U.S. patent application number 13/920434 was filed with the patent office on 2013-10-24 for xinafoate salt of n4-(2,2-difluoro-4h-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-n2-[3-(methyla- minocarbonylmethyleneoxy)phenyl]2,4-pyrimidinediamine.
This patent application is currently assigned to Rigel Pharmaceuticals, Inc.. The applicant listed for this patent is Rigel Pharmaceuticals, Inc.. Invention is credited to Stefan Colin John Taylor.
Application Number | 20130281446 13/920434 |
Document ID | / |
Family ID | 40293576 |
Filed Date | 2013-10-24 |
United States Patent
Application |
20130281446 |
Kind Code |
A1 |
Taylor; Stefan Colin John |
October 24, 2013 |
XINAFOATE SALT OF
N4-(2,2-DIFLUORO-4H-BENZO[1,4]OXAZIN-3-ONE)-6-YL]-5-FLUORO-N2-[3-(METHYLA-
MINOCARBONYLMETHYLENEOXY)PHENYL]2,4-PYRIMIDINEDIAMINE
Abstract
The present invention relates to the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine. This
compound is a suitable drug substance and is useful in the
treatment of conditions including asthma.
Inventors: |
Taylor; Stefan Colin John;
(Sandwich, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rigel Pharmaceuticals, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Rigel Pharmaceuticals, Inc.
|
Family ID: |
40293576 |
Appl. No.: |
13/920434 |
Filed: |
June 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13467850 |
May 9, 2012 |
8486935 |
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13920434 |
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12676075 |
Mar 2, 2010 |
8193181 |
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PCT/IB2008/002288 |
Aug 27, 2008 |
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13467850 |
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60970030 |
Sep 5, 2007 |
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Current U.S.
Class: |
514/230.5 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 1/00 20180101; A61P 43/00 20180101; A61P 1/04 20180101; A61P
11/02 20180101; A61P 11/08 20180101; A61P 11/00 20180101; A61P
19/02 20180101; A61P 31/00 20180101; A61K 45/06 20130101; A61K
31/538 20130101; A61P 29/00 20180101; A61P 25/00 20180101; A61P
19/10 20180101; A61P 27/02 20180101; C07D 413/12 20130101; A61P
9/12 20180101; A61P 35/02 20180101; A61P 31/06 20180101; A61P 31/18
20180101; A61P 11/06 20180101 |
Class at
Publication: |
514/230.5 |
International
Class: |
A61K 31/538 20060101
A61K031/538; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method, comprising administering to a mammal a therapeutically
effective amount of a xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.
2. The method of claim 1 wherein the xinafoate salt has shifts at
about -69.2, -72.4 and -164.0 ppm when characterized by fluorine
solid state NMR referenced to an external sample of trifluoroacetic
acid (50% by volume in H.sub.2O) assigned a resonance at -76.54
ppm.
3. The method according to claim 1 for treating a disease for which
a Syk kinase inhibitor is indicated.
4. The method according to claim 1 wherein the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo
[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)-
phenyl]-2,4-pyrimidinediamine is administered as a composition
comprising
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine, an
excipient, a second pharmacologically active substance, or
combinations thereof.
5. The method according to claim 4 for treating a disease for which
a Syk kinase inhibitor is indicated.
6. The method according to claim 4 for treating asthma.
7. The method according to claim 4 wherein the second
pharmacologically active substance is selected for treating a
disease for which a Syk kinase inhibitor is indicated.
8. The method according to claim 4 wherein the second
pharmacologically active substance is selected for treating
asthma.
9. The method according to claim 1 wherein administering comprises
administering using a dry powder inhaler.
10. A composition, comprising: a xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine; and a
second pharmacologically active substance.
11. The composition according to claim 10 formulated for treating a
disease for which a Syk kinase inhibitor is indicated.
12. The composition according to claim 10 formulated for treating
asthma.
13. The composition according to claim 10 wherein the second
pharmacological substance is selected for treating a disease for
which a Syk kinase inhibitor is indicated.
14. The composition according to claim 10 wherein the second
pharmacological substance is selected for treating asthma.
15. A method for making a composition, comprising: providing a
xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-
-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;
and making a composition comprising the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.
16. The method according to claim 15 where the composition is
formulated for treating a disease for which a Syk kinase inhibitor
is indicated.
17. The method according to claim 15 where the composition is
formulated for treating asthma.
18. The method according to claim 15 wherein making the composition
comprises mixing the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine with
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine, an
excipient, a second pharmacologically active substance, or
combinations thereof.
19. The method according to claim 18 wherein the second
pharmacologically active substance is selected for treating a
disease for which a Syk kinase inhibitor is indicated
20. The method according to claim 18 wherein the second
pharmacologically active substance is selected for treating asthma.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation application of Ser. No. 13/467,850,
filed on May 9, 2012, which is a continuation of U.S. patent
application Ser. No. 12/676,075, filed on Mar. 2, 2010, which
issued as U.S. Pat. No. 8,193,181 on Jun. 5, 2012, which is the
U.S. National Stage of International Application No.
PCT/IB2008/002288, having an international filing date of Aug. 27,
2008, and published in English under PCT Article 21(2), which in
turn claims the benefit of the earlier filing date of U.S.
Provisional Application No. 60/970,030, filed on Sep. 5, 2007. Each
of these prior applications is incorporated herein in its
entirety.
[0002] The present invention relates to the xinafoate salt of
N4-[(2,2-difluoro-4Hbenzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyla-
minocarbonylmethylene oxy)phenyl]-2,4-pyrimidinediamine and to
pharmaceutical compositions comprising and to processes for making
such a compound. The invention further relates to the use of the
salt and its compositions in the treatment of various conditions,
particularly in the treatment of inflammatory conditions such as
asthma.
[0003] The compound
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine, having the
structural formula (I):
##STR00001##
is disclosed in WO-A-03/063794 as Example 7.3.907 on page 440. The
compound, which is also known as
2-{3-[4-(2,2-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)5-f-
luoro-pyrimidin-2-ylamino]phenoxy}N-methyl-acetamide, is one of a
genus of compounds which are disclosed to be inhibitors of Syk
kinase and therefore useful in the treatment of inflammatory
conditions such as chronic obstructive pulmonary disease (COPD). It
is noted that the compounds can be formulated in a pharmaceutical
composition in their free form or in the form of a hydrate,
solvate, N-oxide or pharmaceutically acceptable salt (pages 70-71).
A pharmaceutical composition suitable for inhalation comprising one
of the compounds and a suitable powder base, such as lactose or
starch, is specifically mentioned (page 72).
[0004] If a compound is to be developed as a drug, it is important
to provide a form of that compound (commonly known as a drug
substance) which can be reliably prepared and purified on a large
scale, which is stable and which does not degrade on storage. Such
characteristics are normally found in a drug substance which is
crystalline and of high melting point; a high-melting point
crystalline solid tends to be easy to purify by recrystallization
and stable on storage. Furthermore, the drug substance must be
suitable for formulation in a dosage form chosen according to the
intended route of administration. For formulation as a dry powder
suitable for inhalation, nonhygroscopicity is particularly
important in order to obtain good flow characteristics.
Compatibility with conventional excipients such as lactose and
starch is a further mandatory requirement. Further, the drug
substance will usually require processing in order to achieve a
particle size suitable for inhalation and any crystalline form must
be stable during such processing so that the properties of the
final product are predictable and reliable. In short, whether or
not a compound is suitable for commercialisation as a drug is
dependent on finding a form of the compound with a unique
combination of properties determined according to the intended
route of administration.
[0005] The free form of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine disclosed
in WO-A-03/063794 is not suitable for commercialisation as a drug
since it is predominantly amorphous, or exists in a disordered
crystalline faun and is prone to hydration and solvation. There is
therefore a need to provide a new form of
N4-[(2,2-difluoro-4Hbenzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyla-
minocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine which has
the required characteristics. Salt formation is one possible avenue
of enquiry, but the properties of salts are hard to predict and,
worse still, the compound will not form salts with many common
pharmaceutically acceptable acids. Many salt forms that do form,
such as the mesylate, fumarate, hemifumarate, hydrobromide,
hydrochloride, D-tartrate, hemisulphate and isethionate salts, have
one or more unsatisfactory properties such as poor crystallinity
and the propensity to form hydrates and/or solvates.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 is a differential scanning calorimetry trace of the
xinafoate salt.
[0007] FIG. 2 is a powder X-ray diffraction pattern of the
xinafoate salt.
[0008] FIG. 3 is a simulated crystal X-ray analysis of the
xinafoate salt.
[0009] FIG. 4 is a Fourier Transform IR spectrum of the xinafoate
salt.
[0010] FIG. 5 is a fingerprint region of the FIRT spectrum of FIG.
4.
[0011] FIG. 6 is a Fourier transform Raman spectrum of the
xinafoate salt.
[0012] FIG. 7 is a fingerprint region of the Fourier Transform
Raman spectrum of FIG. 6.
[0013] FIG. 8 is a proton decoupled C.sup.13 solid state NMR of the
xinafoate salt.
[0014] FIG. 9 is a fluorine solid state NMR of the xinafoate
salt.
[0015] As a result of extensive research, however, it has now been
possible to design a form of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine which has a
unique set of characteristics making it ideal for administration in
a dry powder foimulation. The xinafoate salt is highly crystalline,
has a melting point of about 233.degree. C., is essentially
non-hygroscopic and can be micronised by jet milling without
inducing any change in crystalline form. Furthermore, it shows good
stability when blended with lactose monohydrate and stored under
aggressive conditions of heat and humidity and the lactose blend
aerosolises well when used in conjunction with standard dry powder
inhalers.
[0016] The present invention therefore provides, in a first aspect,
the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine, having the
structure shown in Formula (II) below. Xinafoate is the common name
for 1-hydroxy-2-naphthoate. It should be noted that this molecule
can be depicted in several different tautomeric forms depending on
the location of the proton, all of which are equivalent.
##STR00002##
[0017] The invention further provides: the xinafoate salt of
N4-[(2,2-difluoro-4Hbenzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyla-
minocarbonylmethyleneoxy) phenyl]-2,4-pyrimidinediamine for use as
a medicament; the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidinediamine for use in
treating a condition for which a Syk kinase inhibitor is indicated;
the use of the xinafoate salt of
N4-[(2,2-difluoro-4Hbenzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyla-
minocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine for the
manufacture of a medicament to treat a disease for which a Syk
kinase inhibitor is indicated; a pharmaceutical composition
comprising the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine and a
pharmaceutically acceptable excipient; a pharmaceutical composition
for the treatment of a disease for which a Syk kinase inhibitor is
indicated comprising the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine; and a
method of treating a disease for which a Syk kinase inhibitor is
indicated in a mammal comprising administering to the mammal in
need thereof a therapeutically effective amount of the xinafoate
salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine. Preferred
diseases for which a Syk inhibitor is indicated are inflammatory
respiratory diseases such as asthma, rhinitis and COPD,
particularly asthma.
[0018] The xinafoate salt can be prepared by dissolving
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy) phenyl]-2,4-pyrimidinediamine and
between 1 and 1.1 molar equivalents 1-hydroxy-2-naphthoic acid in
the minimum amount of a suitable organic solvent and cooling the
solution slowly, optionally with stirring, until the salt
precipitates from the solution. Suitable solvents are acetone,
acetonitrile and methyl ethyl ketone (MEK), each optionally
containing a small amount of water (e.g. less than 10%). Methyl
ethyl ketone is particularly suitable and is preferably used with
about 5% by volume of water. The reactants are typically dissolved
in the solvent at a temperature higher than room temperature but
below the boiling point of the solvent.
[0019]
N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(-
methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine may
be prepared by the general and specific methods disclosed in
WO-A-03/063794. It may, for example, be prepared by reacting a
compound of formula
##STR00003##
with a compound of formula
##STR00004##
[0020] The reaction is typically carried out in a suitable solvent,
preferably an alcohol such as isoamyl alcohol or isopropyl alcohol,
and in the presence of an acid catalyst such as trifluoroacetic
acid. The reaction is best carried out at an elevated temperature.
If amyl alcohol is selected as the solvent, for example, a
temperature of about 100.degree. C. is preferred.
[0021] A compound of formula (III) may be prepared by the route set
out in Scheme 1 below.
##STR00005##
[0022] A compound of formula (III) may be prepared by reducing the
nitro group in a compound of formula (V). In a preferred procedure,
hydrogenation is used. Typically, a solution of the compound of
formula (V) in a suitable organic solvent, such as a mixture of
ethanol (EtOH) and ethyl acetate (EtOAc), is treated with a
hydrogenation catalyst, such as palladium on carbon, and exposed to
hydrogen gas. The hydrogen is usually applied at a pressure above
atmospheric, preferably at 30 pounds per square inch (psi).
[0023] A compound of formula (V) may be prepared by condensing the
acid of formula (VI) with methylamine, or a salt thereof (such as
the hydrochloride salt). Any condensing agent suitable for the
formation of amide bonds may be used in principle, but the use of
2-(1H-benzatriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU) is preferred. The condensation catalysed
by TBTU is carried out in a suitable organic solvent, such as
N,N-dimethylformamide (DMF), and in the presence of a base such as
N,Ndiisopropylethylamine (DIPEA).
[0024] A compound of formula (VI) may be prepared by alkylating
3-nitrophenol (VII) with bromoacetic acid. The reaction is
typically carried out in a suitable solvent, such as water or
aqueous ethanol (EtOH), in the presence of a base, such as sodium
hydroxide (NaOH), and at elevated temperature, e.g. at the reflux
temperature of the chosen solvent.
[0025] A compound of formula (IV) can be prepared by the route set
out in Scheme 2 below.
##STR00006##
[0026] A compound of formula (IV) may be prepared by reacting a
compound of formula (VIII) with 5-fluoro-2,4-dichloropyrimidine. In
a typical procedure, a solution of the reactants in a suitable
organic solvent, such as ethanol (EtOH) or a mixture of ethanol and
tetrahydrofuran (THF), is treated with a base such as sodium
hydrogencarbonate.
[0027] A compound of formula (VIII) may be prepared by the reducing
the nitro group in a compound of formula (IX). In a preferred
procedure, hydrogenation is used. Typically, a solution of the
compound of formula (IX) in a suitable organic solvent, such as
ethanol (EtOH), is treated with a hydrogenation catalyst, such as
palladium on carbon, and exposed to hydrogen gas. The hydrogen is
usually applied at a pressure above atmospheric, preferably at 30
pounds per square inch (psi).
[0028] A compound of formula (IX) may be prepared by the
cyclisation of a compound of formula (X). In a typical procedure, a
solution of a compound of formula (X) in a suitable organic
solvent, such as N,N-dimethylformamide (DMF) or isopropyl acetate,
is treated with a base, such as potassium carbonate, and heated,
for example at the reflux temperature of the solvent. When DMF is
chosen as solvent, a temperature of about 120.degree. C. is
preferred. When isopropyl acetate is chosen as solvent, a
temperature of about 85.degree. C. is preferred.
[0029] A compound of formula (X) may be prepared by acylation of
the aniline of formula (XI) with 2-bromo-2,2-difluoroacetyl
chloride. The reaction is preferably carried out in a suitable
organic solvent, such as dichloromethane (DCM) or acetonitrile, in
the presence of a base, such as triethylamine. The reaction is
exothermic and cooling, for example to 0.degree. C., may therefore
be required.
[0030] The present invention includes all crystalline and
pharmaceutically acceptable isotopically-labeled forms of the
xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy) phenyl]-2,4-pyrimidinediamine. In an
isotopically-labeled form, one or more atoms are replaced by an
atom or atoms having the same atomic number, but an atomic mass or
mass number different from the atomic mass or mass number which
predominates in nature.
[0031] Suitable isotopes include isotopes of hydrogen, such as
.sup.2H and .sup.3H; carbon, such as .sup.11C, .sup.13C and
.sup.14C; nitrogen, such as .sup.13N and .sup.15N; oxygen, such as
.sup.15O, .sup.17O and .sup.18O; and sulphur, such as .sup.35S.
Certain isotopically-labeled compounds, such as those incorporating
a radioactive isotope, are useful in drug and/or substrate tissue
distribution studies. The radioactive isotopes tritium, i.e.
.sup.3H, and carbon-14, i.e. .sup.14C, are particularly useful for
this purpose in view of their ease of incorporation and ready means
of detection. Substitution with heavier isotopes such as deuterium,
i.e. .sup.2H, may afford certain therapeutic advantages resulting
from greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances. Substitution with positron
emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O and .sup.13
N, can be useful in Positron Emission Topography (PET) studies for
examining substrate receptor occupancy. Isotopically-labeled
compounds can generally be prepared by conventional techniques
known to those skilled in the art or by processes analogous to
those described in the accompanying Examples and Preparations using
an appropriate isotopically-labeled reagent in place of the
non-labeled reagent previously employed.
[0032]
N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(-
methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine is a
Syk kinase inhibitor and is able to inhibit the degranulation of
immune cells, such as mast, basophile, neutrophil and/or eosinophil
cells. It may be useful, in the form of the xinafoate salt
disclosed by the present invention and otherwise, in the treatment
of the following conditions: [0033] Treatable obstructive,
restrictive or inflammatory airways diseases of whatever type,
etiology, or pathogenesis, in particular an obstructive,
restrictive or inflammatory airways disease such as: [0034] asthma,
in particular atopic asthma, allergic asthma, atopic bronchial
IgE-mediated asthma, non-atopic asthma, bronchial asthma,
non-allergic asthma, essential asthma, true asthma, intrinsic
asthma caused by pathophysiologic disturbances, essential asthma of
unknown or inapparent cause, emphysematous asthma, exercise-induced
asthma, emotion-induced asthma, extrinsic asthma caused by
environmental factors, cold air induced asthma, occupational
asthma, infective asthma caused by or associated with bacterial,
fungal, protozoal, or viral infection, incipient asthma, wheezy
infant syndrome, bronchiolitis, cough variant asthma or
drug-induced asthma; [0035] bronchial hyper-responsivity to
environmental agents; [0036] rhinitis or sinusitis of whatever
type, etiology, or pathogenesis, in particular seasonal allergic
rhinitis, perennial allergic rhinitis, perennial rhinitis,
vasomotor rhinitis, post-nasal drip, purulent or nonpurulent
sinusitis, acute or chronic sinusitis and ethmoid, frontal,
maxillary, or sphenoid sinusitis; [0037] chronic obstructive
pulmonary disease (COPD), chronic obstructive lung disease (COLD),
chronic obstructive airways disease (COAD) or small airways
obstruction of whatever type, etiology, or pathogenesis, in
particular chronic bronchitis, pulmonary emphysema, bronchiectasis,
cystic fibrosis, bronchiolitis obliterans, bronchiolitis obliterans
organizing pneumonia (BOOP), chronic organizing pneumonia (COP),
bronchiolitis fibrosa obliterans, follicular bronchiolitis or
dyspnea associated therewith; [0038] bronchitis of whatever type,
etiology, or pathogenesis, in particular acute bronchitis, acute
laryngotracheal bronchitis, arachidic bronchitis, catarrhal
bronchitis, croupus bronchitis, chronic bronchitis, dry bronchitis,
infectious asthmatic bronchitis, productive bronchitis,
staphylococcus or streptococcal bronchitis and vesicular
bronchitis; [0039] bronchiectasis of whatever type, etiology, or
pathogenesis, in particular cylindric bronchiectasis, sacculated
bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis,
cystic bronchiectasis, cystic fibrosis, Kartageners's syndrome, dry
bronchiectasis or follicular bronchiectasis; [0040] pulmonary
eosinophilic syndromes of whatever type, etiology, or pathogenesis,
in particular acute eosinophilic pneumonia (idiopathic or due to
drugs or parasites), simple pulmonary eosinophilia, Loeffler's
syndrome, tropical pulmonary eosinophilia, chronic eosinophilic
pneumonia, allergic bronchopulmonary mycosis, allergic
bronchopulmonary aspergillosis (ABPA), Churg-Strauss syndrome or
idiopathic hypereosinophilic syndrome; [0041] interstitial lung
diseases (ILD) or pulmonary fibrosis of whatever type, etiology, or
pathogenesis, in particular idiopathic pulmonary fibrosis,
crytogenic fibrosing alveolitis, fibrosing alveolitis, ILD or
pulmonary fibrosis associated with connective tissue disease
(systemic lupus erythematosis, mixed connective tissue disease,
polymyositis, dermatomyositis, Sjorgen's syndrome, systemic
sclerosis, scleroderma, rheumatoid arthritis), usual interstitial
pneumonia (UIP), desquamative interstitial pneumonia (DIP),
granulomatous lung disease, sarcoidosis, Wegener's granulomatosis,
histiocytosis X, Langerhan's cell granulomatosis, hypersensitivity
pneumonitis, extrinsic allergic alveolitis, silicosis, chronic
eosinophilic pneumonia, lymphangiolyomatosis, drug-induced ILD or
pulmonary fibrosis, radiation-induced ILD or pulmonary fibrosis,
alveolar proteinosis, graft-versus-host-disease (GVHD), lung
transplant rejection, ILD or pulmonary fibrosis due to
environmental/occupational exposure, BOOP, COP, bronchiolitis
fibrosa obliterans, follicular bronchiolitis, idiopathic acute
interstitial pneumonitis (Hamman Rich syndrome) or alveolar
hemorrhage syndromes; [0042] pneumoconiosis of whatever type,
etiology, or pathogenesis, in particular aluminosis or bauxite
workers' disease, anthracosis or miners' asthma, progressive
massive fibrosis (PMF), asbestosis or steam-fitters' asthma,
chalicosis or flint disease, ptilosis caused by inhaling the dust
from ostrich feathers, siderosis caused by the inhalation of iron
particles, silicosis or grinders' disease, byssinosis or
cotton-dust asthma or talc pneumoconiosis; [0043] Acute Respiratory
Distress Syndrome (ARDS), adult respiratory distress syndrome or
acute lung injury of whatever type, etiology, or pathogenesis;
[0044] aspiration disorders of whatever type, etiology, or
pathogenesis leading to aspiration pneumonitis or aspiration
pneumonia; [0045] alveolar hemorrhage of whatever type, etiology,
or pathogenesis, in particular a member of the group consisting of
idiopathic pulmonary hemosiderosis, alveolar hemorrhage due to
drugs or other exogenous agents, alveolar hemorrhage associated
with HIV or bone marrow transplant or autoimmune alveolar
hemorrhage (e.g. associated with systemic lupus erythematosis,
Goodpasture's syndrome, Wegener's granulomatosis, microscopic
polyangiitis, Churg-Strauss syndrome, pauci-immune
glomerulonephritis); [0046] acute or chronic laryngitis or
pharyngitis; [0047] cough of whatever type, etiology, or
pathogenesis in particular idiopathic cough or cough associated
with gastro-esophageal reflux disease (GERD), drugs, bronchial
hyper-responsivity, asthma, COPD, COLD, COAD, bronchitis,
bronchiectasis, pulmonary eosinophilic syndromes, pneumoconiosis,
interstitial lung disease, pulmonary fibrosis, aspiration
disorders, rhinitis, laryngitis or pharyngitis; [0048] anaphylaxis
and type 1 hypersensitivity reactions of whatever aetiology; [0049]
atopic, allergic, autoimmune or inflammatory skin disorders of
whatever type, etiology, or pathogenesis, in particular atopic
dermatitis, allergic dermatitis, contact dermatitis, allergic or
atopic eczema, lichen planus, mastocytosis, erythema nodosum,
erythema multiforme, benign familial pemphigus, pemphigus
erythematosus, pemphigus foliaceus, and pemphigus vulgaris, bullous
pemphigoid, epidermolysis bullosa, deiniatitis hepetiformis,
psoriasis, immune-mediated urticaria, complement-mediated
urticaria, urticariogenic material-induced urticaria, physical
agent-induced urticaria, stress-induced urticaria, idiopathic
urticaria, acute urticaria, chronic urticaria, angioedema,
cholinergic urticaria, cold urticaria in the autosomal dominant
form or in the acquired form, contact urticaria, giant urticaria or
papular urticaria; [0050] conjunctivitis of whatever type,
etiology, or pathogenesis, in particular actinic conjunctivitis,
acute catarrhal conjunctivitis, acute contagious conjunctivitis,
allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal
conjunctivitis, purulent conjunctivitis or vernal conjunctivitis;
[0051] multiple sclerosis of whatever type, etiology, or
pathogenesis, in particular primary progressive multiple sclerosis
or relapsing remitting multiple sclerosis; [0052]
autoimmune/inflammatory diseases of whatever type, etiology, or
pathogenesis, in particular autoimmune hematological disorders,
hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic
thrombocytopenic purpura, rheumatoid arthritis, systemic lupus
erythematosus, scleroderma, systemic sclerosis, oolymyalgia
rheumatica, dermatomyositis, polymyositis, polychondritis, Wegner's
granulomatosis, chronic active hepatitis, myasthenia gravis,
Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory
bowel diseases, Crohn's disease, ulcerative colitis, endocrine
opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic
hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile
diabetes or diabetes mellitus type I, keratoconjunctivitis sicca,
epidemic keratoconjunctivitis, glomerulonephritis with or without
nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic
syndrome, minimal change nephropathy, autoimmune disorders
associated with interstitial lung disease and/or pulmonary fibrosis
or autoimmune or inflammatory skin disorders; [0053] inflammatory
bowel disease (IBD) of whatever type, etiology, or pathogenesis, in
particular collagenous colitis, colitis polyposa, transmural
colitis, ulcerative colitis or Crohn's disease (CD); [0054]
pulmonary hypertension of whatever type, etiology or pathogenesis
including pulmonary arterial hypertension, pulmonary venous
hypertension, pulmonary hypertension associated with disorders of
the respiratory system and/or hypoxemia, pulmonary hypertension due
to chronic thrombotic and/or embolic disease and pulmonary
hypertension due to disorders directly affecting the pulmonary
vasculature; [0055] arthritis of whatever type, etiology, or
pathogenesis, in particular rheumatoid arthritis, osteorthritis,
gouty arthritis, pyrophosphate arthropathy, acute calcific
periarthritis, chronic inflammatory arthritis, arthritis associated
with a connective tissue disorder (e.g. systemic lupus
erythematosis, polymyositis, dermatomyositis, systemic sclerosis,
scleroderma), sarcoidosis, polymyalgia rheumatica, degenerative
arthritis, infectious arthritis, Lyme arthritis, proliferative
arthritis, psoriatic arthritis, ankylosing spondylitis, cervical
spondylosis, vertebral arthritis, juvenile arthritis (Still's
disease), amyloidosis, ankylosing vertebral hyperostosis
(Forrestier's disease), Behcet's syndrome, drug-induced arthritis,
familial Mediterranean fever, hypermobility syndrome,
osteochondritis dessicans, osteochondromatosis, palindromic
rheumatism, pigmented villonodular synovitis, relapsing
polychondritis, temporomandibular pain dysfunction syndrome or
arthritis associated with hyperlipidemia; [0056] an
eosinophil-related disorder of whatever type, etiology, or
pathogenesis, in particular pulmonary eosinophilic syndromes,
aspergilloma, granulomas containing eosinophils, allergic
granulomatous angiitis or Churg-Strauss syndrome, polyarteritis
nodosa (PAN) or systemic necrotizing vasculitis; [0057] uveitis of
whatever type, etiology, or pathogenesis, in particular
inflammation of all or part of the uvea, anterior uveitis, iritis,
cyclitis, iridocyclitis, granulomatous uveitis, nongranulomatous
uveitis, phacoantigenic uveitis, posterior uveitis, choroiditis or
chorioretinitis; [0058] septic shock of whatever type, etiology, or
pathogenesis; [0059] disorders of bone deposition/resorption,
including osteoporosis and osteopenia; [0060] lymphoproliferative
disorders (e.g. lymphoma, myeloma); [0061] HIV or AIDs related
disorders; [0062] infection, especially infection due to viruses
wherein such viruses increase the production of TNF-.alpha. in
their host, or wherein such viruses are sensitive to upregulation
of TNF-.alpha. in their host so that their replication or other
vital activities are adversely impacted, including a virus which is
a member selected from the group consisting of HIV-1, HIV-2, and
HIV-3, cytomegalovirus (CMV), influenza, adenoviruses and Herpes
viruses including Herpes zoster and Herpes simplex; [0063] yeast
and fungal infections wherein the yeast or fungus is sensitive to
upregulation by TNF-.alpha. or elicits TNF-.alpha. production in
the host, e.g., fungal meningitis, particularly when administered
in conjunction with other drugs of choice for the treatment of
systemic yeast and fungus infections, including but are not limited
to, polymixins (e.g. Polymycin B), imidazoles (e.g. clotrimazole,
econazole, miconazole, and ketoconazole), triazoles (e.g.
fluconazole and itranazole) and amphotericins (e.g. Amphotericin B
and liposomal Amphotericin B); and [0064] Mycobacterial infections
e.g. due to mycobacterium tuberculosis.
[0065] The xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (henceforth
referred to as the compound of the invention) may be administered
alone but will generally be administered as a formulation in
association with one or more pharmaceutically acceptable
excipients. The term `excipient` is used herein to describe any
ingredient other than the compound of the invention. The choice of
excipient will to a large extent depend on factors such as the
particular mode of administration, the effect of the excipient on
solubility and stability, and the nature of the dosage form.
[0066] Pharmaceutical compositions suitable for the delivery of the
compound of the invention and methods for their preparation will be
readily apparent to those skilled in the art. Such compositions and
methods for their preparation may be found, for example, in
Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing
Company, 1995).
[0067] The compound of the invention may be administered orally.
Oral administration may involve swallowing, so that the compound
enters the gastrointestinal tract, or buccal or sublingual
administration may be employed by which the compound enters the
blood stream directly from the mouth.
[0068] Formulations suitable for oral administration include solid
formulations such as tablets, capsules containing particulates,
liquids, or powders, lozenges (including liquid-filled), chews,
multi- and nano-particulates, gels, solid solution, liposome,
films, ovules, sprays and liquid formulations.
[0069] Liquid formulations include suspensions, solutions, syrups
and elixirs. Such formulations may be employed as fillers in soft
or hard capsules and typically comprise a carrier, for example,
water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying
agents and/or suspending agents. Liquid formulations may also be
prepared by the reconstitution of a solid, for example, from a
sachet.
[0070] The compound of the invention may also be used in
fast-dissolving, fast-disintegrating dosage forms such as those
described in Expert Opinion in Therapeutic Patents, 11 (6),
981-986, by Liang and Chen (2001).
[0071] For tablet dosage forms, depending on dose, the compound of
the invention may make up from 1 weight % to 80 weight % of the
dosage form, more typically from 5 weight % to 60 weight % of the
dosage form.
[0072] In addition, tablets generally contain a disintegrant.
Examples of disintegrants include sodium starch glycolate, sodium
carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl
cellulose, microcrystalline cellulose, lower alkyl-substituted
hydroxypropyl cellulose, starch, pregelatinised starch and sodium
alginate. Generally, the disintegrant will comprise from 1 weight %
to 25 weight %, preferably from 5 weight % to 20 weight % of the
dosage form.
[0073] Binders are also generally used to impart cohesive qualities
to a tablet formulation. Suitable binders include microcrystalline
cellulose, gelatin, sugars, polyethylene glycol, natural and
synthetic gums, polyvinylpyrrolidone, pregelatinised starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets
may also contain diluents, such as lactose (monohydrate,
spray-dried monohydrate, anhydrous and the like), mannitol,
xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose,
starch and dibasic calcium phosphate dihydrate.
[0074] Tablets may also optionally comprise surface active agents,
such as sodium lauryl sulfate and polysorbate 80, and glidants such
as silicon dioxide and talc. When present, surface active agents
may comprise from 0.2 weight % to 5 weight % of the tablet, and
glidants may comprise from 0.2 weight % to 1 weight % of the
tablet.
[0075] Tablets also generally contain lubricants such as magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
and mixtures of magnesium stearate with sodium lauryl sulphate.
Lubricants generally comprise from 0.25 weight % to 10 weight %,
preferably from 0.5 weight % to 3 weight % of the tablet.
[0076] Other possible tablet ingredients include anti-oxidants,
colouring agents, flavouring agents, preservatives and
taste-masking agents.
[0077] Exemplary tablets contain up to about 80% drug, from about
10 weight % to about 90 weight % binder, from about 0 weight % to
about 85 weight % diluent, from about 2 weight % to about 10 weight
% disintegrant, and from about 0.25 weight % to about 10 weight %
lubricant.
[0078] Tablet blends may be compressed directly or by roller
compaction to form tablets. Tablet blends or portions of blends may
alternatively be wet-, dry-, or melt-granulated, melt congealed, or
extruded before tabletting. The final formulation may comprise one
or more layers and may be coated or uncoated; it may even be
encapsulated.
[0079] The formulation of tablets is discussed in Pharmaceutical
Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman
(Marcel Dekker, New York, 1980).
[0080] The compound of the invention may also be orally
administered in the form of a consumable oral film for human or
veterinary use. Such a film is typically a pliable water-soluble or
water-swellable thin film dosage form which may be rapidly
dissolving or mucoadhesive and typically comprises the compound of
the invention, a film-forming polymer, a binder, a solvent, a
humectant, a plasticiser, a stabiliser or emulsifier, a
viscosity-modifying agent and a solvent. Some components of the
formulation may perform more than one function.
[0081] The film-forming polymer may be selected from natural
polysaccharides, proteins, or synthetic hydrocolloids and is
typically present in the range 0.01 to 99 weight %, more typically
in the range 30 to 80 weight %.
[0082] Other possible film ingredients include anti-oxidants,
colouring agents, flavourings and flavour enhancers, preservatives,
salivary stimulating agents, cooling agents, cosolvents (including
oils), emollients, bulking agents, anti-foaming agents, surfactants
and taste-masking agents.
[0083] Films in accordance with the invention are typically
prepared by evaporative drying of thin aqueous films coated onto a
peelable backing support or paper. This may be done in a drying
oven or tunnel, typically a combined coater dryer, or by
freeze-drying or vacuum drying.
[0084] Solid formulations for oral administration may be formulated
to be immediate and/or modified release. Modified release includes
delayed, sustained, pulsed, controlled, targeted and programmed
release.
[0085] Suitable modified release formulations for the purposes of
the invention are described in U.S. Pat. No. 6,106,864. Details of
other suitable release technologies such as high energy dispersions
and osmotic and coated particles are to be found in Pharmaceutical
Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of
chewing gum to achieve controlled release is described in
WO-A-00/35298.
[0086] The compound of the invention may also be administered
directly into the blood stream, into muscle, or into an internal
organ. Such parenteral administration may be via the intravenous,
intraarterial, intraperitoneal, intrathecal, intraventricular,
intraurethral, intrasternal, intracranial, intramuscular or
subcutaneous route. Suitable devices for parenteral administration
include needle (including microneedle) injectors, needle-free
injectors and infusion techniques.
[0087] Parenteral formulations are typically aqueous solutions
which may contain excipients such as salts, carbohydrates and
buffering agents (preferably to a pH of from 3 to 9), but, for some
applications, they may be more suitably formulated as a sterile
non-aqueous solution or as a dried form to be used in conjunction
with a suitable vehicle such as sterile, pyrogen-free water.
[0088] The preparation of parenteral formulations under sterile
conditions, for example, by lyophilisation, may readily be
accomplished using standard pharmaceutical techniques well known to
those skilled in the art.
[0089] Formulations for parenteral administration may be formulated
to be immediate and/or modified release. Modified release includes
delayed, sustained, pulsed, controlled, targeted and programmed
release. Thus compound of the invention may be formulated as a
solid, semi-solid or thixotropic liquid for administration as an
implanted depot providing modified release of the compound of the
invention. Examples of such formulations include drug-coated stents
and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
[0090] The compound of the invention may also be administered
topically to the skin or mucosa, i.e. dermally or transdermally.
Typical formulations for this purpose include gels, hydrogels,
lotions, solutions, creams, ointments, dusting powders, dressings,
foams, films, skin patches, wafers, implants, sponges, fibres,
bandages and microemulsions. Liposomes may also be used. Typical
carriers include alcohol, water, mineral oil, liquid petrolatum,
white petrolatum, glycerin, polyethylene glycol and propylene
glycol. Penetration enhancers may be incorporated--see, for
example, J. Pharm. Sci., 88 (10), 955-958, by Finnin and Morgan
(October 1999).
[0091] Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and
microneedle or needle-free (e.g. Powderject.TM., Bioject.TM.)
injection.
[0092] Formulations for topical administration may be formulated to
be immediate and/or modified release. Modified release includes
delayed, sustained, pulsed, controlled, targeted and programmed
release.
[0093] The compound of the invention can also be administered
intranasally or by inhalation, typically in the form of a dry
powder (either alone, as a mixture, for example, in a dry blend
with lactose, or as a mixed component particle, for example, mixed
with phospholipids, such as phosphatidylcholine) from a dry powder
inhaler or as an aerosol spray from a pressurised container, pump,
spray, atomiser (preferably an atomiser using electrohydrodynamics
to produce a fine mist), or nebuliser, with or without the use of a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder
may comprise a bioadhesive agent, for example, chitosan or
cyclodextrin. Administration in the form of a dry powder from a dry
powder inhaler is a particularly preferred form of delivery.
[0094] The pressurised container, pump, spray, atomizer or
nebuliser contains a solution or suspension of the compound of the
invention comprising, for example, ethanol, aqueous ethanol or a
suitable alternative agent for dispersing, solubilising or
extending release of the active, a propellant(s) as solvent and an
optional surfactant, such as sorbitan trioleate, oleic acid or an
oligolactic acid.
[0095] Prior to use in a dry powder or suspension formulation, the
drug product is micronised to a size suitable for delivery by
inhalation (typically less than 5 microns). This may be achieved by
any appropriate comminuting method, such as spiral jet milling,
fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenisation or spray drying.
[0096] Capsules (made, for example, from gelatin or
hydroxypropylmethylcellulose), blisters and cartridges for use in
an inhaler or insufflator may be formulated to contain a powder mix
of the compound of the invention, a suitable powder base such as
lactose or starch and a performance modifier such as l-leucine,
mannitol or magnesium stearate. The lactose may be anhydrous or in
the form of the monohydrate, preferably the latter. Other suitable
excipients include dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose and trehalose.
[0097] A suitable solution formulation for use in an atomiser using
electrohydrodynamics to produce a fine mist may contain from 1
.mu.g to 20 mg of the compound of the invention per actuation and
the actuation volume may vary from 1 .mu.l to 100 .mu.l. A typical
formulation may comprise a compound of formula I, propylene glycol,
sterile water, ethanol and sodium chloride. Alternative solvents
which may be used instead of propylene glycol include glycerol and
polyethylene glycol.
[0098] Suitable flavouring agents, such as menthol and levomenthol,
or sweeteners, such as saccharin or saccharin sodium, may be added
to those formulations of the invention intended for
inhaled/intranasal administration.
[0099] Formulations for inhaled/intranasal administration may be
formulated to be immediate and/or modified release using, for
example, PGLA. Modified release includes delayed, sustained,
pulsed, controlled, targeted and programmed release.
[0100] In the case of dry powder inhalers and aerosols, the dosage
unit may be determined by means of a valve which delivers a metered
amount. The overall daily dose may be administered in a single dose
or, more usually, as divided doses throughout the day.
[0101] The compound of the invention may be administered rectally
or vaginally, in the faun, for example, of a suppository, pessary
or enema. Cocoa butter is a traditional suppository base, but
various alternatives may be used as appropriate. The compound of
the invention may also be administered by the ocular or aural
route.
[0102] The compound of the invention may be combined with a soluble
macromolecular entity, such as a cyclodextrin or a suitable
derivative thereof or a polyethylene glycol-containing polymer, in
order to improve its solubility, dissolution rate, taste-masking,
bioavailability and/or stability for use in any of the
aforementioned modes of administration.
[0103] Drug-cyclodextrin complexes, for example, are found to be
generally useful for most dosage forms and administration routes.
Both inclusion and non-inclusion complexes may be used. As an
alternative to direct complexation with the drug, the cyclodextrin
may be used as an auxiliary additive, i.e. as a carrier, diluent,
or solubiliser. Most commonly used for these purposes are alpha-,
beta- and gamma-cyclodextrins, examples of which may be found in
WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
[0104] For administration to human patients, the total daily dose
of the compound of the invention will typically be in the range
0.002 mg/kg to 100 mg/kg depending, of course, on the mode of
administration. The total daily dose may be administered in single
or divided doses and may, at the physician's discretion, fall
outside of the typical range given herein.
[0105] For the avoidance of doubt, references herein to "treatment"
include references to curative, palliative and prophylactic
treatment.
[0106] Syk kinase inhibitors, such as the compound of the
invention, may advantageously be administered in combination with
one or more other therapeutic agents, particularly in the treatment
of respiratory diseases such as asthma. Examples of such further
therapeutic agents include: (i) 5-lipoxygenase (5-LO) inhibitors or
5-lipoxygenase activating protein (FLAP) antagonists; (ii)
leukotriene antagonists (LTRAs) including antagonists of LTB.sub.4,
LTC.sub.4, LTD.sub.4, and LTE.sub.4; (iii) histamine receptor
antagonists including H.sub.1, H.sub.3 and H.sub.4 antagonists;
(iv) .alpha..sub.1- and .alpha..sub.2-adrenoceptor agonist
vasoconstrictor sympathomimetic agents for nasal decongestant use;
(v) muscarinic M.sub.3 receptor antagonists or anticholinergic
agents; (vi) PDE inhibitors, e.g. PDE.sub.3, PDE.sub.4 and
PDE.sub.5 inhibitors; (vii) theophylline; (viii) sodium
cromoglycate; (ix) COX inhibitors both non-selective and selective
COX-1 or COX-2 inhibitors (NSAIDs); (x) oral and inhaled
glucocorticosteroids, such as DAGR (dissociated agonists of the
corticoid receptor); (xi) monoclonal antibodies active against
endogenous inflammatory entities; (xii) anti-tumor necrosis factor
(anti-TNF-.alpha.) agents; (xiii) adhesion molecule inhibitors
including VLA-4 antagonists; (xiv) kinin-B.sub.1- and
B.sub.2-receptor antagonists; (xv) immunosuppressive agents; (xvi)
inhibitors of matrix metalloproteases (MMPs); (xvii) tachykinin
NK.sub.1, NK.sub.2 and NK.sub.3 receptor antagonists; (xviii)
elastase inhibitors; (xix) adenosine A.sub.2a receptor agonists;
(xx) inhibitors of urokinase; (xxi) compounds that act on dopamine
receptors, e.g. D2 agonists; (xxii) modulators of the
NF.sub..kappa..beta. pathway, e.g. IKK inhibitors; (xxiii)
modulators of cytokine signaling pathways such as a p38 MAP kinase
or JAK kinase inhibitor; (xxiv) agents that can be classed as
mucolytics or anti-tussive; (xxv) antibiotics; (xxvi) HDAC
inhibitors; (xxvii) PI3 kinase inhibitors; (xxviii) .beta..sub.2
agonists; and (xxix) dual compounds active as .beta..sub.2 agonists
and muscarinic M.sub.3 receptor antagonists. Preferred examples of
such therapeutic agents include: (a) glucocorticosteroids, in
particular inhaled glucocorticosteroids with reduced systemic side
effects, flunisolide, triamcinolone acetonide, beclomethasone
dipropionate, budesonide, fluticasone propionate, ciclesonide, and
mometasone furoate; (b) muscarinic M.sub.3 receptor antagonists or
anticholinergic agents including ipratropium salts such as the
bromide, tiotropium salts such as the bromide, oxitropium salts
such as the bromide, perenzepine and telenzepine; and (c)
.beta..sub.2 agonists including salbutamol, terbutaline,
bambuterol, fenoterol, salmeterol, formoterol, tulobuterol. Any of
the agents specifically mentioned may optionally be used in the
form of a pharmaceutically acceptable salt.
[0107] Where it is desirable to administer a combination of active
compounds, two or more pharmaceutical compositions, at least one of
which contains the compound of the invention, may conveniently be
combined in the form of a kit suitable for co-administration.
[0108] Such a kit comprises two or more separate pharmaceutical
compositions, at least one of which contains the compound of the
invention, and means for separately retaining said compositions,
such as a container, divided bottle, or divided foil packet. An
example of such a kit is the familiar blister pack used for the
packaging of tablets, capsules and the like.
[0109] Such a kit is particularly suitable for administering
different dosage foams, for example, oral and parenteral dosage
forms, for administering the separate compositions at different
dosage intervals, or for titrating the separate compositions
against one another. To assist compliance, the kit typically
comprises directions for administration and may be provided with a
so-called memory aid.
PREPARATIVE EXAMPLE
[0110] The following example illustrates the preparation of the
xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-
-(methylaminocarbonyl
methyleneoxy)phenyl]-2,4-pyrimidinediamine.
##STR00007##
[0111] A suspension of
2-{3-[4-(2,2-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)5-f-
luoro-pyrimidin-2-ylamino]phenoxy}N-methyl-acetamide (1.18 kg, 2.49
mmol, 1 equiv) in methyl ethyl ketone (MEK) (23.6 L, 20 ml/g) was
heated to 55.degree. C., whereupon water (1.18 L, 1 ml/g) was
added, resulting in a solution. The solution was passed through a
filter for clarification then held at 55.degree. C. for 1 hour. The
subsequent addition of a pre-formed spec-free solution of
1-hydroxy-2-naphoic acid (515 g, 2.74 mol, 1.1 equiv) in MEK (4.72
L, 4 ml/g) resulted in precipitation of a white solid after
.about.10 mins. The reaction was cooled to ambient temp, stirred
overnight (18 hours) and then cooled to 5.degree. C. for 2 hours
before filtration. The filtered solid was washed with MEK
(2.times.2.36 L, 2.times.2 ml/g) and dried under reduced pressure
at 50.degree. C. for 16 hours. The product,
2-{3-[4-(2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)5-f-
luoro-pyrimidin-2-ylamino]phenoxy}N-methyl-acetamide
1-hydroxy-2-naphoic acid salt, was isolated as a white solid (1.32
kg, 80%).
[0112] When analysed by conventional proton NMR (300 MHz,
d.sub.6-DMSO), the xinafoate salt gives the following spectrum:
.delta. 2.65 (d, J=4.5 Hz, 3H), 4.34, (s, 2H), 6.46-6.52 (m, 1H),
7.10 (t, J=8.0 Hz, 1H), 7.23-7.28 (m, 2H), 7.36-7.41 (m, 2H),
7.45-7.48 (m, 1H), 7.55-7.62 (m, 2H), 7.64-7.71 (m, 1H), 7.73-7.77
(m, 1H), 7.86-7.95 (m, 2H), 8.14 (d, J=4.0 Hz, 1H), 8.26-8.32 (m,
1H), 9.14 (s, 1H), 9.56 (s, 1H), 11.90-11.96 (m, 1H).
[0113] When analysed by differential scanning calorimetry (DSC)
(8.588 mg of the sample was heated from 25 to 250.degree. C. at
20.degree. C. per minute using a Perkin Elmer Diamond DSC with
autosampler and a 4 hole side wall vented aluminum pan and lid with
nitrogen flow gas), the xinafoate salt shows a sharp endothermic
melting peak at 233.degree. C..+-.2.degree. C. The DSC trace is
shown in FIG. 1.
[0114] When characterised by powder X-ray diffraction (PXRD), the
xinafoate salt gives the pattern shown in FIG. 2. The
characteristic peaks are given in Table 1 below. The main
characteristic peaks are at 8.0, 8.9, 11.6, 24.5 and 27.7 degrees
two theta (.+-.0.1 degree).
TABLE-US-00001 TABLE 1 Characteristic PXRD peaks Angle 2-Theta
Relative intensity Angle 2-Theta Relative intensity (degrees) (%)
(degrees) (%) 8.0 68.7 22.4 16.5 8.9 36.5 23.0 24.1 11.6 42.6 23.2
19.9 13.2 42.5 23.5 22.8 13.5 23.8 23.6 20.9 14.0 18.7 24.1 38.1
15.3 15.0 24.5 100.0 15.6 17.4 24.7 20.6 16.1 44.5 26.6 41.1 16.4
20.1 27.5 12.3 17.3 14.5 27.7 73.7 17.5 21.4 28.1 14.1 17.8 30.3
29.3 16.6 19.0 28.9 29.5 11.4 19.8 54.0 31.2 11.8 20.0 28.8 32.4
14.4 20.4 13.0 33.4 22.5 22.1 15.0
[0115] The powder X-ray diffraction pattern was determined using a
Bruker-AXS Ltd D4 powder X-ray diffractometer fitted with an
automatic sample changer, a theta-theta goniometer, automatic beam
divergence slit, and a PSD Vantec-1 detector. The sample was
prepared for analysis by mounting on a low background silicon wafer
specimen mount. The specimen was rotated whilst being irradiated
with copper K-alpha 1 X-rays (wavelength=1.5406 .ANG.ngstroms) with
the X-ray tube operated at 40 kV/30 mA. The analyses were performed
with the goniometer running in continuous mode set for a 0.2 second
count per 0.018.degree. step over a two theta range of 2.degree. to
55.degree.. Peaks were selected manually using Bruker-AXS Ltd
evaluation software. The data were collected at 21.degree. C.
[0116] As will be appreciated by the skilled person, the relative
intensities of the various peaks within Table 1 given below may
vary due to a number of factors such as for example orientation
effects of crystals in the X-ray beam or the purity of the material
being analysed or the degree of crystallinity of the sample. The
peak positions may also shift for variations in sample height but
the peak positions will remain substantially as defined in given
Table 1. The skilled person will also appreciate that measurements
using a different wavelength will result in different shifts
according to the Bragg equation-n.lamda.=2d sin .theta.. Such
alternative PXRD patterns generated by use of alternative
wavelengths are nevertheless representations of the same
material.
[0117] The main PXRD peaks which have been simulated from a single
crystal X-ray analysis are listed in Table 2 below and the
corresponding simulated pattern is shown in FIG. 3.
TABLE-US-00002 TABLE 2 Characteristic simulated PXRD peaks Angle
2-Theta Relative intensity Angle 2-Theta Relative intensity
(degrees) (%) (degrees) (%) 8.0 72.5 18.9 11.7 8.9 41.3 19.0 13.2
9.4 10.5 19.9 15.8 11.4 11.5 20.1 25.1 11.6 43.0 23.0 15.2 13.5
16.6 23.2 11.5 14.0 19.2 23.5 10.2 15.3 13.3 23.6 12.1 15.7 10.2
24.1 28.5 16.0 14.3 24.4 14.1 16.1 17.6 24.5 100.0 16.4 17.1 24.7
11.9 17.5 19.4 27.7 58.5 17.9 20.3
[0118] When characterised by Fourier Transform Infra-red (FT-IR)
spectroscopy, the xinafoate salt gives the pattern shown in FIG. 4.
The fingerprint region is shown in expanded form in FIG. 5. The
characteristic peaks are given in Table 3 below (w=weak, s=strong,
m=medium). The main characteristic peaks are 1228 (m), 1152 (m),
1078 (s) and 858 (s).
TABLE-US-00003 TABLE 3 Characteristic FT-IR peaks Wavenumber
Wavenumber Wavenumber Wavenumber (cm.sup.-1) (cm.sup.-1)
(cm.sup.-1) (cm.sup.-1) 3230* (w) 1501 (w) 1174 (m) 810 (w) 3069
(w) 1455 (m) 1161 (m) 796 (m) 3015 (w) 1431 (s) 1152 (m) 764 (s)
1717 (s) 1407 (s) 1107 (w) 747 (s) 1669 (m) 1364 (w) 1078 (s) 734
(w) 1659 (m) 1331 (w) 1020 (w) 721 (w) 1625 (m) 1316 (w) 928 (w)
683 (m) 1608 (m) 1283 (w) 888 (m) 653 (m) 1587 (m) 1272 (w) 877 (w)
1569 (m) 1228 (m) 858 (s) 1523 (m) 1212 (m) 823 (m)
[0119] The FT-IR spectrum was acquired using a ThermoNicolet Nexus
FTIR spectrometer equipped with a `DurasamplIR` single reflection
ATR accessory (diamond surface on zinc selenide substrate) and
d-TGS KBr detector. The spectrum was collected at 2 cm.sup.-1
resolution and a co-addition of 256 scans for all compounds.
Happ-Genzel apodization was used. Because the FT-IR spectrum was
recorded using single reflection ATR, no sample preparation was
required. Using ATR FT-IR will cause the relative intensities of
infrared bands to differ from those seen in a transmission FT-IR
spectrum using KBr disc or nujol mull sample preparations. Due to
the nature of ATR FT-IR, the bands at lower wavenumber are more
intense than those at higher wavenumber. Experimental error, unless
otherwise noted, was .+-.2 cm.sup.-1. Peaks were picked using
ThermoNicolet Omnic 6.0a software.
[0120] When characterised by Fourier Transform Raman spectroscopy,
the xinafoate salt gives the pattern shown in FIG. 6. The
fingerprint region is shown in greater detail in FIG. 7. The
characteristic peaks are given in Table 4 below (w=weak, s=strong,
m=medium). The main characteristic peaks are 1626 (m), 1205 (m),
998 (s), 156 (s) and 91 (s).
TABLE-US-00004 TABLE 4 Characteristic FT-Raman peaks Wavenumber
Wavenumber Wavenumber Wavenumber (cm.sup.-1) (cm.sup.-1)
(cm.sup.-1) (cm.sup.-1) 3092 (w) 1473 (w) 1253 (m) 332 (w) 3071 (w)
1465 (w) 1205 (m) 302 (w) 1679 (w) 1434 (m) 1162 (w) 286 (w) 1659
(m) 1414 (w) 1026 (w) 253 (w) 1626 (m) 1379 (m) 998 (s) 221 (m)
1161 (w) 1365 (m) 879 (w) 192 (w) 1596 (w) 1353 (m) 726 (m) 156 (s)
1584 (w) 1333 (s) 542 (w) 130 (m) 1574 (w) 1296 (m) 495 (w) 110 (s)
1525 (m) 1276 (w) 434 (w) 91 (s) 1502 (m) 1260 (m) 352 (w) 62
(s)
[0121] The Raman spectrum was collected using a Bruker Vertex70
with RamII module FT-Raman spectrometer equipped with a 1064 nm
NdYAG laser and LN-Germanium detector. The spectrum was recorded
using 2 cm-1 resolution and Blackman-Harris 4-term apodization.
Laser power was 300 mW and 2048 co-added scans were collected. Each
sample was placed in a glass vial and exposed to the laser
radiation. The data is presented as intensity as a function of
Raman shift and is corrected for instrument response and frequency
dependent scattering using a white light spectrum from a reference
lamp. The Bruker Raman Correct function was used to do the
correction. (Bruker software--OPUS 6.0). Experimental error, unless
otherwise noted, was .+-.2 cm-1. Peaks were picked using
ThermoNicolet Omnic 6.0a software.
[0122] When characterised by proton decoupled .sup.13C solid state
NMR, the xinafoate salt gives the spectrum shown in FIG. 8. The
characteristic shifts are given in Table 5 below. The main
characteristic shifts are 176.8, 159.4, 137.1, 118.2, 104.9 and
25.4 ppm. Intensities can vary depending on the actual setup of the
experimental parameters and the thermal history of the sample and
are not therefore necessarily quantitative.
TABLE-US-00005 TABLE 5 Characteristic .sup.13C solid state NMR
shifts Chemical shift Chemical shift (ppm) Intensity (ppm)
Intensity 176.8 6.48 128.4 4.88 171.8 6.04 126.9 9.39 159.4 10.46
125.8 11.22 157.5 4.33 123.0 6.03 150.0 4.66 121.6 9.38 148.3 4.83
118.2 7.96 140.9 6.12 110.9 12 139.2 2.37 109.0 4.37 137.1 9.88
104.9 3.99 134.4 6.97 69.3 4.01 133.1 6.41 25.4 6.37
[0123] Approximately 80 mg of sample were tightly packed into a 4
mm ZrO.sub.2 spinner. The spectrum was collected at ambient
conditions on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned
into a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR
spectrometer. The sample was positioned at the magic angle and spun
at 15.0 kHz. The fast spinning speed minimized the intensities of
the spinning side bands. The number of scans was adjusted to obtain
adequate S/N. The .sup.13C solid state spectrum was collected using
a proton decoupled cross-polarization magic angle spinning
experiment (CPMAS). A proton decoupling field of approximately 85
kHz was applied. 656 scans were collected with the recycle delay
adjusted to 80 seconds. The spectrum was referenced using an
external standard of crystalline adamantane, setting its upfield
resonance to 29.5 ppm.
[0124] When characterised by fluorine solid state NMR, the
xinafoate salt gives the spectrum shown in FIG. 9. The
characteristic shifts are -69.2, -72.4 and -164.0 ppm. Intensities
can vary depending on the actual setup of the experimental
parameters and the thermal history of the sample and are not
therefore necessarily quantitative.
[0125] The same apparatus was used to acquire the fluorine NMR
spectrum as that used to acquire the .sup.13C spectrum. The
.sup.19F solid state spectrum was collected using a proton
decoupled magic angle spinning (MAS) experiment. The proton
decoupling field of approximately 85 kHz was applied and 8 scans
were collected. The recycle delay was set to 750 s to ensure
acquisition of quantitative spectra. Proton longitudinal relaxation
times (.sup.1H T.sub.1) were calculated based on a fluorine
detected proton inversion recovery relaxation experiment. Fluorine
longitudinal relaxation times (.sup.19F T.sub.1) were calculated
based on a fluorine detected fluorine inversion recovery relaxation
experiment. The spectrum was referenced using an external sample of
trifluoroacetic acid (50% by volume in H.sub.2O), setting its
resonance to -76.54 ppm.
Stability Data
[0126] In contrast to the free base, the xinafoate salt of
N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methyl-
aminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine is
essentially non-hygroscopic. Hygroscopicity was assessed using
dynamic vapour sorption equipment (Surface Measurement Systems Ltd,
model DVS-1). The analysis was conducted at 30.degree. C. with a
nitrogen gas flow of 200 cc/min. Water sorption and desorption were
determined in the range 0 to 90% relative humidity (RH) using 15%
RH intervals. Exposure was for a minimum of 2 hours at each
humidity or until the rate of weight change was less than
0.0003%/minute (averaged over 10 minutes). Sample weight was 12.6
mg. The sample was weighed using a CAHN D-200, seven place digital
recording balance, which is an integral part of the equipment. The
compound showed only 0.6% water sorption at 90% RH. Furthermore,
following micronisation using jet milling, there was no change in
solid form, a negligible decrease in the degree of crystallinity
and no significant change in hygroscopicity (0.9% water sorption at
90% relative humidity).
[0127] Furthermore, the xinafoate salt does not show any hydration
or salvation. Solvation/Hydration was assessed by thermogravimetric
analysis (TGA) using a TA Instruments Hi-Res TGA 2950 instrument
measuring the weight loss of a 8.8 mg sample in an open platinum
pan. The sample was heated at 20.degree. C./min from ambient to
300.degree. C. utilizing a nitrogen furnace purge gas. Whereas a
single form of the xinafoate salt has hitherto been identified, the
free base hydrates to form a hemihydrate and formed a different
solvated form in each of nine solvents tested.
[0128] In order to test for solid state stability and excipient
compatibility, a sample of the xinafoate salt was micronised by jet
milling (particle size: D10=0.24 .mu.m, D50=1.15 .mu.m, D90=4.29
.mu.m) and the resulting powder was blended at a 1:100 weight ratio
with lactose monohydrate (Respitose grade SV008). Samples were
stored for 12 weeks at 25.degree. C./60% relative humidity and
40.degree. C./75% relative humidity and assayed for remaining drug
content and impurities at 4, 8 and 12 weeks. The results are shown
in Table 6. A control sample was stored at 5.degree. C./0%
humidity.
TABLE-US-00006 TABLE 6 Stability data % main band remaining versus
control Sample 4 weeks 8 weeks 12 weeks 25.degree. C./60% RH 100.2
99.9 100.1 40.degree. C./75% RH 100.4 100.0 100.0
[0129] The results show that lactose blends of the xinafoate salt
have good stability. During the experiment, no change in physical
form was detected and no significant degradation was observed.
* * * * *