NZ621440B2 - 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy) napththalen-1-yl) ureas as p38 map kinase inhibitors - Google Patents
1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy) napththalen-1-yl) ureas as p38 map kinase inhibitors Download PDFInfo
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- NZ621440B2 NZ621440B2 NZ621440A NZ62144012A NZ621440B2 NZ 621440 B2 NZ621440 B2 NZ 621440B2 NZ 621440 A NZ621440 A NZ 621440A NZ 62144012 A NZ62144012 A NZ 62144012A NZ 621440 B2 NZ621440 B2 NZ 621440B2
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Abstract
Disclosed is a compound of formula (I) which is an inhibitor of the family of p38 mitogen-activated protein kinase enzymes, and to its use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, such as asthma and COPD. The compound of formula (I) is: 1-(3-tert-butyl-1-p-tolyl-1 H-pyrazol-5-yl)-3-(4-(2-(phenylamino)pyrimidin-4-yloxy)naphthalen-1-yl)urea asthma and COPD. The compound of formula (I) is: 1-(3-tert-butyl-1-p-tolyl-1 H-pyrazol-5-yl)-3-(4-(2-(phenylamino)pyrimidin-4-yloxy)naphthalen-1-yl)urea
Description
-PYRAZOLYL 4- 2-ANILINOPYRIMIDINYL OXY NAPTHTHALENYL UREAS
AS 938 MAP KINASE TORS
Field of the invention
The invention relates to compounds which are inhibitors of the family of p38 mitogen-
activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for
example the alpha and gamma kinase sub-types thereof, and of Syk kinase and the Src
family of ne kinases, and to their use in y, ing in pharmaceutical
1O combinations, especially in the treatment of inflammatory diseases, in particular inflammatory
diseases of the lung, such as asthma and COPD, as well as those of the gastrointestinal
tract, such as ulcerative colitis and Crohn’s disease and of the eye, such as uveitis.
Background of the invention
Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively), have been identified
each displaying different patterns of tissue expression in man. The p38 MAPK alpha and
beta isoforms are found ubiquitously in the body, being present in many different cell types.
The alpha isoform is well terized in terms of its role in inflammation. Although studies
using a chemical genetic approach in mice indicate that the p38 MAPK beta isoform does not
play a role in inflammation (O’Keefe, S.J. et al., J. Biol. Chem, 2007, 282(48):34663-71.), it
may be ed in pain mechanisms through the regulation of COX2 expression
(Fitzsimmons, BL. 92‘ al., Neuroreport, 2010, 21(4):313-7). These isoforms are inhibited by a
number of previously described small molecular weight compounds. Early classes of
inhibitors were highly toxic due to the broad tissue distribution of these isoforms which
resulted in multiple off-target effects of the compounds. Furthermore, development of a
substantial number of inhibitors has been discontinued due to unacceptable safety profiles in
clinical studies (Pettus, L.H. and Wurz, R.P., Curr. Top. Med. Chem, 2008, 8(16):1452—67.).
As these adverse effects vary with chemotype, and the compounds have distinct kinase
selectivity ns, the observed toxicities may be structure-related rather than p38
mechanism-based.
Less is known about the p38 MAPK gamma and delta isoforms, which, unlike the alpha and
beta isozymes are sed in specific tissues and cells. The p38 MAPK-delta isoform is
expressed more highly in the pancreas, testes, lung, small intestine and the kidney. It is also
abundant in macrophages and able in neutrophils, CD4+ T cells and in elial
cells (Shmueli, O. et al., s Rendus Biologies, 2003, 326(10-11):1067-1072; Smith, S.
J. Br. J. Pharmacol., 2006, 3-404; Hale, K. K., J. lmmuno/., 1999, 162(7):4246—52;
Wang, X. S. et al., J. Biol. Chem, 1997, 272(38):23668-23674.) Very little is known about the
4o distribution of p38 MAPK gamma although it is expressed more highly in brain, al
muscle and heart, as well as in lymphocytes and macrophages (Shmueli, O. et al., Comptes
Rendus Biologies, 2003, 326(10-11):1067-1072; Hale, K. K., J. Immunol., 1999, :4246-
52; Court, N. W. et al., J. Mol. Cell. Cardiol., 2002, 34(4):413-26; Mertens, S. et al., FEBS
Lett., 1996, 383(3):273—6.).
Selective small molecule inhibitors of p38 MAPK gamma and p38 MAPK delta are not
currently available, although one previously disclosed compound, BIRB 796, is known to
possess pan-isoform inhibitory activity. The inhibition of p38 MAPK gamma and delta
isoforms is observed at higher concentrations of the compound than those required to inhibit
p38 MAPK alpha and p38 beta (Kuma, Y., J. Biol. Chem., 2005, 280:19472-19479.). in
addition BIRB 796 also impaired the phosphorylation of p38 MAPKs or JNKs by the
upstream kinase MKK6 or MKK4. Kuma discussed the ility that the conformational
change caused by the binding of the inhibitor to the MAPK protein may affect the structure of
both its orylation site and the docking site for the upstream activator, thereby impairing
the phosphorylation of p38 MAPKs or JNKs.
p38 MAP kinase is believed to play a pivotal role in many of the signalling pathways that are
involved in initiating and maintaining chronic, persistent inflammation in human disease, for
example, in severe asthma and in COPD (Chung, F., Chest, 2011, 139(6):1470—i479.).
There is now an nt literature which trates that p38 MAP kinase is activated by
a range of pro-inflammatory cytokines and that its activation results in the recruitment and
release of additional pro—inflammatory cytokines. indeed, data from some clinical studies
demonstrate beneficial changes in e activity in patients during treatment with p38 MAP
kinase inhibitors. For instance Smith bes the inhibitory effect of p38 MAP kinase
inhibitors on TNFo (but not iL-8) release from human PBMCs.
The use of inhibitors of p38 MAP kinase in the treatment of chronic obstructive pulmonary
disease (COPD) has also been proposed. Small molecule inhibitors targeted to p38 MAPK
o/B have proved to be effective in reducing various parameters of inflammation in cells and in
tissues obtained from ts with COPD, who are generally corticosteroid insensitive,
(Smith, S.J., Br. J. Pharmacol., 2006, 149:393—404.) as well as in various in vivo animal
models (Underwood, D.C. ez‘ al., Am. J. Physiol., 2000, 279:L895-902; Nath, P. et al., Eur. J.
Pharmacoi., 2006, 544:160—167.). Irusen and gues have also suggested the possible
involvement of p38 MAPK (1/6 with corticosteroid insensitivity via the reduction of binding
affinity of the giucocorticoid receptor (GR) in nuclei (irusen, E. et al., J. Allergy Clin.
lmmunol., 2002, 9657.). Clinical experience with a range of p38 MAP kinase
inhibitors, ing , BIRB 796, VX702, SClO469 and SCIO323 has been
described (Lee, MR. and uez, C., CurrentMed. Chem, 2005, 12:2979-2994.).
COPD is a condition in which the underlying mation is reported to be ntially
resistant to the anti-inflammatory effects of inhaled osteroids. Consequently, a superior
strategy for treating COPD would be to develop an intervention which has both inherent anti-
inflammatory effects and the ability to increase the sensitivity of the lung tissues of COPD
patients to inhaled corticosteroids. A recent publication of Mercado (Mercado, N., et a/., Mol.
40 Pharmacol., 2011, 80(6):1128-1135.) demonstrates that silencing p38 MAPK v has the
potential to e sensitivity to osteroids. Consequently there may be a dual benefit
for patients in the use of a p38 MAP kinase tor for the treatment of COPD and severe
asthma. However, the major obstacle hindering the utility of p38 MAP kinase inhibitors in the
treatment of human chronic inflammatory diseases has been the severe toxicity observed in
patients resulting in the withdrawal from clinical development of many compounds including
all those specifically mentioned above.
Many patients diagnosed with asthma or with COPD continue to suffer from rolled
symptoms and from exacerbations of their medical condition that can result in hospitalisation.
This occurs despite the use of the most advanced, currently available treatment regimens,
comprising of combination products of an inhaled corticosteroid and a long acting B-agonist.
Data accumulated over the test decade indicates that a failure to manage effectively the
underlying inflammatory component of the disease in the lung is the most likely reason that
1O exacerbations occur. Given the established efficacy of corticosteroids as nflammatory
agents and, in particular, of d corticosteroids in the treatment of asthma, these gs
have provoked e investigation. Resulting studies have identified that some
environmental insults invoke corticosteroid—insensitive inflammatory changes in patients'
lungs. An example is the se arising from virally-mediated upper respiratory tract
infections , which have ular significance in increasing morbidity associated with
asthma and COPD.
Epidemiological investigations have revealed a strong association between viral ions of
the upper respiratory tract and a substantial percentage of the exacerbations suffered by
patients already diagnosed with chronic respiratory diseases. Some of the most compelling
data in this regard derives from longitudinal studies of en suffering from asthma
(Papadopoulos, N.G., Papi, A., s, S. and Johnston, S.L., Paediatr. Respir. Rev,. 2004,
(3):255-260.). A variety of onal studies support the conclusion that a viral infection can
precipitate exacerbations and increase disease severity. For example, experimental clinical
infections with rhinovirus have been reported to cause ial hyper—responsiveness to
histamine in asthmatics that is unresponsive to treatment with corticosteroids (Grunberg, K.,
Sharon, R.F., et al., Am. J. Respir. Crit. Care Med, 2001, 164(10):1816—1822.). Further
evidence derives from the association observed between disease exacerbations in patients
with cystic fibrosis and HRV infections (Wat, D., Gelder, C., et al., J. Cyst. Fibros,. 2008,
72320-328.) Also consistent with this body of data is the finding that respiratory viral
infections, including irus, represent an independent risk factor that correlates
negatively with the 12 month al rate in paediatric, lung transplant recipients (Liu, M.,
Worley, 8., etal., Transpl. . 01's,. 2009, 11(4):304-312.).
Clinical research indicates that the viral load is proportionate to the observed symptoms and
complications and, by implication, to the severity of inflammation. For example, following
mental rhinovirus infection, lower respiratory tract symptoms and ial hyper-
responsiveness correlated significantly with virus load (Message, S.D., Laza-Stanca, V., et
al., PNAS, 2008; 105(36):13562-13567.). rly, in the absence of other viral agents,
40 rhinovirus infections were commonly associated with lower atory tract ions and
wheezing, when the viral load was high in immunocompetent paediatric patients (Gerna, G.,
Piralla, A., etal., J. Med. Virol,. 2009, 81(8):1498—1507.).
interestingly, it has been reported recently that prior exposure to rhinovirus reduced the
45 cytokine responses evoked by bacterial products in human alveolar macrophages (Oliver,
B.G., Lim, 8., et al., Thorax, 2008, 63:519-525.). Additionally, infection of nasal epithelial
cells with rhinovirus has been documented to promote the adhesion of bacteria, including 8.
aureus and H. influenzae (Wang, J.H., Kwon, H.J. and Yong, J.J., The Laryngoscope, 2009,
119(7):1406-1411.). Such cellular effects may contribute to the increased probability of
ts suffering a lower respiratory tract infection following an infection in the upper
respiratory tract. ingly, it is therapeutically relevant to focus on the ability of novel
interventions to decrease viral load in a variety of in vitro s, as a surrogate predictor of
their benefit in a clinical setting.
High risk groups, for whom a rhinovirus infection in the upper respiratory tract can lead to
severe secondary complications, are not limited to patients with chronic respiratory disease.
They include, for example, the immune compromised who are prone to lower respiratory tract
infection, as well as patients undergoing chemotherapy, who face acute, hreatening
fever. it has also been suggested that other chronic diseases, such as diabetes, are
associated with a compromised immuno-defence response. This increases both the
likelihood of acquiring a respiratory tract infection and of being alised as a result
’15 (Peleg, A.Y., Weerarathna, T., et al., Diabetes Metab. Res. Rev., 2007, 23(1):3-13; Kornum,
J.B., , W., eta/., Diabetes Care, 2008, 31(8):1541-1545.).
Whilst upper respiratory tract viral infections are a cause of erable morbidity and
mortality in those patients with underlying disease or other risk factors; they also represent a
significant healthcare burden in the general population and are a major cause of missed days
at school and lost time in the ace (Rollinger, J.M. and Schmidtke, M., Med. Res. Rev.,
2010, Doi 10.1002/med.20176.). These considerations make it clear that novel medicines,
that possess improved efficacy over current therapies, are urgently required to prevent and
treat rhinovirus—mediated upper atory tract infections. In general the strategies adopted
for the discovery of improved antiviral agents have targeted various proteins produced by the
virus, as the point of therapeutic intervention. However, the wide range of rhinovirus
pes makes this a particularly challenging approach to pursue and may explain why, at
the t time, a medicine for the prophylaxis and treatment of rhinovirus ions has yet
to be approved by any regulatory agency.
Viral entry into the host cell is associated with the activation of a number of intracellular
signalling pathways which are believed to play a prominent role in the initiation of
inflammatory processes (reviewed by , S, 2007; Signal Transduction, 7:81—88.) and of
viral propagation and subsequent release. One such mechanism, which has been
ined to play a role in influenza virus propagation in vitro, is activation of the
phosphoinositide 3—kinase /Akt pathway. it has been reported that this signalling pathway is
activated by the N81 protein of the virus (Shin, Y.K., Liu, Q. at al., J. Gen. Virol., 2007,
88:13-18.) and that its inhibition reduces the titres of progeny virus (Ehrhardt, C., Marjuki, H.
et a/., Cell Microbiol., 2006, 8:1336—1348.).
rmore, the MEK inhibitor U0126 has been documented to inhibit viral ation
without eliciting the emergence of ant variants of the virus (Ludwig, S., Wolff, T. at al.,
FEBS Lett, 2004, 561(1-3):37—43.). More recently, studies targeting inhibition of Syk kinase
have trated that the enzyme plays an ant role in mediating rhinovirus entry into
cells and also virus—induced inflammatory responses, including [CAM-1 up—regulation
(Sanderson, M.P., Lau, C.W. et al., Inflamm. Allergy Drug Targets, 2009, 8287-95.). Syk
activity is reported to be controlled by c-Src as an upstream kinase in HRV infection (Lau, C.
et al., J. l., 2008, 180(2):870-880.). A small number of studies have appeared that
link the activation of cellular Src (Src1 or p60-Src) or Src family kinases to ion with
s. These e a report that irus elicits a PI3 kinase mediated activation of Akt
through a c-Src dependent ism. it has also been suggested that Rhinovirus—39
induced lL—8 production in epithelial cells depends upon Src kinase tion (Bentley, J.K.,
Newcomb, D.C., J. Virof., 2007, 81:1186—1194.). Finally, it has been proposed that activation
of Src kinase is involved in the induction of mucin production by rhinovirus-14 in epithelial
cells and sub—mucosa! glands (lnoue, D. and Yamaya, M., Resp/r. l. Neurobiol., 2006,
154(3):484—499.).
It has been disclosed previously that compounds that inhbit the activity of both c—Src and Syk
kinases are effective agents against rhinovirus replication (Charron, C.E. at at, WO
2011/158042.) and that compounds that inhibit p59—HCK are effective against influenza virus
ation (Charron, C.E. et al., .). For the reasons ised above,
compounds designed to treat chronic respiratory diseases that combine these nt
ties with the inhibition of p38 MAPKs, are ed to be particularly efficacious.
Certain p38 MAPK inhibitors have also been described as inhibitors of the replication of
respiratory syncitial virus (Cass, L. et al., W0 20111158039.)
Furthermore, it is noteworthy that a p38 MAPK inhibitor was found to deliver benefit for
patients with IBD after one week’s treatment which was not sustained over a four week
course of treatment (Schreiber, S. etal., Clin. Gastro. Hepatology, 2006, 42325—334).
In addition to playing key roles in cell signalling events which control the activity of pro—
inflammatory pathways, kinase enzymes are now also recognised to regulate the activity of a
range of cellular ons. Among those which have been discussed recently are the
maintenance of DNA integrity (Shilo, Y. Nature Reviews Cancer, 2003, 3:155—168.) and co—
ordination of the complex processes of cell division. An illustration of recent findings is a
publication describing the impact of a set of inhibitors acting upon the so-called “Olaharsky
kinases” on the frequency of micronucleus formation in vitro (Olaharsky, A.J. et al., PLoS
Comput. Bio/., 2009, 5(7):e1000446.). Micronucleus formation is implicated in, or associated
with, disruption of mitotic processes and is therefore an undesirable station of
potential toxicity. Inhibition of glycogen synthase kinase 3d (GSK3or) was found to be a
particularly significant factor that ses the likelihood of a kinase inhibitor promoting
ucleus formation. Recently, inhibition of the kinase GSKBB with RNAi was also
40 reported to promote micronucleus formation (Tighe, A. et al., BMC Cell Biology, 2007, 8:34.).
It may be possible to attenuate the adverse effects arising from drug interactions with
Olaharsky kinases, such as GSKSd, by optimisation of the dose and/or by ng the route
of administration. However, it would be more advantageous to identify therapeutically useful
molecules that demonstrate low or undectable activity t these off-target enzymes and
consequently elicit little or no disruption of c processes, as measured in mitosis assays.
It is evident from consideration of the literature cited hereinabove that there remains a need
to identify and develop new p38 MAP kinase inhibitors that have improved eutic
potential over currently available ents. Desirable compounds are those that exhibit a
superior therapeutic index by exerting, at the least, an equally efficacious effect as us
agents but, in one or more respects, are less toxic at the relevant therapeutic dose. An
objective of the present invention therefore, is to provide such novel compounds that inhibit
the enzyme activity of p38 MAP kinase, for example with certain sub—type icities,
together with Syk kinase and ne kinases within the Src family (particularly c-Src)
thereby possessing good anti-inflammatory properties, and suitable for use in therapy, or to
at least provide a useful ative.
The Compound (I) exhibits a longer duration of action and/or persistence of action in
comparison to the previously disclosed allosteric p38 MAP kinase inhibitor BIRB 796
(Pargellis, C. et al., Nature Struct. Bio/., 2002, 68—272.). An additional embodiment
provides such novel compound in one or more solid, lline forms that s high
chemical and physical ity suitable for formulation as inhaled medicaments.
Summary of the invention
Thus in one aspect of the invention there is provided a compound of formula (l):
\ /
\N %WN/N
Compound (I)
or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers and
tautomers thereof.
“Compound of formula (l)" may also be referred to herein as “Compound (l)”.
in another aspect of the invention there is provided Compound (l) as defined above as the
free base.
In another aspect of the invention there is provided Compound (I) as defined above as the
anhydrous free base.
In another aspect of the invention there is provided Compound (I) as defined above as the
anhydrous free base in solid crystalline form.
In a further aspect of the ion there is provided Compound (I) as defined above as the
anhydrous free base in solid crystalline polymorphic form A.
In a further aspect of the invention there is provided Compound (I) as defined above as the
anhydrous free base in solid crystalline polymorphic form B.
Brief description of figures
Figure 1 shows an X-ray powder diffraction (XRPD) pattern obtained from a sample of
nd (I) as the anhydrous free base in solid crystalline polymorphic form A.
Figure 2 displays an XRPD pattern acquired from a sample of Compound (I) as the
anhydrous free base in solid crystalline polymorphic form B, post micronization.
Figure 3 reveals the results of thermogravimetric analysis of a sample of Compound (I) as
the anhydrous free base in solid crystalline polymorphic form B, post micronization.
Figure 4 represents dynamic vapour sorption (DVS) isotherm plots d from samples of
Compound (I) as the ous free base in solid lline rphic form B post
micronization.
Figure 5 represents the results of a hysterisis experiment conducted on Compound (I) as the
anhydrous free base in solid, crystalline, polymorphic form B, post micronization, to
determine the degree and rate of moisture tion/desorption with time against changes
in relative humidity.
Figure 6 is the infrared (IR) spectrum obtained from a sample of Compound (I) as the
ous free base in solid crystalline polymorphic form B post micronization.
Figure 7 shows l analysis of a sample of Compound (I) as the anhydrous free base in
solid crystalline polymorphic form B (micronized) by differential scanning calorimetry (DSC).
Detailed description of the invention
The compound of formula (I) disclosed herein is: 1-(3-tert-butyI—1-p—tolyl-1H—pyrazoIyI)-3—
(4-(2-(phenylamino)pyrimidin—4-yloxy)naphthalen-t—yl)urea. es of salts of Compound
(I) include all pharmaceutically acceptable salts, such as, without limitation, acid addition
saIts of strong mineral acids such as HCI and HBr salts and addition salts of strong organic
acids such as methanesulfonic acid.
As employed herein below the definition of a compound of formula (I) is intended to e
salts, solvates, and all tautomers of said compound, unless the context specifically indicates
otherwise. es of solvates include hydrates.
The invention provided herein extends to prodrugs of the compound of formula (I), that is to
say compounds which break down and/or are metabolised in vivo to provide an active
compound of formula (I). General examples of prodrugs include simple esters, and other
esters such as mixed carbonate esters, carbamates, glycosides, ethers, acetals and ketals.
The ion embraces all isotopic derivatives of Compound (I). Thus the invention
embraces compounds which are compounds of Compound (I) having one or more atoms
that have been replaced by an atom having an atomic mass or mass number different from
the atomic mass or mass number most commonly found in nature, or in which the tion
‘IO of an atom having an atomic mass or mass number found less commonly in nature has been
increased (the latter concept being referred to as pic enrichment”). Thus the
compounds of the disclosure include those where the atom ied is a naturally occurring
or non-naturally occurring isotope. In one embodiment the isotope is a stable isotope. Thus
the nds of the sure include, for example deuterium containing compounds and
the like. Thus, in one embodiment of the invention Compound (I) contains an enriched level
of deuterium in one or more hydrogen atoms (eg. for a given hydrogen atom the level of the
deuterium e exceeds 20%, 50%, 75%, 90%, 95% or 99% by number). Examples of
other isotopes that can be incorporated into nd (I) or enriched in Compound (I)
include isotopes of en, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as
3H, “C, 13C, 14C, 15N, 18F, 123I or 125I, which may be naturally occurring or non-naturally
occurring isotopes.
In a further aspect of the invention there is ed one or more metabolites of the
compound of formula (I), in particular a metabolite that retains one or more of the therapeutic
activities of the compound of formula (I). A metabolite, as employed herein, is a compound
that is produced in vivo from the metabolism of the compound of formula (I), such as, without
limitation, oxidative lites and/or metabolites generated, for example, from O-
dealkylation.
The disclosure also extends to all rphic forms of the compounds herein defined.
A route suitable for the preparation of the compound of formula (I) is shown below (Scheme
W0 2013;’050757 PCT/G32012/052445
Scheme 1
fINC/ 1. PhNHzl
H N Cw/N
2 DBU MeCN HzN NY 2 33“
.HCI Step2
Step 1 Cl
PhOC(O)C|/
/ \ Na2C03
N‘N NH2 kOPh + OON/N
Step3 H2N NIY
H\©N
EtaN
, N/ N\
22/ 00Wl
Step 4 0%
Compound (I)
Protective groups may be required to protect chemically sensitive groups during one or more
of the reactions described above, to ensure that the process can be carried out and/or is
efficient. Thus if desired or necessary, intermediate compounds may be protected by the use
of conventional protective groups. Protective groups and the means for their l are
described in “Protective Groups in Organic Synthesis”, by Theodora W. Greene and Peter G.
M. Wuts, published by John Wiley & Sons Inc; 4th Rev Ed., 2006, 0: 0471697540.
A detailed preparation of Compound (I) is provided in e 1.
Novel intermediates as described herein form an aspect of the invention.
In another aspect of the ion, there is provided Compound (I) as the anhydrous free
base in solid, crystalline form. In a further aspect of the invention, there is ed
Compound (I) as the anhydrous free base in solid, crystalline, rphic form A which may
be obtained, for example, by crystallising Compound (I) from pyl acetate. In a particular
aspect of the invention, there is provided Compound (I) as the anhydrous free base in solid,
crystalline, polymorphic form B, which may be obtained, for example, by crystallising
Compound (I) from acetone and water. A typical ratio of acetone to water that is suitable for
this process is between 5:1 and 200:1 e.g. around 10:1. atively, form B may be
obtained by llising Compound (I) from acetone alone. Detailed preparations of
Compound (I) as the anhydrous free base in solid crystalline polymorphic forms A and B are
provided in Examples 1 and 3 of the Experimental Section, respectively.
In a further aspect of the invention, the solid state properties of Compound (I) may be
improved by further slurrying or recrystallization steps to e, for example, material with
improved morphology and/0r containing a reduced level of residual solvent. For example,
residual solvent may be removed from Compound (I) as the anhydrous free base in solid,
lline, polymorphic form B by slurrying Compound (I) in polymorphic form B, in water, or
alternatively by further tallization from acetone. A detailed description of an exemplary
slurrying procedure is ed in Example 33 of the Experimental Section.
In one embodiment, there is provided solid, crystalline polymorphic form A of nd (I)
as the anhydrous free base having an XRPD pattern substantially as shown in Figure 1. The
method of obtaining the XRPD data is described in ical Methods and the data
discussed in Example 5.
Thus, there is provided Compound (I) as the anhydrous free base in solid, crystalline,
polymorphic form A having an XRPD pattern with at least one (for example one, two, three,
four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or all sixteen)
peak(s) at 7.8, 8.7, 10.3, 11.2, 12.4, 15.2, 16.2, 17.5, 19.7, 20.8, 22.6, 23.1, 24.6, 25.5, 26.7,
27.4 (i 0.2 degrees, 2-theta values), these peaks being teristic of the solid, crystalline,
polymorphic form A. The peaks at 10.3, 15.2, 17.5, 23.1, 24.6, 26.7 and 27.4 are particularly
characteristic for the solid, crystalline, polymorphic form A and therefore it is preferable that
at least one (for example one, two, three, four, five, six or all seven) of these peaks is
observable in the XRPD pattern.
In another embodiment, there is ed solid, crystalline, polymorphic form B of Compound
(I) as the anhydrous free base (micronized) having an XRPD pattern substantially as shown
in Figure 2. The method of micronization is described in Example 4 and the method of
obtaining the XRPD data is bed in Analytical s and the data discussed in
Example 5.
Thus, there is provided Compound (I) as the anhydrous free base in solid crystalline
polymorphic form B (micronized) having an XRPD pattern with at least one (for e one,
two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen,
sixteen, seventeen or all eighteen) peaks at 3.9, 6.1, 7.7, 8.6, 10.9, 11.8, 12.7, 14.3, 15.9,
16.7, 18.3, 18.7, 19.9, 20.9, 22.0, 22.6, 25.2, 28.9 (i 0.2 degrees, 2-theta values), these
peaks being characteristic of the solid crystalline polymorphic form B. The peaks at 3.9, 6.1,
11.8, 14.3, 16.7, 18.3, 18.7 and 28.9 are particularly characteristic for the solid, crystalline,
polymorphic form B and ore it is preferable that at least one (for example one, two,
three, four, five, six, seven or all eight) of these peaks is observable in the XRPD pattern.
The melting points of Compound (I) as the ous free base in solid, crystalline,
polymorphic forms A and B were ined using differential scanning calorimetry as
described in Example 6. Compound (I) as the anhydrous free base in solid, crystalline,
polymorphic form A was found to have a melting point of 191.6 °C, and Compound (I) as the
anhydrous free base in solid, crystalline, polymorphic form B was found to have a melting
point of 214 °C. Polymorphic form B was also found to have a higher heat of fusion than
polymorphic form A. As explained in Example 6, these results suggest that polymorphic form
B is thermodynamically more stable than polymorphic form A.
The al and chemical stabilities of Compound (I) as the ous free base in solid,
lline, polymorphic form B, were investigated, the results of which are disclosed herein.
In order to assess physical stability, nd (I) as the anhydrous free base in solid,
crystalline, polymorphic form B was micronized following the procedure described in
Example 4, and samples of the resulting material were stored in open containers and
subjected to different ambient temperatures and relative humidities. The physical properties
and stabilities of the samples were investigated using TGA, DSC, DVS, IR spectroscopy and
XRPD analysis. Full experimental procedures are provided in the General Procedures
section and the results are summarised in Example 7 (Table 8). As discussed in Example 7,
Compound (I) as the anhydrous free base in solid, crystalline, polymorphic form B
(micronized) was found to have good physical stability. The same experimental procedures
were also carried out using Compound (I) as the anhydrous free base in solid, crystalline,
polymorphic form B in cronized form and the results were found to be ntially
similar to those obtained for the micronized material i.e. Compound (I) as the anhydrous free
base in solid, lline, polymorphic form B in both micronized and unmicronized forms was
found to have good physical stability.
In order to assess chemical stability, Compound (I) as the ous free base in solid,
crystalline, polymorphic form B was micronized following the procedure described in
Example 4. Micronized samples were stored in open containers and ted to different
ambient temperatures and relative humidities. The al stabilities of the samples were
analysed by HPLC. The results are summarised in Example 8 (Table 9) where it is indicated
that Compound (I) as the anhydrous free base in solid, crystalline, polymorphic form B, post
3O microniastion was found to be ally stable, although some sensitivity towards light was
detected.
As a result of the solid state s sed herein, it is concluded that nd (I) as
the anhydrous free base in solid, crystalline, polymorphic form B can be ized and that
the resulting material has good physical and chemical stability.
The compound of formula (I) is a p38 MAP kinase inhibitor (especially of the alpha subtype)
and in one aspect the compound is useful in the treatment of inflammatory diseases, for
example COPD and/or asthma.
Surprisingly, the compound exhibits a long duration of action and/or tence of action in
comparison to the previously disclosed p38 MAP kinase inhibitor BIRBYQG.
WO 50757
Persistence of action as used herein is related to the dissociation rate or dissociation
constant of the compound from the target (such as a receptor). A low dissociation rate may
lead to persistence.
A low dissociation rate in combination with a high association rate tends to e potent
therapeutic entities.
The compound of a (l) is expected to be potent in vivo.
lly, the prior art compounds developed to date have been intended for oral
administration. This gy es optimizing nds which achieve their duration of
action by an appropriate pharmacokinetic profile,.thereby ng that a sufficiently high
drug concentration is established and maintained between doses to provide clinical benefit.
The inevitable consequence of this approach is that all bodily tissues, and especially the liver
and the gut, are exposed to supra-therapeutically active concentrations of the drug, whether
or not they are adversely affected by the disease being treated.
An alternative strategy is to design treatment paradigms in which the drug is dosed ly to
the inflamed organ (topical therapy). While this approach is not suitable for treating all
chronic inflammatory diseases, it has been extensively exploited in lung diseases (asthma,
COPD), skin conditions (atopic dermatitis and psoriasis), nasal diseases (allergic rhinitis) and
gastrointestinal disorders (ulcerative colitis).
ln topical y, efficacy can be achieved either by ensuring that the drug has a sustained
on of action and is ed in the relevant organ to ze the risks of systemic
toxicity or by producing a formulation which generates a “reservoir” of the active drug. which
is available to sustai its desired effects. The first approach is exemplified by the
anticholinergic drug tiotropium (Spiriva).,This compound is administered topically to the lung
as a treatment for COPD, and has an exceptionally high affinity for its target or,
3O resulting in a very slow off rate and a consequent sustained duration of action.
in one aspect of the disclosure the compound of formula (I) is particularly suitable for topical
delivery, such as topical delivery to the lungs, in particular for the treatment of respiratory
disease, for example chronic respiratory diseases such as COPD and/or asthma.
In one embodiment the compound of formula (I) is suitable for sensitizing patients to
treatment with a corticosteroid who have become refractory to such treatment regimens.
The compound of formula (I) may also be useful for the ent of rheumatoid arthritis.
The compound of formula (I) may have antiviral properties, for example the y to prevent
infection of cells (such as respiratory epithelial cells) with a avirus, in particular a
rhinovirus, influenza or respiratory syncytial virus.
PCT/G32012/052445
Thus the compound is thought to be an antiviral agent, in particular le for the
prevention, treatment or ration of picornavirus infections, such as rhinovirus infection,
influenza or respiratory syncytial virus.
In one embodiment the nd of formula (I) is able to reduce inflammation induced by
viral ion, such as rhinovirus infection and in particular viral ions that result in the
release of cytokines such as IL—8, especially in vivo. This activity may, for example, be tested
in vitro employing a rhinovirus induced lL-8 assay as described in the Examples herein.
1O In one embodiment the compound of formula (I) is able to reduce ICAM1 expression induced
by rhinovirus, especially in vivo. ICAM1 is the receptor mechanism used by so-called major
groove rhinovirus serotypes to infect cells. This ty may be measured, for example by a
method described in the Examples herein.
It is expected that the above properties render the compound of formula (I) particularly
suitable for use in the treatment and/or prophylaxis of exacerbations of inflamatory diseases,
in particular viral exacerbations, in patients with one or more of the following c
conditions such as congestive heart failure, COPD, , diabetes, cancer and/or in
immunosuppressed patients, for example post-organ transplant.
In particular, the compound of formula (I) may be useful in the treatment of one or more
respiratory disorders including COPD (including chronic bronchitis and emphysema),
asthma, paediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic
rhinitis, rhinitis, sinusitis, especially asthma, and COPD (including chronic bronchitis and
emphysema).
The compound of formula (I) may also be useful in the treatment of one or more conditions
which may be treated by topical or local therapy including allergic conjunctivitis,
conjunctivitis, allergic dermatitis, contact dermatitis, psoriasis, tive colitis, ed
joints secondary to rheumatoid tis or to osteoarthritis.
It is also expected that the compound of formula (I) may be useful in the treatment of certain
other conditions including rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growth
and asis of tumours including non-small cell lung carcinoma, breast carcinoma, gastric
carcinoma, colorectal carcinomas and malignant melanoma.
The compound of a (I) may be useful in the treatment of eye diseases or disorders
including allergic ctivitis, ctivitis, diabetic pathy, macular oedema
(including wet macular oedema and dry macular oedema), post-operative cataract
40 inflammation or, particularly, uveitis (including posterior, anterior and pan uveitis).
The compound of formula (I) may be useful in the treatment of gastrointestinal diseases or
disorders ing tive colitis or Crohn’s disease.
The nd of formula (I) may also re-sensitise the t’s condition to treatment with a
corticosteroid, when the patient’s condition has become refractory to the same.
Furthermore, the present invention provides a pharmaceutical composition comprising a
compound according to the disclosure optionally in combination with one or more
pharmaceutically acceptable diluents or carriers.
The present invention also provides a process for preparing such a pharmaceutical
composition which comprising mixing the ingredients.
Diluents and rs may include those suitable for parenteral, oral, topical, mucosal and
rectal administration.
As mentioned above, such compositions may be prepared e.g. for parenteral, aneous,
intramuscular, intravenous, intra—articular or pen-articular administration, particularly in the
form of liquid solutions or suspensions; for oral administration, particularly in the form of
tablets or capsules; for l e.g. pulmonary or intranasal administration, particularly in the
form of powders, nasal drops or aerosols and transdermal administration; for mucosal
administration e.g. to buccal, gual or vaginal , and for rectal administration e.g.
in the form of a itory.
The compositions may conveniently be stered in unit dosage form and may be
prepared by any of the methods well-known in the pharmaceutical art, for example as
described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,
, PA., (1985). Formulations for parenteral administration may contain as excipients
sterile water or saline, ne glycols such as propylene glycol, polyalkylene glycols such
as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
Formulations for nasal administration may be solid and may contain excipients, for example,
lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or
metered sprays. For buccal administration typical excipients include sugars, calcium
stearate, magnesium stearate, pregelatinated starch, and the like.
Compositions suitable for oral administration may comprise one or more physiologically
compatible carriers and/or excipients and may be in solid or liquid form. Tablets and
capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol,
tragacanth, or poly—vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium
phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene
glycol, or ; and surfactants, such as sodium lauryl sulfate. Liquid compositions may
40 contain tional additives such as suspending , for example sorbitol syrup,
methyl cellulose, sugar syrup, gelatin, ymethyl—cellulose, or edible fats; emulsifying
agents such as in, or acacia; ble oils such as almond oil, t oil, cod liver oil,
or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated
ytoluene (BHT). Liquid compositions may be encapsulated in, for example, gelatin to
provide a unit dosage form.
Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin
(SEG) capsules.
A dry shell formulation typically ses of about 40% to 60% w/w tration of gelatin,
about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene
glycol) and about a 30% to 40% concentration of water. Other materials such as
1O preservatives, dyes, opacifiers and flavours also may be present. The liquid fill material
comprises a solid drug that has been dissolved, solubilized or sed (with suspending
agents such as x, hydrogenated castor oil or polyethylene glycol 4000) or a liquid
drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides,
glycols, polyols and e—active agents.
Suitably the nd of formula (I) is administered topically to the lung. Hence we provide
according to the invention a pharmaceutical ition comprising Compound (I) of the
disclosure optionally in combination with one or more topically acceptable diluents or
rs. Topical administration to the lung may be achieved by use of an aerosol formulation.
Aerosol formulations typically comprise the active ient suspended or dissolved in a
suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon
(HFC). Suitable CFC propellants include oromonofluoromethane (propellant 11),
rotetrafluoro methane (propellant 114), and dichlorodifluoromethane (propellant 12).
Suitable HFC propellants e tetrafluoroethane (HFC—134a) and heptafluoropropane
(HFC-227). The propellant lly comprises 40% to 99.5% e.g. 40% to 90% by weight of
the total inhalation composition. The formulation may comprise excipients including co—
solvents (e.g. ethanol) and surfactants (e.g. lecithin, an trioleate and the like). Aerosol
formulations are packaged in canisters and a suitable dose is delivered by means of a
metering valve (e.g. as supplied by Bespak, Valois or 3M).
Topical stration to the lung may also be achieved by use of a non-pressurised
formulation such as an aqueous solution or suspension. This may be administered by means
of a nebuliser. Nebulisers may be portable or non—portable Topical administration to the lung
may also be achieved by use of a wder formulation. A dry powder formulation will
contain the compound of the disclosure in finely divided form, typically with a mass mean
aerodynamic diameter (MMAD) of 1-10 pm. The formulation will typically contain a topically
able diluent such as lactose, usually of larger particle size e.g. an MMAD of 50 pm or
more, e.g. 100 pm or more. An alternative topically acceptable diluent is mannitol. Examples
of dry powder delivery systems include SPlNHALER, DlSKHALER, TURBOHALER, DISKUS
40 and CLlCKHALER. Further examples of dry powder inhaler s include ECLIPSE,
ROTAHALER, HANDIHALER, AEROLlSER, CYCLOHALER, BREEZHALER/NEOHALER,
FLOWCAPS, TWINCAPS, X—CAPS, TURBOSPlN, ELPENHALER, TURBUHALER,
MlATHALER, TWISTHALER, NOVOLlZER, SKYEHALER, ORIEL dry powder inhaler,
MICRODOSE, ACCUHALER, PULVINAL, LER, ULTRAHALER, TAIFUN,
PULMOJET, LER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.
One aspect of the invention relates to a dry powder pharmaceutical formulation for inhalation
comprising:
(i) Compound (I)
,w N/N
\N gmGMT)
nd (l)
that is 1-(3-ten‘-butyI—i-p~tonI—1H-pyrazoI-S-yl)-3—(4-(2-(phenyiamino)pyrimidin-4—
yloxy)naphthalen-i-yI)urea or a pharmaceutically acceptable salt thereof, including all
stereoisomers and tautomers thereof, in particulate form (e.g. solid crystalline Form
B) as active ingredient;
(ii) particulate lactose as carrier; and
(iii) a particulate metal salt of stearic acid, such as magnesium stearate.
The invention also provides for an inhalation device comprising one or more doses of said
formulation.
The nd of formula (I) has therapeutic ty. In a further aspect, the present
invention provides a compound of the sure for use as a medicament. Thus, in a r
aspect, the present ion provides a compound as bed herein for use in the
treatment of one or more of the above mentioned conditions.
In a further aspect, the present invention es use of Compound (I) as described herein
for the manufacture of a medicament for the treatment of one or more of the above
mentioned conditions.
In a further aspect, the present invention provides a method of treatment of one or more of
the above mentioned conditions which comprises administering to a subject an effective
amount of Compound (I) of the disclosure or a pharmaceutical composition comprising the
compound.
The word “treatment” is intended to embrace prophylaxis as well as therapeutic treatment.
Compound (I) of the invention may also be administered in ation with one or more
other active ingredients e.g. active ingredients suitable for treating the above mentioned
conditions. For example possible combinations for treatment of respiratory disorders include
combinations with steroids (e.g. nide, beclomethasone dipropionate, fluticasone
nate, mometasone furoate, fluticasone furoate), beta agonists (e.g. terbutaline,
amol, salmeterol, formoterol) and/or xanthines (e.g. theophylline). Other le
actives include anticholinergics, such as tiotropium and anti-viral agents such as, but not
limited to, vir or oseltamivir, for example as the phosphate. Other anti-viral agents
include peramivir and laninamivir. Further possible combinations for ent of respiratory
disorders include combinations with steroids such as flunisolide, ciclesonide and
triamcinolone; beta agonists such bambuterol, levalbuterol, clenbuterol, fenoterol, broxaterol,
indacaterol, reproterol, procaterol and vilanterol; muscarinic antagonists, (e.g. ipratropium,
tiotropium, oxitropium, glycopyrronium, glycopyrrolate, aclidinium, trospium) and leukotriene
antagonists (e.g. zafirlukast, kast, zileuton, montelukast). It will be understood that any
of the aforementioned active ingredients may be employed in the form of a pharmaceutically
acceptable salt.
in one embodiment the compound of formula (l) and the other active ingredient(s) are co-
formulated in the same pharmaceutical formulation. In another embodiment the other active
ingredient(s) are administered in one or more separate ceutical formulations.
Hence, another aspect of the ion provides a combination product sing:
(A) a compound of the present invention (i.e. a compound of formula (l) as defined
above, or a pharmaceutically acceptable salt thereof); and
(B) another therapeutic agent,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-
acceptable diluent or carrier.
In this aspect of the invention, the combination product may be either a single (combination)
ceutical formulation or a kit—of—parts.
Thus, this aspect of the ion encompasses a pharmaceutical formulation including a
compound of the present invention and another eutic agent, in admixture with a
pharmaceutically acceptable diluent or carrier (which formulation is hereinafter referred to as
a “combined preparation”).
it also encompasses a kit of parts comprising components:
(i) a ceutical formulation including a compound of the present invention in
admixture with a pharmaceutically acceptable diluent or carrier; and
(ii) a pharmaceutical formulation including another therapeutic agent, in admixture with a
ceutically—acceptable diluent or carrier,
which components (i) and (ii) are each provided in a form that is suitable for administration in
conjunction with the other.
Component (i) of the kit of parts is thus ent (A) above in admixture with a
pharmaceutically acceptable diluent or carrier. Similarly, component (ii) is component (B)
above in admixture with a ceutically acceptable diluent or carrier.
The other therapeutic agent (i.e. component (B) above) may be, for example, any of the
active ingredients mentioned above in connection with the treatment of respiratory disorders.
The data ed hereinbelow in relation to the antiviral ties of the nd of
formula (I) provides evidence that other antiviral therapies in combination with a compound of
formula (I) would be useful in the treatment or prevention of virally-induced exacerbations (for
example respiratory viral infections) suffered by patients with respiratory disease such as
COPD andIor asthma and/or one or more of the indications listed above. Thus, in one aspect
there is provided the use of Compound (I) in combination with an anti—viral therapy such as,
but not limited to, zanamavir or oseltamivir (for example oseltamivir phosphate) in the
1O treatment or tion of respiratory viral infections suffered by patients with atory
disease such as COPD and/or .
The inventors also believe that other antiviral therapies in combination with Compound (l)
would be useful in the ent or prevention of y induced exacerbations (for example
respiratory viral infections) in patients with chronic conditions other than respiratory diseases,
for example conditions such as congestive heart e, diabetes, cancer, or ions
suffered by immunosuppressed patients, for example post-organ transplant. Thus, in a
further aspect there is provided the use of a compound of the invention in combination with
an anti-viral therapy, such as, but not limited to, zanamavir or oseltamivir (for example
oseltamivir ate), in the treatment or prevention of respiratory viral infections in
patients with chronic conditions such as congestive heart failure, diabetes, cancer, or in
conditions suffered by immunosuppressed patients, for example post-organ transplant.
EXPERIMENTAL SECTION
Abbreviations used herein are defined below (Table 1). Any abbreviations not defined are
intended to convey their generally accepted g.
Table 1: Abbreviations
AcOH glacial acetic acid
Aq aqueous
ATP adenosine~5'-triphosphate
BALF bronchoalveolae lavage fluid
BEGM bronchial lial cell growth media
br broad
BSA bovine serum albumin
t® catalytic cartridge
CDl 1,1 -carbony|—diimidazole
COPD chronic obstructive pulmonary disease
CXCL1 chemokine (C-X—C motif) ligand “i
d doublet
DCM dichloromethane
DMSO dimethyl sulfoxide
DSC differential scanning calorimetry
d-U937 cells PMA differentiated U-937 cells
DVS c vapour sorption
(ESi) electrospray ionization, positive mode
Et ethyl
EtOAc ethyl e
FCS foetal calf serum
FRET fluorescence resonance energy transfer
GSKSa glycogen synthase kinase 30
HBEC primary human bronchial epithelial cells
hr hour(s)
HRP horseradish peroxidise
HRV human irus
lCAM-1 inter-cellular adhesion molecule 1
IR infrared
JNK c-Jun N-terminal kinase
KC keratinocyte chemoattractant
Kd dissociation constant
LPS Lipopolysaccharide
(M+H)+ protonated molecular ion
MAPK mitogen protein activated n kinase
—K2 mitogen-activated protein kinase—activated protein kinase-2
Me methyl
MeCN acetonitrile
MeOH methanol
MHZ megahertz
min minute(s)
MlP1a macrophage inflammatory protein 1 alpha
MMAD mass median aerodynamic diameter
MOI multiplicity of infection
m.p. melting point
MTT —dimethylthiazol-2—yl)-2,5-dlphenyltetrazolium bromide
m/z: mass-to—charge ratio
NMR nuclear magnetic nce (spectroscopy)
PBMC peripheral blood mononuclear cell
PBS phosphate buffered saline
Ph phenyl
PHA phytohaemagglutinin
PMA phorbol myristate acetate
pTSA 4—methylbenzenesulfonic acid
PCT/G32012/052445
q t
RT room temperature
RP HPLC e phase high performance liquid chromatography
RSV respiratory syncytical virus
8 singlet
sat saturated
SCX solid supported cation exchange (resin)
SDS sodium dodecyl sulphate
SNAr nucleophilic aromatic substitution
t triplet
TCleo 50% tissue culture infectious dose
TGA thermogravimetric analysis
THF tetrahydrofuran
TNFd tumor necrosis factor alpha
XRPD X-ray powder diffraction
General Procedures
All ng materials and solvents were obtained either from commercial s or prepared
ing to the ture citation. Unless otherwise stated all reactions were stirred. Organic
solutions were ely dried over anhydrous magnesium sulfate. Hydrogenations were
performed on a Thales H—cube flow reactor under the conditions stated. Column
chromatography was performed on pre-packed silica (230-400 mesh, 40—63 pm) cartridges
1O using the amount indicated. SCX was purchased from Supelco and treated with 1M
hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was
first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded
directly onto the SCX and washed with MeOH. The desired material was then eluted by
washing with 1% NH3 in MeOH.
Preparative Reverse Phase High Performance Liquid Chromatography: Agilent Scalar
column C18, 5 pm (21.2 X 50 mm), flow rate 28 mL min‘1 eluting with a HgO-MeCN gradient
containing 0.1% v/v formic acid over 10 min using UV detection at 215 and 254 nm. Gradient
information: 0.0—0.5 min; 95% H20-5% MeCN; 0.5-7.0 min; ramped from 95% H20—5% MeCN
to 5% HgO-95% MeCN; 7.0-7.9 min; held at 5% % MeCN; 7.9-8.0 min; ed to
95% H20-5% MeCN; .0 min; held at 95% H20—5% MeCN.
Analytical Methods
Reverse Phase High Performance Liquid Chromatography: (Method 1): Agilent Scalar
column C18, 5 pm (4.6 X 50 mm) or Waters XBridge C18, 5 pm (4.6 x 50 mm) flow rate 2.5
mL min‘1 eluting with a HZO-MeCN gradient containing either 0.1% v/v formic acid (Method 1
acidic) or NH3 d 1 basic) over 7 min employing UV detection at 215 and 254 nm.
Gradient ation: 0.0~0.1 min, 95% H20-5% MeCN; 0.1—5.0 min, ramped from 95% H20-
% MeCN to 5% H20—95% MeCN; 5.0-5.5 min, held at 5% H20-95% MeCN; 5.5—5.6 min,
held at 5% H20-95% MeCN, flow rate increased to 3.5 mL min'1; 5.6-6.6 min, held at 5%
H20-95% MeCN, flow rate 3.5 mL min'1; 6.6-6.75 min, returned to 95% H20—5% MeCN, flow
rate 3.5 mL min'1; 6.75-6.9 min, held at 95% H20-5% MeCN, flow rate 3.5 mL.min'1; 0
min, held at 95% HZO-5% MeCN, flow rate reduced to 2.5 mL min'1.
Reverse Phase High Performance Liquid Chromatography: (Method 2): Agilent Extend C18
column, 1.8 pm (4.6 x 30 mm) at 40°C; flow rate 2.5—4.5 mL min"1 eluting with a HZO—MeCN
1O gradient containing 0.1% v/v formic acid over 4 min employing UV detection at 254 nm.
Gradient information: 0-3.00 min, ramped from 95% H20~5% MeCN to 5% H20—95% MeCN;
3.00-3.01 min, held at 5% H20~95% MeCN, flow rate increased to 4.5 mL min“; 3.01 3.50
min, held at 5% H20-95% MeCN; 3.50360 min, ed to 95% H20-5% MeCN, flow rate
reduced to 3.50 mL min"; 3.60-3.90 min, held at 95% H20-5% MeCN; 3.90-4.00 min, held at
95% H20-5% MeCN, flow rate reduced to 2.5 mL min".
1H NMR Spectroscopy: Spectra were acquired on a Bruker Avance ||l spectrometer at 400
MHz using residual undeuterated solvent as reference.
Dynamic Vapour Sorption: Plots were obtained using a Surface Measurement Systems
dynamic vapor sorption model DVS—1 using about 10 mg of the sample. The weight change
was recorded with respect to atmospheric humidity at 25°C and was determined using the
following parameters: drying: 60 min under dry nitrogen; equilibrium: 60 min/step; data
interval: 0.05% or 2.0 min. The relative humidity [RH %] ement points were as
follows:
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: 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 0.
X-Ray Powder Diffraction: Patterns were obtained on a PANalytical (Philips) X’PertPRO
MPD diffractometer equipped with a Cu LFF X—ray tube (45 kV; 40 mA; Bragg-Brentano;
spinner stage) and were acquired using Cu Ker radiation under the ing measurement
conditions: scan mode: continuous; scan range: 3 to 50° 29; step size: 0.02°/step; counting
time: 30 sec/step; r revolution time: 1 sec; nt beam path: program. divergence
slit: 15 mm; Soller slit: 0.04 rad; beam mask: 15 mm; anti scatter slit: 1°; beam knife: +;
Diffracted beam path: long anti scatter shield: +; Soller slit: 0.04 rad; Ni filter: +; detector:
X'Celerator. s were ed by spreading on a zero background sample holder.
Infrared Spectroscopy: Micro attenuated total reflectance (microATR) was used and the
sample was analyzed using a suitable TR accessory and the following measurement
40 conditions: apparatus: Thermo Nexus 670 FTIR ometer; number of scans: 32;
tion: 1 cm“; wavelength range:4000 to 400 cm“; detector: DTGS with KBr windows;
beamsplitter: Ge on KBr; micro ATR accessory: Harrick Split Pea with Si crystal.
WO 50757
Differential Scanning Calorimetry: Data were collected on a TA—lnstruments Q1000 MTDSC
equipped with R08 cooling unit. Typically 3 mg of each compound, in a standard aluminium
trument sample pan, was heated at 10 °C/min from 25 C to 300°C. A nitrogen
purge at
50 mL/min was maintained over the sample.
Thermogravimetric is: Data were collected on a TA—lnstruments Q500
thermogravimeter Typically 10 mg of each sample was transferred into a ore-weighed
aluminium pan and was heated at 20 °C/min from ambient temperature to 300 °C or
< 80[(w/w)%] unless otherwise stated.
al Stability by HPLC: Analyses were carried out on a Waters Xbridge C18 column (3.0
x 150 mm; 3.5 pm) using the following operating conditions: column temperature: 40°C;
sample temperature: 5°C; flow rate: 0.45 mL/min; ion volume: 7 uL; UV detection at 260
nm; mobile phase composition comprised of Phase A: 10 mM ammonium acetate + 0.1%, v/v
trifluoroacetic acid in water and Phase B: acetonitrile, using the gradient defined by the
parameters below (Table 2).
Table 2: Gradient Conditions for Chemical Stability Studies by HPLC.
% Composition at Run Time (min)
Eluent O 20 25 26 32
Phase A 70 0 O 70 7O
PhaseB 30 100 100 30 30
Experimental methods for biological testing
Enzyme Inhibition Assays
The kinase enzyme g activities of compounds sed herein were determined using
a proprietary assay which measures active site-directed competition binding to an
immobilized ligand (Fabian, MA. et al., Nature Biotechnol, 2005, 23:329—336). These
assays
were conducted by DiscoverX rly Ambit; San Diego, CA). The Kd value (Dissociation
constant value) was calculated as the index of affinity of the compounds to each kinase.
Enzyme Inhibition Assays
The enzyme tory activities of compounds sed herein were determined by FRET
using synthetic peptides labelled with both donor and acceptor fluorophores (Z-LYTE,
lnvitrogen Ltd., Paisley, UK).
p38 MAPKa Enzyme Inhibition
The inhibitory activities of test compounds against the p38 MAPKG isoform (MAPK14:
ogen), were evaluated indirectly by determining the level of activation 1' phosphorylation
of the down-stream molecule, MAPKAP-KZ. The p38 MAPKa protein (80 ng/mL, 2.5 uL) was
mixed with the test compound (2.5 uL of either 4 ug/mL, 0.4 ug/mL, 0.04 ug/mL or 0.004
ug/mL) for 2 hr at RT. The mix solution (2.5 uL) of the p38o inactive target MAPKAP—K2
(lnvitrogen, 600 ng/mL) and FRET peptide (8 uM; a phosphorylation target for MAPKAP—KZ)
was then added and the kinase reaction was initiated by adding ATP (40 mm, 2.5pL). The
1O mixture was incubated for 1 hr at RT. Development reagent (protease, 5 uL) was added for 1
hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, ThermoFisher
ific).
p38 MAPKv Enzyme Inhibition
The inhibitory activities of compounds of the invention t p38MAPKv (MAPK12:
Invitrogen), were evaluated in a similar fashion to that described hereinabove. The enzyme
(800 ng/mL, 2.5 uL) was incubated with the test compound (2.5uL at either 4 ug/mL, 0.4
ug/mL, 0.04 ug/mL, or 0.004 ug/mL) for 2 hr at RT. The FRET peptides (8 uM, 2.5 uL), and
2O appropriate ATP on (2.5 uL, 400 uM) was then added to the enzymes / nd
mixtures and incubated for 1 hr. pment reagent (protease, 5 uL) was added for 1 hr
prior to detection in a fluorescence microplate reader (Varioskan® Flash, Thermo Scientific).
C—Src and Syk Enzyme Inhibition
The inhibitory activities of compounds of the invention against c-Src and Syk enzymes
(Invitrogen), were evaluated in a similar fashion to that described hereinabove. The relevant
enzyme (3000 ng/mL or 2000 ng/mL respectively, 2.5 uL) was incubated with the test
compound (either 4 ug/mL, 0.4 ug/mL, 0.04 ug/mL, or 0.004 ug/mL, 2.5 uL each) for 2 hr at
RT. The FRET peptides (8 uM, 2.5 uL), and appropriate ATP solutions (2.5 uL, 800 uM for c—
Src, and 60 uM ATP for Syk) were then added to the enzyme / compound mixtures and
incubated for 1 hr. Development reagent (protease, 5 0L) was added for 1 hr prior to
detection in a fluorescence microplate reader skan® Flash, ThermoFisher Scientific).
GSK 3a Enzyme tion
The inhibitory activities of test compounds t the GSK 3o enzyme isoform (lnvitrogen),
were ted by determining the level of activation / phosphorylation of the target e.
The GSK3-o protein (500 ng/mL, 2.5 uL) was mixed with the test compound (2.5 uL at either
40 4 pg/mL, 0.4 ug/mL, 0.04 ug/mL, or 0.004 ug/mL) for 2 hr at RT. The FRET peptide (8 uM,
2.5 uL), which is a phosphorylation target for GSK3c, and ATP (40 uM, 2.5 pL) were then
added to the enzyme / compound mixture and the resulting mixture incubated for 1 hr.
Development reagent (protease, 5 uL) was added for 1 hr prior to detection in a fluorescence
microplate reader (Varioskan® Flash, Fisher Scientific).
in all cases, the site-specific se cleaves non-phosphorylated peptide only and
eliminates the FRET signal. Phosphorylation levels of each reaction were calculated using
the ratio of coumarin emission (donor) over fluorescein emission (acceptor), for which low
ratios indicate high phosphorylation and high ratios indicate low phosphorylation levels. The
percentage inhibition of each reaction was calculated relative to non—inhibited control and the
50% inhibitory concentration (K350 value) was then calculated from the concentration-
response curve.
1O Cellular Assays
LPS-induced TNFa / IL-8 Release in d-U937Cells
U937 cells, a human tic cell line, were differentiated into macrophage—type cells by
incubation with PMA (100 ng/mL) for 48 to 72 hr. Cells were pre—incubated with final
concentrations of test compound for 2 hr and were then stimulated with LPS (0.1 pg/mL; from
E. Coli: O111:B4, Sigma) for 4 hr. The supernatant was collected for determination of TNFa
and lL—8 concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibition of TNFor
production was calculated as a tage of that achieved by 10 pg/mL of BIRBTQS at each
concentration of test compound by comparison t vehicle control. The relative 50%
effective tration (REC50) was determined from the resultant concentration—response
curve. The inhibition of IL-8 production was calculated at each concentration of test
compound by comparison with vehicle control. The 50% inhibitory concentration (ICso) was
determined from the resultant tration—response curve.
LPS—induced TNFa Release in THP-‘l Cells
THP-1 cells, a human monocytic cell line, were ated with 3 ug/mL of LPS (from E. Coli;
0111284, Sigma) for 4 hr and the supernatant collected for ination of the TNFoc
concentration by sandwich ELISA (Duo-set, R&D systems). The inhibition of TNch
production was calculated at each tration by comparison with vehicle control. The
50% inhibitory concentration (ICSO) was determined from the resultant concentration-
response curve.
Poly l:C-induced [CAM-1 Expression in BEASZB Cells
Poly l:C was used in these studies as a , RNA virus mimic. Poly l:C-Oligofectamine
mixture (1 pg/mL Poly l:C, i 2% Oligofectamine, 25 pL; lnvivogen Ltd., San Diego, CA, and
lnvitrogen, Carlsbad, CA, tively) was transfected into BEASZB cells (human bronchial
40 lial cells, ATCC). Cells were pre-incubated with final trations of test compounds
for 2 hr and the level of lCAlVl—1 expression on the cell e was determined by cell-based
ELISA. At a time point 18 hr after poly l:C transfection, cells were fixed with 4%
formaldehyde in PBS (100 pL) and then endogenous peroxidase was quenched by the
addition of washing buffer (100 uL, 0.05% Tween in PBS: PBS—Tween) containing 0.1%
PCT/G32012/052445
sodium azide and 1% hydrogen peroxide. Cells were washed with wash-buffer (3 x 200 uL).
and after blocking the wells with 5% milk in PBS-Tween (100 uL) for 1 hr, the cells were
ted with uman ICAM—1 antibody (50 uL; Cell Signaling Technology, Danvers,
MA) in 1% BSA PBS overnight at 4°C.
The cells were washed with PBS-Tween (3 X 200 uL) and incubated with the secondary
antibody (100 uL; HRP-conjugated anti—rabbit lgG, Dako Ltd., Glostrup, Denmark). The cells
were then ted with of substrate (50 uL) for 2~20min, followed by the addition of stop
solution (50 uL, 1N H2804).The ICAM-1 signal was detected by reading and reading the
absorbance at 450 nm against a reference wavelength of 655 nm using a
spectrophotometer. The cells were then washed with PBS—Tween (3 x 200 uL) and total cell
numbers in each well were determined by reading absorbance at 595 nm after Crystal Violet
staining (50 LL of a 2% on in PBS) and elution by 1% SDS solution (100 pL) in distilled
water. The measured OD 450—655 readings were corrected for cell number by dividing with
the OD595 reading in each well. The inhibition of lCAM-1 expression was calculated at each
concentration of test compound by comparison with vehicle control. The 50% inhibitory
concentration (le0) was determined from the resultant concentration-response curve.
Cell Mitosis Assay
Peripheral blood mononucleocytes (PBMCs) from healthy subjects were ted from
whole blood (Quintiles, London, UK) using a y gradient paque®-1077, Sigma—
Aldrich, Poole, UK). The PBMCs (3 million cells per ) were subsequently treated with
2% PHA (Sigma—Aldrich, Poole, UK) for 48 hr, followed by a 20 hr exposure to varying
concentrations of test compounds. At 2 hr before collection, PBMCs were treated with
demecolcine (0.1 ug/mL; lnvitrogen, Paisley, UK,) to arrest cells in metaphase. To observe
mitotic cells, PBlVle were permeabilised and fixed by adding Intraprep (50 pL; n
Coulter, France), and stained with anti-phospho—histone 3 (0.26 ng/L; #9701; Cell Signalling,
Danvers, MA) and propidium iodide (1 mg/mL; Sigma-Aldrich, Poole, UK,) as previously
3O described (Muehlbauer PA. and Schuler M.J., Mutation Research, 2003, 537:117-130).
scence was observed using an ATTUNE flow cytometer (lnvitrogen, Paisley, UK),
gating for lymphocytes. The percentage tion of mitosis was calculated for each
treatment relative to vehicle (0.5% DMSO) treatment.
Rhinovirus-induced lL-8 Release and ICAM-1 sion
Human rhinovirus RV16 was ed from the American Type Culture Collection
(Manassas, VA). Viral stocks were generated by infecting Hela cells with HRV until 80% of
the cells were cytopathic.
BEASZB cells were infected with HRV at an MOl of 5 and incubated for 2 hr at 33°C with
gentle shaking for to e absorption. The cells were then washed with PBS, fresh media
added and the cells were incubated for a further 72 hr. The supernatant was collected for
assay of IL-8 concentrations using a Duoset ELISA development kit (R&D systems,
Minneapolis, MN).
The level of cell surface lCAM-1 expression was determined by cell-based ELISA. At 72 hr
after infection, cells were fixed with 4% formaldehyde in PBS. After quenching nous
peroxidase by adding 0.1% sodium azide and 1% en peroxide, wells were washed
with wash—buffer (0.05% Tween in PBS: PBS-Tween). After blocking well with 5% milk in
PBS-Tween for 1 hr, the cells were incubated with uman ICAM—i antibody in 5% BSA
PBS—Tween ) overnight. Wells were washed with PBS—Tween and incubated with the
ary antibody (HRP-conjugated anti-rabbit lgG, Dako Ltd.). The lCAM-1 signal was
detected by adding substrate and reading at 450 nm with a reference wavelength of 655 nm
using a spectrophotometer. The wells were then washed with PBS—Tween and total cell
numbers in each well were determined by reading ance at 595 nm after Crystal Violet
staining and elution by 1% SDS solution. The measured OD450-555 readings were corrected
for cell number by dividing with the OD595 g in each well. Compounds were added 2 hr
before HRV infection and 2 hr after infection when non-infected HRV was washed out.
Assessment of HRV16 induced CPE in MRC5 cells
MRC-5 cells were infected with HRV16 at an MOI OH in DMEM containing 5% FCS and 1.5
mM MgCl2, followed by incubation for 1 hr at 33°C to promote adsorption. The supernatants
were aspirated, and then fresh media added followed by incubation for 4 days. Where
appropriate, cells were pre-incubated with compound or DMSO for 2 hr, and the compounds
and DMSO added again after washout of the virus.
Supernatants were aspirated and incubated with methylene blue solution (100 uL, 2%
formaldehyde, 10% methanol and 0.175 % Methylene Blue) for 2 hr at RT. After washing, 1%
SDS in distilled water (100 uL) was added to each well, and the plates were shaken lightly for
1—2 hr prior to reading the absorbance at 660 nm. The percentage tion for each well
3O was calculated. The IC50 value was calculated from the concentration—response curve
generated by the serial dilutions of the test compounds.
In vitro RSV virus load in primary bronchial epithelial cells.
Normal human bronchial epithelial cells (NHBEC) grown in 96 well plates were infected with
RSV A2 (Strain A2, HPA, Salisbury, UK) at an MOl of 0.001 in the LHC8 MediazRPMI—164O
(50:50) containing 15 mM ium chloride and incubated for 1 hr at 37°C for adsorption.
The cells were then washed with PBS (3 x 200 uL), fresh media (200 uL) was added and
tion continued for 4 days. Where appropriate, cells were pre-incubated with the
40 compound or DMSO for 2 hr, and then added again after t of the virus.
The cells were fixed with 4% formaldehyde in PBS solution (50 uL) for 20 min, washed with
washing buffer (3 X 200 uL; PBS including 0.5% BSA and 0.05% Tween—20) and incubated
with blocking solution (5% condensed milk in PBS) for 1 hr. Cells were then washed with
washing buffer (3 x 200 uL) and incubated for 1 hr at RT with anti- RSV (2F7) F-fusion
protein antibody (40 pL; mouse monoclonal, lot 798760, Cat. No. ab43812, Abcam) in 5%
BSA in PBS-tween). After washing, cells were incubated with an HRP-conjugated secondary
antibody solution (50 uL) in 5% BSA in PBS-Tween (lot 70, Cat.No. P0447, Dako)
and then TMB substrate (50 pL; substrate reagent pack, lot , Cat. No. DY999, R&D
Systems, Inc.) was added. This reaction was stopped by the addition of 2N H2804 (50 uL)
and the resultant signal was determined colorimetrically (OD: 450 nm with a reference
ngth of 655 nm) in a microplate reader (Varioskan® Flash, ThermoFisher Scientific).
Cells were then washed and a 2.5% l violet solution (50 uL; lot 8656, Cat. No. PL7000,
Pro-Lab Diagnostics) was applied for 30 min. After washing with washing buffer, 1% SDS in
distilled water (100 uL) was added to each well, and plates were shaken lightly on the shaker
for 1 hr prior to reading the absorbance at 595 nm. The measured OD450_555 readings were
corrected to the cell number by dividing the OD450-655 by the OD595 gs. The percentage
inhibition for each well was calculated and the leO value was calculated from the
concentration-response curve generated from the serial dilutions of compound.
The Effect of Test Compounds on Cell Viability: MTT Assay
Differentiated U937 cells were pre-incubated with each test compound (final concentration 1
ug/mL or 10 uglmL in 200 uL media indicated below) under two protocols: the first for 4 hr in
% FCS RPMI164O media and the second in 10% FCS RPM|1640 media for 24 h. The
supernatant was replaced with new media (200 pL) and MTT stock solution (10 uL, 5 mg/mL)
was added to each well. After incubation for 1 hr the media were removed, DMSO (200 uL)
was added to each well and the plates were shaken lightly for 1 hr prior to reading the
absorbance at 550 nm. The percentage loss of cell viability was calculated for each well
relative to vehicle (0.5% DMSO) treatment. Consequently an apparent increase in cell
viability for drug treatment relative to vehicle is tabulated as a negative tage.
3O ne production in sputum hages from COPD.
ts with COPD were d with a nebulised solution of 3% (w/v) onic saline
using an onic nebuliser (Devilbiss, Carthage, MO) with tidal breathing for 5 min. This
procedure was repeated 3 maximum of three times until enough sputum was obtained. The
sputum s were homogenized and mixed vigorously using a vortex mixer in 0.02% v/v
dithiothreitol (DTT) solution. The samples were re—suspended in PBS (40 mL) followed by
centrifugation at 1500 rpm at 4°C for 10 min to obtain sputum cell pellets. The pellets were
washed twice with PBS (40mL). The sputum cells were then re—suspended in macrophage
serum-free medium phage-SFM, Life technologies, Paisley, UK; to achieve 2x106/well
40 in a 24 well plate) containing 20 U/mL penicillin, 0.02 mg/mL streptomycin and 5 ug/mL
amphotericin B and seeded on high bound 96-well plate, followed by incubation for 2 hr at
37°C and at 5% 002 to allow the macrophages to attach to the bottom of the plate. The cells
on the plate were washed with fresh macrophage—SFM (200 l) to remove neutrophils
and other contaminated cells. The adherent cells (mainly sputum macrophages) on the plate
PCT/G32012/052445
were used for further analysis. Sputum induction and isolation were conducted in Quintiles
Drug Research Unit at Guys Hospital and ethics approval and written informed consent was
obtained by Quintiles.
Where appropriate, 1 uL of a solution containing either the test compound or reference article
at the stated concentrations or alternatively 1 uL of DMSO as the vehicle control was added
to each well (200 uL in media) and the cells were incubated for 2 hr. The cells were
stimulated with LPS solution (50 uL, final concentration: 1 uglmL) and incubated for 4hr at
37°C and 5% 002. The supernatant was then collected and kept at —80°C. Millipore’s luminex
1O kits were used to measure the four analytes. After thawing the supernatant, the magnetic
antibody beads were multiplexed and incubated in a 96—well plate with standard, background
solution or the appropriate volume of sample overnight with shaking at 4°C. After washing
twice with 200 pL of wash buffer provided by the kit per well using a magnetic plate washer,
the beads were incubated for 1 hr at RT with 25 uL of the biotin conjugated antibody solution
provided by the kit with shaking. Streptavidin solution was added for 30 min with shaking at
RT. After g with 200uL wash buffer per well, the beads were ended in sheath
fluid (150 uL) and analyzed immediately. The level of each analyte in the supernatant was
calculated using Xcel Fit software with a 4 or meter equation using each standard
curve. The inhibitions of each cytokine tion were calculated at each tration by
comparison with vehicle control. The ICSO values were determined from tration-
inhibition curves using XL—Fit (idbs, Guildford, UK)
Cytokine production in primary bronchial lial cells from COPD.
Primary airway epithelial cells obtained from patients with COPD were purchased from
Asterand on, UK), and ined in bronchial epithelial cell growth media that was
prepared by mixing together LHCS (lnvitrogen) (500 mL), with LHC9 (lnvitrogen) (500 mL)
and 3 uL of retinoic acid solution (5 mg/mL in neat DMSO
. The media was removed by
aspiration and fresh BEGM (200 uL) was added to each well. Where appropriate, 1 pL of a
solution of the test compound at the state concentrations or 1 uL of DMSO as the vehicle
control was added and the cells were incubated for 2 hr. The cells were ated with
TNFoc (50 pL; final concentration 50 ng/mL) and then incubated for 4hr at 37°C and 5% 002.
The supernatant was then collected and kept at —20°C.
The levels of lL-6 and lL-8 were determined by ELlSA using R&D Systems’ Human lL-6
IL-8 Duoset® Elisa Kits. The inhibition of |L-6 and lL-8 production was calculated at each
concentration by ison with vehicle control. The 50% inhibitory concentrations (I050)
were determined from the resultant tration-response curves using XL-Fit (idbs,
Guildford, UK).
WO 2013050757 2012/052445
In Vivo Screening: Pharmacodynamics and Anti-inflammatory Activity
LPS-induced neutrophil accumulation in mice
sted Balblc mice were dosed by the intra tracheal route with either vehicle, or the test
substance at the indicated times (within the range 2—8 hr) before stimulation of the
inflammatory response by application of an LPS challenge. At T = 0, mice were placed into
an exposure chamber and exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBS) for 30 min).
After a further 8 hr the animals were etized, their tracheas cannuiated and BALF
1O extracted by infusing and then withdrawing from their lungs 1.0 mL of PBS via the tracheal
catheter. Total and differential white cell counts in the BALF samples were measured using a
Neubaur haemocytometer. Cytospin smears of the BALF samples were prepared by
fugation at 200 rpm for 5 min at RT and stained using a Difouik stain system (Dade
Behring). Cells were counted using oil immersion microscopy. Data for neutrophil numbers
in BAL are shown as mean i S.E.M. (standard error of the mean). The percentage inhibition
of neutrophil accumulation was calculated for each treatment relative to vehicle treatment.
tte Smoke Model
A/J mice (males, 5 weeks old) were exposed to cigarette smoke (4% cigarette smoke, diluted
with air) for 30 min/day for 11 days using a Tobacco Smoke inhalation ment System
for small s (Model SIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test
substances were administered intra-nasally (35 uL of solution in 50% DMSO/PBS) once daily
for 3 days after the final cigarette smoke exposure. At 12 hr after the last dosing, each of the
animals was anesthetized, the trachea cannulated and bronchoaiveolar lavage fluid (BALF)
was collected. The s of alveolar macrophages and phils were determined by
FACS analysis (EPICS® ALTRA ll, Beckman Coulter, |nc., Fullerton, CA, USA) using anti-
mouse MOMAZ antibody (macrophage) or anti-mouse 7/4 antibody ophil). BALF was
centrifuged and the supernatant was collected. The level of keratinocyte chemoattractant
(KC; CXCL1) in BALF was quantitated using a Quentikine® mouse KC ELISA kit (R&D
systems, Inc, Minneapolis, MN, USA).
Example 1- Preparation of Compound (I)
The following intermediates used to prepare Compound (I) of the invention have been
previously described and were prepared using the procedures contained in the references
cited below (Table 3).
W0 50757
Table 3: Previously bed intermediates.
Intermediate Structure Name, LCMS Data and Reference
m 3-tert-butylp-toiyi-1H-pyrazoiamine.
\ NH
N 2 R‘2.46 min (Method 1 ; m/z 230 (M+H)*,
(ES+ ).
Cirillo, P. F. eta/., W0 2000I43384, 27 Jul 2000.
ow 4-((2—chloropyrimldinyl)oxy)naphthalen-1—amine. '
B Rt 1.80 min (Method 2); m/z 272/274 (M+H)- + +
HZN 00 NYN
, (ES ).
Cirillo, P. F. at 6]., W0 2002/92576, 21 Nov 2000.
intermediate C: 4-((4-Aminonaphthalenyl)oxy)-N-phenylpyrimidinamine.
Aniline 0
intermediate B —-————-> D | Intermediate C
pTSA HzN
HN\©
To a nitrogen purged on of e of intermediate B (50.0 g, 184 mmol) and aniline
(42.0 mL, 460 mmol) in THF (200 mL) was added pTSA (17.5 g, 92.0 mmol) in a single
portion. The reaction mixture was heated to 70 °C for 1.5 hr during which time which a
precipitate formed. The mixture was cooled to RT and diluted with THF (200 mL). The
precipitate was collected by filtration, washed with THF (2 x 100mL) and then suspended in a
heterogeneous mixture of DCM (600 mL) and aq. NaOH (2M, 200 mL) and stirred vigorously
for 1 hr, during which time the suspended solids dissolved. The layers were separated and
the aq layer was extracted with DCM (200 mL). The DCM extracts were combined, dried and
evaporated in vacuo. The residue was triturated with ether (150 mL) and the resulting solid
was washed with ether (2 x 50 mL) to afford intermediate C as an off white solid (26 g,
43%); R‘1.95 min (Method 2); m/z 329 (M+H)+ (ES+).
WO 50757 2012/052445
Compound (I): 1-(3-(tert-Butyl)(p-tolyl)-1H-pyrazoly|)(4-((2-(pheny|amino)
pyrimidinyl)oxy)naphthalenyl)urea.
o \
1. PhOC(O)Cl
ediateA ———> N/ \ Y}
)L O
\N N N NYN
2.lntermediateC H H
Me Compound 1
A heterogeneous mixture of a solution of Na2003 (3.84 g, 36 mmol) in water (42 mL) and
intermediate A (10.5 g, 45.7 mmol) in isopropyl acetate (130 mL, 1.082 mol) was stirred
vigorously at RT for 5 min and was then treated with phenyl carbonochloridate (5.77 mL,
45.7 mmol). Stirring of the mixture was continued for a further 4 hr after which the layers
were separated. The organic phase was added to a solution of Intermediate C (10.0 g, 30.5
1O mmol) and ylamine (423 uL, 3.05 mmol) in isopropyl acetate (60 mL, 511 mmol). The
reaction mixture was warmed to 48 °C for 1 hr, then diluted with isopropyl acetate (190 mL)
and cooled to RT for a further 18 hr, during which time a precipitate formed. The precipitate
was isolated by filtration, washed with isopropyl e and then dried in vacuo at 40 °C to
afford the title compound, Compound (1) as a white solid (anhydrous free base, polymorphic
form A) (16.5 g, 92 %); R‘2.74 min (Method 2); m/z 584 (M+H)+ (ESf); 1H NMR (400 MHz,
s) 6: 1.30 (9H, s), 2.41 (3H, s), 6.43 (1H, s), 6.58 (1H, d), 6.78 (1H, t), 6.97 (2H, t),
7.28 (2H, br m), 7.39 (2H, d), 7.40 (1H, d), 7.49 (2H, d), 7.56 (1H, m), 7.63 (1H, m), 7.82 (1H,
dd), 7.95 (1H, d), 8.10 (1H, d), 8.40 (1H, d), 8.77 (1H, s), 9.16 (1H, br s), 9.50 (1H, br 3).
Example 2 - Summary of in Vitro and In Vivo Screening Results
The in Vitro profile of Compound (l) sed herein, as determined using the protocols
described above, are presented below (Tables 4a-f) in comparison with a structurally related
Reference Compound which is N—(4-(4-(3—(3-terf—butyl—1~p—tolyl-1H-pyrazol—5-yl)ureido)
naphthalen—1~yloxy)pyridinyl)methoxyacetamide, which has been previously described
as a potent anti-inflammatory agent with anti—viral activity (lto, K. et a/., ,
2010/050575, 7 Oct 2010 and Ito, K. et 31., , PCT/GBZOOQ/051702,
17 Jun 2010.
The compound of the present ion demonstrates a very similar inhibitory profile to the
Reference Compound in the range of kinase enzyme assays with the marked exception of
the inhibitory activity of Compound (I) against the enzyme GSK3G, which is very much
weaker than the Reference Compound (Table 4a).
Table 4a: p38 MAPK, c—Src, Syk and GSK3 or Enzyme Profile of Compound (I)
IC5o Values for Enzyme Inhibition (nM)
Test
C°mp°und
p38 MAPKa p38 MAPKv c-Src Syk GSKSa
Compound (I) 60 3739 22 334 >17000
Reference
12 344 5 42 45
Compound
The kinase binding profile of Compound (I) of the t ion was also compared with
the Reference Compound against p38 MAPK, HCK, cSrc, Syk, and GSKBG/B. Compound
(I) displayed a very different phenotype, demonstrating nd inhibition of binding versus
p38MAPK, HCK, cSrc and Syk kinases, t significant effect against GSK3d (Table 4b).
Table 4b: Comparison of the Enzyme Binding Profile of Compound (I) with the Reference
Compound.
Kd value for kinase binding (nM)
Test
Compound p33 p38
HCK cSrc GSK3d
MAPKa Syk GSK3B
MAPKy
Compound (I) 20 43 8 10 14 20000 1200
W—-——-—-——————
1 5 5 4 9 180 24
compound
The compound of the present ion demonstrates a similar profile to the nce
Compound in cellular assays that reveal anti—inflammatory ties against endotoxin
mediated release of both TN For and lL-8 (Table 4c). The profiles of the compounds are also
similar in ar systems measuring their effects on respiratory virus ation (HRV
induced ICAM1 and CPE expression and RSV stimulated expression of F—protein) as well as
virus—induced inflammation (HRV evoked release of lL~8; Table 4d).
Table 4c: Inhibition of LPS Induced TNFa and lL—8 Release and Polle Induced ICAM-
Expression for Compound (I)
LPS Induced Release (nM)
polylc I
ICAM1 (nM)
Test “L “:8
————
Compound |C5o (THP1) RECso (du937) leo (du937) lcso (BEASZB)
Compound (I) 3.4 2.3 2.2 10.2
Reference
13 0'13 1'3 2‘1
Compound
Table 4d: The Effect of nd (I) on HRV-16 Propagation (CPE) and Inflammation
(Expression of ICAM-1 and lL-8 Release) and on RSV Propagation (F-Protein Expression).
lC5o Values (nM) for HRV |C50 Values (nM) for RSV
Test Stimulated Release/Expression Stimulated Expression
Substance lL-8 ICAM1 CPE F-Protein
(BEASZB) (BEASZB) (MRCS) (HBEC)
Compound (I) 0.036 0.023 17.1 15.4
Reference
0.065 0.37 4.7 22.0
Compound
The compound of the present invention demonstrated higher efficacy in pro-inflammatory
ne production in sputum hage and bronchial epithelial cells obtained from
COPD patients, which were largely insensitive to asone propionate, a corticosteroid.
(Table 4e).
Table 4e: The Effect of nd (I) and asone propionate on pro-inflammatory
cytokine release in sputum macrophages and bronchial epithelial cell from COPD patients.
IC50 values (nM) and /or E max (% in
parentheses)1 for Test Substance Indicated
Cells Type Cytokine Compound (I) Fluticasone Propionate
lL-6 43 (79) (26)
lL-8 68 (64)
Sputum (19)
Macmphage TNFd 17 (86) (18)
MIP1a 7.5 (89) (20)
Epithelial Cell IL-8 0.85 (100) (17)
1. E-max values (maximum inhibiton) were ated as the % tion obtained at 0.1 ug/mL
However, advantageously, Compound (I) shows markedly less activity in assay systems that
measure its impact on cell viability and cell division (mitosis) indicating that the compound is
likely to possess a superior therapeutic index over the Reference Compound (Table 4f).
Table 4f: Effect of Compound (I) on Cellular Viability and Cell Division
MTT Assay1 s Assay
Test Cell viability at time point % Inhibition at 5 uglmL
Substance indicated in d-U937 CeIls in PBMC Cells
4h 24h
Compound (I) -ve ~ve 31.3
§::;:::: -ve +ve 87.8
1. Cell viability : —ve and +ve indicate the value is below and above respectively, the
no significant effect threshold defined as 30% inhibition at 1 ug/mL at the time point
indicated.
Treatment of mice with Compound (I) was found to produce a dose dependent inhibition on
LPS—induced neutrophil lation and a time course ment revealed that the drug
substance had a long duration of action (Table 5).
Table 5: The Effects of Treatment with Compound (I) on LPS-Induced Airway Neutrophilia
in Mice.
Neutrophil numbers in BALF (x105imL)
at pre-dose time indicated (% inhibition)‘
Compound (I)
(mg/mL) 2 hr 8hr 12hr
Vehicle 18.9 i 2.5 - -
0.05 15.6 i 2.1 (18) - -
0.2 9.8 i 1.6 (48) -
1.0 4.4 i 0.89 (77) 9.9 i 1.8 (48) 18.3 i 2.3 (4)
1. N = 8 per group
The result of treatment with Compound (I) on macrophage and phil lation in
BALF in the mouse cigarette smoke model was investigated (Table 6a). The cigarette smoke
model used for this study is reported to be a corticosteroid refractory system, (Medicherla S.
et at, J. col. Exp. Ther., 2008, 324(3):921-9.) and it was confirmed that quticasone
propionate did not t either neutrophil or macrophage accumulation into airways at 1.75
ug/mouse (35 1.1L, bid, i.n.), the same dose that produced >80% inhibition of LPS—induced
neutrophil accumulation.
Treatment of mice with Compound (I) was found to produce a dose—dependent inhibition on
both macrophage and neutrophil accumulation in BALF induced by cigarette smoke.
PCT/G32012/052445
Table 6a: The Effects of Treatment with Compound (I) on Tobacco Smoke in Mice.
Cell numbers in BALF x 104/mL (% inhibition)
Treatment
compound (I) (uglmL)
Macrophage phil
Vehicle + Air 4.3 i 0.45 2.6 i 0.21
Vehicle + Tobacco Smoke 14.4 i 0.33 13.7 i 0.31
0.32 13.3 i 0.20 (11) 12.4 i 0.32 (12)
1.6 11.6 i: 0.42 (28) 10.5 i 0.06 (29)
8.0 10.1 i 0.42 (43) 9.1 i 0.28 (41)
40 7.9 i 0.20 (64) 7.9 i 0.34 (52)
The data for cell numbers are shown as the mean 1* SEM, N=5
Treatment of mice with Compound (I) also inhibited cigarette smoke d CXCL1 (KC)
production in BALF in a dose-dependent manner (Table 6b).
Table 6b: The Effects of Treatment with nd (I) on CXCL1 (KC) release in BALF on
Tobacco Smoke in Mice.
Treatment CXCL1 in BALF
Compound (I) (uglmL) pg/mL (% inhibition)
Vehicle + Air 8.2 i 0.30
Vehicle + Tobacco Smoke 13.6 i 1.69
0.32 13.6 i 1.69 (0)
1.6 12.2 i 0.96 (26)
8.0 11.4:0.15(41)
40 9.5 i 0.84 (76)
The data for CXCL level are shown as the mean 1- SEM, N=5
In summary, these results suggest that the Compound (I) has r anti-inflammatory
properties to the Reference Compound disclosed above and, advantageously, is associated
with a superior therapeutic index.
e 3: Preparation of nd (I) as the anhydrous free base in solid,
crystalline, polymorphic form B
Compound (I) (398 g, in polymorphic form A) was taken up in acetone (3.98 L) and the
solution heated to 50°C. NORIT A SUPRA (19.9 9, an activated carbon) and diatomaceous
PCT/G32012/052445
earth, flux~calcined (3.98 g; a filter agent) were then added and the mixture was heated to
reflux (56°C) for 15 min. The mixture was filtered and the resulting solid was washed with
acetone (100 mL). The combined filtrate and washing acetone was warmed to reflux (56°C),
and 900 mL of solvent was removed via distillation under atmospheric pressure at 56°C. The
mixture was cooled to 50°C and water (398 mL) was then added over a period of 1 hr whilst
the temperature was ined at 50°C. After an additional 30 min at 50°C the
heterogeneous mixture was cooled to 20°C over 6h and then stirred at 20°C for 10 hr. The
resulting product was filtered and the cake was washed with acetone (318 mL). The product
was dried in vacuo at 45°C for 20 hr to produce nd (I) as the anhydrous free base in
1O solid, crystalline, polymorphic form B (240.9 g; 60.5% yield).
The above method may optionally be adapted to facilitate crystallization with seeding.
Example 3a: Preparation of Compound (I) as the anhydrous free base in solid,
crystalline, polymorphic form B containing reduced residual solvent
Optionally, Compound (I) as the anhydrous free base in solid, crystalline, polymorphic form
B, as prepared ing to the procedure described above (Example 3) or a similar
method, may be re-slurried from water in order to reduce al solvent as follows:
Compound (I) as the anhydrous free base in solid, lline, polymorphic form B (230 g, as
ed according to Example 3) was suspended in deionized water (2.30 L) and was
stirred at 20°C for 4hr. The mixture was filtered and the product was washed with deionized
water (2 x 115 mL) and was then dried at 45°C in vacuo to e Compound (I) as the
anhydrous free base in solid, crystalline, polymorphic form B ning reduced residual
solvent (22? g, 98.7%).
Example 4: Micronization of Compound (I) as the anhydrous free base in solid,
crystalline, polymorphic form B
Micronized crystalline polymorphic form B of Compound (I) as the anhydrous free base was
prepared using a jet mill micronization device (1.5 bar using a manual feeder with an injector
pressure of 1.5 bar) (manufactured by Hosokawa Alpine). The particle size distribution was
measured using laser ction rn Mastersizer 20008 ment). Particle size
distributions may be represented using D10, D50 and D90 values. The D50 median value of
particle size butions is defined as the particle size in s that divides the distribution
in half. The measurement derived from laser diffraction is more accurately described as a
volume distribution, and consequently the D50 value obtained using this procedure is more
meaningfully referred to as a Dv5o value (median for a volume distribution). As used herein
40 Dv values refer to particle size distributions measured using laser diffraction. rly, D10
and D90 values, used in the context of laser diffraction, are taken to mean Dv1o and DVgo
values and refer to the particle size whereby 10% of the distribution lies below the D10 value,
and 90% of the distribution lies below the D90 value, respectively. Micronized crystalline
W0 20137050757
polymorphic form B of nd (I) as the anhydrous free base had the ing le
size distribution: D10 of 0.850 um; D50 of1.941 pm and D90 of 4.563 pm.
Example 5: XRPD analysis of Compound (l) as the anhydrous free base in solid,
crystalline, polymorphic forms A and B
XRPD analysis of Compound (I) as the anhydrous free base in solid crystalline polymorphic
forms A and B (polymorphic form B was micronized following the procedure of Example 4)
was undertaken using the method described in General Procedures. The resulting diffraction
1O patterns are shown in Figures 1 and 2 respectively. Both XRPD patterns showed diffraction
peaks without the presence of a halo, thereby indicating that both materials are crystalline.
Peaks and their intensities are listed below (Table 7a and Table 7b).
Table 7a: Characteristic XRPD peaks and their intensities for Compound (I) as the
anhydrous free base in solid, crystalline, form A
XRPD Peaks
2-Theta 1 Intensities
7.8 19.7
8.7 20.8
.3 22.6
11.2 23.1
12.4 24.6
.2 25.5
16.2 26.7
17.5 27.4
1. Values are :r 0.2 degrees
Table 7b: Characteristic XRPD peaks for Compound (l) as the ous free base in solid
lline form B, post micronization.
XRPD peaks
2-Theta Values1 Intensities
3.9 16.7
6.1 18.3
7.7 18.7
8.6 19.9
.9 20.9
11.8 22.0
12.7 22.6
14.3 25.2
.9 28.9
1. Values are i 0.2 degrees
Example 6: Melting point determination of Compound (l) as the anhydrous free base in
solid, crystalline, polymorphic forms A and B
The melting points of Compound (I) as the anhydrous free base in solid crystalline
polymorphic forms A and B (the latter post micronization) were obtained using ential
scanning calorimetry (DSC), as bed in the General Procedures. Polymorphic form A
melted at 191.6°C and rphic form B melted at 214.0°C. From the DSC data it was
calculated that form B had a higher heat of fusion than form A. Since form B also has a
higher melting point than form A, this tes that polymorphic forms A and B are
monotropic related, meaning that higher melting polymorphic form B will be more stable than
lower melting polymorphic form A, at all temperatures. As such, it can be expected that
polymorphic form B is thermodynamically more stable than polymorphic form A.
Example 7: Thermal analysis of Compound (l) as the anhydrous free base in solid,
crystalline, polymorphic form B, post micronization.
Thermal analysis of Compound (I) as the anhydrous free base in lline polymorphic form
B (micronized) was undertaken using TGA, DVS, XRPD analysis, lR spectroscopy and DSC
as described in General ures. Where appropriate, a sample at ambient ature
and relative humidity (reference sample/ ”0 days”) was compared with samples stored at
s temperatures and relative humidities (comparative samples).
Thermogravimetric Analysis: The reference sample (t = 0) and the comparative samples that
were exposed prior to analysis to different storage conditions, were heated at a rate of
°C/min from RT to 300°C. The TGA curve of the reference sample (t = 0) is illustrated in
Figure 3 and the results for all samples are ised below (Table 8). As can be seen
from Figure 3, a weight loss of 0.6% was observed in the temperature range from RT to
180°C, which was due to solvent evaporation. The weight loss that occurred above 180°C
was due to evaporation and decomposition of the product. ing this weight loss profile
with those of the comparative samples in Table 8, no icant differences were observed.
Dynamic vapour sorption: The DVS isotherm plot for the micronized reference sample is
illustrated in Figure 4 and the DVS change in mass plot for the micronized reference sample
is illustrated in Figure 5. During the l drying step, no weight loss was registered and the
product showed no hygroscopic behavior. The product adsorbed up to 0.4% moisture
depending on the atmospheric humidity. The product was found to dry out tely and
ed in the same lline solid state (form B) during the test, as evidenced by the R
spectrum and XRPD pattern being substantially the same before and after the DVS analysis.
XRPD Analysis and JR Spectroscopy: The XPRD diffraction pattern of the reference sample
(t = 0) is illustrated in Figure 2 and the IR trace is illustrated in Figure 6. The ction
pattern and IR trace were compared with those of the comparative samples (exposed to
different storage conditions) and the results are summarised in Table 8. The diffraction
patterns and IR traces were identical for all samples.
ential ng Calorimetry. The reference sample (t = 0) and comparative samples,
previously exposed to different storage ions, were heated at a rate of 10°C/min from
°C to 300°C. The DSC curve of the reference sample is illustrated in Figure 7 and the
results for all samples are summarised below (Table 8). From Figure 7, it is evident that the
reference sample melted with decomposition at 214.0°C.
Table 8: Thermal analysis of Compound (I) as the anhydrous free base in solid crystalline
polymorphic form B post micronization.
Stota'ge W 2 IR DSC3 Appearance
Conditions
<100°C <180°C
_ Cryst. Cryst.
T - zero 0.6 214 off-white
Ref Ref
1 week i 80°C NT NT ~Ref ~Ref NT off—white
NT NT Ref Ref NT off—white.
_81'L__
4 weeks l RT/
0.8 0.5 ~Ref Ref 214 off—white'
<5 % RH
4 weeks / RT/
0-5 0.4 Ref ~Ref 214 off—whlte‘
56% RH
4 weeks / RT /
0.9 0.5 Ref Ref 21 4 off—white_
4 weeks / 50°C 1.3 0.5 ~Ref ~Ref 214 off-white
0.8 0.3 ~Ref ~Ref 214 off—white‘
75% RH
1. Cryst.: crystalline; 2..~Ref: pattern identical with reference sample, 3. max (°C); NT: Not tested in
this assay
In summary, it is evident that Compound (I) as the anhydrous free base in solid, crystalline,
polymorphic form B has good physical stability.
PCT/G32012/052445
Example 8: HPLC analysis of Compound (l) as the anhydrous free base in solid,
crystalline, polymorphic form B post micronization.
The chemical stability of Compound (l) as the anhydrous free base in solid, crystalline,
polymorphic form B, following ization, was determined by comparing a sample
maintained at t temperature and relative humidity (reference sample) with samples
stored at various temperatures and relative humidities as set out hereinabove (the
comparative s, Table 8). The reference and comparative samples were then analyzed
by HPLC using the method described in General ures and by visual inspection. The
1O results from this study (data summarised in Table 9) reveal that Compound (I), prepared as
the anhydrous free base in solid, crystalline, polymorphic form B is chemically stable
gh some sensitivity to light was observed.
Table 9: Chemical stability of Compound (l) as the anhydrous free base in solid, crystalline,
polymorphic form B, post ization.
Sum of impurities by
HPLC (%)1 ance1
Storage
Conditions 1 week 4 weeks 1 week 4 weeks
T = zero 0.66 NT off-white NT
0.3 day, lCH light2 1.44 NT ite NT
80°C 0.73 NT Off-white NT
70°C I 75% RH 0.73 NT Off—White NT
40°C / 75% RH 0.66 0.68 Off—White Off—White
50°C 0.69 0.66 Off-White Off-White
RT/ <5% RH NT 0.67 NT Off-White
RT / 56% RH NT 0.67 NT Off-White
RT / 75% RH NT 0.67 NT Off-White
1. NT in this assay ; 2. Stimulated daylight: light t 700 W/mz.
Example 9 — Preparation of pharmaceutical formulations
An exemplary pharmaceutical formulation of the invention would consist of 0.4 wt.% of
Compound (I) (as the anhydrous free base in solid crystalline polymorphic form B), 98.6 wt.%
lactose drate (inhalation grade) and 1.0 wt.% magnesium stearate, wherein the wt.%
of all components is based on the weight of the dry pharmaceutical formulation.
Throughout the specification and the claims which follow, unless the context requires
otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be
understood to imply the ion of a stated integer, step, group of integers or group of steps
but not to the exclusion of any other integer, step, group of integers or group of steps.
All patents and patent applications referred to herein are incorporated by reference in their
entirety.
Claims (4)
1. A compound of formula (I) mtowO \ N\ N /N i ~ N H H O Y HN\© Me (I) or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.
2. A compound according to claim 1, as the free base.
3. A compound according to claim 2, as the ous free base in solid crystalline form.
4. A compound according to claim 3, wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having the X-ray powder ction pattern substantially as shown in
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11183688.8A EP2578582A1 (en) | 2011-10-03 | 2011-10-03 | 1-Pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl)ureas as p38 MAP kinase inhibitors |
EP11183682 | 2011-10-03 | ||
EP11183688.8 | 2011-10-03 | ||
EP11183682.1 | 2011-10-03 | ||
EP12168396 | 2012-05-16 | ||
EP12168395 | 2012-05-16 | ||
EP12168396.5 | 2012-05-16 | ||
EP12168395.7 | 2012-05-16 | ||
PCT/GB2012/052445 WO2013050757A1 (en) | 2011-10-03 | 2012-10-03 | 1-pyrazolyl-3- (4- ( (2 -anilinopyrimidin- 4 - yl) oxy) napththalen- 1 - yl) ureas as p38 map kinase inhibitors |
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NZ621440B2 true NZ621440B2 (en) | 2015-05-28 |
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