2.degree. and 27.7.degree..+-.0.2.degree..
4. The mono-hydrochloric salt of claim 3 wherein the X-ray powder
diffraction pattern further comprises peaks at
7.6.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree. and
12.5.degree..+-.0.2.degree..
5. The mono-hydrochloric salt of claim 1 wherein the crystalline
form has an infrared spectrometry micro attenuated reflectance
spectrum with peaks at 3119.+-.1 cm.sup.-1, 2756.+-.1 cm.sup.-1,
1634.+-.1 cm.sup.-1, 1475.+-.1 cm.sup.-1, 1371.+-.1 cm.sup.-1,
1333.+-.1 cm.sup.-1, 1275.+-.1 cm.sup.-1, 1226.+-.1 cm.sup.-1,
1128.+-.1 cm.sup.-1 and 1066 cm.sup.-1.+-.1 cm.sup.-1.
6. The mono-hydrochloric salt of claim 1 wherein the crystalline
form has a differential scanning calorimetry curve with an
endothermic peak at about 216.8.degree. C.
7. The mono-hydrochloric salt of claim 1 wherein the crystalline
form adsorbs up to 0.6% water at high relative humidity.
8. The mono-hydrochloric salt of claim 1 in hydrate form wherein
said hydrate form has an X-ray powder diffraction pattern
comprising peaks at 10.0.degree..+-.0.2.degree.,
13.4.degree..+-.0.2.degree. and 26.5.degree..+-.0.2.degree..
9. The mono-hydrochloric salt of claim 8 wherein the X-ray powder
diffraction pattern further comprises peaks at
21.6.degree..+-.0.2.degree. and 24.9.degree..+-.0.2.degree..
10. The mono-hydrochloric salt of claim 8 wherein the crystalline
form has an infrared spectrometry micro attenuated reflectance
spectrum with peaks at 3558.+-.1 cm.sup.-1, 3238.+-.1 cm.sup.-1,
1607.+-.1 cm.sup.-1 and 997 cm.sup.-1.+-.1 cm.sup.-1.
11. The mono-hydrochloric salt of claim 1 wherein crystalline Form
I is essentially pure.
12. The mono-hydrochloric salt of claim 1 wherein crystalline Form
II is essentially pure.
13. The mono-hydrochloric salt of claim 1 wherein the hydrate form
is essentially pure.
14. A process for preparing the crystalline form according to claim
1 comprising: a) dissolving compound of formula (XVIII) in an
alcoholic solvent containing less than 0.1% w/w of water, while
heating to between 50.degree. C. and 70.degree. C.; b) adding
hydrochloric acid to the reaction mixture; and c) stirring the
reaction mixture while maintaining the temperature at between
50.degree. C. and 70.degree. C.
15. The process of claim 14 comprising between step a) and b)
seeding the mixture with Form I.
16. A process for preparing the hydrate form according to claim 2
comprising a) dissolving the compound of formula (XVIII), in an
ethanol/water or methanol/water mixture comprising more than 5% of
water, while heating to between 50.degree. C. and 70.degree. C.,
preferably 50.degree. C. and 60.degree. C. of the solvent; b)
adding hydrochloric acid to the reaction mixture; and c) stirring
the reaction mixture while maintaining the temperature at between
50.degree. C. and 70.degree. C., preferably between 50.degree. C.
and 60.degree. C. more preferably at 55.degree. C.
17. A process for preparing the compound of formula (XVIII)
comprising a) reacting the intermediate of formula (VIII) with the
intermediate of formula (XI) in the presence of a suitable solvent,
##STR00025## b) reacting the intermediate of formula (I) with the
intermediate of formula (II) in a suitable solvent followed by
reduction and salt formation giving the intermediate of formula
(XIII), ##STR00026## c) conversion of the intermediate of formula
(XIII) by base neutralization, basic hydrolysis and acidification
with hydrochloric acid into the intermediate of formula (XVII) and
##STR00027## d) reacting the intermediate of formula (XVII) with
O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, in the presence of an
appropriate coupling reagents. ##STR00028##
18. The process of claim 17 wherein the amount of water in
intermediate (XVII) is between 15 and 25 v/v %.
19. A process for the preparation of the compound of formula (XI)
comprising reacting an intermediate of formula (IX) with an
intermediate of formula (X) in the presence of a suitable solvent.
##STR00029##
20. A compound of formula (XI), (XIII), (XVII) or (XVIII).
##STR00030## an N-oxide, addition salt or stereochemically isomeric
form thereof.
21. (canceled)
22. (canceled)
23. (canceled)
24. A pharmaceutical composition comprising the mono-hydrochloric
salt of claim 1 and a pharmaceutically acceptable excipient.
25. Use of the mono-hydrochloric salt according to claim 1 as
seeding material for preparing Form I.
26. A combination of the mono-hydrochloric salt of claim 1 with
another anticancer agent.
27. The mono-hydrochloric salt of claim 2 in crystalline Form I
wherein said crystalline form has an X-ray powder diffraction
pattern comprising peaks at 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., 23.4.degree..+-.0.2.degree.,
24.4.degree..+-.0.2.degree. and 27.7.degree..+-.0.2.degree..
28. The mono-hydrochloric salt of claim 27 wherein the X-ray powder
diffraction pattern further comprises peaks at
7.6.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree. and
12.5.degree..+-.0.2.degree..
29. The mono-hydrochloric salt of claim 2 wherein the crystalline
form has an infrared spectrometry micro attenuated reflectance
spectrum with peaks at 3119.+-.1 cm.sup.-1, 2756.+-.1 cm.sup.-1,
1634.+-.1 cm.sup.-1, 1475.+-.1 cm.sup.-1, 1371.+-.1 cm.sup.-1,
1333.+-.1 cm.sup.-1, 1275.+-.1 cm.sup.-1, 1226.+-.1 cm.sup.-1,
1128.+-.1 cm.sup.-1 and 1066 cm.sup.-1.+-.1 cm.sup.-1.
30. The mono-hydrochloric salt of claim 3 wherein the crystalline
form has an infrared spectrometry micro attenuated reflectance
spectrum with peaks at 3119.+-.1 cm.sup.-1, 2756.+-.1 cm.sup.-1,
1634.+-.1 cm.sup.-1, 1475.+-.1 cm.sup.-1, 1371.+-.1 cm.sup.-1,
1333.+-.1 cm.sup.-1, 1275.+-.1 cm.sup.-1, 1226.+-.1 cm.sup.-1,
1128.+-.1 cm.sup.-1 and 1066 cm.sup.-1.+-.1 cm.sup.-1.
31. The mono-hydrochloric salt of claim 4 wherein the crystalline
form has an infrared spectrometry micro attenuated reflectance
spectrum with peaks at 3119.+-.1 cm.sup.-1, 2756.+-.1 cm.sup.-1,
1634.+-.1 cm.sup.-1, 1475.+-.1 cm.sup.-1, 1371.+-.1 cm.sup.-1,
1333.+-.1 cm.sup.-1, 1275.+-.1 cm.sup.-1, 1226.+-.1 cm.sup.-1,
1128.+-.1 cm.sup.-1 and 1066 cm.sup.-1.+-.1 cm.sup.-1.
32. The mono-hydrochloric salt of claim 2 wherein the crystalline
form has a differential scanning calorimetry curve with an
endothermic peak at about 216.8.degree. C.
33. The mono-hydrochloric salt of claim 3 wherein the crystalline
form has a differential scanning calorimetry curve with an
endothermic peak at about 216.8.degree. C.
34. The mono-hydrochloric salt of claim 4 wherein the crystalline
form has a differential scanning calorimetry curve with an
endothermic peak at about 216.8.degree. C.
35. The mono-hydrochloric salt of claim 5 wherein the crystalline
form has a differential scanning calorimetry curve with an
endothermic peak at about 216.8.degree. C.
36. The mono-hydrochloric salt of claim 6 wherein the crystalline
form has a differential scanning calorimetry curve with an
endothermic peak at about 216.8.degree. C.
37. The mono-hydrochloric salt of claim 2 in hydrate form wherein
said hydrate form has an X-ray powder diffraction pattern
comprising peaks at 10.0.degree..+-.0.2.degree.,
13.4.degree..+-.0.2.degree. and 26.5.degree..+-.0.2.degree..
38. The mono-hydrochloric salt of claim 37 wherein the X-ray powder
diffraction pattern further comprises peaks at
21.6.degree..+-.0.2.degree. and 24.9.degree..+-.0.2.degree..
39. The mono-hydrochloric salt of claim 9 wherein the crystalline
form has an infrared spectrometry micro attenuated reflectance
spectrum with peaks at 3558.+-.1 cm.sup.-1, 3238.+-.1 cm.sup.-1,
1607.+-.1 cm.sup.-1 and 997 cm.sup.-1.+-.1 cm.sup.-1.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel crystalline forms of
mono-HCl salts and a mono-HCl salt hydrate of JNJ-26481585, an
inhibitor of histone deacetylases. The invention also relates to
processes for production of these forms, to intermediates used in
these processes, to pharmaceutical compositions comprising these
forms, and to the use of these forms in medical treatment for
instance as a medicine to inhibit proliferative conditions, such as
cancer and leukemia.
BACKGROUND ART
[0002] Many pharmaceutical solids can exist in different physical
forms, e.g. in an amorphous form, in one or several crystal form(s)
(e.g. anhydrous or solvated forms), in the form of mixture of
different crystal forms, or as a mixture of an amorphous form and
crystal form(s).
[0003] An amorphous form is a form in which a three-dimensional
long-range order does not exist. In the amorphous form the position
of the molecules relative to one another are essentially random,
i.e. without regular arrangement of the molecules on a lattice
structure. Amorphous and disordered materials often have improved
properties, but generating and stabilising this state can be a big
challenge.
[0004] A crystal or crystalline form is the form in which the
position of the molecules relative to one another is organised
according to a three-dimensional lattice structure. Crystalline
forms typically include polymorphs and pseudopolymorphs. Polymorphs
are different crystalline forms of the same compound resulting from
different arrangement of the molecules in the solid state.
Different polymorphs have different crystal structures due to a
different packing of the molecules in the lattice. This results in
a different crystal symmetry and/or unit cell parameters.
Polymorphs differ from each other in their physicochemical
parameters but not in their chemical composition. Polymorphism is
usually difficult to control and poses challenges to the galenists.
Pseudopolymorphs, also referred to as solvates, are a particular
case of solid state crystalline forms in which either
stoichiometric or non-stoichiometric amounts of solvent molecules
are present or incorporated into the lattice structure of the
compound. A water solvate is also referred to as a hydrate.
[0005] Solid state chemistry is of interest to the pharmaceutical
industry and especially to those involved in the development of
suitable dosage forms. For example, solid state transformations may
seriously impact the stability of pharmaceutical drugs
(shelf-life). A metastable pharmaceutical solid form can change
into a crystalline structure (e.g. from amorphous to crystalline)
or solvate/desolvate in response to changes in environmental
conditions, processing, or over time.
[0006] Different crystal forms or amorphous form of the same drug
may have substantial differences in such pharmaceutically important
properties as dissolution rates, thermodynamic solubility and
bioavailability. The rate of dissolution of an active ingredient in
a patient's stomach fluid may have therapeutic consequences since
it imposes an upper limit on the rate at which an
orally-administered active ingredient may reach the patient's
bloodstream. The rate of dissolution is thus a consideration in
formulating solid dosage forms and liquid medicaments such as
syrups and elixirs.
[0007] Likewise, different crystals or amorphous form may have
different processing properties, such as hygroscopicity,
flowability, compactation, and the like, which could affect their
suitability as active pharmaceuticals for commercial
production.
[0008] During the clinical development of pharmaceutical drugs, if
the polymorphic form is not held constant, the exact dosage form
used or studied may not be comparable from one lot to another. It
is also desirable to have processes for producing a compound with
the selected polymorphic form in high purity when the compound is
used in clinical studies or commercial products since impurities
present may produce undesired toxicological effects. Certain
polymorphic forms may exhibit enhanced thermodynamic stability or
may be more readily manufactured in high purity in large
quantities, and thus are more suitable for inclusion in
pharmaceutical formulations.
[0009] JNJ-26481585 has the following structure:
##STR00001##
[0010] The compound is an inhibitor of histone deacetylase
(HDAC).
[0011] WO 2006/010750 published on 2 Feb. 2006 discloses an
amorphous form of JNJ-26481585.C.sub.2HF.sub.3O.sub.2 salt and a
di-HCl salt and processes for obtaining them.
[0012] The synthesis of JNJ-26481585.C.sub.2HF.sub.3O.sub.2 salt as
originally described in WO 97/21701, is presented in scheme 1.
[0013] Therein, in step 1 intermediates of formula (III) were
prepared by reacting an intermediate of formula (I) with the
carboxaldehyde of formula (II), in the presence of sodium
tetrahydroborate, in methanol.
[0014] In step 2 intermediates of formula (IV) were prepared by
reacting an intermediate of formula (III) with sodium hydroxide in
ethanol.
[0015] In step 3, intermediates of formula (V) were prepared by
reacting an intermediate of formula (IV) with
O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, in the presence of
appropriate reagents such as
N'-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,
monohydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBT). The
reaction was performed in a mixture of dichloromethane and
tetrahydrofuran.
[0016] In step 4, the hydroxamic acid C.sub.2HF.sub.3O.sub.2 salt
of formula (VI) was prepared by reacting the intermediate of
formula (V), with trifluoro acetic acid. Said reaction was
performed in methanol.
##STR00002##
[0017] Alternatively, the JNJ-26481585. 2 HCl salt as originally
described in WO 97/21701, was prepared by reacting the intermediate
of formula (III), with hydroxylamine, in the presence of sodium
hydroxide. Said reaction is performed in methanol, further
conversion to the di-HCl salt was prepared in ethanol.
[0018] The process disclosed in WO 2006/010750 is unsuitable for
large scale production as the consequence of low yields and high
amount of impurities in the different process steps, which
consequently requires several chromatographic steps. The
purification of compounds using chromatography is expensive and
environmentally unfriendly due to solvent consumption and the
specialised equipment required to perform a large scale
chromatography.
[0019] The problem solved by the present invention is the provision
of novel crystalline forms of mono-HCl salts and a mono-HCl salt
hydrate of JNJ-26481585. Another aspect of the present invention is
a process wherein the novel crystalline HCl salt and HCl salt
hydrate form are obtained in high yield and high purity. The
advantageous properties of the present HCl forms are superior
physicochemical properties including its non-hygroscopic nature and
chemical stability enabling drugability of this compound.
DESCRIPTION OF THE FIGURES
[0020] FIG. 1 is an Infrared (IR) spectrum representation of Form
I
[0021] FIG. 2 is an X-ray powder Diffraction (XPRD) pattern
representation of Form I
[0022] FIG. 3 is a Differential Scanning Calorimetry (DSC) curve of
Form I
[0023] FIG. 4 is the weight change of Form I as a function of
relative humidity
[0024] FIG. 5 is adsorption-desorption (ADS/DES) curve
representation of Form I
[0025] FIG. 6 is an IR spectrum representation of Form II
[0026] FIG. 7 is an XPRD pattern representation of Form II
[0027] FIG. 8 is DSC curve of Form II
[0028] FIG. 9 is the weight change of Form II as a function of
relative humidity
[0029] FIG. 10 is an ADS/DES curve representation of Form II
[0030] FIG. 11 is an IR spectrum representation of the hydrate
form
[0031] FIG. 12 is an XPRD pattern representation of the hydrate
form
[0032] FIG. 13 is an XPRD pattern overlay slurry conversion studies
of Form I and Form II in ethanol at different temperatures
[0033] FIG. 14 is an XPRD pattern overlay slurry conversion studies
of Form I and Form II in ethanol/water (90/10, v/v %) at different
temperatures
[0034] FIG. 15 is an XPRD pattern overlay slurry conversion studies
of Form I and Form II in water at different temperatures
[0035] FIG. 16 is an XPRD pattern overlay slurry conversion studies
of the hydrate in ethanol at different temperatures
DESCRIPTION OF THE INVENTION
Preparation of the Intermediates
A. Preparation of the Intermediate of Formula (I)
##STR00003##
[0037] a) The intermediate of formula (XI) can be prepared by
reacting an intermediate of formula (IX) with an intermediate of
formula (X) in the presence of a suitable solvent such as a polar
or apolar non-protic hydrocarbon solvent e.g. toluene, methylene
chloride, isopropyl acetate, ethyl acetate, tetrahydrofuran and the
like. Other aromatic or aliphatic aldehydes can be used in the
process. This reaction can also be performed in protic solvents
e.g. methanol, ethanol, isopropanol and the like. The reaction can
be performed at a temperature between 25.degree. C. and 60.degree.
C., preferably at a temperature of 45.degree. C. Higher
temperatures are not recommended due to potential instability of
the intermediate of formula (X).
##STR00004##
[0038] b) The intermediate of formula (VIII) can be prepared by
converting the intermediate of formula (VII) in the presence of a
suitable oxidant such as meta-chloroperoxy benzoic acid (MCPBA), in
a suitable solvent such as a polar or apolar non-protic hydrocarbon
solvent e.g. toluene, methylene chloride, isopropyl acetate, ethyl
acetate, tetrahydrofuran and the like. The reaction can be
performed at a temperature between .+-.20.degree. C. and 40.degree.
C., preferably at a temperature between 0.degree. C. and 5.degree.
C. more preferably at 0.degree. C. At higher temperatures
meta-chloroperoxy benzoic acid is unstable and the intermediates of
formula (VIII) may decompose. Complete conversion of intermediate
(VII) into intermediate (VIII) can be obtained by addition of the
appropriate amount of MCPBA. Thus the amount of MCPBA is preferably
>1 equivalent.
##STR00005##
[0039] c) The intermediate of formula (I) can be prepared by
reacting the intermediate of formula (VIII) with the intermediate
of formula (XI) in the presence of a suitable solvent such as a
polar or apolar non-protic hydrocarbon solvent or mixture thereof
e.g. toluene, methylene chloride, isopropyl acetate,
tetrahydrofuran, a mixture of diisopropylethylamine or other
tertiary amine bases and ethylacetate and the like. The reaction
can be performed at a temperature between -20.degree. C. and
40.degree. C., preferably at a temperature between 0.degree. C. and
5.degree. C. more preferably at 0.degree. C. with warming up to
25.degree. C.
##STR00006##
[0040] This synthesis with the temporary protection of the
aminopiperidine of formula (IX) with the p-nitrobenzaldehyde of
formula (X) with the formation of the intermediate of formula (XI),
allows for the preferential reaction of the more substituted ring
nitrogen. If this protection is not performed, large amounts of
dimer (A) and isomer (B) are formed as both nitrogens of the
intermediate of formula (IX) will react with the intermediate of
formula (VIII). Warming up the reaction mixture overnight ensures
complete reaction of the intermediate of formula (XI) to the
intermediate of formula (I) and complete conversion of any
remaining intermediate of formula (IX) to the dimer (A) which,
together with remaining MCPBA, can be easily removed in the
subsequent acidic workup.
##STR00007##
[0041] An embodiment of the present invention comprises the
intermediate of formula (XI).
B. Preparation of the Intermediate of Formula (XIII)
##STR00008##
[0043] a) The intermediate of formula (XII) can be prepared by
reacting the intermediate of formula (I) with the intermediate of
formula (II) in a suitable solvent. The reaction can be performed
at a temperature between 50.degree. C. and 150.degree. C.,
preferably at a temperature of 110.degree. C. (reflux temperature
of toluene). Azeotropic removal of water is required for this
reaction to proceed. As solvent a polar or apolar non-protic
hydrocarbon solvent can be used, such as toluene, isopropyl acetate
and the like. These solvents azeotrope water well.
##STR00009##
[0044] b) the intermediate of formula (XII) is treated with sodium
tetrahydroborate in a suitable solvent such as polar or apolar
non-protic and protic hydrocarbon solvents and mixtures thereof
e.g. toluene, isopropyl acetate, ethanol, methanol, isopropanol and
the like. The reduction with sodium tetrahydroborate can occur
between 0.degree. C. and 50.degree. C., preferably at 10.degree. C.
Low temperature during reduction is preferred to avoid formation of
over-reduced impurities
[0045] c) Subsequently, salt formation is performed with fumaric
acid in a mixture of acetone/ethanol with 5% v/v water, with the
formation of the intermediate of formula (XIII).
##STR00010##
[0046] An embodiment of the present invention comprises the
fumarate salt of formula (XIII).
C. Preparation of Intermediate of Formula (XVIII)
[0047] In a first attempt to find a better synthesis method for the
production of JNJ-26481585, the intermediate of formula (III) was
reacted with O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, in the
presence of a base and a solvent but without coupling reagent. This
attempt was not successful.
[0048] In a second attempt it was tried to protect the amino and
hydroxamic acid moieties with acid labile protecting groups in
order to effect simultaneous deprotection-salt formation.
[0049] Therefore the intermediate of formula (XIII) was converted
to the free base, giving the intermediate of formula (III) and
further converted to the intermediate of formula (XIV), wherein R
is tertiair butyl, benzyl or fulveneyl followed by hydrolysis with
NaOH in ethanol and isolation of the intermediate of formula (XV)
by acidification and crystallization directly from the reaction
mixture.
##STR00011##
[0050] Coupling of the intermediate of formula (XV) with
O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine under standard aminoacid
coupling conditions (EDC, HOBT, triethylamine, tetrahydrofuran)
afforded the intermediate of formula (XVI) in excellent yield. The
coupling reaction for intermediates of formula (XV) wherein R is
fulvenyl caused some cleavage of the fulvenyl-group due to the
triethylamine needed for optimal coupling.
##STR00012##
[0051] Attempts to deprotect the intermediate of formula (XVI),
wherein R is tertiary butyl, were then undertaken under a variety
of conditions (solvents: ethanol, ethylacetate, toluene, acetone,
methyl isobutyl ketone, dimethylformamide; Acids: ethane sulfonic
acid, methane sulfonic acid, hydrochloric acid, trifluoroacetic
acid).
[0052] Unfortunately either at ambient temperature (2-3 hours) or
at 50.degree. C. (10 min) the only products observed were products
from cleavage of the indole moiety.
[0053] The hydrogenolysis of intermediates of formula (XVI),
wherein R is benzyl, was attempted under hydrogen atmosphere and in
the presence of an appropriate catalyst such as, for example,
palladium-on-charcoal and was judged unsuccessful due to competing
cleavage (up to 20%) of the N--O bond on the hydroxamic acid
product. On the other hand, cleavage of the fulvenyl group of the
intermediate of formula (XVI), wherein R is fulvenyl, herein
referred to as the intermediate of formula (XVI-a) under mild
conditions and trapping the fulvene by-product by using thiol
silica gel was successful. The corresponding free amine of formula
(V) can give the compound of formula (XIX) under similar conditions
(1.05 equivalents of hydrochloric acid, ethanol, 70.degree. C.) as
described below.
##STR00013##
[0054] a) Finally, the free base of intermediate (XIII) can be
obtained by an aqueous sodium hydroxide neutralization and
extraction in methyltetrahydrofuran. The organic layer containing
the free base is then submitted to a basic hydrolysis with 3 mole
equivalents sodium hydroxides in water at reflux. The sodium salt
in the water layer is then separated from the methyltetrahydrofuran
layer and acidified with 5 mole equivalents HCl at 10.degree.
C.
[0055] The intermediate of formula (XVII) can have a variable water
content. Immediately after drying the water content is 0.7%. When
the sample was left 24 h at the atmosphere, the water content
increased and stabilized at 8% water which represents 2 mole of
water.
##STR00014##
[0056] b) The effect of water in intermediate (XVII) is crucial, as
the below coupling reaction requires a specific amount of water to
be successful. The amount of water in intermediate (XVII) is
preferably between 15 and 25 v/v %, most preferably ca 16 v/v
%.
[0057] The intermediates of formula (XVIII) can be prepared by
reacting the intermediate of formula (XVII) with
O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, in the presence of
appropriate reagents such as
N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,
monohydrochloride (EDC) as coupling reagent. The reaction can be
performed in polar or apolar non-protic and protic hydrocarbon
solvents and mixtures thereof e.g. methyltetrahydrofuran,
dimethylformamide (DMF), dichloromethane (DCM), toluene,
isopropanol, ethanol, acetonitrile, ethyl acetate, isopropanol
acetate, mixture thereof and mixture of one or more of the
different solvents with water, preferably a mixture of ethylacetate
and ethanol, more preferably a mixture of ethylacetate, ethanol and
water. The temperature during the reaction can be between
10.degree. C.-40.degree. C., preferably at room temperature.
##STR00015##
[0058] The reaction is fast and complete when enough water is
present. The reaction is slower under dry conditions, more
impurities are present and the reaction rate towards product drops
down.
[0059] c) The intermediate with formula (XVIII) can be dissolved in
a solvent such as dimethylformamide or dimethylacetamide,
preferably dimethylacetamide. Addition of a co-solvent allows the
product to crystallize out. Co-solvents such as acetone, methyl
isobutyl ketone or methyl ethyl ketone, preferably methyl isobutyl
ketone, can be used. Purification can be performed at a temperature
between 25.degree. C.-90.degree. C., preferably between 50.degree.
C. and 70.degree. C. Crystallization time should not be longer than
5 h. At higher temperatures or longer crystallization periods the
yield of the final product goes down. Recrystallization can be
performed in a solvent such as ethanol in the presence of a
co-solvent such as methyl ethyl ketone at a temperature between
50.degree. C. and 70.degree. C., preferably at 70.degree. C.
[0060] An embodiment of the present invention comprises the
hydrochloric salts of formula (XVII) and (XVIII)
Preparation of Crystalline Forms
[0061] The intermediate of formula (XVIII) can be converted into
the HCl salt of formula (XIX) by adding hydrochloric acid in a
suitable solvent such as ethanol or methanol while the reaction
mixture is at the desired temperature.
##STR00016##
[0062] The present invention provides a process for preparing the
crystalline mono-HCl salt Form I comprising: [0063] a) dissolving
compound of formula (XVIII) in an alcoholic solvent containing less
than 0.1% w/w of water, while heating to between 50.degree. C. and
70.degree. C., preferably 50.degree. C. and 60.degree. C. of the
solvent; [0064] b) adding hydrochloric acid to the reaction
mixture; and [0065] c) stirring the reaction mixture while
maintaining the temperature at between 50.degree. C. and 70.degree.
C., preferably between 50.degree. C. and 60.degree. C. more
preferably at 55.degree. C.
[0066] In one embodiment, the process mentioned in the paragraph
above for preparing Form I comprises adding ethanol or methanol in
a concentration between 10.3 and 20.6 L/mol, preferably in a
concentration of 10.3 L/mol.
[0067] In another embodiment, the processes mentioned above for
preparing Form I comprises in step a) dissolving the compound in a
time slot of 30 min to 3 h, preferable in a time slot of 30 min to
45 min.
[0068] In another embodiment, the processes mentioned above for
preparing Form I comprises in step b) adding hydrochloric acid at a
concentration of 0.05 to 0.4 equivalents of concentrated HCl
preferably at a concentration between 0.05 to 1.1 equivalents,
preferable at a concentration between 0.05 to 0.4 equivalents.
[0069] In another embodiment, the process mentioned in paragraph 1
to 3 above for preparing Form I comprises in step b) adding
hydrochloric acid at a concentration of 0.03 to 0.07 equivalents of
HCl (1 Molar) preferably at a concentration between 0.03 to 0.05
equivalents.
[0070] In another embodiment, the process mentioned in paragraph 1
to 3 above for preparing Form I comprises in step b) adding
hydrochloric acid at a concentration of 0.03 to 0.05 equivalents of
HCl in isopropanol.
[0071] In another embodiment, the processes mentioned above for
preparing Form I comprises in step c) dissolving the compound in a
time slot of 30 min to 3 h, preferable in a time slot of 30 min to
45 min.
[0072] In another embodiment, the processes mentioned above for
preparing Form I comprises in step c) stirring the mixture between
30 min and 16 h, preferably for 16 h.
[0073] The present invention further provides a process for
preparing the hydrate form comprising: [0074] a) dissolving the
compound of formula (XVIII), in an ethanol/water or methanol/water
mixture comprising more than 5% of water, while heating to between
50.degree. C. and 70.degree. C., preferably 50.degree. C. and
60.degree. C. of the solvent; [0075] b) adding hydrochloric acid to
the reaction mixture; and [0076] c) stirring the reaction mixture
while maintaining the temperature at between 50.degree. C. and
70.degree. C., preferably between 50.degree. C. and 60.degree. C.
more preferably at 55.degree. C.
[0077] In one embodiment, the process mentioned in the paragraph
above for preparing the hydrate form comprises adding ethanol or
methanol in a concentration between 10.3 and 20.6 L/mol, preferably
in a concentration of 10.3 L/mol.
[0078] In another embodiment, the processes mentioned above for
preparing the hydrate form comprises in step a) dissolving the
compound in a time slot of 30 min to 3 h, preferable in a time slot
of 30 min to 45 min.
[0079] In another embodiment, the processes mentioned above for
preparing the hydrate form comprises in step b) adding hydrochloric
acid at a concentration of 0.05 to 0.4 equivalents of concentrated
HCl preferably at a concentration between 0.05 to 1.1 equivalents,
preferable at a concentration between 0.05 to 0.4 equivalents.
[0080] In another embodiment, the process mentioned in paragraph 1
to 3 above for preparing the hydrate form comprises in step b)
adding hydrochloric acid at a concentration of 0.03 to 0.0.07
equivalents of HCl (1 Molar) preferably at a concentration between
0.03 to 0.05 equivalents.
[0081] In another embodiment, the process mentioned in paragraph 1
to 3 above for preparing the hydrate form comprises in step b)
adding hydrochloric acid at a concentration of 0.03 to 0.05
equivalents of HCl in isopropanol.
[0082] In another embodiment, the processes mentioned above for
preparing the hydrate form comprises in step c) dissolving the
compound in a time slot of 30 min to 3 h, preferable in a time slot
of 30 min to 45 min.
[0083] In another embodiment, the processes mentioned above for
preparing the hydrate form comprises in step c) stirring the
mixture between 30 min and 16 h, preferably for 16 h.
[0084] The present invention further provides slurrying processes
for preparing Form I comprising: [0085] slurrying Form II in a
solvent selected from ethanol or methanol at a temperature of at
least 50.degree. C., preferably at 70.degree. C. or higher; or
[0086] slurrying a mixture of Form I and Form II in a solvent
selected from ethanol or methanol at a temperature of at least
50.degree. C., preferably at 70.degree. C. or higher.
[0087] In another embodiment, the slurrying processes mentioned
above for preparing Form I may comprise 10% of water, preferably
<2% of water most preferably <0.07% of water.
[0088] In another embodiment, the slurrying processes for preparing
Form I further comprise stirring during at least 4 to 7 days.
[0089] The present invention further provides slurrying processes
for preparing the hydrate form comprising: [0090] slurrying Form II
in an ethanol/water or methanol/water mixture comprising at least
10% of water; [0091] slurrying a mixture of Form I and Form II in
an ethanol/water or methanol/water mixture comprising at least 10%
of water; [0092] slurrying a mixture of Form I and Form II in an
aqueous medium comprising at least 90% of water.
[0093] In another embodiment, the slurrying processes for preparing
the hydrate form further comprise stirring during 4 to 7 days.
[0094] In another embodiment, the processes for preparing Form I
further comprise filtering the precipitates obtained after
slurrying Form II in an alcoholic solvent, or after slurrying a
mixture of Form I and Form II in a solvent as indicated above.
[0095] In another embodiment, the slurrying processes for preparing
Form I further comprise, after the filtering step of the paragraph
above, washing the filtered precipitates obtained after slurrying
Form II in an alcoholic solvent, or after slurrying a mixture of
Form I and Form II in a solvent as indicated above, wherein the
washing step is performed with the same solvent employed during the
slurrying step.
[0096] For the preparation of any of the Forms of the present
invention, which proceeds from a solution of the compound of
formula (XVIII), it should be recognized by those skilled in the
art that the solid form of the starting material has no influence
on the solid form of the end product and control of the resulting
solid Form is performed via the control of the process
parameters.
[0097] The invention provides as well the above processes for
preparing Form I comprising between step a) and b) seeding the
mixture with Form I.
[0098] The invention provides as well the above processes for
preparing the hydrate form comprising between step a) and b)
seeding the mixture with Form I.
[0099] The invention provides as well a process wherein the
obtained crystalline form is isolated by filtration or
centrifugation, optionally combined with washing and drying.
[0100] The starting material used for the processes of the present
invention may be any crystalline form of the compound of formula
(XVIII).
[0101] With the term "compounds of the present invention" is meant
a compound of formula (XI), (XIII), (XVII), (XVIII) or (XIX).
[0102] In one embodiment, the solvents employed in the preparation
of the crystalline forms of the present invention are
pharmaceutically acceptable solvents. In another embodiment, the
solvents employed in the preparation of the crystalline forms of
the present invention are pharmaceutically non-acceptable solvents
since they may also find their use in the preparation of
pharmaceutically acceptable polymorphs.
[0103] The processes for the production of the crystal forms of the
present invention typically include obtaining a crystalline solid
material from a solution or dispersion of the compound of formula
(XIX) in a solvent medium, or from slurrying the compound of
formula (XIX).
[0104] One skilled in the art would appreciate that the conditions
concerning crystallization may be modified in order to improve the
crystallization process or to induce precipitation, and without
affecting the form of the polymorph obtained. These conditions may
include bringing the solution, dispersion, or slurry of compound of
formula (XVIII) or (XIX) and the solvent(s) to a desired
concentration, bringing the said solution, dispersion, or slurry to
a desired temperature, adding the desired concentration of
hydrochloric acid, adding crystal seeds, effecting any suitable
pressure, removing and/or separating any undesired material or
impurities, drying the formed crystals to obtain the polymorphs in
a solid state, if such state is desired.
[0105] A preferred way of inducing precipitation is to reduce the
solubility of the compounds of the invention. The solubility of the
compound may be reduced, for example, by adding an
anti-solvent.
[0106] Bringing the solution, dispersion, or slurry of the
compounds of the invention and solvents to a desired concentration
does not necessarily imply an increase in the concentration of the
compounds of the invention. In certain cases, a decrease or no
change in concentration of the compound of the invention could be
preferable. The techniques used for obtaining a desired
concentration are those common in the art, for instance,
evaporation by atmospheric distillation, vacuum distillation,
fractioned distillation, azeotropic distillation, film evaporation,
heating, cooling, other techniques well known in the art and
combinations thereof. An optional process for obtaining a desired
concentration could as well involve the saturation of the solution
of the compounds of the invention and solvents, for example, by
adding a sufficient volume of a non-solvent to the solution to
reach the saturation point. Other suitable techniques for
saturating the solution include, by way of example, the
introduction of additional compound of the invention to the
solution and/or evaporation of a portion of the solvent from the
solution. As referred to herein, a saturated solution encompasses
solutions at their saturation points or exceeding their saturation
points, i.e. supersaturated. A nearly saturated solution refers to
solutions that are near saturation but have not reached their
saturation points.
[0107] A way to improve the crystallization process of the present
invention, in particular of accelerating crystallization, is by
seeding with a crystal of the product or scratching the inner
surface of the crystallization vessel with a glass rod. Other
times, crystallization may occur spontaneously without any
inducement. The present invention encompasses both embodiments
where crystallization of a particular form of compound of formula
(XIX) occurs spontaneously, or is induced or accelerated, unless if
such inducement or acceleration is critical for obtaining a
particular form.
[0108] The term "seeding" refers to the addition of a crystalline
material to facilitate crystallization. The term "crystal seeds"
means powder of a previously obtained crystalline form of the
compound of formula (XIX). Particular crystal seeds or seeding
material of the present invention, which can be useful for
preparing Form I, are the following: [0109] crystal seeds of a
mixture of Form I of compound (XIX) and the compound of formula
(XVIII); [0110] crystal seeds of Form I; or [0111] crystal seeds of
Form II.
[0112] By bringing the said solution, dispersion, or slurry to a
desired temperature, one will understand the acts of heating,
cooling or leaving at ambient temperature. Warming of the solution,
dispersion, or slurry may be necessary to completely dissolve the
compounds of the invention.
[0113] Removing and/or separating any undesired material or
impurities may be performed by purification, filtering, washing,
precipitation or similar techniques. Separation, for example, can
be conducted by known solid-liquid separation techniques. Filtering
procedures known to those skilled in the art can as well be used in
the present process. The filtrations can be performed, amongst
other methods, by passing the solution, dispersion, or slurry
through paper, sintered glass filter or other membrane material, by
centrifugation, or using Buchner style filter, Rosenmund filter or
plates, or frame press. Preferably, in-line filtration or safety
filtration may be advantageously intercalated in the processes
disclosed above, in order to increase the purity of the resulting
polymorphic form. Additionally, filtering agents such as silica
gel, Celite.RTM., Arbocel.RTM., dicalite diatomite, or the like,
may also be employed to separate impurities from the crystals of
interest.
[0114] Crystals obtained may be also dried, and such drying process
may optionally be used in the different crystallization passages,
if more than one crystallization passage is applied. Drying
procedures include all techniques known to those skilled in the
art, such as heating, applying vacuum, circulating air or gas,
adding a desiccant, freeze-drying, spray-drying, evaporating, or
the like, or any combination thereof.
[0115] Processes for crystallization of polymorphs of the compound
of formula (XIX) may embrace multiple combinations of techniques
and variations thereof. As such, and by way of example,
crystallization of polymorphs of compound of formula (XIX) may be
executed by dissolving, dispersing, or slurrying compound of
formula (XIX) at a suitable temperature in the solvent whereby
portion of the said solvent evaporates increasing the concentration
of the compound of formula (XIX) in the said solution, dispersion,
or slurry, cooling the said mixture, and optionally washing and/or
filtering and drying the resulting crystals of compound of formula
(XIX). Optionally, polymorphs of compound of formula (XIX) may be
prepared by dissolving, dispersing, or slurrying compound of
formula (XIX) in a solvent medium, cooling said solution,
dispersion, or slurry and subsequently filtering and drying the
obtained polymorph. Another example of preparation of crystal forms
of compound of formula (XIX) could be by saturating compound of
formula (XIX) in the solvent medium, and optionally filtering,
washing and drying obtained crystals.
[0116] Crystal formation may as well involve more than one
crystallization process. In certain cases, one, two or more extra
crystallization steps may be advantageously performed for different
reasons, such as, to increase the quality of the resulting crystal
form.
[0117] By dissolving, dispersing, or slurrying the compound of the
invention in the solvent, one may obtain different degrees of
dispersion, such as suspensions, slurries or mixtures; or
preferably obtain homogeneous one-phase solutions. The term
"suspension" refers to a two-phase system consisting of a finely
divided solid, in amorphous, crystalline form, or mixtures thereof,
dispersed (suspended) in a liquid or dispersing medium, usually the
solvent. The term "slurry" refers to a suspension formed when a
quantity of powder is mixed into a liquid in which the solid is
only slightly soluble (or not soluble). "Slurrying" refers to the
making of a slurry.
[0118] Optionally, the solvent medium may contain additives, for
example one or more dispersing agents, surfactants or other
additives, or mixtures thereof of the type normally used in the
preparation of crystalline suspensions and which are well
documented in the literature. The additives may be advantageously
used in modifying the shape of crystal by increasing the leniency
and decreasing the surface area.
[0119] The solvent medium containing the solid may optionally be
stirred for a certain period of time, or vigorously agitated using,
for example, a high shear mixer or homogeniser or a combination of
these, to generate the desired particle size for the organic
compound.
[0120] Control of precipitation temperature and seeding may be
additionally used to improve the reproducibility of the
crystallization process, the particle size distribution and form of
the product. As such, the crystallization can be effected without
seeding with crystals of the compound of the formula (XIX) or
preferably in the presence of crystals of the compound of the
formula (XIX), which are introduced into the solution by seeding.
Seeding can also be effected several times at various temperatures.
The amount of the seed material depends on the scale of the
experiment and can readily be determined by a person skilled in the
art. Typically, the amount of seeding material is about 0.1 to 1
weight % of the amount of crystalline material expected from the
reaction.
[0121] The time for crystallization in each crystallization step
will depend on the conditions applied, the techniques employed
and/or solvents used.
[0122] Breaking up the large particles or aggregates of particles
after crystal conversion may additionally be performed in order to
obtain a desired and homogeneous particle size. Accordingly, the
crystals, powder aggregates and coarse powder of the polymorphic
forms of compound of formula (XIX) may be optionally milled and
sorted by size after undergoing conversion. Milling or grinding
refers to physically breaking up the large particles or aggregates
of particles using methods and apparatus well known in the art for
particle size reduction of powders. Resulting particle sizes may
range from millimeters to nanometers, yielding i.e. nanocrystals,
microcrystals.
[0123] A preferred apparatus for milling or grinding is a fluid
energy mill, or micronizer, because of its ability to produce
particles of small size in a narrow size distribution. Micronizers
use the kinetic energy of collision between particles suspended in
a rapidly moving fluid stream to cleave the particles. An air jet
is a preferred fluid energy mill. The suspended particles are
injected under pressure into a recirculating particle stream.
Smaller particles are carried aloft inside the mill and swept into
a vent connected to a particular size classifier such as a cyclone.
One of skill in the art would appreciate that some crystalline
forms may undergo a transition to another form during particle size
reduction.
Characterization of the Crystalline Forms
[0124] The present invention provides mono-HCl salts of formula
(XIX) in solid state further characterized in that it is in
crystalline form. In one embodiment, the invention provides the
crystalline forms of the compound of formula (XIX) selected from
Form I, Form II and the hydrated form. These forms are
substantially free from impurities. Suitably, these forms contain
no more than 10% of impurities, more suitably they contain no more
than 5% of impurities, even more suitably they contain no more than
1% of impurities. Polymorphic purity may be tested by XPRD, with
the area under the peaks used to calculate polymorphic purity.
These forms are essentially pure. With the term "essentially pure"
is meant more than 90% pure, suitably more than 95% pure, more
suitably more than 97% pure, most suitably more than 99% pure.
[0125] The present invention further provides a mixture of two or
more crystalline forms of compound of formula (XIX), wherein the
crystalline forms are selected from Form I, Form II and the
hydrated form.
[0126] In one embodiment, there is provided a mixture comprising
Form I and Form II of compound of formula (XIX).
[0127] In another embodiment, there is provided a mixture
comprising Form I and the hydrated form of the compound of formula
(XIX).
[0128] In another embodiment, there is provided a mixture
comprising the hydrated form and Form II of the compound of formula
(XIX).
[0129] In another embodiment, there is provided a mixture
comprising Form I, the hydrated form and form II of the compound of
formula (XIX).
[0130] The present invention further provides a mixture of one or
more crystalline forms of compound of formula (XIX) and an
amorphous form of a non HCl salt of the compound of formula (XIX),
wherein the crystalline forms are selected from Form I, Form II,
and the hydrated form.
[0131] The characterising XPRD intensity peak positions of Form I,
Form II and the hydrate form are given in degrees 2-theta.
[0132] Form I of compound (XIX) is characterized by typical
diffraction peaks at two-theta positions
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree.,
23.4.degree..+-.0.2.degree., 24.4.degree..+-.0.2.degree. and
27.7.degree..+-.0.2.degree.. Form I is further characterized by
X-ray powder diffraction peaks at two-theta positions
7.6.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree. and
12.5.degree..+-.0.2.degree..
[0133] Form II of compound (XIX) is characterized by typical
diffraction peaks at two-theta positions
10.8.degree..+-.0.2.degree., 13.7.degree..+-.0.2.degree.,
17.8.degree..+-.0.2.degree. and 26.7.degree..+-.0.2. Form II is
further characterized by X-ray powder diffraction peaks at
two-theta positions 7.4.degree..+-.0.2.degree. and
22.9.degree..+-.0.2.degree..
[0134] The hydrate form of compound (XIX) is characterized by
typical diffraction peaks at two-theta positions
10.0.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree. and
26.5.degree..+-.0.2.degree.. The Hydrate is further characterized
by X-ray powder diffraction peaks at two-theta positions
21.6.degree..+-.0.2.degree. and 24.9.degree..+-.0.2.degree..
[0135] The X-ray powder diffraction pattern (XPRD) of Form I is as
substantially depicted in FIG. 2. The X-ray powder diffraction
pattern of Form II is as substantially depicted in FIG. 7. The
X-ray powder diffraction pattern of the hydrated form is as
substantially depicted in FIG. 12.
[0136] The XPRD data and pattern representations of all forms were
obtained using a Philips X'PertPRO MPD diffractometer PW3050/60
with a generator PW3040. The instrument was equipped with a Cu LFF
X-ray tube PW3373/00. The compound to be analysed was spread on a
zero background sample holder. The instruments parameters were as
follows:
TABLE-US-00001 generator voltage: 45 kV generator amperage: 40 mA
geometry: Bragg-Brentano stage: spinner stage.
[0137] The scanning parameters for Forms I, II and the hydrated
form were as follows: the range was 3.degree. to 50.degree. 2-theta
with a continuous scan at a rate of 0.01675.degree./step, at 29.845
sec/step. The spinner revolution time was 1 sec, the radiation type
CuK.alpha., and the radiation wavelength was 1.54056 .ANG..
[0138] The scanning parameters for Forms I and II were as follows:
the range was 3.degree. to 50.degree. 2-theta with a continuous
scan at a rate of 0.01675.degree./step, at 29.845 sec/step. The
spinner revolution time was 1 sec, the radiation type CuK.alpha.,
and the radiation wavelength was 1.54056 .ANG..
[0139] The scanning parameters for the hydrated form was as
follows: the range was 3.degree. to 50.degree. 2-theta with a
continuous scan at a rate of 0.01675.degree./step, at 59.690
sec/step. The spinner revolution time was 1 sec, the radiation type
CuK.alpha., and the radiation wavelength was 1.54056 .ANG..
[0140] The Incident beam path parameters for Forms I, II and the
hydrated form were as follows:
TABLE-US-00002 program. divergence slit: 15 mm Soller slit: 0.04
rad beam mask: 15 mm anti scatter slit: 1.degree. beam knife: +
[0141] The diffracted beam path parameters for Forms I, II and the
hydrated form were as follows:
TABLE-US-00003 long anti scatter shield: + Soller slit: 0.04 rad Ni
filter: + detector: X'Celerator
[0142] The accuracy of the XPRD peak positions provided for Forms
I, II and the hydrated form is defined as 0.2.degree. due to
experimental differences, such as instrumentations, sample
preparations, and the like.
[0143] The characterising IR absorbance peak positions of Forms I,
II and the hydrated form are given in wavenumbers cm.sup.-1.
[0144] Form I of compound (XIX) is characterized by an infrared
spectrometry (IR) micro attenuated reflectance spectrum with
typical absorption bands at 3119.+-.2 cm.sup.-1, 2756.+-.2
cm.sup.-1, 1634.+-.2 cm.sup.-1, 1475.+-.2 cm.sup.-1, 1371.+-.2
cm.sup.-1, 1333.+-.2 cm.sup.-1, 1275.+-.2 cm.sup.-1, 1226.+-.2
cm.sup.-1, 1128.+-.2 cm.sup.-1 and 1066 cm.sup.-1.+-.2
cm.sup.-1.
[0145] Form II of compound (XIX) is characterized by an infrared
spectrometry micro attenuated reflectance spectrum with typical
absorption bands at about 3553.+-.2 cm.sup.-1, 3203.+-.2 cm.sup.-1,
3014.+-.2 cm.sup.-1 and 1541 cm.sup.-1.+-.2 cm.sup.-1.
[0146] The hydrate form of compound (XIX), after 42 days storage at
40.degree. C./75% relative humidity, is characterized by an
infrared spectrometry micro attenuated reflectance spectrum with
typical absorption bands at about 3558.+-.2 cm.sup.-1, 3238.+-.2
cm.sup.-1, 1607.+-.2 cm.sup.-1 and 997 cm.sup.-1.+-.2
cm.sup.-1.
[0147] The IR pattern of Form I is as substantially depicted in
FIG. 1. The IR pattern of Form II is as substantially depicted in
FIG. 6. The IR pattern of the hydrate form is as substantially
depicted in FIG. 11.
[0148] The IR data and pattern representations were obtained using
infrared spectrometry micro Attenuated Total Reflectance (microATR)
with a Nexus FTIR spectrophotometer. The micro ATR accessory was a
Harrick Split Pea with Si crystal. The detector used was a DTGS
with KBr windows. The scan parameters for Forms I, II and the
hydrate form were as follows:
TABLE-US-00004 number of scans: 32 resolution: 2 cm.sup.-1
wavelength range: 4000 to 400 cm.sup.-1 baseline correction: yes
beamsplitter: Ge on KBr.
[0149] The accuracy of the IR absorbance peaks provided for Forms
I, II and the hydrated form is defined as 2 cm.sup.-1 due to
experimental differences, such as instrumentations, sample
preparations, and the like.
[0150] The characterising differential scanning calorimetry (DSC)
endothermic peak positions or ranges of Forms I and II are given in
.degree. C.
[0151] Form I of compound (XIX) melts with decomposition. An
exothermic signal is observed at about 216.8.degree. C.
[0152] Form II of compound (XIX) melts with decomposition at about
197.3.degree. C. An exothermic signal is observed at about
203.6.degree. C. An extra endothermic signal in the DSC curve is
observed at about 71.5.degree. C. due to solvent evaporation.
[0153] The DSC curve of Form I is as substantially depicted in FIG.
3. The DSC curve of Form II is as substantially depicted in FIG.
8.
[0154] The DSC data and curve representations were obtained using a
TA-Instruments Q1000 MTDSC equipped with a RCS cooling unit. The
weight of the samples was about 3 mg, which were transferred into a
standard aluminum TA-Instrument sample pan. The samples were
scanned at a rate of 10.degree. C./min from 25.degree. C. to a
final temperature of 300.degree. C. The oven was constantly purged
with nitrogen gas at a flow rate of 50 ml/min.
[0155] The tolerance of the DSC curves provided for Forms I and II
is defined as 3.degree. C. due to experimental differences, such as
instrumentations, sample preparations, and the like. The
adsorption-desorption characteristics of Form I and Form II are
given as % change in Mass.
[0156] Form I of compound (XIX) adsorbs up to 0.6% water at high
relative humidity, it shows no hygroscopic behavior and remains
crystalline during the test.
[0157] Form II of compound (XIX) is a hygroscopic product. It
adsorbs up to 9.6% water at high relative humidity. The product
dries completely during the desorption cycle and remains
crystalline during the test.
[0158] The ADS/DES curve of Form I is as substantially depicted in
FIG. 5. The ADS/DES curve of Form II is as substantially depicted
in FIG. 10.
[0159] The ADS/DES data were obtained using a SMS dynamic vapor
sorption model DVS-1 and the weight change was recorded with
respect to the atmospheric humidity at 25.degree. C. The weight of
the samples was about 17 mg of Form 1 and 24 mg of Form II. The
samples were dried for 60 min under dry nitrogen. The equilibrium
was lower or equal to 0.01%/min. for minimal 15 min and maximal 60
min. The data interval was 0.05% or 2.0 min.
[0160] Relative Humidity (%) measurement points were:
first set: 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 90, 80, 70,
60, 50, 40, 30, 20, 10, 5 second set: 5, 10, 20, 30, 40, 50, 60,
70, 80, 90, 95, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 0.
Pharmaceutical Use of the Crystalline Forms
[0161] The present invention further provides Form I, Form II or
the hydrate form of the compound of formula (XIX), a mixture of two
or more crystalline forms of the compound of formula (XIX), or a
mixture of at least Form I or the hydrate form of the compound of
formula (XIX) and the amorphous form of a non-HCl salt of the
compound of formula (XIX), for use as a medicament. In one
embodiment, the crystalline form, alone or in any of the above
mixtures, for use as a medicament, is selected from Form I, Form II
or the hydrated form.
[0162] The present invention further provides the use of at least
Form I, Form II or the hydrate form of the compound of formula
(XIX), a mixture of two or more crystalline forms of the compound
of formula (XIX), or a mixture of at least Form I or the hydrate
form of the compound of formula (XIX) and the amorphous form of a
non-HCl salt of the compound of formula (XIX), in the manufacture
of a medicament for the treatment of HDAC related conditions. In
one embodiment, the crystalline form, alone or in any of the above
mixtures, used in the manufacture of a medicament is selected from
Form I, Form II and the hydrate form.
[0163] The present invention provides as well a method of treating
a mammal suffering from HDAC-related conditions comprising
administering at least Form I, Form II or the hydrate form of the
compound of formula (XIX), a mixture of two or more crystalline
forms of the compound of formula (XIX), or a mixture of at least
Form I or the hydrate form of the compound of formula (XIX) and the
amorphous form of a non-HCl salt of the compound of formula (XIX),
to the mammal in need thereof. In one embodiment, the method of
treatment comprises administering a crystalline form, alone or in
any of the above mixtures, selected from Form I, Form II and the
hydrate form.
[0164] As used herein, the terms "histone deacetylase" and "HDAC"
are intended to refer to any one of a family of enzymes that remove
acetyl groups from the .epsilon.-amino groups of lysine residues at
the N-terminus of a histone.
[0165] Unless otherwise indicated by context, the term "histone" is
meant to refer to any histone protein, including H1, H2 A, H2B, H3,
H4, and H5, from any species. Human HDAC proteins or gene products,
include, but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4,
HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-11. The
histone deacetylase can also be derived from a protozoal or fungal
source.
[0166] The term "treatment" refers to any treatment of a pathologic
condition in a mammal, particularly a human, and includes one or
more of the following acts:
(i) preventing the pathologic condition from occurring in a subject
which may be predisposed to the condition but has not yet been
diagnosed with the condition and, accordingly, the treatment
constitutes prophylactic treatment for the disease condition; (ii)
inhibiting the pathologic condition, i.e., arresting its
development; (iii) relieving the pathologic condition, i.e.,
causing regression of the pathologic condition; or (iv) relieving
the symptoms mediated by the pathologic condition.
[0167] With the term "polymorph(s) of the present invention" is
meant at least Form I, Form II or the hydrate form of the compound
of formula (XIX), a mixture of two or more crystalline forms of the
compound of formula (XIX), or a mixture of at least Form I or the
hydrate form of the compound of formula (XIX) and the amorphous
form of a non-HCl salt of the compound of formula (XIX).
[0168] This invention provides a method for inhibiting the abnormal
growth of cells, including transformed cells, by administering an
effective amount of a polymorph of the present invention. Abnormal
growth of cells refers to cell growth independent of normal
regulatory mechanisms (e.g. loss of contact inhibition). This
includes the inhibition of tumour growth both directly by causing
growth arrest, terminal differentiation and/or apoptosis of cancer
cells, and indirectly, by inhibiting neovascularization of
tumours.
[0169] This invention also provides a method for inhibiting tumour
growth by administering an effective amount of a polymorph of the
present invention, to a subject, e.g. a mammal (and more
particularly a human) in need of such treatment. In particular,
this invention provides a method for inhibiting the growth of
tumours by the administration of an effective amount of a polymorph
of the present invention. Examples of tumours which may be
inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma
and including non-small cell lung cancer), pancreatic cancers (e.g.
pancreatic carcinoma such as, for example exocrine pancreatic
carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for
example, colon adenocarcinoma and colon adenoma), prostate cancer
including the advanced disease, hematopoietic tumours of lymphoid
lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma,
Burkitt's lymphoma), Hodgkins disease and non-Hodgkins disease,
myeloid leukemias (for example, acute myelogenous leukemia (AML)),
thyroid follicular cancer, myelodysplastic syndrome (MDS), tumours
of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas),
melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumour
of the skin (e.g. keratoacanthomas), breast carcinoma (e.g.
advanced breast cancer), kidney carcinoma, ovary carcinoma, bladder
carcinoma and epidermal carcinoma.
[0170] The present invention provides furthermore a pharmaceutical
composition comprising at least Form I, Form II or the hydrate form
of the compound of formula (XIX), a mixture of two or more
crystalline forms of the compound of formula (XIX), or a mixture of
at least Form I or the hydrate form of the compound of formula
(XIX) and the amorphous form of a non-HCl salt of the compound of
formula (XIX), and a pharmaceutically acceptable excipient. In one
embodiment, the pharmaceutical composition comprises a crystalline
form, alone or in any of the above mixtures, selected from Form I,
Form II and the hydrate form.
[0171] Pharmaceutical compositions may be prepared as medicaments
to be administered orally, parenterally (including subcutaneously,
intramuscularly, and intravenously), rectally, transdermally,
bucally, or nasally. Suitable forms for oral administration include
powders, granulates, aggregates, tablets, compressed or coated
pills, dragees, sachets, hard or gelatin capsules, syrups and
suspensions. Suitable forms of parenteral administration include an
aqueous or non-aqueous solution or emulsion, while for rectal
administration suitable forms for administration include
suppositories with hydrophilic or hydrophobic vehicle. For topical
administration the invention provides suitable transdermal delivery
systems known in the art, and for nasal delivery there are provided
suitable aerosol delivery systems known in the art. Although the
most suitable administration in any given case will depend on the
nature and severity of the condition being treated, the most
preferred route of the present invention is oral.
[0172] The dosages may be conveniently presented in unit dosage
form and prepared by any of the methods well-known in the
pharmaceutical arts. Alternatively, the dosage forms may be
presented as one, two, three or four or more subdoses administered
at appropriate intervals throughout the day. The unit dosage used
is preferably from about 1 mg to about 1000 mg of compound of
formula (XIX) base equivalent, more preferably from about 5 to
about 400 mg.
[0173] Pharmaceutical compositions of the present invention
comprise Form I, Form II or the hydrate form of the compound of
formula (XIX). The pharmaceutical composition may comprise only a
single form of Form I, Form II or the hydrate form of the compound
of formula (XIX), or a mixture of various forms of compound of
formula (XIX), with or without amorphous forms of a non-HCl salt of
the compound of formula (XIX). In addition to the active
ingredient(s), the pharmaceutical composition comprises one or more
excipients or adjuvants. Selection of excipients and the amounts to
use may be readily determined by the galenist based upon experience
and consideration of standard procedures and reference works in the
field.
[0174] Examples of suitable excipients are gum arabic, magnesia,
magnesium carbonate, potassium phosphate, lactose, glucose, or
starch, in particular, corn starch. Suitable oily excipients or
solvents are vegetable or animal oils, such as sunflower oil or cod
liver oil. Suitable solvents for aqueous or alcoholic solutions are
water, ethanol, sugar solutions, or mixtures thereof. Polyethylene
glycols and polypropylene glycols are also useful as further
auxiliaries for other administration forms.
[0175] For subcutaneous or intravenous administration, the
polymorphs of the present invention, if desired with the substances
customary therefor such as solubilizers, emulsifiers or further
auxiliaries, are brought into solution, suspension, or emulsion.
The polymorphs of the present invention can also be lyophilized and
the lyophilizates obtained used, for example, for the production of
injection or infusion preparations. Suitable solvents are, for
example, water, physiological saline solution or alcohols, e.g.
ethanol, propanol, glycerol, in addition also sugar solutions such
as glucose or mannitol solutions, or alternatively mixtures of the
various solvents mentioned.
[0176] Suitable pharmaceutical compositions for administration in
the form of aerosols or sprays are, for example, solutions,
suspensions or emulsions of the polymorphs of the invention in a
pharmaceutically acceptable solvent, such as ethanol or water, or a
mixture of such solvents. If required, the formulation can also
additionally contain other pharmaceutical auxiliaries such as
surfactants, emulsifiers and stabilizers as well as a propellant.
Such a preparation customarily contains the active compound in a
concentration from approximately 0.1 to 50%, in particular from
approximately 0.3 to 3% by weight.
[0177] It should be understood that in addition to the ingredients
particularly mentioned above, the pharmaceutical compositions of
the present invention may include other agents conventional in the
art having regard to the type of formulation in question, for
example those suitable for oral administration may include
flavouring agents or taste masking agents.
[0178] As another aspect of the present invention, a combination of
Form I, Form II or the hydrate form of the compound of formula
(XIX), a mixture of two or more crystalline forms of the compound
of formula (XIX), or a mixture of at least Form I or the hydrate
form of the compound of formula (XIX) and the amorphous form of a
non-HCl salt of the compound of formula (XIX), with another
anticancer agent is envisaged, especially for use as a medicine,
more specifically in the treatment of cancer or related
diseases.
[0179] For the treatment of the above conditions, a polymorph of
the present invention may be advantageously employed in combination
with one or more other medicinal agents, more particularly, with
other anti-cancer agents. Examples of anti-cancer agents include
but are not limited to: [0180] platinum coordination compounds for
example cisplatin, carboplatin or oxalyplatin; [0181] taxane
compounds for example paclitaxel or docetaxel; [0182] topoisomerase
I inhibitors such as camptothecin compounds for example irinotecan
or topotecan; [0183] topoisomerase II inhibitors such as
anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for
example etoposide or teniposide; [0184] anti-tumour vinca alkaloids
for example vinblastine, vincristine or vinorelbine; [0185]
anti-tumour nucleoside derivatives for example 5-fluorouracil,
leucovorin, gemcitabine or capecitabine; [0186] alkylating agents
such as nitrogen mustard or nitrosourea for example
cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan or
lomustine; [0187] anti-tumour anthracycline derivatives for example
daunorubicin, doxorubicin, doxil, idarubicin or mitoxantrone;
[0188] molecules that target the IGF-1 receptor for example
picropodophilin; [0189] tetracarcin derivatives for example
tetrocarcin A; [0190] glucocorticoiden for example prednisone;
[0191] antibodies for example trastuzumab (HER2 antibody),
rituximab (CD20 antibody), gemtuzamab, cetuximab, pertuzumab or
bevacizumab; [0192] estrogen receptor antagonists or selective
estrogen receptor modulators for example tamoxifen, fulvestrant,
toremifene, droloxifene, faslodex or raloxifene; [0193] aromatase
inhibitors such as exemestane, anastrozole, letrazole and vorozole;
[0194] differentiating agents such as retinoids, vitamin D or
retinoic acid and retinoic acid metabolism blocking agents (RAMBA)
for example accutane; [0195] DNA methyl transferase inhibitors for
example azacytidine or decitabine; [0196] antifolates for example
premetrexed disodium; [0197] antibiotics for example antinomycin D,
bleomycin, mitomycin C, dactinomycin, caminomycin or daunomycin;
[0198] antimetabolites for example chlofarabine, aminopterin,
cytosine arabinoside or methotrexate; [0199] apoptosis inducing
agents and antiangiogenic agents such as Bcl-2 inhibitors for
example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or
decanoic acid; [0200] tubuline-binding agents for example
combrestatin, colchicines or nocodazole; [0201] kinase inhibitors
for example flavoperidol, imatinib mesylate, erlotinib or
gefitinib; [0202] farnesyltransferase inhibitors for example
tipifarnib; [0203] histone deacetylase (HDAC) inhibitors for
example sodium butyrate, suberoylanilide hydroxamide acid (SAHA),
depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585 or
trichostatin A; [0204] Inhibitors of the ubiquitin-proteasome
pathway for example PS-341, MLN 0.41 or bortezomib; [0205]
Yondelis; [0206] Telomerase inhibitors for example telomestatin;
[0207] Matrix metalloproteinase inhibitors for example batimastat,
marimastat, prinostat or metastat.
[0208] In view of their useful pharmacological properties, the
components of the combinations according to the invention, i.e. the
other medicinal agent and the polymorphs of the invention, may be
formulated into various pharmaceutical forms for administration
purposes. The components may be formulated separately in individual
pharmaceutical compositions or in a unitary pharmaceutical
composition containing both components.
[0209] One embodiment of the present invention therefore also
relates to a pharmaceutical composition comprising the other
medicinal agent and the polymorphs of the present invention
together with one or more pharmaceutical carriers.
[0210] The present invention further relates to the use of a
combination according to the invention in the manufacture of a
pharmaceutical composition for inhibiting the growth of tumour
cells.
[0211] The present invention further relates to a product
containing as first active ingredient a polymorph according to the
invention and as second active ingredient an anticancer agent, as a
combined preparation for simultaneous, separate or sequential use
in the treatment of patients suffering from cancer.
[0212] The other medicinal agent and the polymorph of the invention
may be administered simultaneously (e.g. in separate or unitary
compositions) or sequentially in either order. In the latter case,
the two compounds will be administered within a period and in an
amount and manner that is sufficient to ensure that an advantageous
or synergistic effect is achieved. It will be appreciated that the
preferred method and order of administration and the respective
dosage amounts and regimes for each component of the combination
will depend on the particular other medicinal agent and the
polymorph being administered, their route of administration, the
particular tumour being treated and the particular host being
treated. The optimum method and order of administration and the
dosage amounts and regime can be readily determined by those
skilled in the art using conventional methods and in view of the
information set out herein.
[0213] The platinum coordination compound is advantageously
administered in a dosage of 1 to 500 mg per square meter
(mg/m.sup.2) of body surface area, for example 50 to 400
mg/m.sup.2, particularly for cisplatin in a dosage of about 75
mg/m.sup.2 and for carboplatin in about 300 mg/m.sup.2 per course
of treatment.
[0214] The taxane compound is advantageously administered in a
dosage of 50 to 400 mg per square meter (mg/m.sup.2) of body
surface area, for example 75 to 250 mg/m.sup.2, particularly for
paclitaxel in a dosage of about 175 to 250 mg/m.sup.2 and for
docetaxel in about 75 to 150 mg/m.sup.2 per course of
treatment.
[0215] The camptothecin compound is advantageously administered in
a dosage of 0.1 to 400 mg per square meter (mg/m.sup.2) of body
surface area, for example 1 to 300 mg/m.sup.2, particularly for
irinotecan in a dosage of about 100 to 350 mg/m.sup.2 and for
topotecan in about 1 to 2 mg/m.sup.2 per course of treatment.
[0216] The anti-tumour podophyllotoxin derivative is advantageously
administered in a dosage of 30 to 300 mg per square meter
(mg/m.sup.2) of body surface area, for example 50 to 250
mg/m.sup.2, particularly for etoposide in a dosage of about 35 to
100 mg/m.sup.2 and for teniposide in about 50 to 250 mg/m.sup.2 per
course of treatment.
[0217] The anti-tumour vinca alkaloid is advantageously
administered in a dosage of 2 to 30 mg per square meter
(mg/m.sup.2) of body surface area, particularly for vinblastine in
a dosage of about 3 to 12 mg/m.sup.2, for vincristine in a dosage
of about 1 to 2 mg/m.sup.2, and for vinorelbine in dosage of about
10 to 30 mg/m.sup.2 per course of treatment.
[0218] The anti-tumour nucleoside derivative is advantageously
administered in a dosage of 200 to 2500 mg per square meter
(mg/m.sup.2) of body surface area, for example 700 to 1500
mg/m.sup.2, particularly for 5-FU in a dosage of 200 to 500
mg/m.sup.2, for gemcitabine in a dosage of about 800 to 1200
mg/m.sup.2 and for capecitabine in about 1000 to 2500 mg/m.sup.2
per course of treatment.
[0219] The alkylating agents such as nitrogen mustard or
nitrosourea is advantageously administered in a dosage of 100 to
500 mg per square meter (mg/m.sup.2) of body surface area, for
example 120 to 200 mg/m.sup.2, particularly for cyclophosphamide in
a dosage of about 100 to 500 mg/m.sup.2, for chlorambucil in a
dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of
about 150 to 200 mg/m.sup.2, and for lomustine in a dosage of about
100 to 150 mg/m.sup.2 per course of treatment.
[0220] The anti-tumour anthracycline derivative is advantageously
administered in a dosage of 10 to 75 mg per square meter
(mg/m.sup.2) of body surface area, for example 15 to 60 mg/m.sup.2,
particularly for doxorubicin in a dosage of about 40 to 75
mg/m.sup.2, for daunorubicin in a dosage of about 25 to 45
mg/m.sup.2, and for idarubicin in a dosage of about 10 to 15
mg/m.sup.2 per course of treatment.
[0221] The antiestrogen agent is advantageously administered in a
dosage of about 1 to 100 mg daily depending on the particular agent
and the condition being treated. Tamoxifen is advantageously
administered orally in a dosage of 5 to 50 mg, preferably 10 to 20
mg twice a day, continuing the therapy for sufficient time to
achieve and maintain a therapeutic effect. Toremifene is
advantageously administered orally in a dosage of about 60 mg once
a day, continuing the therapy for sufficient time to achieve and
maintain a therapeutic effect. Anastrozole is advantageously
administered orally in a dosage of about 1 mg once a day.
Droloxifene is advantageously administered orally in a dosage of
about 20-100 mg once a day. Raloxifene is advantageously
administered orally in a dosage of about 60 mg once a day.
Exemestane is advantageously administered orally in a dosage of
about 25 mg once a day.
[0222] Antibodies are advantageously administered in a dosage of
about 1 to 5 mg per square meter (mg/m.sup.2) of body surface area,
or as known in the art, if different. Trastuzumab is advantageously
administered in a dosage of 1 to 5 mg per square meter (mg/m.sup.2)
of body surface area, particularly 2 to 4 mg/m.sup.2 per course of
treatment.
[0223] These dosages may be administered for example once, twice or
more per course of treatment, which may be repeated for example
every 7, 14, 21 or 28 days.
[0224] It may be convenient to store the polymorphs of the
invention in packaging materials which are protective to
mechanical, environmental, biological or chemical hazards, or
degradation. Conditioning drug substances can be achieved by
employing packaging materials impermeable to moisture, such as
sealed vapour lock bags. Conditioning drug products, such as
tablets, capsules, can be achieved by employing for instance,
aluminium blisters.
EXPERIMENTAL PART
[0225] The following examples are intended to illustrate the
present invention and not to limit it thereto.
Example 1
Preparation of Intermediate (I)
##STR00017##
[0227] a) 4-piperidinemethanamine (2.6 mol) and ethyl acetate (5.2
L) was brought in an inert reactor (20 L) and warmed up to
45.degree. C. 4-nitrobenzaldehyde (2.7 mol) was added and the
reaction mixture was stirred for 2 h at 45.degree. C. The reaction
was cooled to 0.degree. C. and then diisopropylethylamine (6.6 mol)
was added giving solution 1.
[0228] b) 2-(methylthio)-5-pyrimidinecarboxylic acid ethyl ester
(2.7 mol) and ethyl acetate (2.6 L) was brought in an inert reactor
and cooled to 0.degree. C. A solution of meta-chloroperoxy benzoic
acid (1.2 mol) in ethyl acetate (2.6 L) was added over a time
period of 1 h at a temperature between 0.degree. C. and 5.degree.
C. The reaction mixture was stirred for 30 min at 0.degree. C.
giving solution 2.
[0229] c) Solution 2 was added to solution 1 over a time period of
1 h at a temperature between 0.degree. C. and 5.degree. C. The
reaction mixture was left overnight at room temperature. The
mixture was acidified to a pH of 2, with a solution of 640 ml
concentrated hydrochloric acid in 10 L water. The aqueous layer was
collected and washed with 1 L ethyl acetate. The aqueous layer was
collected and 1 L of dichloromethane was added. The mixture was
basified to a pH of 10, with 450 ml sodium hydroxide 50%. The
mixture was stirred for 30 min at room temperature. The organic
layer was collected giving fraction 1. The aqueous layer was
further extracted with 2 L dichloromethane and the organic layer
was collected giving fraction 2. Fraction 1 and 2 were combined and
dichloromethane was evaporated giving 511.25 g (1.93 mol) of
intermediate (I) (yield 74%).
Example 2
Preparation of Intermediate (XIII)
##STR00018##
[0231] a) Intermediate (I)(0.97 mol), and toluene (4.5 L) was added
in an inert reactor (20 L). 1-methyl-1H-Indole-3-carboxaldehyde
(0.97 mol) was added to the reaction mixture at room temperature.
The reaction mixture was warmed to reflux temperature, refluxed
overnight and cooled to room temperature. Ethanol (1.5 L)
degenerated with methanol was added giving solution 3.
[0232] b) Sodium tetrahydroborate (55.2 g) and toluene (1.5 L) was
added in an inert reactor (20 L). The mixture was brought to
10.degree. C. under continuous stirring. Solution 3 was added to
the mixture over a time period of 1 h at a temperature #10.degree.
C. The mixture was stirred for 1 h at a temperature #10.degree. C.
The reaction mixture was brought at room temperature. Acetone (8.79
mol) was added over a time period of 30 min. The reaction mixture
was stirred for 4 h. Water (5.1 L) was dripped to the reaction
mixture over a time period of 15 min. The reaction mixture was
stirred for 1 h at room temperature. The aqueous layer was
disregarded and the organic layer was washed two times with a
solution of 300 g sodium bicarbonate in 4.1 L water. The organic
layer was filtered over magnesium sulfate and evaporated giving
fraction 3 (397 g of residue after evaporation).
[0233] c) Ethanol (5 L) degenerated with 2% methylethylketone is
added to fraction 3 at room temperature. Concentrated acetone (5 L)
and 0.5 L water is added at room temperature and the mixture is
subsequently warmed to 50.degree. C. A mixture of fumaric acid
(0.97 mol), ethanol (1.4 L) degenerated with 2% methylethylketone,
acetone (1.4 L) and 140 ml water was prepared giving solution 4.
Solution 4 was added to the reaction mixture over a time period of
2 h at a temperature of 50.degree. C. The reaction mixture was
stirred for 2 h at 50.degree. C., cooled for 4 h to room
temperature and stirred overnight at room temperature. The sediment
was collected and was subsequently washed with 1.4 L ethanol
degenerated with 2% methylethylketone, 1.4 L concentrated acetone
and 140 ml of water. The sediment was dried overnight at 50.degree.
C., giving 371 g (0.7 mol) of intermediate (XIII) (yield 73%).
Example 3
Preparation of Intermediate (XVII)
##STR00019##
[0235] A four necked flask (2 L) was charged with intermediate
(XIII) (100 g; 191.0 mmoles). Water (3 L/mol-pure limiting reagent;
573.0 ml) and 2-methyltetrahydrofuran (2.2 L/mol-pure-limiting
reagent; 420.2 ml) was added. After stirring, sodium hydroxide 50%
(2.5 moles/mol-pure-limiting reagent; 477.5 mmoles; 25.13 ml) was
added. The reaction mixture was further stirred for 40-60 min at
room temperature, whereafter the reaction was left to settle. The
upper organic layer was collected and washed with water (2
L/mol-pure-limiting reagent; 382.0 ml). Water (1.5
L/mol-pure-limiting reagent; 286.5 ml) and sodium hydroxide (3
moles/mol-pure-limiting reagent; 573.0 mmoles; 45.84 g) were added
to the organic layer. The reaction mixture was warmed to 80.degree.
C. and stirred during 16 h. The reaction mixture was cooled to room
temperature and the lower water layer was collected. Isopropyl
alcohol (90 ml; 1.177 moles) was added and the mixture was cooled
to 10.degree. C. in an ice bath. The reaction mixture was acidified
with concentrated hydrochloric acid (5 moles/mol-pure-limiting
reagent; 954.9 mmoles; 100.9 g) to pH 1 (pH 13.8: dark green
solution; pH 7.5 old pink solution; pH 4.7: pink solution, white
precipitate). The reaction mixture was stirred for 4 h at
10.degree. C. The white precipitate was filtered, washed 4 times
with water and dried under vacuum at 40.degree. C. giving 84 g
intermediate (XVII) (yield: 97%).
Example 4
Preparation of Intermediate (XVIII)
##STR00020##
[0237] a) A four-necked flask (1 L) was charged with 0.093 mol of
intermediate (XVII) and 220 ml of ethyl acetate was added. The
reaction mixture was stirred and 5 ml of water was added giving
solution 5. A 250 ml flask was charged with 0.122 mol of
N'-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,
monohydrochloride (EDC) in 130 ml of ethanol and the reaction
mixture was stirred giving solution 6.
O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.123 mol) was added to
solution 5 and the addition funnel was washed with 26 ml of ethyl
acetate Immediately thereafter 200 ml of solution 6 was added to
the reaction mixture comprising solution 5 over a time period of 1
h 30 min (the reaction mixture became homogeneous when 90% of
solution 6 was added, then the desired product crystallized out).
The reaction mixture was stirred at room temperature for 5 h. The
precipitate was filtered and washed with 55 ml ethyl acetate and
dried under vacuum at 50.degree. C. during 16 h, giving 35.7 g
(0.07 mol) of intermediate (XVIII) (yield: 71%).
[0238] b) A four-necked flask (1 L) was charged with 0.073 mol of
intermediate (XVIII) under nitrogen atmosphere. N,N dimethyl
acetamide (377 ml) and 377 ml methylisobutylketone were added and
the mixture was warmed to 70.degree. C. The reaction mixture was
stirred for 5 h at 70.degree. C., then cooled down over a time
period of 1 h to 25.degree. C. and then stirred for another hour at
25.degree. C. The precipitate was filtered and subsequently washed
with 94 ml of a mixture of N,N dimethyl acetamide and
methylisobutylketone, then 150 ml of methylisobutylketone in a
slurry wash and then 150 ml of methylisobutylketone in a
displacement wash. The precipitate was dried under vacuum at
50.degree. C. during 2 days giving 33.4 g of purified intermediate
(XVIII) (yield: 89%).
Example 5
Preparation of JNJ-26481585 HCl Salt Crystal Form I
##STR00021##
[0240] a) An inert four-necked flask (0.5 L) was charged with 0.03
mol of purified intermediate (XVIII). Ethanol (300 ml) was added
(typical water content is 0.07% (w/w)). The reaction mixture was
stirred and warmed to 57.degree. C.-60.degree. C. 30 mg of
intermediate (XVIII) JNJ-26481585.HCl (30 mg) Form I was seeded.
Concentrated hydrochloric acid (0.05 mol %) was added to the
reaction mixture at 57.degree. C. and the reaction mixture was
stirred during 16 h. The precipitate was filtered at 50.degree. C.
and washed 3 times with 20 ml of ethanol giving 10 g JNJ-26481585
HCl salt crystal Form I.
[0241] b) An inert four-necked flask (50 ml) was charged with 2.6 g
of JNJ-26481585 HCl salt crystal Form I obtained in step a).
Ethanol (20 ml) was added. The reaction mixture was stirred under
nitrogen and in the dark and warmed to 50.degree. C. The reaction
mixture was stirred during 12 h at 50.degree. C., cooled to
40.degree. C. over a time period of 1 h and filtered. The
precipitate was washed one time with 20 ml ethanol and two times
with 20 ml acetone. Then the product was dried at 50.degree. C.
under vacuum for 16 h yielding 2 g (80%) of purified JNJ-26481585
HCl salt crystal Form I.
Example 6
Transformation of a Mixture of Polymorph I and II Using a Slurry
Procedure
a) Preparation of the Slurries
[0242] About 25 mg of Form I and about 25 mg of Form II were
weighted in a vial. About 0.2 ml ethanol was added and the vial was
closed. Three vials were prepared and each vial was stored for 4
days at a different temperature, at 4.degree. C. (refrigerator),
40.degree. C. and 70.degree. C.
[0243] This was repeated for the slurries in ethanol/water (90/10,
v/v %) and in water. The slurries were stored for 4 days and 7 days
at the different temperatures. After storage the vial was opened
and the sample was dried by spreading a few mg of the slurry on a
paper filter.
b) Analytical Techniques (Powder XRD)
[0244] All obtained fractions were analyzed using powder XRD.
[0245] X-ray powder diffraction (XRPD) analyses were carried out on
a Philips X'PertPRO MPD diffractometer PW3050/60 with generator
PW3040. The instrument was equipped with a Cu LFF X-ray tube
PW3373/00.
[0246] The compound was spread on a zero background sample
holder.
Instrument Parameters
TABLE-US-00005 [0247] generator voltage: 45 kV generator amperage:
40 mA geometry: Bragg-Brentano stage: spinner stage
Measurement Conditions
TABLE-US-00006 [0248] scan mode: continuous scan range: 3 to
50.degree. 2.theta. step size: 0.01675.degree./step counting time:
29.85 sec/step spinner revolution time: 1 sec radiation type:
CuK.alpha. radiation wavelength: 1.54056 .ANG.
TABLE-US-00007 Incident beam path Diffracted beam path program.
divergence slit: 15 mm long anti scatter shield: + Soller slit:
0.04 rad Soller slit: 0.04 rad beam mask: 15 mm Ni filter: + anti
scatter slit: 1.degree. detector: X'Celerator beam knife: +
c) Results
[0249] The results obtained in the slurry conversion studies after
4 days and 7 days storage in ethanol were collected in the
following Table A.
TABLE-US-00008 Slurry Time and after 4 days after 7 days
Temperature ethanol ethanol 4.degree. C. refrigerator Mixture of
Solvate + Mixture of Solvate + Form I + Form I Form II 40.degree.
C. Mixture of Form I + Mixture of Solvate + Form II (*) Form I
70.degree. C. Form I Form II
[0250] The XRD pattern of the solvated form is comparable to the
XRD pattern of the Hydrate
[0251] The results obtained in the slurry conversion studies after
4 days and 7 days storage in ethanol/water (90/10, v/v %) are
collected in the following Table B.
TABLE-US-00009 after 7 days after 4 days ethanol/water Slurry Time
and ethanol/water (90/10, Temperature (90/10, v/v %) v/v %)
4.degree. C. refrigerator Mixture of Hydrate + Mixture of Hydrate +
Form I Form I 40.degree. C. Mixture of Form I + Mixture of Hydrate
+ Form II (*) Form I 70.degree. C. Mixture of Hydrate + Form I +
traces of Form I Hydrate (*) The solvent present in the slurry was
completely evaporated. After four days storage again 0.2 ml solvent
was added to the mixture.
[0252] The results obtained in the slurry conversion studies after
4 days storage in water are collected in the following Table C.
TABLE-US-00010 Slurry Time and after 4 days Temperature water
4.degree. C. refrigerator Hydrate 40.degree. C. Hydrate 70.degree.
C. Hydrate
[0253] These hydrated samples (ex slurries in water) were stored
for 3 days with 0.1 ml ethanol at different temperatures,
40.degree. C., 50.degree. C. and 70.degree. C.
[0254] The hydrated samples stored for 3 days at 40.degree. C. and
50.degree. C. remained hydrate.
[0255] The hydrated sample stored for 3 days at 70.degree. C. was
completely liquefied (oil).
Example 7
Stability of Form I
a) Compound Information
[0256] Graphic Formula:
##STR00022##
[0257] Chemical name:
N-hydroxy-2-[4-[[[(1-methyl-1H-indol-3-yl)methyl]amino]methyl]-1-piperidi-
nyl]-5-pyrimidinecarboxamide hydrochloride
[0258] Molecular formula: C.sub.21H.sub.26N.sub.6O.sub.2.HCl
[0259] Molecular weight: 430.94
b) Adsorption/Desorption Study
[0260] The adsorption and desorption of water at 25.degree. C. at
different conditions of relative humidity was investigated on 17 mg
Form I.
[0261] The weight change as a function of relative humidity was
registered. The result were displayed in the FIG. 4.
[0262] Form I fraction adsorbs up to 0.6% water at high relative
humidity, it showed no hygroscopic behavior and remained
crystalline during the test.
c) Solubility
[0263] Aqueous solubilities of Form I were measured in solvents
with different pH. An excess of the solute was equilibrated with
the solvent at 20.degree. C. for 24 hours. After removing the
undissolved compound, the concentration in solution was determined
using UV spectrometry.
[0264] The solubilities were listed in the following Table D:
TABLE-US-00011 Solvent Form I Solubility (mg/ml solution) water 1.4
(pH 4.5) 0.01N HCl 1.4 (pH 2.0) 0.001N HCl 1.5 (pH 2.9) Buffer pH2
(citric acid/NaOH/HCl) 0.95 (pH 2.0) Buffer pH4 (citric
acid/HCl/NaOH) 1.2 (pH 3.9) Buffer pH6 (citric acid/NaOH) 1.5 (pH
6.0) Buffer pH8 (boric acid/HCl/NaOH) 1.3 (pH 7.8) Buffer pH10
(boric acid/KCl/NaOH) 1.3 (pH 9.8)
d) Crystallographic Stability
[0265] The stability of the crystal structure of Form I was studied
after storage of the compound in open conditions for a period of
six weeks at room temperature (RT) under <5%, 56% and 75%
relative humidity (RH), 50.degree. C. and 40.degree. C./75% RH.
[0266] The samples are analyzed with thermogravimetry (TGA),
differential scanning calorimetry (DSC), X-ray powder diffraction
(XRPD) and infrared spectroscopy (IR).
[0267] The results of the tests are reported in the following table
E.
TABLE-US-00012 DSC product TGA Exotherm Form I condition
<100.degree. C. <200.degree. C. XRD IR Max (.degree. C.) App
.HCl 0 days 0.4 0.9 Cryst., Cryst., 216.8 Beige-gray Ref Ref
RT/<5% 0.8 0.5 ~Ref ~Ref 216.7 Beige-gray RH RT/56% RH 0.5 0.4
~Ref ~Ref 216.9 Beige-gray RT/75% 0.9 0.4 ~Ref ~Ref 217.0
Beige-gray RH 50.degree. C. 0.5 0.3 ~Ref ~Ref 216.9 Beige-gray
40.degree. C./75% 1.0 0.3 ~Ref ~Ref 216.9 Beige-gray RH ~Ref:
identical with reference Cryst.: crystalline
[0268] Form I melted with decomposition, therefore no heat of
fusion was reported.
[0269] Form I is crystallographically stable.
[0270] No changes are observed after storage under the different
conditions.
[0271] The IR spectra, XRD patterns and the DSC curves remain the
same before and after storage.
e) Chemical Stability
[0272] Form I was stored in different open conditions for periods
of 1, 4 and 8 weeks. These conditions are 40.degree. C./75% RH,
50.degree. C., RT/<5% RH, RT/56% RH, RT/75% RH and 0.3 da ICH
light.
[0273] The compounds were analyzed after storage by HPLC and by
visual inspection.
[0274] The results of the tests were reported in the following
table F.
TABLE-US-00013 HPLC Sum of impurities Appearance product condition
1 week 4 weeks 8 weeks 1 week 4 weeks 8 weeks Form I Reference 3.14
-- -- beige-gray -- -- HCl salt 0.3da ICH light 4.58 -- --
beige-gray -- -- 40.degree. C./75% RH 3.31 3.13 3.59 beige-gray
beige-gray beige-gray 50.degree. C. 3.19 3.20 3.16 beige-gray
beige-gray beige-gray RT/<5% RH -- 3.42 3.16 -- beige-gray
beige-gray RT/56% RH -- 3.27 3.15 -- beige-gray beige-gray RT/75%
RH -- 3.43 3.39 -- beige-gray beige-gray
[0275] Form I showed a sensitivity towards light, as the sum of
impurities increased after storage in 0.3 da ICH light
conditions.
Example 8
Stability of Form II
a) Compound Information
[0276] Graphic Formula:
##STR00023##
[0277] Chemical name:
N-hydroxy-2-[4-[[[(1-methyl-1H-indol-3-yl)methyl]amino]methyl]-1-piperidi-
nyl]-5-pyrimidinecarboxamide hydrochloride
[0278] Molecular formula: C.sub.21H.sub.26N.sub.6O.sub.2.HCl
[0279] Molecular weight: 430.94
b) Adsorption/Desorption Study
[0280] The adsorption and desorption of water at 25.degree. C. at
different conditions of relative humidity was investigated on about
24 mg Form II
[0281] The weight change as a function of relative humidity was
registered.
[0282] The result were displayed in the FIG. 9.
[0283] During the initial drying step a weight loss of 1.67% is
registered for Form II. The obtained dried product was hygroscopic.
It adsorbed up to 9.6% water at high relative humidity.
[0284] The product dried completely during the desorption cycle and
remained crystalline during the test.
c) Crystallographic Stability
[0285] The stability of the crystal structure of Form II was
studied after storage of the compound in open conditions for a
period of six weeks at room temperature (RT) under <5%, 56% and
75% relative humidity (RH), 50.degree. C. and 40.degree. C./75%
RH.
[0286] The samples were analyzed with thermogravimetry (TGA),
differential scanning calorimetry (DSC), X-ray powder diffraction
(XRPD) and infrared spectroscopy (IR).
[0287] The results of the tests were reported in the following
table G.
TABLE-US-00014 DSC TGA Extra Max product condition <100.degree.
C. <170.degree. C. XRD IR (.degree. C.) (.degree. C.) App .HCl
salt 0 days 3.3 0.4 Cryst., Cryst., 71.5 .+-.198 white Ref Ref (78
J/g) RT/<5% 1.9 0.4 ~Ref ~Ref 75.1 .+-.198 white RH (68 J/g)
RT/56% RH 5.2 0.3 .noteq.Ref .noteq.Ref 87.1 .+-.198 slightly (144
J/g) pink RT/75% 4.9 0.3 .noteq.Ref .noteq.Ref 85.2 .+-.198
slightly RH (153 J/g) pink 50.degree. C. 2.1 0.2 ~Ref ~Ref 74.6
.+-.198 white (66 J/g) 40.degree. C./75% 6.0 0.2 .noteq.Ref
.noteq.Ref 83.9 .+-.198 pink RH (151 J/g) ~Ref: identical with
reference Cryst.: crystalline
[0288] Form II melted with decomposition, therefore no heat of
fusion was reported. The extra endothermic signal in the DSC curve
was due to solvent evaporation.
[0289] Form II is crystallographically not stable.
[0290] Changes are observed after storage under the different humid
conditions. The IR spectra and XRD patterns are different from the
starting material after storage under RT/56% RH, RT/75% RH and
40.degree. C./75% RH condition.
[0291] The changes after storage under RT/56% RH, RT/75% RH and
40.degree. C./75% RH condition were due to the uptake of water.
d) Chemical Stability
[0292] Form II was stored in different open conditions for periods
of 1, 4 and 8 weeks. These conditions were 40.degree. C./75% RH,
50.degree. C., RT/<5% RH, RT/56% RH, RT/75% RH and 0.3 da ICH
light.
[0293] The compounds were analyzed after storage by HPLC and by
visual inspection.
[0294] The results of the tests are reported in the following table
H.
TABLE-US-00015 HPLC Sum of impurities Appearance product condition
1 week 4 weeks 8 weeks 1 week 4 weeks 8 weeks Form II Reference
5.04 -- -- white -- -- HCl salt 0.3da ICH light 7.42 -- --
orange-brown -- -- 40.degree. C./75% RH 4.96 4.99 4.90 slightly
pink pink pink 50.degree. C. 4.96 5.00 4.90 white white slightly
pink RT/<5% RH -- 5.10 4.98 -- white white RT/56% RH -- 5.05
4.94 -- slightly slightly pink pink RT/75% RH -- 5.03 4.97 --
slightly slightly pink pink
[0295] The chemical stability study of the R425754 resulted in the
following observations:
[0296] R425754 showed a sensitivity towards light, as the sum of
impurities increases after storage in 0.3 da ICH light
conditions.
[0297] Also a discoloration from white to or orange-brown is
observed after storage in 0.3 da ICH light and from white to pink
after storage in humid conditions RT/56% RH, RT/75% RH and
40.degree. C./75% RH and elevated temperature 50.degree. C.
* * * * *