U.S. patent application number 15/138277 was filed with the patent office on 2016-08-18 for novel polymorphs and salts.
The applicant listed for this patent is Glaxo Group Limited. Invention is credited to Julie Nicole HAMBLIN, Paul Spencer JONES, Suzanne Elaine KEELING, Joelle LE, Charlotte Jane MITCHELL, Nigel James PARR, Robert David WILLACY.
Application Number | 20160237073 15/138277 |
Document ID | / |
Family ID | 51488540 |
Filed Date | 2016-08-18 |
United States Patent
Application |
20160237073 |
Kind Code |
A1 |
HAMBLIN; Julie Nicole ; et
al. |
August 18, 2016 |
Novel Polymorphs and Salts
Abstract
The present invention is directed to novel polymorphs and salts
of a compound which is an inhibitor of kinase activity.
Inventors: |
HAMBLIN; Julie Nicole;
(Stevenage, GB) ; JONES; Paul Spencer; (Stevenage,
GB) ; KEELING; Suzanne Elaine; (Stevenage, GB)
; LE; Joelle; (Stevenage, GB) ; MITCHELL;
Charlotte Jane; (Stevenage, GB) ; PARR; Nigel
James; (Stevenage, GB) ; WILLACY; Robert David;
(Stevenage, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Glaxo Group Limited |
Brentford |
|
GB |
|
|
Family ID: |
51488540 |
Appl. No.: |
15/138277 |
Filed: |
April 26, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14753141 |
Jun 29, 2015 |
9353098 |
|
|
15138277 |
|
|
|
|
14251778 |
Apr 14, 2014 |
9102668 |
|
|
14753141 |
|
|
|
|
13821585 |
Mar 8, 2013 |
8735390 |
|
|
PCT/EP2011/065419 |
Sep 6, 2011 |
|
|
|
14251778 |
|
|
|
|
61380748 |
Sep 8, 2010 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 413/14
20130101 |
International
Class: |
C07D 413/14 20060101
C07D413/14 |
Claims
1-15. (canceled)
16. A salt of
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide which
is selected from the group consisting of from sodium, tosylate,
maleate, hemi pamoate, hemi naphthalenedisulfonate,
mesitylenesulfonate, hemi biphenyldisulfonate,
2-naphthalenesulfonate (napsylate), hemi cinnamate, hemi sebacate,
hemi pyromellitate and hemi benzenediacrylate.
17. A pharmaceutical composition comprising a salt according to
claim 16 and one or more pharmaceutically acceptable excipients.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to novel polymorphs and
salts of a compound which is an inhibitor of kinase activity, more
specifically a compound which is an inhibitor of the activity or
function of phosphoinositide 3'OH kinase isoform delta (hereinafter
PI3K.delta.), processes for their preparation, pharmaceutical
compositions comprising them, and their use in the treatment of
various disorders.
BACKGROUND OF THE INVENTION
[0002] Cellular membranes represent a large store of second
messengers that can be enlisted in a variety of signal transduction
pathways. In relation to function and regulation of effector
enzymes in phospholipids signaling pathways, class I PI3-kinases
(e.g. PI3K.delta.) generate second messengers from the membrane
phospholipid pools. Class I PI3Ks convert the membrane phospholipid
PI(4,5)P.sub.2 into PI(3,4,5)P.sub.3, which functions as a second
messenger. PI and PI(4)P are also substrates of PI3K and can be
phosphorylated and converted into PI3P and PI(3,4)P.sub.2,
respectively. In addition, these phosphoinositides can be converted
into other phosphoinositides by 5'-specific and 3'-specific
phophatases. Thus, PI3K enzymatic activity results either directly
or indirectly in the generation of two 3'-phosphoinositide subtypes
which function as second messengers in intracellular signal
transduction pathways (Trends Biochem. Sci. 22(7) p. 267-72 (1997)
by Vanhaesebroeck et al.; Chem. Rev. 101(8) p. 2365-80 (2001) by
Leslie et al.; Annu. Rev. Cell Dev. Biol. 17 p. 615-75 (2001) by
Katso et al.; and Cell. Mol. Life Sci. 59(5) p. 761-79 (2002) by
Toker). To date, eight mammalian PI3Ks have been identified,
divided into three main classes (I, II, and III) on the basis of
sequence homology, structure, binding partners, mode of activation,
and substrate preference. In vitro, class I PI3Ks can phosphorylate
phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P),
and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P.sub.2) to
produce phosphatidylinositol-3-phosphate (PI3P),
phosphatidylinositol-3,4-bisphosphate (PI(3,4)P.sub.2, and
phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P.sub.3,
respectively. Class 11 PI3Ks can phosphorylate PI and PI4P. Class
III PI3Ks can only phosphorylate PI (Vanhaesebroeck et al. (1997),
above; Vanhaesebroeck et al. Exp. Cell Res. 253(1) p. 239-54
(1999); and Leslie et al. (2001), above).
[0003] Class I PI3K is a heterodimer consisting of a p110 catalytic
subunit and a regulatory subunit, and the family is further divided
into class Ia and class Ib enzymes on the basis of regulatory
partners and mechanism of regulation. Class Ia enzymes consist of
three distinct catalytic subunits (p110.alpha., p110.beta., and
p110.delta.) that dimerise with five distinct regulatory subunits
(p85.alpha., p55.alpha., p50.alpha., p85.beta., and p55.gamma.),
with all catalytic subunits being able to interact with all
regulatory subunits to form a variety of heterodimers. Class Ia
PI3K are generally activated in response to growth
factor-stimulation of receptor tyrosine kinases, via interaction of
the regulatory subunit SH2 domains with specific phospho-tyrosine
residues of the activated receptor or adaptor proteins such as
IRS-1. Small GTPases (ras as an example) are also involved in the
activation of PI3K in conjunction with receptor tyrosine kinase
activation. Both p110.alpha. and p110.beta. are constitutively
expressed in all cell types, whereas p110.delta. expression is more
restricted to leukocyte populations and some epithelial cells. In
contrast, the single Class Ib enzyme consists of a p110.gamma.
catalytic subunit that interacts with a p101 regulatory subunit.
Furthermore, the Class Ib enzyme is activated in response to
G-protein coupled receptor (GPCR) systems and its expression
appears to be limited to leukocytes.
##STR00001##
[0004] As illustrated in Scheme A above, phosphoinositide 3-kinases
(PI3Ks) phosphorylate the hydroxyl of the third carbon of the
inositol ring. The phosphorylation of phosphoinositides to generate
PtdIns(3,4,5)P.sub.3, PtdIns(3,4)P.sub.2 and PtdIns(3)P, produces
second messengers for a variety of signal transduction pathways,
including those essential to cell proliferation, cell
differentiation, cell growth, cell size, cell survival, apoptosis,
adhesion, cell motility, cell migration, chemotaxis, invasion,
cytoskeletal rearrangement, cell shape changes, vesicle trafficking
and metabolic pathway (Katso et al. (2001), above; and Mol. Med.
Today 6(9) p. 347-57 (2000) by Stein et al.).
[0005] The activity of PI3-kinases responsible for generating these
phosphorylated signalling products was originally identified as
being associated with viral oncoproteins and growth factor receptor
tyrosine kinases that phosphorylate phosphatidylinositol (PI) and
its phosphorylated derivatives at the 3'-hydroxyl of the inositol
ring (Panayotou et al. Trends Cell Biol. 2 p. 358-60 (1992)).
However, more recent biochemical studies have revealed that class I
PI3-kinases (e.g. class IA isoform PI3K.delta.) are dual-specific
kinase enzymes, meaning they display both lipid kinase
(phosphorylation of phosphoinositides) as well as protein kinase
activity, which have been shown to be capable of phosphorylation of
other protein as substrates, including auto-phosphorylation as an
intramolecular regulatory mechanism (EMBO J. 18(5) p. 1292-302
(1999) by Vanhaesebroeck et al.). Cellular processes in which PI3Ks
play an essential role include suppression of apoptosis,
reorganization of the actin skeleton, cardiac myocyte growth,
glycogen synthase stimulation by insulin, TNF.alpha.-mediated
neutrophil priming and superoxide generation, and leukocyte
migration and adhesion to endothelial cells.
[0006] PI3-kinase activation, is believed to be involved in a wide
range of cellular responses including cell growth, differentiation,
and apoptosis (Parker, Current Biology 5(6) p. 577-79 (1995); and
Yao et al. Science 267(5206) p. 2003-06 (1995)). PI3-kinase appears
to be involved in a number of aspects of leukocyte activation. A
p85-associated PI3-kinase has been shown to physically associate
with the cytoplasmic domain of CD28, which is an important
costimulatory molecule for the activation of T-cells in response to
antigen (Pages et al. Nature 369 p. 327-29 (1994); and Rudd,
Immunity 4 p. 527-34 (1996)). Activation of T cells through CD28
lowers the threshold for activation by antigen and increases the
magnitude and duration of the proliferative response. These effects
are linked to increases in the transcription of a number of genes
including interleukin-2 (IL2), an important T cell growth factor
(Fraser et al. Science 251(4991) p. 313-16 (1991)).
[0007] PI3K.gamma. has been identified as a mediator of G
beta-gamma-dependent regulation of JNK activity, and G beta-gamma
are subunits of heterotrimeric G proteins (Lopez-IIasaca et al. J.
Biol. Chem. 273(5) p. 2505-8 (1998)). Recently, (Laffargue et al.
Immunity 16(3) p. 441-51 (2002)) it has been described that
PI3K.gamma. relays inflammatory signals through various
G(i)-coupled receptors and is central to mast cell function,
stimuli in the context of leukocytes, and immunology including
cytokines, chemokines, adenosines, antibodies, integrins,
aggregation factors, growth factors, viruses or hormones for
example (J. Cell Sci. 114 (Pt 16) p. 2903-10 (2001) by Lawlor et
al.; Laffargue et al. (2002), above; and Curr. Opinion Cell Biol.
14(2) p. 203-13 (2002) by Stephens et al.).
[0008] Specific inhibitors against individual members of a family
of enzymes provide invaluable tools for deciphering functions of
each enzyme. Two compounds, LY294002 and wortmannin (hereinafter),
have been widely used as PI3-kinase inhibitors. These compounds are
non-specific PI3K inhibitors, as they do not distinguish among the
four members of Class I PI3-kinases. For example, the IC.sub.50
values of wortmannin against each of the various Class I
PI3-kinases are in the range of 1-10 nM. Similarly, the IC.sub.50
values for LY294002 against each of these PI3-kinases is about
15-20 .mu.M (Fruman et al. Ann. Rev. Biochem. 67 p. 481-507
(1998)), also 5-10 microM on CK2 protein kinase and some inhibitory
activity on phospholipases. Wortmannin is a fungal metabolite which
irreversibly inhibits PI3K activity by binding covalently to the
catalytic domain of this enzyme. Inhibition of PI3K activity by
wortmannin eliminates subsequent cellular response to the
extracellular factor. For example, neutrophils respond to the
chemokine fMet-Leu-Phe (fMLP) by stimulating PI3K and synthesizing
PtdIns (3, 4, 5)P.sub.3. This synthesis correlates with activation
of the respiratory burst involved in neutrophil destruction of
invading microorganisms. Treatment of neutrophils with wortmannin
prevents the fMLP-induced respiratory burst response (Thelen et al.
Proc. Natl. Acad. Sci. USA 91 p. 4960-64 (1994)). Indeed, these
experiments with wortmannin, as well as other experimental
evidence, show that PI3K activity in cells of hematopoietic
lineage, particularly neutrophils, monocytes, and other types of
leukocytes, is involved in many of the non-memory immune response
associated with acute and chronic inflammation.
##STR00002##
[0009] Based on studies using wortmannin, there is evidence that
PI3-kinase function is also required for some aspects of leukocyte
signaling through G-protein coupled receptors (Thelen et al.
(1994), above). Moreover, it has been shown that wortmannin and
LY294002 block neutrophil migration and superoxide release.
[0010] It is now well understood that deregulation of oncogenes and
tumour suppressor genes contributes to the formation of malignant
tumours, for example by way of increased cell growth and
proliferation or increased cell survival. It is also now known that
signaling pathways mediated by the PI3K family have a central role
in a number of cell processes including proliferation and survival,
and deregulation of these pathways is a causative factor a wide
spectrum of human cancers and other diseases (Katso et al. Annual
Rev. Cell Dev. Biol. (2001) 17 p. 615-675 and Foster et al. J. Cell
Science (2003) 116(15) p. 3037-3040). PI3K effector proteins
initiate signalling pathways and networks by translocating to the
plasma membrane through a conserved Pleckstrin Homology (PH)
domain, which specifically interacts with PtdIns(3,4,5)P3
(Vanhaesebroeck et al. Annu. Rev. Biochem. (2001) 70 p. 535-602).
The effector proteins signalling through PtdIns(3,4,5)P3 and PH
domains include Serine/Threonine (Ser/Thr) kinases, Tyrosine
kinases, Rac or Arf GEFs (Guanine nucleotide exchange factors) and
Arf GAPs (GTPase activating proteins).
[0011] In B and T cells PI3Ks have an important role through
activation of the Tec family of protein tyrosine kinases which
include Bruton's tyrosine kinase (BTK) in B cells and
Interleukin-2-inducible T-cell kinase (ITK) in T cells. Upon PI3K
activation, BTK or ITK translocate to the plasma membrane where
they are subsequently phosphorylated by Src kinases. One of the
major targets of activated ITK is phospholipase C-gamma
(PLC.gamma.1), which hydrolyses PtdIns(4,5)P2 into Ins(3,4,5)P3 and
initiates an intracellular increase in calcium levels and
diacylglycerol (DAG) which can activate Protein Kinases C in
activated T cells.
[0012] Unlike the Class IA p110.alpha. and p110.beta., p110.delta.
is expressed in a tissue restricted fashion. Its high expression
level in lymphocytes and lymphoid tissues suggests a role in
PI3K-mediated signalling in the immune system. The p110.delta.
kinase dead knock-in mice are also viable and their phenotype is
restricted to defects in immune signalling (Okkenhaug et al.
Science (2002) 297 p. 1031-4). These transgenic mice have offered
insight into the function of PI3K.delta. in B-cell and T-cell
signalling. In particular, p110.delta. is required for
PtdIns(3,4,5)P3 formation downstream of CD28 and/or T cell Receptor
(TCR) signalling. A key effect of PI3K signalling downstream of TCR
is the activation of Akt, which phosphorylates anti-apoptotic
factors as well as various transcription factors for cytokine
production. As a consequence, T cells with inactive p110.delta.
have defects in proliferation and Th1 and Th2 cytokine secretion.
Activation of T cells through CD28 lowers the threshold for TCR
activation by antigen and increases the magnitude and duration of
the proliferative response. These effects are mediated by the
PI3K.delta.-dependent increase in the transcription of a number of
genes including IL2, an important T cell growth factor.
[0013] Therefore, PI3K inhibitors are anticipated to provide
therapeutic benefit via its role in modulating T-cell mediated
inflammatory responses associated to respiratory diseases such as
asthma, COPD and cystic fibrosis. In addition, there is indication
that T-cell directed therapies may provide corticosteroid sparing
properties (Alexander et al. Lancet (1992) 339 p. 324-8) suggesting
that it may provide a useful therapy either as a standalone or in
combination with inhaled or oral glucocorticosteroids in
respiratory diseases. A PI3K inhibitor might also be used alongside
other conventional therapies such as a long acting beta-agonists
(LABA) in asthma.
[0014] In the vasculature, PI3K.delta. is expressed by endothelial
cells and participates in neutrophil trafficking by modulating the
proadhesive state of these cells in response to TNFalpha (Puri et
al. Blood (2004) 103(9) p. 3448-56). A role for PI3K.delta. in
TNFalpha-induced signalling of endothelial cells is demonstrated by
the pharmacological inhibition of Akt phosphorylation and PDK1
activity. In addition, PI3K.delta. is implicated in vascular
permeability and airway tissue edema through the VEGF pathway (Lee
et al. J. Allergy Clin. Immunol. (2006) 118(2) p. 403-9). These
observations suggest additional benefits of PI3K.delta. inhibition
in asthma by the combined reduction of leukocyte extravasation and
vascular permeability associated with asthma. In addition,
PI3K.delta. activity is required for mast cell function both in
vitro and in vivo (Ali et al. Nature (2004) 431 p. 1007-11; and Ali
et al. J. Immunol. (2008) 180(4) p. 2538-44) further suggesting
that PI3K inhibition should be of therapeutical benefit for
allergic indications such asthma, allergic rhinitis and atopic
dermatitis.
[0015] The role of PI3K.delta. in B cell proliferation, antibody
secretion, B-cell antigen and IL-4 receptor signalling, B-cell
antigen presenting function is also well established Okkenhaug et
al. (2002), above; Al-Alwan et al. J. Immunol. (2007) 178(4) p.
2328-35; and Bilancio et al. Blood (2006) 107(2) p. 642-50) and
indicates a role in autoimmune diseases such as rheumatoid
arthritis or systemic lupus erythematosus. Therefore PI3K
inhibitors may also be of benefit for these indications.
[0016] Pharmacological inhibition of PI3K.delta. inhibits
fMLP-dependent neutrophil chemotaxis on an ICAM coated agarose
matrix integrin-dependent biased system (Sadhu et al., J. Immunol.
(2003) 170(5) p. 2647-54). Inhibition of PI3K.delta. regulates
neutrophil activation, adhesion and migration without affecting
neutrophil mediated phagocytosis and bactericidal activity over
Staphylococcus aureus (Sadhu et al. Biochem. Biophys. Res. Commun.
(2003) 308(4) p. 764-9). Overall, the data suggest that PI3K.delta.
inhibition should not globally inhibit neutrophil functions
required for innate immune defense. PI3K.delta.'s role in
neutrophils offers further scope for treating inflammatory diseases
involving tissue remodeling such as COPD or rheumatoid
arthritis.
[0017] In addition, there is also good evidence that class Ia PI3K
enzymes also contribute to tumourigenesis in a wide variety of
human cancers, either directly or indirectly (Vivanco and Sawyers,
Nature Reviews Cancer (2002) 2(7) p. 489-501). For example,
inhibition of PI3K.delta. may have a therapeutic role for the
treatment of malignant haematological disorders such as acute
myeloid leukaemia (Billottet et al. Oncogene (2006) 25(50) p.
6648-59). Moreover, activating mutations within p110.alpha.(PIK3CA
gene) have been associated with various other tumors such as those
of the colon and of the breast and lung (Samuels et al. Science
(2004) 304(5670) p. 554).
[0018] It has also been shown that PI3K is involved in the
establishment of central sensitization in painful inflammatory
conditions (Pezet et al. The J. of Neuroscience (2008) 28 (16) p.
4261-4270).
[0019] A wide variety of retroviruses and DNA based viruses
activate the PI3K pathway as a way of preventing host cell death
during viral infection and ultimately exploiting the host cell
synthesis machinery for its replication (Virology 344(1) p. 131-8
(2006) by Vogt et al.; and Nat. Rev. Microbiol. 6(4) p. 265-75
(2008) by Buchkovich et al.). Therefore PI3K inhibitors may have
anti-viral properties in addition to more established oncolytic and
anti-inflammatory indications. These antiviral effects raise
interesting prospects in viral induced inflammatory exacerbations.
For example, the common cold human rhinovirus (HRV) is responsible
for more than 50% of respiratory tract infections but complications
of these infections can be significant in certain populations. This
is particularly the case in respiratory diseases such as asthma or
chronic obstruction pulmonary disease (COPD). Rhinoviral infection
of epithelial cells leads to a PI3K dependent cytokine and
chemokine secretion (J. Biol. Chem. (2005) 280(44) p. 36952 by
Newcomb et al.). This inflammatory response correlates with
worsening of respiratory symptoms during infection. Therefore PI3K
inhibitors may dampen an exaggerated immune response to an
otherwise benign virus. The majority of HRV strains infect
bronchial epithelial cells by initially binding to the ICAM-1
receptor. The HRV-ICAM-1 complex is then further internalised by
endocytosis and it has been shown that this event requires PI3K
activity (J. Immunol. (2008) 180(2) p. 870-880 by Lau et al.).
Therefore, PI3K inhibitors may also block viral infections by
inhibiting viral entry into host cells.
[0020] PI3K inhibitors may be useful in reducing other types of
respiratory infections including the fungal infection aspergillosis
(Mucosal Immunol. (2010) 3(2) p. 193-205 by Bonifazi et al.). In
addition, PI3K.delta. deficient mice are more resistant towards
infections by the protozoan parasite Leishmania major (J. Immunol.
(2009) 183(3) p. 1921-1933 by Liu et al.). Taken with effects on
viral infections, these reports suggest that PI3K inhibitors may be
useful for the treatment of a wide variety of infections.
[0021] PI3K inhibition has also been shown to promote regulatory T
cell differentiation (Proc. Natl. Acad. Sci. USA (2008) 105(22) p.
7797-7802 by Sauer et al.) suggesting that PI3K inhibitors may
serve therapeutic purposes in auto-immune or allergic indications
by inducing immuno-tolerance towards self antigen or allergen.
Recently the PI3K.delta. isoform has also been linked to smoke
induced glucocorticoid insensitivity (Am. J. Respir. Crit. Care
Med. (2009) 179(7) p. 542-548 by Marwick et al.). This observation
suggests that COPD patients, which otherwise respond poorly to
corticosteroids, may benefit from the combination of a PI3K
inhibitor with a corticosteroid.
[0022] PI3K has also been involved in other respiratory conditions
such as idiopathic pulmonary fibrosis (IPF). IPF is a fibrotic
disease with progressive decline of lung function and increased
mortality due to respiratory failure. In IPF, circulating
fibrocytes are directed to the lung via the chemokine receptor
CXCR4. PI3K is required for both signalling and expression of CXCR4
(Int. J. Biochem. and Cell Biol. (2009) 41 p. 1708-1718 by Mehrad
et al.). Therefore, by reducing CXCR4 expression and blocking its
effector function, a PI3K inhibitor should inhibit the recruitment
of fibrocytes to the lung and consequently slow down the fibrotic
process underlying IPF, a disease with high unmet need.
[0023] Compounds which are PI3-kinase inhibitors may therefore be
useful in the treatment of disorders associated with inappropriate
kinase activity, in particular inappropriate PI3-kinase activity,
for example in the treatment and prevention of disorders mediated
by PI3-kinase mechanisms. Such disorders include respiratory
diseases including asthma, chronic obstructive pulmonary disease
(COPD) and idiopathic pulmonary fibrosis (IPF); viral infections
including viral respiratory tract infections and viral exacerbation
of respiratory diseases such as asthma and COPD; non-viral
respiratory infections including aspergillosis and leishmaniasis;
allergic diseases including allergic rhinitis and atopic
dermatitis; autoimmune diseases including rheumatoid arthritis and
multiple sclerosis; inflammatory disorders including inflammatory
bowel disease; cardiovascular diseases including thrombosis and
atherosclerosis; hematologic malignancies; neurodegenerative
diseases; pancreatitis; multiorgan failure; kidney diseases;
platelet aggregation; cancer; sperm motility; transplantation
rejection; graft rejection; lung injuries; and pain including pain
associated with rheumatoid arthritis or osteoarthritis, back pain,
general inflammatory pain, post hepatic neuralgia, diabetic
neuropathy, inflammatory neuropathic pain (trauma), trigeminal
neuralgia and Central pain.
[0024] Attempts have been made to prepare compounds which inhibit
PI3-kinase activity and a number of such compounds have been
disclosed in the art.
[0025] International patent application PCT/EP2010/055666
(publication number WO2010/125082) describes compounds having the
general formula (I):
##STR00003##
and salts thereof.
[0026] The examples of international patent application
PCT/EP2010/055666 (publication number WO2010/125082) describe the
preparation of
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide which
may be represented by the formula (II):
##STR00004##
hereinafter referred to as "Compound A".
[0027] The present inventors have now found novel polymorphs and
salts of Compound A.
[0028] In one embodiment, the salts of Compound A may have
properties, for example solubility, which make them particularly
suitable for administration as a drug, for example as an inhaled
drug.
SUMMARY OF THE INVENTION
[0029] The invention is directed to novel polymorphs and salts of
Compound A.
BRIEF DESCRIPTION OF THE FIGURES
[0030] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern for
the Form (II) polymorph of Compound A.
[0031] FIG. 2 shows an XRPD pattern for the Form (III) polymorph of
Compound A.
[0032] FIG. 3 shows an XRPD pattern for the Form (IV) polymorph of
Compound A.
DETAILED DESCRIPTION OF THE INVENTION
[0033] In one aspect, the invention is directed to novel polymorphs
of Compound A.
[0034] In one embodiment, the invention provides a polymorph (Form
II) of Compound A characterised in that it provides an XRPD pattern
comprising peaks (.degree.2.theta.) at about 4.6, about 9.2, about
11.4 and/or about 12.7.
[0035] In another embodiment, the invention provides a polymorph
(Form II) of Compound A characterised in that it provides an XRPD
pattern comprising peaks substantially as set out in Table 1.
[0036] In a further embodiment, the invention provides a polymorph
(Form II) of Compound A characterised in that it provides an XRPD
pattern substantially in accordance with FIG. 1.
[0037] In one embodiment, the invention provides a polymorph (Form
III) of Compound A characterised in that it provides an XRPD
pattern comprising peaks (.degree.2.theta.) at about 6.7, about
8.2, about 9.7 and/or about 12.6.
[0038] In another embodiment, the invention provides a polymorph
(Form III) of Compound A characterised in that it provides an XRPD
pattern comprising peaks substantially as set out in Table 2.
[0039] In a further embodiment, the invention provides a polymorph
(Form III) of Compound A characterised in that it provides an XRPD
pattern substantially in accordance with FIG. 2.
[0040] In one embodiment, the invention provides a polymorph (Form
IV) of Compound A characterised in that it provides an XRPD pattern
comprising peaks (.degree.2.theta.) at about 5.8, and/or about
11.6.
[0041] In another embodiment, the invention provides a polymorph
(Form IV) of Compound A characterised in that it provides an XRPD
pattern comprising peaks substantially as set out in Table 3.
[0042] In a further embodiment, the invention provides a polymorph
(Form IV) of Compound A characterised in that it provides an XRPD
pattern substantially in accordance with FIG. 3.
[0043] When it is indicated herein that there is a peak in an XRPD
pattern at a given value, it is typically meant that the peak is
within .+-.0.2 of the value quoted, for example within .+-.0.1 of
the value quoted.
[0044] In a further aspect, the invention is directed to novel
salts of Compound A.
[0045] In one embodiment, the invention provides a salt of Compound
A selected from sodium, tosylate, maleate, hemi pamoate, hemi
naphthalenedisulfonate, mesitylenesulfonate, hemi
biphenyldisulfonate, 2-naphthalenesulfonate (napsylate), hemi
cinnamate, hemi sebacate, hemi pyromellitate and hemi
benzenediacrylate.
[0046] In another embodiment, the invention provides a salt of
Compound A selected from sodium, tosylate, maleate, hemi pamoate
and hemi naphthalenedisulfonate.
[0047] In another embodiment, the invention provides a salt of
Compound A selected from hemi pamoate, hemi naphthalenedisulfonate,
mesitylenesulfonate, hemi biphenyldisulfonate, hemi cinnamate, hemi
sebacate, hemi pyromellitate and hemi benzenediacrylate.
[0048] In another embodiment, the invention provides a salt of
Compound A selected from hemi naphthalenedisulfonate,
mesitylenesulfonate, hemi biphenyldisulfonate, hemi cinnamate, hemi
sebacate, hemi pyromellitate and hemi benzenediacrylate.
[0049] In another embodiment, the invention provides a salt of
Compound A selected from hemi pamoate and hemi
naphthalenedisulfonate.
[0050] In another embodiment, the invention provides the hemi
pamoate salt of Compound A.
[0051] In a further embodiment, the invention provides the hemi
naphthalenedisulfonate salt of Compound A.
[0052] The sodium salt of Compound A is the salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
sodium hydroxide in a stoichiometric ratio of about 1:1. The
tosylate salt of Compound A is the mono tosylate salt formed
between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
p-toluenesulfonic acid in a stoichiometric ratio of about 1:1. The
maleate salt of Compound A is the mono maleate salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
maleic acid in a stoichiometric ratio of about 1:1. The hemi
pamoate salt of Compound A is the salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
pamoic acid in a stoichiometric ratio of about 2:1. The hemi
naphthalenedisulfonate salt of Compound A is the salt formed
between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
naphthalenedisulfonic acid in a stoichiometric ratio of about
2:1.
[0053] The mesitylenesulfonate salt of Compound A is the mono
mesitylenesulfonate salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
mesitylenesulfonic acid dihydrate in a stoichiometric ratio of
about 1:1. The hemi biphenyldisulfonate salt of Compound A is the
salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazo-
l-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
and biphenyldisulfonic acid in a stoichiometric ratio of about 2:1.
The 2-naphthalenesulfonate (napsylate) salt of Compound A is the
mono 2-naphthalenesulfonate (napsylate) salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
2-naphthalenesulfonic acid in a stoichiometric ratio of about 1:1.
The hemi cinnamate salt of Compound A is the salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
trans-cinnamic acid in a stoichiometric ratio of about 2:1. The
hemi sebacate salt of Compound A is the salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
sebacic acid in a stoichiometric ratio of about 2:1. The hemi
pyromellitate salt of Compound A is the salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
pyromellitic acid in a stoichiometric ratio of about 2:1. The hemi
benzenediacrylate salt of Compound A is the salt formed between
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide and
1,4-benzenediacrylic acid in a stoichiometric ratio of about
2:1.
[0054] Also included within the scope of the invention are any
solvates, for example hydrates, complexes and polymorphic forms of
the salts of the invention.
[0055] The salts of the invention may exist in crystalline or
noncrystalline form, or as a mixture thereof. For salts of the
invention that are in crystalline form, the skilled artisan will
appreciate that pharmaceutically acceptable solvates may be formed
wherein solvent molecules are incorporated into the crystalline
lattice during crystallization. Solvates may involve nonaqueous
solvents such as ethanol, isopropanol, DMSO, acetic acid,
ethanolamine, and EtOAc, or they may involve water as the solvent
that is incorporated into the crystalline lattice. Solvates wherein
water is the solvent that is incorporated into the crystalline
lattice are typically referred to as "hydrates". Hydrates include
stoichiometric hydrates as well as compositions containing variable
amounts of water. In one embodiment, the invention provides the
sodium salt of Compound A as a hydrate.
[0056] The invention encompasses the polymorphs and salts of
Compound A isolated in pure form or when admixed with other
materials, for example other polymorphs, or salts or solvates
(inclusive of their polymorphs) of Compound A, or any other
material.
[0057] Thus, in one aspect there is provided a polymorph or salt of
Compound A in isolated or pure form. "Isolated" or "pure" form
refers to a sample in which the polymorph or salt is present in an
amount of >75%, particularly >90%, more particularly >95%
and even more particularly >99% relative to other materials
which may be present in the sample.
TERMS AND DEFINITIONS
[0058] As used herein the symbols and conventions used in these
processes, schemes and examples are consistent with those used in
the contemporary scientific literature, for example, the Journal of
the American Chemical Society or the Journal of Biological
Chemistry. Standard single-letter or three-letter abbreviations are
generally used to designate amino acid residues, which are assumed
to be in the L-configuration unless otherwise noted. Unless
otherwise noted, all starting materials were obtained from
commercial suppliers and used without further purification.
Specifically, the following abbreviations may be used in the
examples and throughout the specification:
CLR Controlled lab reactor DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM Dichloromethane
[0059] DMPU 1,3-Dimethyl-3,4,5,6-tetrahydo-2-(1H)-pyrimidinone
DMSO Dimethylsulfoxide
Et Ethyl
[0060] EtOAc Ethyl acetate
g Grams
[0061] h hour(s) HPLC High performance liquid chromatography IMS
Industrial methylated spirits IPA Isopropyl alcohol LCMS Liquid
chromatography mass spectroscopy
L Litre
M Molar
[0062] MDAP Mass directed automated preparative HPLC
Me Methyl
MeCN Acetonitrile
MeOH Methanol
mg Milligrams
[0063] mins Minutes
ml Millilitres
[0064] mmol Millimoles Rt Retention time RT Room temperature
SCX Strong Cation Exchange
SPE Solid Phase Extraction
[0065] TFA Trifluoroacetic acid
THF Tetrahydrofuran
[0066] UPLC Ultra high performance liquid chromatography
UV Ultraviolet
[0067] All references to brine are to a saturated aqueous solution
of NaCl.
[0068] Polymorph and Salt Preparation
[0069] The invention is also directed to processes for preparing
the polymorphs and salts of Compound A.
[0070] In one aspect, the invention provides a process for
preparing a polymorph of Compound A which comprises: [0071] a)
stirring Compound A in a suitable solvent such as ethyl acetate or
methanol, at a suitable temperature such as room temperature, or
[0072] b) heating a saturated solution of Compound A in a suitable
solvent such as tetrahydrofuran.
[0073] In a further aspect, the invention provides a process for
preparing a salt of Compound A which comprises contacting Compound
A with a suitable base or acid such as sodium hydroxide,
p-toluenesulfonic acid, maleic acid, pamoic acid,
mesitylenesulfonic acid dihydrate, biphenyldisulfonic acid,
2-naphthalenesulfonic acid, trans-cinnamic acid, sebacic acid,
pyromellitic acid or 1,4-benzenediacrylic acid, in the presence or
a suitable solvent such as methanol, tert-butylmethylether,
tetrahydrofuran and/or isopropylacetate. In one embodiment, the
invention provides a process for preparing a salt of Compound A
which comprises contacting Compound A with a suitable base or acid
such as sodium hydroxide, p-toluenesulfonic acid, maleic acid or
pamoic acid, in the presence or a suitable solvent such as
methanol, tert-butylmethylether, tetrahydrofuran and/or
isopropylacetate. In a further embodiment, the invention provides a
process for preparing a salt of Compound A which comprises
contacting Compound A with a suitable acid such as
mesitylenesulfonic acid dihydrate, biphenyldisulfonic acid,
2-naphthalenesulfonic acid, trans-cinnamic acid, sebacic acid,
pyromellitic acid or 1,4-benzenediacrylic acid, in the presence or
a suitable solvent such as methanol, tert-butylmethylether,
tetrahydrofuran and/or isopropylacetate.
[0074] Compound A may be prepared according to known procedures,
such as those disclosed in international patent application
PCT/EP2010/055666 (publication number WO2010/125082) and the
Examples section below. The disclosure of international patent
application PCT/EP2010/055666 (publication number WO2010/125082) is
incorporated herein by reference.
[0075] Methods of Use
[0076] The polymorphs and salts of the invention may be useful in
the treatment of disorders wherein the underlying pathology is (at
least in part) attributable to inappropriate PI3-kinase activity,
such as asthma and chronic obstructive pulmonary disease (COPD).
"Inappropriate PI3-kinase activity" refers to any PI3-kinase
activity that deviates from the normal PI3-kinase activity expected
in a particular patient. Inappropriate PI3-kinase may take the form
of, for instance, an abnormal increase in activity, or an
aberration in the timing and or control of PI3-kinase activity.
Such inappropriate activity may result then, for example, from
overexpression or mutation of the protein kinase leading to
inappropriate or uncontrolled activation. Accordingly, in another
aspect the invention is directed to methods of treating such
disorders.
[0077] Such disorders include respiratory diseases including
asthma, chronic obstructive pulmonary disease (COPD) and idiopathic
pulmonary fibrosis (IPF); viral infections including viral
respiratory tract infections and viral exacerbation of respiratory
diseases such as asthma and COPD; non-viral respiratory infections
including aspergillosis and leishmaniasis; allergic diseases
including allergic rhinitis and atopic dermatitis; autoimmune
diseases including rheumatoid arthritis and multiple sclerosis;
inflammatory disorders including inflammatory bowel disease;
cardiovascular diseases including thrombosis and atherosclerosis;
hematologic malignancies; neurodegenerative diseases; pancreatitis;
multiorgan failure; kidney diseases; platelet aggregation; cancer;
sperm motility; transplantation rejection; graft rejection; lung
injuries; and pain including pain associated with rheumatoid
arthritis or osteoarthritis, back pain, general inflammatory pain,
post hepatic neuralgia, diabetic neuropathy, inflammatory
neuropathic pain (trauma), trigeminal neuralgia and Central pain.
In one embodiment, such disorders include respiratory diseases
including asthma and chronic obstructive pulmonary disease (COPD);
allergic diseases including allergic rhinitis and atopic
dermatitis; autoimmune diseases including rheumatoid arthritis and
multiple sclerosis; inflammatory disorders including inflammatory
bowel disease; cardiovascular diseases including thrombosis and
atherosclerosis; hematologic malignancies; neurodegenerative
diseases; pancreatitis; multiorgan failure; kidney diseases;
platelet aggregation; cancer; sperm motility; transplantation
rejection; graft rejection; lung injuries; and pain including pain
associated with rheumatoid arthritis or osteoarthritis, back pain,
general inflammatory pain, post hepatic neuralgia, diabetic
neuropathy, inflammatory neuropathic pain (trauma), trigeminal
neuralgia and Central pain
[0078] The methods of treatment of the invention comprise
administering a safe and effective amount of a polymorph or salt of
the invention to a patient in need thereof. Individual embodiments
of the invention include methods of treating any one of the
above-mentioned disorders by administering a safe and effective
amount of a polymorph or salt of the invention to a patient in need
thereof.
[0079] As used herein, "treat" in reference to a disorder means:
(1) to ameliorate or prevent the disorder or one or more of the
biological manifestations of the disorder, (2) to interfere with
(a) one or more points in the biological cascade that leads to or
is responsible for the disorder or (b) one or more of the
biological manifestations of the disorder, (3) to alleviate one or
more of the symptoms or effects associated with the disorder, or
(4) to slow the progression of the disorder or one or more of the
biological manifestations of the disorder.
[0080] As indicated above, "treatment" of a disorder includes
prevention of the disorder. The skilled artisan will appreciate
that "prevention" is not an absolute term. In medicine,
"prevention" is understood to refer to the prophylactic
administration of a drug to substantially diminish the likelihood
or severity of a disorder or biological manifestation thereof, or
to delay the onset of such disorder or biological manifestation
thereof.
[0081] As used herein, "safe and effective amount" in reference to
a polymorph or salt of the invention or other
pharmaceutically-active agent means an amount sufficient to treat
the patient's condition but low enough to avoid serious side
effects (at a reasonable benefit/risk ratio) within the scope of
sound medical judgment. A safe and effective amount of a compound
will vary with the particular compound chosen (e.g. consider the
potency, efficacy, and half-life of the compound); the route of
administration chosen; the disorder being treated; the severity of
the disorder being treated; the age, size, weight, and physical
condition of the patient being treated; the medical history of the
patient to be treated; the duration of the treatment; the nature of
concurrent therapy; the desired therapeutic effect; and like
factors, but can nevertheless be routinely determined by the
skilled artisan.
[0082] As used herein, "patient" refers to a human (including
adults and children) or other animal. In one embodiment, "patient"
refers to a human.
[0083] The polymorphs and salts of the invention may be
administered by any suitable route of administration, including
both systemic administration and topical administration. Systemic
administration includes oral administration, parenteral
administration, transdermal administration and rectal
administration. Parenteral administration refers to routes of
administration other than enteral or transdermal, and is typically
by injection or infusion. Parenteral administration includes
intravenous, intramuscular, and subcutaneous injection or infusion.
Topical administration includes application to the skin as well as
intraocular, otic, intravaginal, inhaled and intranasal
administration. Inhalation refers to administration into the
patient's lungs whether inhaled through the mouth or through the
nasal passages. In one embodiment, the polymorphs and salts of the
invention may be administered orally. In another embodiment, the
polymorphs and salts of the invention may be administered by
inhalation. In a further embodiment, the polymorphs and salts of
the invention may be administered intranasally.
[0084] The polymorphs and salts of the invention may be
administered once or according to a dosing regimen wherein a number
of doses are administered at varying intervals of time for a given
period of time. For example, doses may be administered one, two,
three, or four times per day. In one embodiment, a dose is
administered once per day. In a further embodiment, a dose is
administered twice per day. Doses may be administered until the
desired therapeutic effect is achieved or indefinitely to maintain
the desired therapeutic effect. Suitable dosing regimens for a
polymorph or salt of the invention depend on the pharmacokinetic
properties of that polymorph or salt, such as absorption,
distribution, and half-life, which can be determined by the skilled
artisan. In addition, suitable dosing regimens, including the
duration such regimens are administered, for a polymorph or salt of
the invention depend on the disorder being treated, the severity of
the disorder being treated, the age and physical condition of the
patient being treated, the medical history of the patient to be
treated, the nature of concurrent therapy, the desired therapeutic
effect, and like factors within the knowledge and expertise of the
skilled artisan. It will be further understood by such skilled
artisans that suitable dosing regimens may require adjustment given
an individual patient's response to the dosing regimen or over time
as individual patient needs change.
[0085] Typical daily dosages may vary depending upon the particular
route of administration chosen. Typical daily dosages for oral
administration range from 0.001 mg to 50 mg per kg of total body
weight, for example from 1 mg to 10 mg per kg of total body weight.
For example, daily dosages for oral administration may be from 0.5
mg to 2 g per patient, such as 10 mg to 1 g per patient.
[0086] In one aspect, the invention thus provides a method of
treating a disorder mediated by inappropriate PI3-kinase activity
comprising administering a safe and effective amount of a polymorph
or salt of the invention to a patient in need thereof.
[0087] In one embodiment, the disorder mediated by inappropriate
PI3-kinase activity is selected from the group consisting of
respiratory diseases (including asthma, chronic obstructive
pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF));
viral infections (including viral respiratory tract infections and
viral exacerbation of respiratory diseases such as asthma and
COPD); non-viral respiratory infections (including aspergillosis
and leishmaniasis); allergic diseases (including allergic rhinitis
and atopic dermatitis); autoimmune diseases (including rheumatoid
arthritis and multiple sclerosis); inflammatory disorders
(including inflammatory bowel disease); cardiovascular diseases
(including thrombosis and atherosclerosis); hematologic
malignancies; neurodegenerative diseases; pancreatitis; multiorgan
failure; kidney diseases; platelet aggregation; cancer; sperm
motility; transplantation rejection; graft rejection; lung
injuries; and pain (including pain associated with rheumatoid
arthritis or osteoarthritis, back pain, general inflammatory pain,
post hepatic neuralgia, diabetic neuropathy, inflammatory
neuropathic pain (trauma), trigeminal neuralgia and Central
pain).
[0088] In one embodiment, the disorder mediated by inappropriate
PI3-kinase activity is a respiratory disease. In another
embodiment, the disorder mediated by inappropriate PI3-kinase
activity is asthma. In another embodiment, the disorder mediated by
inappropriate PI3-kinase activity is chronic obstructive pulmonary
disease (COPD). In a further embodiment, the disorder mediated by
inappropriate PI3-kinase activity is idiopathic pulmonary fibrosis
(IPF).
[0089] In one embodiment, the disorder mediated by inappropriate
PI3-kinase activity is pain.
[0090] In one embodiment, the present invention provides a method
of treating a respiratory disease comprising administering a safe
and effective amount of a polymorph or salt of the invention to a
patient in need thereof.
[0091] In another embodiment, the present invention provides a
method of treating asthma comprising administering a safe and
effective amount of a polymorph or salt of the invention to a
patient in need thereof.
[0092] In one aspect, the invention provides a polymorph or salt of
the invention for use in medical therapy.
[0093] In another aspect, the invention provides a polymorph or
salt of the invention for use in the treatment of a disorder
mediated by inappropriate PI3-kinase activity.
[0094] In a further aspect, the invention provides the use of a
polymorph or salt of the invention in the manufacture of a
medicament for use in the treatment of a disorder mediated by
inappropriate PI3-kinase activity.
[0095] Compositions
[0096] The polymorphs and salts of the invention will normally, but
not necessarily, be formulated into pharmaceutical compositions
prior to administration to a patient.
[0097] Accordingly, in one aspect the invention is directed to
pharmaceutical compositions comprising a polymorph or salt of the
invention and one or more pharmaceutically acceptable
excipients.
[0098] In another aspect the invention is directed to
pharmaceutical compositions comprising 0.05 to 1000 mg of a
polymorph or salt of the invention and 0.1 to 2 g of one or more
pharmaceutically acceptable excipients.
[0099] In a further aspect the invention is directed to a
pharmaceutical composition for the treatment or prophylaxis of a
disorder mediated by inappropriate PI3-kinase activity comprising a
polymorph or salt of the invention
[0100] The pharmaceutical compositions of the invention may be
prepared and packaged in bulk form wherein a safe and effective
amount of a polymorph or salt of the invention can be extracted and
then given to the patient such as with powders or syrups.
Alternatively, the pharmaceutical compositions of the invention may
be prepared and packaged in unit dosage form wherein each
physically discrete unit contains a polymorph or salt of the
invention. When prepared in unit dosage form, the pharmaceutical
compositions of the invention typically may contain, for example,
from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg
of a polymorph or salt of the invention.
[0101] The pharmaceutical compositions of the invention typically
contain one polymorph or salt of the invention.
[0102] As used herein, "pharmaceutically acceptable excipient"
means a pharmaceutically acceptable material, composition or
vehicle involved in giving form or consistency to the
pharmaceutical composition. Each excipient must be compatible with
the other ingredients of the pharmaceutical composition when
commingled such that interactions which would substantially reduce
the efficacy of the polymorph or salt of the invention when
administered to a patient and interactions which would result in
pharmaceutical compositions that are not pharmaceutically
acceptable are avoided. In addition, each excipient must of course
be pharmaceutically-acceptable eg of sufficiently high purity.
[0103] The polymorph or salt of the invention and the
pharmaceutically acceptable excipient or excipients will typically
be formulated into a dosage form adapted for administration to the
patient by the desired route of administration. For example, dosage
forms include those adapted for (1) oral administration such as
tablets, capsules, caplets, pills, troches, powders, syrups,
elixers, suspensions, solutions, emulsions, sachets, and cachets;
(2) parenteral administration such as sterile solutions,
suspensions, and powders for reconstitution; (3) transdermal
administration such as transdermal patches; (4) rectal
administration such as suppositories; (5) inhalation such as
aerosols, solutions, and dry powders; and (6) topical
administration such as creams, ointments, lotions, solutions,
pastes, sprays, foams, and gels.
[0104] Suitable pharmaceutically acceptable excipients will vary
depending upon the particular dosage form chosen. In addition,
suitable pharmaceutically acceptable excipients may be chosen for a
particular function that they may serve in the composition. For
example, certain pharmaceutically acceptable excipients may be
chosen for their ability to facilitate the production of uniform
dosage forms. Certain pharmaceutically acceptable excipients may be
chosen for their ability to facilitate the production of stable
dosage forms. Certain pharmaceutically acceptable excipients may be
chosen for their ability to facilitate the carrying or transporting
of the polymorph or salt of the invention once administered to the
patient from one organ, or portion of the body, to another organ,
or portion of the body. Certain pharmaceutically acceptable
excipients may be chosen for their ability to enhance patient
compliance.
[0105] Suitable pharmaceutically acceptable excipients include the
following types of excipients: diluents, fillers, binders,
disintegrants, lubricants, glidants, granulating agents, coating
agents, wetting agents, solvents, co-solvents, suspending agents,
emulsifiers, sweetners, flavoring agents, flavor masking agents,
coloring agents, anticaking agents, hemectants, chelating agents,
plasticizers, viscosity increasing agents, antioxidants,
preservatives, stabilizers, surfactants, and buffering agents. The
skilled artisan will appreciate that certain pharmaceutically
acceptable excipients may serve more than one function and may
serve alternative functions depending on how much of the excipient
is present in the formulation and what other excipients are present
in the formulation.
[0106] Skilled artisans possess the knowledge and skill in the art
to enable them to select suitable pharmaceutically-acceptable
excipients in appropriate amounts for use in the invention. In
addition, there are a number of resources that are available to the
skilled artisan which describe pharmaceutically acceptable
excipients and may be useful in selecting suitable pharmaceutically
acceptable excipients. Examples include Remington's Pharmaceutical
Sciences (Mack Publishing Company), The Handbook of Pharmaceutical
Additives (Gower Publishing Limited), and The Handbook of
Pharmaceutical Excipients (the American Pharmaceutical Association
and the Pharmaceutical Press).
[0107] The pharmaceutical compositions of the invention are
prepared using techniques and methods known to those skilled in the
art. Some of the methods commonly used in the art are described in
Remington's Pharmaceutical Sciences (Mack Publishing Company).
[0108] Accordingly, in another aspect the invention is directed to
process for the preparation of a pharmaceutical composition
comprising a polymorph or salt of the invention and one or more
pharmaceutically acceptable excipients which comprises mixing the
ingredients. A pharmaceutical composition comprising a polymorph or
salt of the invention may be prepared by, for example, admixture at
ambient temperature and atmospheric pressure.
[0109] In one embodiment, the polymorph or salt of the invention
will be formulated for oral administration. In another embodiment,
the polymorph or salt of the invention will be formulated for
inhaled administration. In a further embodiment, the polymorph or
salt of the invention will be formulated for intranasal
administration.
[0110] In one aspect, the invention is directed to a solid oral
dosage form such as a tablet or capsule comprising a safe and
effective amount of a polymorph or salt of the invention and a
diluent or filler. Suitable diluents and fillers include lactose,
sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch,
potato starch, and pre-gelatinized starch), cellulose and its
derivatives (e.g. microcrystalline cellulose), calcium sulfate, and
dibasic calcium phosphate. The oral solid dosage form may further
comprise a binder. Suitable binders include starch (e.g. corn
starch, potato starch, and pre-gelatinized starch), gelatin,
acacia, sodium alginate, alginic acid, tragacanth, guar gum,
povidone, and cellulose and its derivatives (e.g. microcrystalline
cellulose). The oral solid dosage form may further comprise a
disintegrant. Suitable disintegrants include crospovidone, sodium
starch glycolate, croscarmelose, alginic acid, and sodium
carboxymethyl cellulose. The oral solid dosage form may further
comprise a lubricant. Suitable lubricants include stearic acid,
magnesium stearate, calcium stearate, and talc.
[0111] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The composition can also
be prepared to prolong or sustain the release as for example by
coating or embedding particulate material in polymers, wax or the
like.
[0112] The polymorphs and salts of the invention may also be
coupled with soluble polymers as targetable drug carriers. Such
polymers can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the polymorphs
and salts of the invention may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-linked or
amphipathic block copolymers of hydrogels.
[0113] In another aspect, the invention is directed to a liquid
oral dosage form. Oral liquids such as solution, syrups and elixirs
can be prepared in dosage unit form so that a given quantity
contains a predetermined amount of a polymorph or salt of the
invention. Syrups can be prepared by dissolving the a polymorph or
salt of the invention in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the polymorph
or salt of the invention in a non-toxic vehicle. Solubilizers and
emulsifiers such as ethoxylated isostearyl alcohols and polyoxy
ethylene sorbitol ethers, preservatives, flavor additive such as
peppermint oil or natural sweeteners or saccharin or other
artificial sweeteners, and the like can also be added.
[0114] In another aspect, the invention is directed to a dosage
form adapted for administration to a patient by inhalation, for
example as a dry powder, an aerosol, a suspension, or a solution
composition. In one embodiment, the invention is directed to a
dosage form adapted for administration to a patient by inhalation
as a dry powder. In a further embodiment, the invention is directed
to a dosage form adapted for administration to a patient by
inhalation via a nebulizer.
[0115] Dry powder compositions for delivery to the lung by
inhalation typically comprise a polymorph or salt of the invention
as a finely divided powder together with one or more
pharmaceutically-acceptable excipients as finely divided powders.
Pharmaceutically-acceptable excipients particularly suited for use
in dry powders are known to those skilled in the art and include
lactose, starch, mannitol, and mono-, di-, and polysaccharides. The
finely divided powder may be prepared by, for example,
micronisation and milling. Generally, the size-reduced (eg
micronised) compound can be defined by a D.sub.50 value of about 1
to about 10 microns (for example as measured using laser
diffraction).
[0116] The dry powder may be administered to the patient via a
reservoir dry powder inhaler (RDPI) having a reservoir suitable for
storing multiple (un-metered doses) of medicament in dry powder
form. RDPIs typically include a means for metering each medicament
dose from the reservoir to a delivery position. For example, the
metering means may comprise a metering cup, which is movable from a
first position where the cup may be filled with medicament from the
reservoir to a second position where the metered medicament dose is
made available to the patient for inhalation.
[0117] Alternatively, the dry powder may be presented in capsules
(e.g. gelatin or plastic), cartridges, or blister packs for use in
a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein
the medicament is comprised within a multi-dose pack containing (or
otherwise carrying) multiple defined doses (or parts thereof) of
medicament. When the dry powder is presented as a blister pack, it
comprises multiple blisters for containment of the medicament in
dry powder form. The blisters are typically arranged in regular
fashion for ease of release of the medicament therefrom. For
example, the blisters may be arranged in a generally circular
fashion on a disc-form blister pack, or the blisters may be
elongate in form, for example comprising a strip or a tape. Each
capsule, cartridge, or blister may, for example, contain between 20
.mu.g-10 mg of the polymorph or salt of the invention.
[0118] Aerosols may be formed by suspending or dissolving a
polymorph or salt of the invention in a liquified propellant.
Suitable propellants include halocarbons, hydrocarbons, and other
liquified gases. Representative propellants include:
trichlorofluoromethane (propellant 11), dichlorofluoromethane
(propellant 12), dichlorotetrafluoroethane (propellant 114),
tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a),
difluoromethane (HFA-32), pentafluoroethane (HFA-12),
heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane,
perfluoropentane, butane, isobutane, and pentane. Aerosols
comprising a polymorph or salt of the invention will typically be
administered to a patient via a metered dose inhaler (MDI). Such
devices are known to those skilled in the art.
[0119] The aerosol may contain additional
pharmaceutically-acceptable excipients typically used with MDIs
such as surfactants, lubricants, cosolvents and other excipients to
improve the physical stability of the formulation, to improve valve
performance, to improve solubility, or to improve taste.
[0120] There is thus provided as a further aspect of the invention
a pharmaceutical aerosol formulation comprising a polymorph or salt
of the invention and a fluorocarbon or hydrogen-containing
chlorofluorocarbon as propellant, optionally in combination with a
surfactant and/or a cosolvent.
[0121] According to another aspect of the invention, there is
provided a pharmaceutical aerosol formulation wherein the
propellant is selected from 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
[0122] The formulations of the invention may be buffered by the
addition of suitable buffering agents.
[0123] Capsules and cartridges for use in an inhaler or
insufflator, of for example gelatine, may be formulated containing
a powder mix for inhalation of a polymorph or salt of the invention
and a suitable powder base such as lactose or starch. Each capsule
or cartridge may generally contain from 20 .mu.g to 10 mg of the
polymorph or salt of the invention. Alternatively, the polymorph or
salt of the invention may be presented without excipients such as
lactose.
[0124] The proportion of the active polymorph or salt in the local
compositions according to the invention depends on the precise type
of formulation to be prepared but will generally be within the
range of from 0.001 to 10% by weight. Generally, for most types of
preparations, the proportion used will be within the range of from
0.005 to 1%, for example from 0.01 to 0.5%. However, in powders for
inhalation or insufflation the proportion used will normally be
within the range of from 0.1 to 5%.
[0125] Aerosol formulations are preferably arranged so that each
metered dose or "puff" of aerosol contains from 20 .mu.g to 10 mg,
preferably from 20 .mu.g to 2000 .mu.g, more preferably from about
20 .mu.g to 500 .mu.g of a polymorph or salt of the invention.
Administration may be once daily or several times daily, for
example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each
time. The overall daily dose with an aerosol will be within the
range from 100 .mu.g to 10 mg, preferably from 200 .mu.g to 2000
.mu.g. The overall daily dose and the metered dose delivered by
capsules and cartridges in an inhaler or insufflator will generally
be double that delivered with aerosol formulations.
[0126] In the case of suspension aerosol formulations, the particle
size of the particulate (e.g., micronised) drug should be such as
to permit inhalation of substantially all the drug into the lungs
upon administration of the aerosol formulation and will thus be
less than 100 microns, desirably less than 20 microns, and in
particular in the range of from 1 to 10 microns, such as from 1 to
5 microns, more preferably from 2 to 3 microns.
[0127] The formulations of the invention may be prepared by
dispersal or dissolution of the medicament and a polymorph or salt
of the invention in the selected propellant in an appropriate
container, for example, with the aid of sonication or a high-shear
mixer. The process is desirably carried out under controlled
humidity conditions.
[0128] The chemical and physical stability and the pharmaceutical
acceptability of the aerosol formulations according to the
invention may be determined by techniques well known to those
skilled in the art. Thus, for example, the chemical stability of
the components may be determined by HPLC assay, for example, after
prolonged storage of the product. Physical stability data may be
gained from other conventional analytical techniques such as, for
example, by leak testing, by valve delivery assay (average shot
weights per actuation), by dose reproducibility assay (active
ingredient per actuation) and spray distribution analysis.
[0129] The stability of the suspension aerosol formulations
according to the invention may be measured by conventional
techniques, for example, by measuring flocculation size
distribution using a back light scattering instrument or by
measuring particle size distribution by cascade impaction or by the
"twin impinger" analytical process. As used herein reference to the
"twin impinger" assay means "Determination of the deposition of the
emitted dose in pressurised inhalations using apparatus A" as
defined in British Pharmacopaeia 1988, pages A204-207, Appendix
XVII C. Such techniques enable the "respirable fraction" of the
aerosol formulations to be calculated. One method used to calculate
the "respirable fraction" is by reference to "fine particle
fraction" which is the amount of active ingredient collected in the
lower impingement chamber per actuation expressed as a percentage
of the total amount of active ingredient delivered per actuation
using the twin impinger method described above.
[0130] The term "metered dose inhaler" or MDI means a unit
comprising a can, a secured cap covering the can and a formulation
metering valve situated in the cap. MDI system includes a suitable
channelling device. Suitable channelling devices comprise for
example, a valve actuator and a cylindrical or cone-like passage
through which medicament may be delivered from the filled canister
via the metering valve to the nose or mouth of a patient such as a
mouthpiece actuator.
[0131] MDI canisters generally comprise a container capable of
withstanding the vapour pressure of the propellant used such as a
plastic or plastic-coated glass bottle or preferably a metal can,
for example, aluminium or an alloy thereof which may optionally be
anodised, lacquer-coated and/or plastic-coated (for example
incorporated herein by reference WO96/32099 wherein part or all of
the internal surfaces are coated with one or more fluorocarbon
polymers optionally in combination with one or more
non-fluorocarbon polymers), which container is closed with a
metering valve. The cap may be secured onto the can via ultrasonic
welding, screw fitting or crimping. MDIs taught herein may be
prepared by methods of the art (e.g. see Byron, above and
WO96/32099). Preferably the canister is fitted with a cap assembly,
wherein a drug-metering valve is situated in the cap, and said cap
is crimped in place.
[0132] In one embodiment of the invention the metallic internal
surface of the can is coated with a fluoropolymer, more preferably
blended with a non-fluoropolymer. In another embodiment of the
invention the metallic internal surface of the can is coated with a
polymer blend of polytetrafluoroethylene (PTFE) and
polyethersulfone (PES). In a further embodiment of the invention
the whole of the metallic internal surface of the can is coated
with a polymer blend of polytetrafluoroethylene (PTFE) and
polyethersulfone (PES).
[0133] The metering valves are designed to deliver a metered amount
of the formulation per actuation and incorporate a gasket to
prevent leakage of propellant through the valve. The gasket may
comprise any suitable elastomeric material such as, for example,
low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and
white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
Suitable valves are commercially available from manufacturers well
known in the aerosol industry, for example, from Valois, France
(e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300, BK357) and
3M-Neotechnic Ltd, UK (e.g. Spraymiser.TM.).
[0134] In various embodiments, the MDIs may also be used in
conjunction with other structures such as, without limitation,
overwrap packages for storing and containing the MDIs, including
those described in U.S. Pat. Nos. 6,119,853; 6,179,118; 6,315,112;
6,352,152; 6,390,291; and 6,679,374, as well as dose counter units
such as, but not limited to, those described in U.S. Pat. Nos.
6,360,739 and 6,431,168.
[0135] Conventional bulk manufacturing methods and machinery well
known to those skilled in the art of pharmaceutical aerosol
manufacture may be employed for the preparation of large-scale
batches for the commercial production of filled canisters. Thus,
for example, in one bulk manufacturing method for preparing
suspension aerosol formulations a metering valve is crimped onto an
aluminium can to form an empty canister. The particulate medicament
is added to a charge vessel and liquefied propellant together with
the optional excipients is pressure filled through the charge
vessel into a manufacturing vessel. The drug suspension is mixed
before recirculation to a filling machine and an aliquot of the
drug suspension is then filled through the metering valve into the
canister. In one example bulk manufacturing method for preparing
solution aerosol formulations a metering valve is crimped onto an
aluminium can to form an empty canister. The liquefied propellant
together with the optional excipients and the dissolved medicament
is pressure filled through the charge vessel into a manufacturing
vessel.
[0136] In an alternative process, an aliquot of the liquefied
formulation is added to an open canister under conditions which are
sufficiently cold to ensure the formulation does not vaporise, and
then a metering valve crimped onto the canister.
[0137] Typically, in batches prepared for pharmaceutical use, each
filled canister is check-weighed, coded with a batch number and
packed into a tray for storage before release testing.
[0138] Suspensions and solutions comprising a polymorph or salt of
the invention may also be administered to a patient via a
nebulizer. The solvent or suspension agent utilized for
nebulization may be any pharmaceutically-acceptable liquid such as
water, aqueous saline, alcohols or glycols, e.g., ethanol,
isopropylalcohol, glycerol, propylene glycol, polyethylene glycol,
etc. or mixtures thereof. Saline solutions utilize salts which
display little or no pharmacological activity after administration.
Both organic salts, such as alkali metal or ammonium halogen salts,
e.g., sodium chloride, potassium chloride or organic salts, such as
potassium, sodium and ammonium salts or organic acids, e.g.,
ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be
used for this purpose.
[0139] Other pharmaceutically-acceptable excipients may be added to
the suspension or solution. The polymorph or salt of the invention
may be stabilized by the addition of an inorganic acid, e.g.,
hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric
acid; an organic acid, e.g., ascorbic acid, citric acid, acetic
acid, and tartaric acid, etc., a complexing agent such as EDTA or
citric acid and salts thereof; or an antioxidant such as
antioxidant such as vitamin E or ascorbic acid. These may be used
alone or together to stabilize the polymorph or salt of the
invention. Preservatives may be added such as benzalkonium chloride
or benzoic acid and salts thereof. Surfactant may be added
particularly to improve the physical stability of suspensions.
These include lecithin, disodium dioctylsulphosuccinate, oleic acid
and sorbitan esters.
[0140] In a further aspect, the invention is directed to a dosage
form adapted for intranasal administration.
[0141] Formulations for administration to the nose may include
pressurised aerosol formulations and aqueous formulations
administered to the nose by pressurised pump. Formulations which
are non-pressurised and adapted to be administered topically to the
nasal cavity are of particular interest. Suitable formulations
contain water as the diluent or carrier for this purpose. Aqueous
formulations for administration to the lung or nose may be provided
with conventional excipients such as buffering agents, tonicity
modifying agents and the like. Aqueous formulations may also be
administered to the nose by nebulisation.
[0142] The polymorph and salts of the invention may be formulated
as a fluid formulation for delivery from a fluid dispenser, for
example a fluid dispenser having a dispensing nozzle or dispensing
orifice through which a metered dose of the fluid formulation is
dispensed upon the application of a user-applied force to a pump
mechanism of the fluid dispenser. Such fluid dispensers are
generally provided with a reservoir of multiple metered doses of
the fluid formulation, the doses being dispensable upon sequential
pump actuations. The dispensing nozzle or orifice may be configured
for insertion into the nostrils of the user for spray dispensing of
the fluid formulation into the nasal cavity. A fluid dispenser of
the aforementioned type is described and illustrated in
WO05/044354, the entire content of which is hereby incorporated
herein by reference. The dispenser has a housing which houses a
fluid discharge device having a compression pump mounted on a
container for containing a fluid formulation. The housing has at
least one finger-operable side lever which is movable inwardly with
respect to the housing to cam the container upwardly in the housing
to cause the pump to compress and pump a metered dose of the
formulation out of a pump stem through a nasal nozzle of the
housing. In one embodiment, the fluid dispenser is of the general
type illustrated in FIGS. 30-40 of WO05/044354.
[0143] Pharmaceutical compositions adapted for intranasal
administration wherein the carrier is a solid include a coarse
powder having a particle size for example in the range 20 to 500
microns which is administered by rapid inhalation through the nasal
passage from a container of the powder held close up to the nose.
Suitable compositions wherein the carrier is a liquid, for
administration as a nasal spray or as nasal drops, include aqueous
or oil solutions of the polymorph or salt of the invention.
[0144] Pharmaceutical compositions adapted for transdermal
administration may be presented as discrete patches intended to
remain in intimate contact with the epidermis of the patient for a
prolonged period of time. For example, the active ingredient may be
delivered from the patch by iontophoresis as generally described in
Pharmaceutical Research, 3(6), 318 (1986).
[0145] Pharmaceutical compositions adapted for topical
administration may be formulated as ointments, creams, suspensions,
lotions, powders, solutions, pastes, gels, sprays, aerosols or
oils.
[0146] Ointments, creams and gels, may, for example, be formulated
with an aqueous or oily base with the addition of suitable
thickening and/or gelling agent and/or solvents. Such bases may
thus, for example, include water and/or an oil such as liquid
paraffin or a vegetable oil such as arachis oil or castor oil, or a
solvent such as polyethylene glycol. Thickening agents and gelling
agents which may be used according to the nature of the base
include soft paraffin, aluminium stearate, cetostearyl alcohol,
polyethylene glycols, woolfat, beeswax, carboxypolymethylene and
cellulose derivatives, and/or glyceryl monostearate and/or
non-ionic emulsifying agents.
[0147] Lotions may be formulated with an aqueous or oily base and
will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents or
thickening agents.
[0148] Powders for external application may be formed with the aid
of any suitable powder base, for example, talc, lactose or starch.
Drops may be formulated with an aqueous or non-aqueous base also
comprising one or more dispersing agents, solubilising agents,
suspending agents or preservatives.
[0149] Topical preparations may be administered by one or more
applications per day to the affected area; over skin areas
occlusive dressings may advantageously be used. Continuous or
prolonged delivery may be achieved by an adhesive reservoir
system.
[0150] For treatments of the eye or other external tissues, for
example mouth and skin, the compositions may be applied as a
topical ointment or cream. When formulated in an ointment, the
polymorph or salt of the invention may be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the a
polymorph or salt of the invention may be formulated in a cream
with an oil-in-water cream base or a water-in-oil base.
[0151] Pharmaceutical compositions adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. The compositions may be presented in unit-dose or
multi-dose containers, for example sealed ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets.
[0152] The polymorphs and salts and pharmaceutical compositions
according to the invention may be used in combination with or
include one or more other therapeutic agents, for example selected
from anti-inflammatory agents, anticholinergic agents (particularly
an M.sub.1/M.sub.2/M.sub.3 receptor antagonist),
.beta..sub.2-adrenoreceptor agonists, antiinfective agents, such as
antibiotics or antivirals, or antihistamines. The invention thus
provides, in a further aspect, a combination comprising a polymorph
or salt of the invention together with one or more other
therapeutically active agents, for example selected from an
anti-inflammatory agent, such as a corticosteroid or an NSAID, an
anticholinergic agent, a .beta..sub.2-adrenoreceptor agonist, an
antiinfective agent, such as an antibiotic or an antiviral, or an
antihistamine. One embodiment of the invention encompasses
combinations comprising a polymorph or salt of the invention
together with a .beta..sub.2-adrenoreceptor agonist, and/or an
anticholinergic, and/or a PDE-4 inhibitor, and/or an
antihistamine.
[0153] In one embodiment, the invention encompasses a method of
treating a disorder mediated by inappropriate PI3-kinase activity
comprising administering a safe and effective amount of a
combination comprising a polymorph or salt of the invention
together with one or more therapeutically active agents.
[0154] In a further aspect, the invention provides a combination
comprising a polymorph or salt of the invention which is selective
for PI3K.delta. together with a compound or pharmaceutically
acceptable salt thereof which is selective for another PI3-kinase,
for example PI3K.gamma..
[0155] One embodiment of the invention encompasses combinations
comprising one or two other therapeutic agents.
[0156] It will be clear to a person skilled in the art that, where
appropriate, the other therapeutic ingredient(s) may be used in the
form of salts, for example as alkali metal or amine salts or as
acid addition salts, or prodrugs, or as esters, for example lower
alkyl esters, or as solvates, for example hydrates to optimise the
activity and/or stability and/or physical characteristics, such as
solubility, of the therapeutic ingredient. It will be clear also
that, where appropriate, the therapeutic ingredients may be used in
optically pure form.
[0157] In one embodiment, the invention encompasses a combination
comprising a polymorph or salt of the invention together with a
.beta..sub.2-adrenoreceptor agonist.
[0158] Examples of .beta..sub.2-adrenoreceptor agonists include
salmeterol (which may be a racemate or a single enantiomer such as
the R-enantiomer), salbutamol (which may be a racemate or a single
enantiomer such as the R-enantiomer), formoterol (which may be a
racemate or a single duastereomer such as the R,R-diastereomer),
salmefamol, fenoterol carmoterol, etanterol, naminterol,
clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol,
indacaterol, terbutaline and salts thereof, for example the
xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol,
the sulphate salt or free base of salbutamol or the fumarate salt
of formoterol. In one embodiment, long-acting
.beta..sub.2-adrenoreceptor agonists, for example, compounds which
provide effective bronchodilation for about 12 hrs or longer, are
preferred.
[0159] Other .beta..sub.2-adrenoreceptor agonists include those
described in WO 02/066422, WO 02/070490, WO 02/076933, WO
03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO
2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO
2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.
[0160] Examples of .beta..sub.2-adrenoreceptor agonists include:
[0161]
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o) hexyl]oxy}butyl)benzenesulfonamide; [0162]
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amin-
o) heptyl]oxy}propyl)benzenesulfonamide; [0163]
4-{(1R)-2-[(6-{2-[(2,
6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl-
) phenol; [0164]
4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hyd-
roxyethyl}-2-(hydroxymethyl)phenol; [0165]
N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]am-
ino]phenyl]ethyl]amino]ethyl]phenyl]formamide; [0166]
N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydr-
oxy-2(1H)-quinolinon-5-yl)ethylamine; and [0167]
5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylam-
ino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.
[0168] The .beta..sub.2-adrenoreceptor agonist may be in the form
of a salt formed with a pharmaceutically acceptable acid selected
from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for
example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted
cinnamic, triphenylacetic, sulphamic, sulphanilic,
naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or
4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
[0169] Suitable anti-inflammatory agents include corticosteroids.
Suitable corticosteroids which may be used in combination with the
polymorphs or salts of the invention are those oral and inhaled
corticosteroids and their pro-drugs which have anti-inflammatory
activity. Examples include methyl prednisolone, prednisolone,
dexamethasone, fluticasone propionate,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-[(-
4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17.beta.-ca-
rbothioic acid S-fluoromethyl ester,
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester (fluticasone furoate),
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxy-androsta-1,4-diene-17.beta.-carbothioic acid
S-(2-oxo-tetrahydro-furan-3S-yl) ester,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17.beta.-
-carbothioic acid S-cyanomethyl ester and
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-(1-
-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17.beta.-carbothioi-
c acid S-fluoromethyl ester, beclomethasone esters (for example the
17-propionate ester or the 17,21-dipropionate ester), budesonide,
flunisolide, mometasone esters (for example mometasone furoate),
triamcinolone acetonide, rofleponide, ciclesonide
(16.alpha.,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11.beta.,21-dihydroxy-p-
regna-1,4-diene-3,20-dione), butixocort propionate, RPR-106541, and
ST-126. Preferred corticosteroids include fluticasone propionate,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-[(-
4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17.beta.-ca-
rbothioic acid S-fluoromethyl ester,
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17.beta.-
-carbothioic acid S-cyanomethyl ester and
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-(1-
-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17.beta.-carbothioi-
c acid S-fluoromethyl ester. In one embodiment the corticosteroid
is
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester.
[0170] Examples of corticosteroids may include those described in
WO2002/088167, WO2002/100879, WO2002/12265, WO2002/12266,
WO2005/005451, WO2005/005452, WO2006/072599 and WO2006/072600.
[0171] Non-steroidal compounds having glucocorticoid agonism that
may possess selectivity for transrepression over transactivation
and that may be useful in combination therapy include those covered
in the following patents: WO03/082827, WO98/54159, WO04/005229,
WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280,
WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590,
WO03/086294, WO04/026248, WO03/061651 and WO03/08277. Further
non-steroidal compounds are covered in: WO2006/000401,
WO2006/000398 and WO2006/015870.
[0172] Examples of anti-inflammatory agents include non-steroidal
anti-inflammatory drugs (NSAID's).
[0173] Examples of NSAID's include sodium cromoglycate, nedocromil
sodium, phosphodiesterase (PDE) inhibitors (for example,
theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors),
leukotriene antagonists, inhibitors of leukotriene synthesis (for
example montelukast), iNOS inhibitors, tryptase and elastase
inhibitors, beta-2 integrin antagonists and adenosine receptor
agonists or antagonists (e.g. adenosine 2a agonists), cytokine
antagonists (for example chemokine antagonists, such as a CCR3
antagonist) or inhibitors of cytokine synthesis, or 5-lipoxygenase
inhibitors. An iNOS (inducible nitric oxide synthase inhibitor) is
preferably for oral administration. Examples of iNOS inhibitors
include those disclosed in WO93/13055, WO98/30537, WO02/50021,
WO95/34534 and WO99/62875. Examples of CCR3 inhibitors include
those disclosed in WO02/26722.
[0174] In one embodiment, the invention provides the use of the
polymorphs and salts of the invention in combination with a
phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a
formulation adapted for inhalation. The PDE4-specific inhibitor
useful in this aspect of the invention may be any compound that is
known to inhibit the PDE4 enzyme or which is discovered to act as a
PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds
which inhibit other members of the PDE family, such as PDE3 and
PDE5, as well as PDE4.
[0175] Compounds include
cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic
acid,
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphe-
nyl)cyclohexan-1-one and
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-
-01]. Also,
cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyli-
c acid (also known as cilomilast) and its salts, esters, pro-drugs
or physical forms, which is described in U.S. Pat. No. 5,552,438
issued 3 Sep., 1996; this patent and the compounds it discloses are
incorporated herein in full by reference.
[0176] Other compounds include AWD-12-281 from Elbion (Hofgen, N.
et al. 15th EFMC Int Symp Med Chem (September 6-10, Edinburgh)
1998, Abst P. 98; CAS reference No. 247584020-9); a 9-benzyladenine
derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and
Schering-Plough; a benzodiazepine PDE4 inhibitor identified as
CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole
derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa
Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J [Annu
Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.
28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a
pthalazinone (WO99/47505, the disclosure of which is hereby
incorporated by reference) from Byk-Gulden; Pumafentrine,
(-)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylb-
enzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a
mixed PDE3/PDE4 inhibitor which has been prepared and published on
by Byk-Gulden, now Altana; arofylline under development by
Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe
Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162),
and T2585.
[0177] Further compounds are disclosed in the published
international patent application WO04/024728 (Glaxo Group Ltd),
WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd)
(e.g. Example 399 or 544 disclosed therein). Further compounds are
also disclosed in WO2005/058892, WO2005/090348, WO2005/090353, and
WO2005/090354, all in the name of Glaxo Group Limited.
[0178] Examples of anticholinergic agents are those compounds that
act as antagonists at the muscarinic receptors, in particular those
compounds which are antagonists of the M.sub.1 or M.sub.3
receptors, dual antagonists of the M.sub.1/M.sub.3 or
M.sub.2/M.sub.3, receptors or pan-antagonists of the
M.sub.1/M.sub.2/M.sub.3 receptors. Exemplary compounds for
administration via inhalation include ipratropium (for example, as
the bromide, CAS 22254-24-6, sold under the name Atrovent),
oxitropium (for example, as the bromide, CAS 30286-75-0) and
tiotropium (for example, as the bromide, CAS 136310-93-5, sold
under the name Spiriva). Also of interest are revatropate (for
example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which
is disclosed in WO01/04118. Exemplary compounds for oral
administration include pirenzepine (CAS 28797-61-7), darifenacin
(CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold
under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the
name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS
124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the
name Detrol), otilonium (for example, as the bromide, CAS
26095-59-0, sold under the name Spasmomen), trospium chloride (CAS
10405-02-4) and solifenacin (CAS 242478-37-1, or CAS 242478-38-2
for the succinate also known as YM-905 and sold under the name
Vesicare).
[0179] Additional compounds are disclosed in WO 2005/037280, WO
2005/046586 and WO 2005/104745, incorporated herein by reference.
The present combinations include, but are not limited to: [0180]
(3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]o-
ctane iodide; [0181]
(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1-
]octane bromide; [0182]
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicycl-
o[2.2.2]octane bromide; and [0183]
(1R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]et-
hyl}-8-azoniabicyclo[3.2.1]octane bromide.
[0184] Other anticholinergic agents include compounds which are
disclosed in U.S. patent application 60/487,981 including, for
example: [0185]
(3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]o-
ctane bromide; [0186]
(3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octan-
e bromide; [0187]
(3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octan-
e 4-methylbenzenesulfonate; [0188]
(3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3-
.2.1]octane bromide; and/or [0189]
(3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo-
[3.2.1]octane bromide.
[0190] Further anticholinergic agents include compounds which are
disclosed in U.S. patent application 60/511,009 including, for
example: [0191]
(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azo-
nia-bicyclo[3.2.1]octane iodide; [0192]
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitri-
le; [0193]
(endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]o-
ctane; [0194]
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamid-
e; [0195]
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-pr-
opionic acid; [0196]
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1-
]octane iodide; [0197]
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1-
]octane bromide; [0198]
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-01-
; [0199]
N-benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-dip-
henyl-propionamide; [0200]
(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3-
.2.1]octane iodide; [0201]
1-benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-
-propyl]-urea; [0202]
1-ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl--
propyl]-urea; [0203]
N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]--
acetamide; [0204]
N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]--
benzamide; [0205]
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-pro-
pionitrile; [0206]
(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyc-
lo[3.2.1]octane iodide; [0207]
N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]--
benzenesulfonamide; [0208]
[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-ur-
ea; [0209]
N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-dipheny-
l-propyl]-methanesulfonamide; and/or [0210]
(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethy-
l-8-azonia-bicyclo[3.2.1]octane bromide.
[0211] Further compounds include: [0212]
(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bic-
yclo[3.2.1]octane iodide; [0213]
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1-
]octane iodide; [0214]
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1-
]octane bromide; [0215]
(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3-
.2.1]octane iodide; [0216]
(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyc-
lo[3.2.1]octane iodide; and/or [0217]
(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethy-
l-8-azonia-bicyclo[3.2.1]octane bromide.
[0218] In one embodiment the invention provides a combination
comprising a polymorph or salt of the invention together with an H1
antagonist. Examples of H1 antagonists include, without limitation,
amelexanox, astemizole, azatadine, azelastine, acrivastine,
brompheniramine, cetirizine, levocetirizine, efletirizine,
chlorpheniramine, clemastine, cyclizine, carebastine,
cyproheptadine, carbinoxamine, descarboethoxyloratadine,
doxylamine, dimethindene, ebastine, epinastine, efletirizine,
fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine,
mizolastine, mequitazine, mianserin, noberastine, meclizine,
norastemizole, olopatadine, picumast, pyrilamine, promethazine,
terfenadine, tripelennamine, temelastine, trimeprazine and
triprolidine, particularly cetirizine, levocetirizine, efletirizine
and fexofenadine. In a further embodiment the invention provides a
combination comprising a polymorph or salt of the invention
together with an H3 antagonist (and/or inverse agonist). Examples
of H3 antagonists include, for example, those compounds disclosed
in WO2004/035556 and in WO2006/045416. Other histamine receptor
antagonists which may be used in combination with the polymorphs
and salts of the present invention include antagonists (and/or
inverse agonists) of the H4 receptor, for example, the compounds
disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960
(2003).
[0219] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with a PDE4 inhibitor.
[0220] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with a .beta..sub.2-adrenoreceptor agonist.
[0221] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with a corticosteroid.
[0222] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with a non-steroidal GR agonist.
[0223] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with an anticholinergic.
[0224] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with an antihistamine.
[0225] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with a PDE4 inhibitor and a .beta..sub.2-adrenoreceptor
agonist.
[0226] The invention thus provides, in a further aspect, a
combination comprising a polymorph or salt of the invention
together with an anticholinergic and a PDE-4 inhibitor.
[0227] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical composition and
thus pharmaceutical compositions comprising a combination as
defined above together with a pharmaceutically acceptable diluent
or carrier represent a further aspect of the invention.
[0228] The individual components of such combinations may be
administered either sequentially or simultaneously in separate or
combined pharmaceutical formulations. In one embodiment, the
individual components will be administered simultaneously in a
combined pharmaceutical formulation. Appropriate doses of known
therapeutic agents will readily be appreciated by those skilled in
the art.
[0229] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with another therapeutically
active agent.
[0230] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with a PDE4 inhibitor.
[0231] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with a
.beta..sub.2-adrenoreceptor agonist.
[0232] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with a corticosteroid.
[0233] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with a non-steroidal GR
agonist.
[0234] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with an anticholinergic.
[0235] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with an antihistamine.
[0236] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with a PDE4 inhibitor and a
.beta..sub.2-adrenoreceptor agonist.
[0237] The invention thus provides, in a further aspect, a
pharmaceutical composition comprising a combination of a polymorph
or salt of the invention together with an anticholinergic and a
PDE4 inhibitor.
[0238] The invention will now be illustrated by way of the
following non-limiting examples.
EXAMPLES
[0239] The following examples illustrate the invention. These
examples are not intended to limit the scope of the present
invention, but rather to provide guidance to the skilled artisan to
prepare and use the polymorphs, salts, compositions, and methods of
the present invention. While particular embodiments of the present
invention are described, the skilled artisan will appreciate that
various changes and modifications can be made without departing
from the spirit and scope of the invention.
[0240] When the name of a commercial supplier is given after the
name of a compound or a reagent, for instance "compound X
(Aldrich)" or "compound)(Aldrich", this means that compound X is
obtainable from a commercial supplier, such as the commercial
supplier named. If not referenced herein the compound or reagent
can be purchased from a standard supplier such as Sigma Aldrich,
Lancaster, Fluorochem, TCI etc.
[0241] The names of the compounds have been obtained using a
compound naming programme which matches structure to name (e.g.
ACD/Name Batch v 9.0).
[0242] General Experimental Details
[0243] Liquid Chromatography Mass Spectroscopy (LCMS) Methods
[0244] LCMS analysis has been carried out using one of the methods
listed below.
[0245] Method A:
[0246] LCMS instrumentation consists of the following:
Column: Acquity UPLC BEH C.sub.18 1.7 .mu.m 2.1 mm.times.50 mm.
Column oven set to 40 degrees centigrade
Solvent A: Water 0.1% Formic Acid+10 mM Ammonium Acetate
Solvent B: MeCN: Water 95:5+0.05% Formic Acid
[0247] Injection volume: 0.5 .mu.l Injection technique: Partial
loop overfill UV detection: 220 to 330 nm UV sampling rate: 40
points per second MS scan range: 100 to 1000 amu MS scanning rate:
0.2 second scan with a 0.1 second inter scan delay MS scan
function: Electrospray with pos neg switching Cycle time: 2 minutes
and 30 seconds
Gradient:
TABLE-US-00001 [0248] Time Flow ml/min % A % B 0 1 97 3 0.1 1 97 3
1.4 1 0 100 1.9 1 0 100 2 1 97 3
[0249] Method B:
[0250] The HPLC analysis was conducted on a Sunfire C18 column (30
mm.times.4.6 mm i.d. 3.5 .mu.m packing diameter) at 30 degrees
centigrade.
Solvent A=0.1% v/v solution of Formic Acid in Water. Solvent B=0.1%
v/v solution of Formic Acid in Acetonitrile.
[0251] The gradient employed was:
TABLE-US-00002 Time (min) Flow Rate (ml/min) % A % B 0 3 97 3 0.1 3
97 3 4.2 3 0 100 4.8 3 0 100 4.9 3 97 3 5.0 3 97 3
[0252] The UV detection was an averaged signal from wavelength of
210 nm to 350 nm and mass spectra were recorded on a mass
spectrometer using alternate-scan positive and negative mode
electrospray ionization.
[0253] Method C:
[0254] The HPLC analysis was conducted on a Phenomenex Luma C18(2)
(50 mm.times.2 mm i.d. 3 .mu.m packing diameter, or validated
equivalent) at 40 degrees centigrade.
Solvent A=0.05% v/v solution of TFA in Water. Solvent B=0.05% v/v
solution of TFA in Acetonitrile.
[0255] The gradient employed was:
TABLE-US-00003 Time (min) Flow Rate (ml/min) % A % B 0 1 100 0 8 1
5 95 8.01 1 100 0
[0256] The UV detection wavelength was analyte dependent and mass
spectra were recorded on a mass spectrometer using positive ion
electrospray.
[0257] Method D:
[0258] The HPLC analysis was conducted on a Phenomenex Luma C18(2)
(50 mm.times.2 mm i.d. 3 .mu.m packing diameter, or validated
equivalent) at 60 degrees centigrade.
Solvent A=0.05% v/v solution of TFA in Water. Solvent B=0.05% v/v
solution of TFA in Acetonitrile.
[0259] The gradient employed was:
TABLE-US-00004 Time (min) Flow Rate (ml/min) % A % B 0 1.5 100 0
2.5 1.5 5 95 2.7 1.5 5 95 2.9 1.5 100 0
[0260] The UV detection wavelength was analyte dependent and mass
spectra were recorded on a mass spectrometer using positive ion
electrospray.
[0261] Mass Directed Automated Preparative HPLC Methods
[0262] The methods for the mass-directed automated preparative HPLC
used for the purification of compounds are described below:
[0263] Method A--High pH
[0264] Column Details:
[0265] Waters_XBRIDGE Prep C18 column 5 um OBD (30.times.150
mm)
[0266] The solvents employed were:
A=10 mM Ammonium Bicarbonate in water adjusted to pH 10 with aq.
Ammonia solution B=Acetontrile+0.1% aq. Ammonia
[0267] Collection was triggered by uv, ms or a combination of the
two. The UV detection was an averaged signal from wavelength of 210
nm to 350 nm. Mass spectra were recorded on a mass spectrometer
using an alternate-scan positive and negative mode electrospray
ionization.
[0268] Method B--Low pH
[0269] Column Details:
[0270] SUNFIRE C18 column (30.times.150 mm id 5 uM packing
diameter)
[0271] The solvents employed were:
A=0.1% v/v solution of Formic Acid in Water. B=0.1% v/v solution of
Formic Acid in Acetontrile.
[0272] Collection was triggered by uv, ms or a combination of the
two. The UV detection was an averaged signal from wavelength of 210
nm to 350 nm. Mass spectra were recorded on a mass spectrometer
using an alternate-scan positive and negative mode electrospray
ionization.
Preparation of Compound A
Intermediates and Examples
Intermediate 1
6-Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole
##STR00005##
[0274] Method A
[0275] 6-Chloro-4-iodo-1H-indazole (30 g, 108 mmol, available from
Sinova) was dissolved in N,N-dimethylformamide (300 ml) and cooled
in an ice water bath under nitrogen. Sodium hydride (5.17 g, 129
mmol) was added portionwise, maintaining the temperature below
10.degree. C. After full addition the reaction mixture was stirred
for 20 mins then benzenesulfonyl chloride (16.5 ml, 129 mmol) was
added dropwise over 15 mins. The reaction was left to warm to RT
overnight then poured onto ice water (2 L). The precipitated
product was collected by filtration, washed with water (ca. 400 ml)
and dried in a vacuum oven overnight to give the title compound
(43.3 g).
[0276] LCMS (Method A): Rt 1.38 mins, MH.sup.+ 419.
[0277] Method B
[0278] To a stirred solution of 6-chloro-4-iodo-1H-indazole (633.6
g) in THF (5.7 L) was added sodium hydroxide (227.4 g) followed by
tetra-n-butylammonium bisulphate (38.0 g) at 20.+-.3.degree. C.,
under a nitrogen atmosphere. The mixture was stirred at
20.+-.3.degree. C. for 1 h 3 min, then benzenesulphonyl chloride
(319 ml) was added at such a rate as to maintain the internal
temperature at <25.degree. C. Residual benzenesulphonyl chloride
was rinsed into the vessel with THF (630 mL), then the mixture
stirred for 1 h 10 min. The mixture was cooled to <5.degree. C.
and water (12.7 L) added at such a rate as to maintain internal
temperature below 5.+-.3.degree. C., then the mixture stirred at
0-5.degree. C. for 1 h 20 min. The solids were collected by vacuum
filtration, washed with water (2.times.1.9 L), sucked dry then
further dried under vacuum with a nitrogen bleed at 40.degree.
C..+-.3.degree. C. overnight to give the title compound (780.8
g).
[0279] LCMS (Method C): Rt 6.28 min, MH.sup.+ 419.
[0280] Method C
[0281] All weights, volumes and equivalents are relative to
6-chloro-4-iodo-1H-indazole.
[0282] 6-Chloro-4-iodo-1H-indazole (1.0 eq., 1 wt, 50 g), sodium
hydroxide (2.25 eq., 0.324 wt, 16.16 g) and tetrabutylammonium
hydrogensulphate (0.05 eq., 0.061 wt, 3.05 g) are stirred in THF
(9.5 vols, 475 ml) at 20.+-.3.degree. C. under a nitrogen
atmosphere for 1 hr. The mixture is cooled to 15.+-.3.degree. C.
and benzenesulfonyl chloride (1.10 eq., 0.51 vols, 25.5 ml) was
added dropwise over 20 mins maintaining the reaction temperature at
<25.degree. C. and is washed in with THF (0.5 vols, 25 ml). The
resulting mixture is then stirred under a nitrogen atmosphere at
20.+-.3.degree. C. for at least 1 hr before checking for completion
by HPLC. The reaction mixture is then added to 0.25 M hydrochloric
acid solution (18 vols, 900 ml) cooled to 0.+-.3.degree. C. over 15
minutes maintaining the temperature of the aqueous suspension at
<20.degree. C. This is washed in with 0.25M hydrochloric acid
solution (2 vols, 100 ml). The resulting orange suspension is then
stirred at 2.+-.3.degree. C. for at least 1 hr. The solid is
filtered, washed with water (2.times.3 vols, 2.times.150 ml) and
sucked dry for 20 mins, then dried under high vacuum at 40.degree.
C. (.+-.3.degree. C.) to constant probe temperature to afford
6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole as an orange
solid.
Intermediate 2
6-Chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole
##STR00006##
[0284] 6-Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole (30 g, 71.7
mmol), tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.01 mmol),
xylene (200 ml), triethylamine (19.98 ml, 143 mmol) and
hexamethylditin (21.8 ml, 105 mmol) were heated at 150.degree. C.
for 2 h. The reaction mixture was filtered hot through Celite,
washing with further xylene and the solvent was evaporated in
vacuo. The residue was triturated with cyclohexane and the
precipitate collected by filtration and dried in a vacuum oven to
give the title compound (14.4 g).
[0285] LCMS (Method A): Rt 1.51 mins, MH.sup.+ 457.
Intermediate 3a
Ethyl
2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carbox-
ylate
##STR00007##
[0287] In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37
g, 2.92 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g,
37.9 mmol, available from Apollo Scientific) and copper(I) iodide
(1.11 g, 5.83 mmol) were added to a solution of
6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole
(13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the
batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89
mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59
mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a
solution of
6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole
(4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth
batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24
mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol)
and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution
of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole
(1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was
heated and stirred at 100.degree. C. under microwave irradiation
for 30 min. The mixtures were allowed to cool to RT and the
combined precipitated product suspended in diethyl ether and
collected by filtration, washing with further diethyl ether then
drying in a vacuum oven for 72 h. Approximately 5.2 g of the
resultant solid was dissolved in dichloromethane and passed through
Celite, eluting with further dichloromethane. The solvent was
evaporated in vacuo to give the title compound as a pale orange
solid (4.95 g).
[0288] LCMS (Method A): Rt 1.38 mins, MH.sup.+ 432.
Intermediate 3b
Methyl
2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carbo-
xylate
##STR00008##
[0290] To a stirred solution of
6-chloro-4-iodo-1-(phenylsulphonyl)-1H-indazole (549.8 g) in
toluene (1.43 L) was added triethylamine (380 ml) at
20.+-.3.degree. C. under an atmosphere of nitrogen. Hexamethylditin
(385 ml) in toluene (825 ml) was added, followed by toluene (275
ml) then tetrakis(triphenylphosphine) palladium (0) (154.7 g). The
reaction mixture was heated to 120.degree. C. and stirred at this
temperature for 3 h. The mixture was allowed to cool to
20.+-.3.degree. C., filtered, then washed with toluene (4.95 L).
The filtrate was transferred to a clean vessel through a 5 .mu.m
Dominick hunter in-line filter, rinsing with further toluene (550
ml). The batch was then washed with 50% aqueous KF solution (5.5
L), the aqueous slurry filtered and the filtrate recombined with
the organic phase. The aqueous was separated and the organics
washed successively with 50% aqueous KF (5.5 L), followed by water
(5.5 L). The organic layer was diluted with DMPU (2.75 L) then
concentrated by vacuum distillation to ca. 5.4 vols. To the
resultant solution was added copper (I) iodide (25.5 g) followed by
methyl 2-chloro-1,3-oxazole-5-carboxylate (279 g, available from
Apollo Scientific) at 20.+-.3.degree. C. The solution was degassed
via vacuum and nitrogen purges (.times.3).
Tetrakis(triphenylphosphine) palladium (0) (78 g) was added, the
mixture degassed (.times.3) and then heated to 85-90.degree. C. for
10 h. The mixture was diluted with DMSO (13.75 L) and cooled to
20.+-.3.degree. C., then water (2.75 L) added in ca. 1 vol portions
over ca. 15 mins until crystallisation was initiated. The resultant
suspension was aged at 20.degree. C..+-.3.degree. C. for 1.5 h. The
solids were collected by vacuum filtration, washed with water
(2.times.2.75 L), sucked dry and then further dried in vacuo with a
nitrogen bleed at 45.degree. C..+-.5.degree. C. overnight to give
the title compound (341.1 g).
[0291] LCMS (Method C): Rt 6.08 mins, MH.sup.+ 418
Intermediate 4
{2-[6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol
##STR00009##
[0293] Method A
[0294] A solution of ethyl
2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carbon/late
(5.11 g, 11.8 mmol) in dichloromethane (80 ml) was cooled to
-25.degree. C. in an oven dried round bottomed flask.
Diisobutylaluminium hydride (25 ml, 37.5 mmol, 1.5M solution in
toluene) was added dropwise and the reaction stirred at -20.degree.
C. for 3 h. A 10% aqueous solution of potassium sodium tartrate (80
ml) was added and the reaction mixture stirred for 5 min. The
precipitated solid was filtered off and partitioned between ethyl
acetate (500 ml) and water (500 ml). The layers were separated and
the aqueous washed with further ethyl acetate (3.times.150 ml). The
combined organics were dried and evaporated in vacuo to give the
title compound as a yellow solid (1.1 g).
[0295] LCMS (Method A): Rt 1.09 mins, MH.sup.+ 390.
[0296] The remaining filtrate was largely concentrated in vacuo and
the residue partitioned between ethyl acetate (500 ml) and water
(500 ml). The layers were separated and the aqueous extracted with
further ethyl acetate (3.times.150 ml). The combined organics were
washed with water (2.times.150 ml), dried over anhydrous sodium
sulfate and evaporated to give the title compound as a yellow solid
(1.9 g).
[0297] LCMS (Method A): Rt 1.09 mins, MH.sup.+ 390.
[0298] Method B To a solution of ethyl
2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carbon/late
(1.15 g) in THF (17.25 ml), stirred under nitrogen in an ice bath
was added a solution of diisobutylaluminium hydride (5.08 ml, 5.64
mmol) in toluene. The reaction mixture was stirred at 0.degree. C.
for 2 h. Sodium sulphate decahydrate (2.5 g) was added, the mixture
stirred at RT for 1 h, then filtered, washed with THF (2.times.5
vols) and concentrated under reduced pressure to give the title
compound (0.98 g).
[0299] LCMS (Method D): Rt 2.20 mins, MH.sup.+ 390.
[0300] Method C
[0301] To a solution of ethyl
2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate
(604.5 g) in THF (8.7 L), stirred under nitrogen at 0.+-.3.degree.
C. was added a solution of approximately 1.3M diisobutylaluminium
hydride (1.8 kg) in toluene. The reaction mixture was stirred at
0.+-.3.degree. C. for 30 mins and then diluted with THF (3 L).
Sodium sulphate decahydrate (1.3 kg) was added, maintaining the
temperature below 5.degree. C. The mixture was stirred at
0.+-.3.degree. C. for 10 mins and was then warmed to
20.+-.3.degree. C. and held at this temperature for 1 h. The
suspension was filtered, washed with THF (4.times.3 L) and
concentrated under reduced pressure to give the title compound
(529.6 g).
[0302] LCMS (Method C): Rt 5.18 min, MH.sup.+ 390.
[0303] Method D
[0304] All weights, volumes and equivalents are relative to
6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole.
[0305] Zinc chloride (3.6 eq, 1.17 wt, 52.7 g) in tetrahydrofuran
(5 vols, 225 ml) is cooled to 0 to 5.degree. C. A solution of the
ethyl oxazole-5-carboxylate (1.1 eq, 0.37 wt, 18.1 g, corrected for
92 wt % assay) in tetrahydrofuran (5 vols, 225 ml) is added to the
vessel. The suspension is cooled to -10.degree. C. (+/-5.degree.
C.) under a nitrogen atmosphere and a 1M solution of
bis-(trimethylsilyl)-lithiumamide in tetrahydrofuran (1.80 eq, 4.30
vols, 193 ml) is added over 15 minutes maintaining the temperature
at -10.degree. C. (+/-5.degree. C.). The resulting solution is
stirred under a nitrogen atmosphere at -10.degree. C. (+/-5.degree.
C.) for 1 hour. To the solution is added
6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole (1.0 eq, 1.0 wt,
45.0 g) and tetrakis triphenylphosphine palladium (0.03 eq, 0.083
wt, 3.73 g) (the mixture is degassed with vacuum/nitrogen 3 times)
and then heated to 60.degree. C. (+/-3.degree. C.) for at least 6
hours. The reaction is then checked by HPLC for completion. The
reaction solution is cooled to 0.degree. C. (+/-3.degree. C.) and a
solution of 25% w/w diisobutylaluminium hydride in toluene (4.0 eq,
6.4 vols, 288 ml) is added maintaining the temperature at
<5.degree. C. The resulting reaction solution is then stirred at
0.degree. C. (+/-3.degree. C.) for at least 1 hour. The reaction is
then checked by
[0306] HPLC (generic) for completion. The reaction mixture is added
portion wise to a solution of citric acid (4.0 eq, 2.0 wt, 90 g) in
water (10 vols, 450 ml) at 0.degree. C. (+/-5.degree. C.) over
.about.1 h. The resulting solution is stirred at 20.degree. C. for
15 minutes, extracted with ethyl acetate (10 vols, 450 ml), the
organic layer is washed with water (2.times.3 vols, 2.times.135 ml)
and filtered through a porosity 4 sinter. The organic layer is then
evaporated under reduced pressure (45.degree. C., 100 mbar) to 2 to
3 volumes, dimethyl sulphoxide (10 vols, 450 ml) is added and the
solution evaporated under reduced pressure (45.degree. C., 50 mbar)
to remove all traces of other solvents. To the solution at
45.degree. C. is added water (5 vols, 225 ml) dropwise over 30
minutes, the resulting reaction mixture is cooled to 20.degree. C.
over 3 hr and stirred at 20.degree. C. for at least 15 hrs. The
product is filtered, washed with a solution of
dimethylsulphoxide:water (1:2) (2 vols, 90 ml), then washed with
water (3 vols, 135 ml), then dried under high vacuum at 60.degree.
C. (.+-.3.degree. C.) to constant probe temperature to afford
(2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol
as a beige solid.
Intermediate 5
4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazol-
e
##STR00010##
[0308] Method A
[0309]
{2-[6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}me-
thanol (1.626 g, 4.17 mmol) was dissolved in anhydrous
dichloromethane (20 ml) and carbon tetrabromide (2.77 g, 8.34 mmol)
added. The reaction mixture was cooled to 0.degree. C. and a
solution of triphenylphosphine (2.188 g, 8.34 mmol) in
dichloromethane (20 ml) added dropwise. After allowing to warm to
RT and stirring for a further 3 h, the solvent was partially
removed in vacuo and the solution purified directly by silica gel
chromatography, eluting with 0-100% ethyl acetate in
dichloromethane. The appropriate fractions were combined to give
the title compound as a cream solid (1.16 g).
[0310] LCMS (Method B): Rt 3.70 mins, MH.sup.+ 454.
[0311] Method B
[0312] Triphenylphosphine dibromide (20.60 g, 48.8 mmol) was added
to a suspension of
{2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol
(9.06 g, 23.2 mmol) in dichloromethane (181 ml) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. until completion.
Water (91 ml) and saturated sodium bicarbonate solution (91 ml)
were added and the mixture stirred, then separated. The aqueous
layer was extracted with further dichloromethane (45 ml) and the
organics combined and washed with water (91 ml). The layers were
separated and the organic concentrated to dryness then redissolved
in methanol (136 ml). After stirring for 30 mins the resultant
white suspension was filtered and the solid dried under vacuum to
give the title compound as an off-white solid (9.58 g). LCMS
(Method D): Rt 2.57 min, MH+ 452/454.
[0313] Method C
[0314] Triphenylphosphine dibromide (1.2 kg) was added to a
suspension of
{2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol
(544.7 g) in dichloromethane (3.8 L) stirred under nitrogen at
10.+-.3.degree. C. The reaction mixture was stirred at
10.+-.3.degree. C. for 20 min. Water (2.7 L) and saturated sodium
bicarbonate solution (5.4 L) were added and the mixture stirred,
then separated. The aqueous layer was extracted with further
dichloromethane (2.7 L) and the organics combined and washed with
water (2.7 L). The layers were separated and the organic
concentrated to dryness then redissolved in methanol (6.5 L). After
stirring for 5 hours the resultant white suspension was filtered,
washed with methanol (2.times.1.1 L) and the solid dried under
vacuum at 40.+-.5.degree. C. to give the title compound as an
off-white solid (514.0 g).
[0315] LCMS (Method C): Rt 6.40 min, MH.sup.+ 453/455.
[0316] Method D
[0317] All weights, volumes and equivalents are relative to
(2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol.
[0318]
(2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methano-
l (1.0 eq., 1 wt, 34.0 g) and triphenylphosphine dibromide (1.3
eq., 1.32 wt, 45.0 g) are stirred in dichloromethane (15 vols, 510
ml) at 20 (.+-.3.degree. C.) under a nitrogen atmosphere for 1 hr.
The reaction is then checked by HPLC for completion. Once complete
methanol (0.8 vols, 27.2 ml) is added to the reaction, with
vigorous stirring 8% w/w sodium hydrogen carbonate solution (10
vols, 340 ml) is added drop wise over 15 minutes (check aqueous pH
>7). The mixture is heated to 30.degree. C. (.+-.3.degree. C.)
and stirred together for 10 minutes, then separated, the aqueous is
back extracted with dichloromethane (5 vols, 170 ml) and the
combined dichloromethane layers are washed with water (5 vols, 170
ml). The dichloromethane solution is then evaporated under reduced
pressure to a volume of approximately 4 vols. To the solution is
added methanol (15 vols, 510 ml) and the solution evaporated under
reduced pressure at 260 mbar, 20.degree. C. to remove the remaining
dichloromethane down to .about.15 vols. The suspension is then
stirred at 20.degree. C. for at least 6 hrs. The solid is filtered,
washed with methanol (2.times.1 vols, 2.times.34 ml), sucked dry
for 20 minutes, then dried under high vacuum at 30.degree. C.
(.+-.3.degree. C.) to constant probe temperature to afford
5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole
as a beige solid.
Intermediate 6
6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl-
)-1-(phenylsulfonyl)-1H-indazole
##STR00011##
[0320] Method A
[0321]
4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H--
indazole (0.580 g, 1.28 mmol) was dissolved in dichloromethane (5
ml) and (2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added.
The reaction mixture was stirred at RT for 3 h then the solvent
removed under a stream of nitrogen. The resultant yellow solid was
dissolved in dichloromethane (5 ml) and washed with water
(2.times.2.5 ml). The layers were separated (hydrophobic frit) and
the organic evaporated in vacuo to give the title compound as a
pale yellow solid (0.60 g).
[0322] LCMS (Method A): Rt 0.86 mins, MH.sup.+ 487.
[0323] .sup.1H NMR (400 MHz, Chloroform-d) .delta. (ppm) 8.93 (d,
J=1.0 Hz, 1H), 8.33 (dd, J=1.0, 1.5 Hz, 1H), 8.04-8.00 (m, 2H),
7.98 (d, J=1.5 Hz, 1H), 7.62 (tt, J=1.5, 7.5 Hz, 1H), 7.51 (t,
J=7.5 Hz, 2H), 7.15 (s, 1H), 3.67 (s, 2H), 3.75-3.66 (m, 2H),
2.79-2.72 (m, 2H), 1.86 (dd, J=10.5, 11.0 Hz, 2H), 1.16 (d, J=6.5
Hz, 6H).
[0324] Method B
[0325] (2R,6S)-2,6-dimethylmorpholine (160 ml) and then
triethylamine (180 ml) were added to a suspension of
4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazo-
le (478.1 g) in acetone (3.8 L) stirred under nitrogen at less than
25.degree. C. The reaction mixture was stirred at 20-25.degree. C.
for 2.5 hours and then water (3.8 L) was added. The resultant
suspension was stirred at than 25.degree. C. for 35 min and was
then filtered, washed with a mixture of 2:1 v/v water:acetone
(2.times.1.0 L) and the solid dried under vacuum at 45.+-.5.degree.
C. to give the title compound as an off-white solid (500.5 g). LCMS
(Method B): Rt 3.43 min, MH.sup.+ 487.
[0326] Method C
[0327] All weights, volumes and equivalents are relative to
5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole
(corrected for assay).
[0328] To a suspension of
5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole
(1 wt, 540 g) in acetone (8.7 vol, 4.7 L) is added
2,6-dimethylmorpholine (0.33 vol, 1.2 eq, 178 ml), followed by
triethylamine (0.37 vol, 1.2 eq, 200 ml) at <25.degree. C. under
a nitrogen atmosphere. The resulting mixture is stirred at
20-25.degree. C. for at least 0.5 hr, then monitored for completion
by HPLC. Water (8.7 vol, 4.7 L) is then added to the mixture over
ca 5 minutes. The resulting suspension is aged at <25.degree. C.
for at least 0.5 hr, then the solids are collected by vacuum
filtration, washed with water/acetone (2:1 v/v, 2.times.2.2 vol,
2.times.1.2 L) and dried in vacuo with a nitrogen bleed at
45.+-.5.degree. C.
[0329] Recrystallisation--All weights, volumes and equivalents are
relative to
((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis--
2,6-dimethylmorpholine. A stirred suspension of
((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis--
2,6-dimethylmorpholine (1 wt, 30 g) in DMSO (9 vol, 270 ml) is
heated to 75-80.degree. C. under a nitrogen atmosphere. The
resulting clear solution is transferred to a crystallising vessel
via a 5 .mu.m Domnick hunter in line filter, then the line is
washed with further DMSO (1.0 vol, 30 ml). The hot solution is
allowed to cool to 20-25.degree. C. over at least 2 hr, then the
resulting suspension is aged at this temperature for at least 1 hr.
The resulting solids are filtered, washed with DMSO (1.5 vol, 45
ml), followed by water/acetone (2:1 v/v, 2.times.2 vol, 2.times.60
ml) before being sucked dry for 0.5 hr. The batch is dried in vacuo
at 45.degree. C. to constant probe temperature to afford
((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis--
2,6-dimethylmorpholine as an off-white solid.
Intermediate 7
2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinami-
ne
##STR00012##
[0331] To 5-bromo-2-(methyloxy)-3-pyridinamine (18.93 g, 93 mmol,
available from Asymchem International) in a 1 L round-bottom flask
was added nitrogen-purged 1,4-dioxane (500 ml) followed by
4,4,4',4',5,5,5',5-octamethyl-2,2'-bi-1,3,2-dioxaborolane (47.4 g,
186 mmol), potassium acetate (27.5 g, 280 mmol) and
dichloro{1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (7.61 g, 9.32 mmol). The mixture was then
stirred at 80.degree. C. under nitrogen for 2 h. The reaction
mixture was allowed to cool then partitioned between ethyl acetate
and water and filtered through a Celite pad. The aqueous layer was
extracted further with ethyl acetate (2.times.) and the combined
organics washed with water, brine and dried over magnesium sulphate
overnight. The mixture was filtered and the filtrate concentrated
in vacuo to give a dark brown solid. The residue was purified by
silica gel chromatography, eluting in 0-50% ethyl
acetate/dichloromethane. The appropriate fractions were combined
and evaporated to dryness and the residue triturated with
cyclohexane. The resultant solid was filtered off and dried in
vacuo to give the title compound as a light pink solid (11.1 g).
LCMS (Method A) Rt 0.91 mins, MH.sup.+ 251.
Intermediate 8
N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridin-
yl]methanesulfonamide
##STR00013##
[0333] To a solution of
2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinam-
ine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added
methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture
stirred at 20.degree. C. for 18 hr then the solvent was removed in
vacuo. The residue was partitioned between saturated sodium
bicarbonate solution (10 ml) and dichloromethane (20 ml), separated
by hydrophobic frit and purified by silica gel chromatography,
eluting with a gradient of dichloromethane and methanol to give the
title compound as a brown solid (0.46 g).
[0334] LCMS (Method A): Rt 0.98 mins, MH.sup.+ 329.
Intermediate 9
N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-
-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfon-
amide
##STR00014##
[0336] Method A
[0337] A suspension of palladium (II) acetate (0.05 g) and
tricyclohexylphosphine (0.16 g) in isopropanol (27 ml) was added to
a suspension of
6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-y-
l)-1-(phenylsulfonyl)-1H-indazole (5.40 g), Potassium
trifluoro{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}borate
(6.19 g) and sodium bicarbonate (2.87 g) in isopropanol (27 ml) and
water (38 ml) stirring under nitrogen at 60-65.degree. C. The
reaction mixture was stirred at 60-65.degree. C. for 2.5 hours and
was then cooled to room temperature. The resultant suspension was
filtered, washed with 1:1 v/v water isopropanol (11 ml then 22 ml)
and the solid dried under vacuum at 40.degree. C. to give the title
compound as a grey solid (7.73 g).
[0338] LCMS (Method B): Rt 2.59 min, MH.sup.+ 653.
[0339] Method B
[0340] All weights, volumes and equivalents are relative to
((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis--
2,6-dimethylmorpholine.
[0341]
((2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl-
)-cis-2,6-dimethylmorpholine (1.00 wt, 460 g),
N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-
methanesulfonamide (0.741 wt, 1.1 eq, 341 g) and potassium
phosphate (0.523 wt, 1.2 eq, 241 g) are combined in IPA (5 vol, 2.3
L) and water (5 vol, 2.3 L) in a clean CLR under nitrogen.
Potassium hydrogen difluoride (0.353 wt, 2.2 eq, 163 g) is added
and the mixture is heated to 75-80.degree. C. and degassed at this
temperature for at least 1 hr. In a separate vessel IPA (5 vol, 2.3
L) is degassed by being heated to reflux, then stirred for a
further 20 min at this temperature under a flow of N.sub.2 before
being cooled to 20-25.degree. C. under a nitrogen atmosphere. To
the degassed IPA (5 vol, 2.3 L) is charged palladium (II) acetate
(0.00922 wt, 0.02 eq, 4.25 g), followed by tricyclohexylphosphine
(0.0230 wt, 0.04 eq, 10.6 g) and the mixture stirred at
20-25.degree. C. for at least 0.5 hr. The resultant yellow solution
is added to the reaction mixture and stirred at 75-80.degree. C.
for at least 2 hr, then monitored for completion by HPLC. The
mixture is cooled to 30.degree. C. over 1 hr and water (5 vol, 2.3
L) is added. The slurry is allowed to cool to 20.degree. C., then
aged at this temperature for at least 0.5 hr, filtered, washed with
IPA:water (1:1 v/v, 2.times.2 vol, 2.times.920 ml) and sucked dry.
The solid is dried in vacuo at 60.degree. C. to constant probe
temperature to afford
N-(5-(4-(5-((cis-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1-(phenylsulf-
onyl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide as
an off-white solid.
Intermediate 10
5-Bromo-2-(methyloxy)-3-nitropyridine
##STR00015##
[0343] Method A
[0344] A solution of 25% wt sodium methoxide in methanol (2.1 L)
was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (1.70
kg) in methanol (6.6 L), stirred under nitrogen at 0-5.degree. C.
The reaction mixture was stirred at 5-10.degree. C. for 2.75 hours
and then water (8.5 L) was added. The reaction mixture was cooled
to 20-25.degree. C. The mixture was then concentrated under vacuum
and the resultant suspension was filtered, washed with water (8.5 L
then 2.times.4.25 L) and the solid dried under vacuum to give the
title compound as an off-white solid (1.37 kg).
[0345] .sup.1H NMR (400 MHz, Chloroform-d) .delta. (ppm) 8.46 (s,
1H), 8.40 (s, 1H).
[0346] Method B
[0347] All weights, volumes and equivalents are relative to
5-bromo-2-chloro-3-nitropyridine.
[0348] To a suspension of 5-bromo-2-chloro-3-nitropyridine (75.0 g,
1 wt, 1 eq) in methanol (300 mL, 4 vols), is added a solution of
sodium methoxide in methanol (25 wt %, 88.6 g, 1.3 eq) over
approximately 1 hour so as to maintain the internal temperature at
20.+-.5.degree. C. The mixture is stirred at 20.degree. C. for at
least 0.5 hr, then monitored for completion by HPLC. Water (375 mL,
5 vols) is then added to the mixture at such a rate as to maintain
the internal temperature below 30.degree. C., then aged at this
temperature for at least 0.5 hr. The batch is then concentrated to
6 vols in vacuo. The resulting slurry is allowed to cool to
20-25.degree. C., then collected by vacuum filtration, washed with
water and dried in vacuo with a nitrogen bleed at 20-25.degree. C.
to constant weight to afford 5-bromo-2-methoxy-3-nitropyridine as a
white solid.
Intermediate 11
5-Bromo-2-(methyloxy)-3-pyridinamine
##STR00016##
[0350] Iron powder (1.17 kg) was added to a suspension of
5-bromo-2-(methyloxy)-3-nitropyridine (1.36 kg) in IMS (6.1 L),
stirred under nitrogen at 20-25.degree. C. Water (0.8 L) was then
added and the mixture cooled to less than 10.degree. C. Aqueous
hydrochloric acid (0.8 L concentrated hydrochloric acid and 0.8 L
water) was then added to the reaction mixture, maintaining the
temperature below 10-15.degree. C. The suspension was warmed to
20-25.degree. C. and then stirred at this temperature for 23 hours.
The suspension was filtered, the filter cake washed with IMS
(2.times.2.7 L) and the combined filtrates concentrated under
vacuum. Water (4.1 L) was added slowly to the concentrated solution
and the resulting suspension was held at 20-25.degree. C. for 1.75
hours. The resultant suspension was filtered, washed with water
(2.times.6.8 L) and the solid dried under vacuum to give the title
compound as an off-white solid (1.13 kg).
[0351] LCMS (Method B): Rt 2.16 min, MH.sup.+ 204.
Intermediate 12
N-[5-Bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide
##STR00017##
[0353] Method A
[0354] Pyridine (540 ml) was added to a suspension of
5-bromo-2-(methyloxy)-3-pyridinamine (902.0 g) in acetonitrile (2.1
L), stirred under nitrogen at less than 25.degree. C. The mixture
was cooled to less than 10.degree. C. and methanesulfonyl chloride
(605.3 g) was added maintaining the temperature below 25.degree. C.
The reaction mixture was stirred at 15-25.degree. C. for 3 hours.
Water (3.6 L) was added slowly to the mixture over 1 hour,
maintaining the temperature below 25.degree. C. The resultant
suspension was filtered, washed with 3:1 v/v water:acetonitrile
(2.times.1.35 L and the solid dried under vacuum at 45.+-.5.degree.
C. to give the title compound as an off-white solid (1.13 kg).
[0355] LCMS (Method B): Rt 1.42 min, MH.sup.+ 282.
[0356] Method B
[0357] All weights, volumes and equivalents are relative to
5-bromo-2-methoxypyridin-3-amine hydrochloride.
[0358] 5-Bromo-2-methoxypyridin-3-amine hydrochloride (100 g, 1 wt,
1 eq) is charged to a CLR containing a mixture of acetonitrile (220
mL, 2.2 vols) and pyridine (101 mL, 1.01 vols, 99 g, 0.99 wt) at
room temperature. Methanesulfonyl chloride (56.4 g, 0.564 wt, 1.18
eq) is then added to the mixture over 20 minutes whilst maintaining
the temperature at 20.degree. C. Having stirred at 20.degree. C.
for a further 1.5 hours, the mixture is sampled and analysed by
HPLC. The completed reaction is quenched by the addition of water
over 1 hour, maintaining the mixture at 20.degree. C. and with
increased stirrer speed. The resulting slurry is stirred for 17
hours and then filtered in vacuo. The cake is washed with 3:1
water:acetonitrile (2.times.50 mL, 2.times.0.5 vols) and then dried
under vacuum at 40-45.degree. C. to afford
N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide.
Intermediate 13
Potassium
trifluoro{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}bo-
rate
##STR00018##
[0360] N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(499.4 g), bis(pinacolato)diboron (498.2 g) and potassium acetate
(361.8 g) were charged to the reaction vessel. The reaction vessel
was purged with nitrogen for 10 min before 1,4-dioxane (8.0 L) was
added. The resultant solution was heated to 95.+-.5.degree. C. and
stirred under nitrogen at this temperature. A degassed solution of
tris(dibenzylidene acetone) dipalladium (0) (16.6 g) and
tricyclohexylphosphine (25.0 g) in 1,4-dioxane (2.5 L) was added to
the reaction vessel over 30 min. The reaction mixture was then
stirred at 95.+-.5.degree. C. for 14 hours. The mixture was cooled
to 20.+-.3.degree. C. and held at this temperature for 1 hour. The
reaction mixture was filtered and concentrated under vacuum. Water
(1.0 L) and potassium hydrogenfluoride (555.0 g) were added and the
resultant mixture was stirred for 1 hour. Water (2.0 L) was added
to the suspension, the aqueous layer was removed and the remaining
organic layer was filtered. 1,4-dioxane (12.0 L) was added to the
solution which was then dried by azeotropic vacuum distillation.
Upon complete distillation the mixture was cooled to
20.+-.3.degree. C. and held at this temperature for 30 min. The
resultant suspension was filtered, washed with 1,4-dioxane
(2.times.1 L), then t-butyl methyl ether (2.times.1.0 L) and the
solid dried under vacuum to give the title compound as an off-white
solid (708.3 g).
[0361] LCMS (Method C): Rt 2.26 min, MH.sup.+ 247.
Intermediate 14
Ethyl oxazole-5-carboxylate
##STR00019##
[0363] All weights, volumes and equivalents are relative to
toluenesulfonylmethyl isocyanide.
[0364] Toluenesulfonylmethyl isocyanide (TosMlc) (12.31 g, 1 wt, 1
eq) is dissolved in DCM (61.6 ml, 5 vols) at 0.degree. C. under
N.sub.2. In a separate vessel, ethyl glyoxalate (50 wt % solution
in toluene, 20.6 g, 20.0 ml, 1.67 wt) is diluted with DCM (61.6 ml,
5 vols) under N.sub.2 and DBU (12.48 g, 12.35 ml, 1.3 eq, 1.01 wt)
is added resulting in a purple solution. The second solution is
added to the TosMlc solution over 1 hr, maintaining temperature at
0.degree. C., then checked by HPLC for completion after a further
20 mins. The reaction is quenched by slow addition of 2M HCl (10
vols, 123 ml) and the DCM layer separated. The aqueous layer is
re-extracted with DCM (5 vols, 61.6 ml), and the combined organics
dried over Na.sub.2SO.sub.4, then evaporated on Buchi, 25.degree.
C., 100 mbar to remove DCM and toluene. Distilled at 12 mbar,
jacket temperature 105.degree. C., vapour temperature 60-80.degree.
C. to afford ethyl oxazole-5-carboxylate as a colourless oil.
Intermediate 15
5-Bromo-2-methoxypyridin-3-amine
##STR00020##
[0366] All weights, volumes and equivalents are relative to
5-bromo-2-methoxy-3-nitropyridine.
[0367] To a nitrogen-purged flask is charged
5-bromo-2-methoxy-3-nitropyridine (1 wt, 5.0 g) and iron powder
(325 mesh, 0.86 wt, 4.31 g). IMS (12 vols, 60 ml) is added water
(0.6 vols, 3 ml) and the mixture is heated to 35-40.degree. C. with
vigorous stirring. A mixture of concentrated HCl (37 wt %, 0.146
vols, 0.73 ml) and water (0.56 vols, 2.8 ml) is prepared. The acid
solution is added to the reaction over at least 2.5 hrs at
35-40.degree. C. The reaction is stirred for at least a further 1.5
hrs and sampled for completion test by HPLC. The reaction is
cooled, filtered through Celite and the vessel and bed washed with
IMS (2.times.2 vols, 2.times.10 ml). The combined filtrates are
distilled under vacuum to 5 vols and toluene (10 vols, 50 ml) is
added, the mixture is distilled, this is repeated until the level
of IMS is <5% by NMR. The solution is cooled and 5M HCl in IPA
(0.9 vols, 1.05 eq, 4.5 ml), is added over at least 30 mins. The
resultant slurry is stirred for at least 60 mins, filtered and the
cake washed with toluene (2.times.2 vols, 2.times.10 ml). The cake
is dried under vacuum at 40.degree. C. overnight to afford
5-bromo-2-methoxypyridin-3-amine hydrochloride as a white
solid.
Intermediate 16
N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)m-
ethanesulfonamide
##STR00021##
[0369] All weights, volumes and equivalents are relative to
N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide.
[0370] Tricyclohexylphosphine (0.1191 g, 0.425 mmol, 0.008 eq,
0.008 wt) and Pd.sub.2(dba).sub.3 (0.1438 g, 0.157 mmol, 0.003 eq,
0.01 wt) are mixed together and then toluene (15.00 mL, 1 vol, 0.86
wt, sparged with nitrogen for 1 hr) is added. The mixture is
stirred and heated to 40-45.degree. C. for 45 mins before being
allowed to cool back to room temp and sit under nitrogen to give an
orange-gold solution with suspended black particulates. In a
separate vessel,
N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (15.0323 g,
53.5 mmol, 1 wt, 1 eq), bis(pinacolato)diboron (16.2962 g, 64.2
mmol, 1.2 eq, 1.08 wt) and potassium acetate (10.4879 g, 107 mmol,
2 eq, 0.70 wt) are mixed together with toluene (150 mL, 10 vols,
8.6 wt). The resultant slurry is stirred and heated to 90.degree.
C. under a flow of nitrogen. Having reached the desired
temperature, the catalyst mixture is added over 10 minutes followed
by a wash of toluene (7.50 mL, 0.5 vol, 0.43 wt). The mixture is
stirred at 90.degree. C. for at least one hour and then sampled for
HPLC analysis. Once complete, the reaction mixture is cooled to
50.degree. C. and filtered to remove inorganic material. The
filtered solid is washed with toluene (2.times.15 mL, 2.times.1
vol, 2.times.0.86 wt) and the liquors and washes combined and
distilled down to 5 vols. The product solution is allowed to cool
to room temperature by which stage it has become a slurry. Heptane
(75 mL, 5 vols, 3.4 wt) is slowly added to the slurry. The slurry
is aged and the supernatant analysed by HPLC to ensure sufficient
crystallisation has occurred. The slurry is filtered and the solid
product is washed with 1:1 toluene:heptane (2.times.15 mL,
2.times.1 vol) and dried under vacuum at 40-50.degree. C. to afford
N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-
methanesulfonamide as an off-white solid.
[0371] Recrystallisation--All weights, volumes and equivalents are
relative to
N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-
methanesulfonamide. A stirred suspension of
N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-
methanesulfonamide (1 wt, 1.01 kg) in propan-2-ol (4 vol, 4.05 L)
is heated to 70-75.degree. C. under a nitrogen atmosphere, then
aged at this temperature for at least 2 hr. The batch is allowed to
cool to 20-25.degree. C. over at least 1 hr, then the suspension is
aged at this temperature for a further 1 hr. The liquors are
sampled by HPLC to ensure complete crystallisation, then the
resulting solids are filtered, washed with propan-2-ol (2.times.1
vol, 2.times.1.01 L) before being sucked dry for 0.5 hr, then the
batch is dried in vacuo at 50.degree. C. to constant probe
temperature to afford
N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-
methanesulfonamide as a white solid.
Example 1
N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-
H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
##STR00022##
[0373] Method A
[0374] To a solution of
6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-y-
l)-1-(phenylsulfonyl)-1H-indazole (0.20 g, 0.411 mmol) and
N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-
methanesulfonamide (0.175 g, 0.534 mmol) in 1,4-dioxane (2 ml) was
added
chloro[2'-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]h-
ept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021
mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol) and water
(0.2 ml). The reaction mixture was heated and stirred at
120.degree. C. under microwave irradiation for 1 h. Additional
chloro[2'-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]h-
ept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021
mmol) and potassium phosphate tribasic (80 mg) were added and the
reaction heated to 120.degree. C. under microwave irradiation for 1
h. Additional potassium phospate tribasic (80 mg) was added and the
reaction heated under the same conditions for a further 1 h. The
reaction mixture was filtered through a silica SPE and eluted with
methanol. The solvent was removed in vacuo and the residue
partitioned between dichloromethane (5 ml) and water (5 ml). The
layers were separated and the aqueous extracted with further
dichloromethane (2.times.2 ml). The combined organics were
concentrated under a stream of nitrogen and the residue dissolved
in MeOH:DMSO (3 ml, 1:1, v/v) and purified by MDAP (method A) in 3
injections.
[0375] The appropriate fractions were combined and concentrated to
give a white solid which was dissolved in MeOH:DMSO (1 ml, 1:1,
v/v) and further purified by MDAP (method B). The appropriate
fractions were basified to pH 6 with saturated sodium bicarbonate
solution and extracted with ethyl acetate (2.times.25 ml). The
combined organics were dried and evaporated in vacuo to give a
white solid which was further dried under nitrogen at 40.degree. C.
for 3 h to give the title compound as a white solid (26 mg).
[0376] LCMS (Method A): Rt 0.53 mins, MH.sup.+ 513.
[0377] Method B
[0378]
N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3--
pyridinyl]methanesulfonamide (101 g, 308 mmol),
6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-y-
l)-1-(phenylsulfonyl)-1H-indazole (83.3 g, 154 mmol) and sodium
bicarbonate (38.8 g, 462 mmol) were suspended in 1,4-dioxane (1840
ml) and water (460 ml) under nitrogen and heated to 80.degree. C.
Chloro[2'-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]h-
ept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (8.63 g, 15.40
mmol) was added and the mixture stirred overnight at 80.degree.
C.
[0379] The reaction mixture was cooled to 45.degree. C., sodium
hydroxide 2M aq. (770 ml, 1540 mmol) added and the reaction heated
to 45.degree. C. for 4 hours. The mixture was cooled to RT and
diluted with water (610 mL). Dichloromethane (920 mL) was added,
and the mixture was filtered twice through Celite (washed with 200
mL 1,4-dioxane/DCM 2:1 each time). The phases were separated, and
aqueous washed with 1,4-dioxane/DCM 2:1 (500 mL). The aqueous phase
was neutralised with hydrochloric acid to pH .about.7 and extracted
with 1,4-dioxane/DCM 2:1 (1 L), then 1,4 dioxane/DCM 1:1
(2.times.500 mL). The organics were washed with brine (500 mL), and
filtered through Celite (washed with 200 mL 1,4 dioxane/DCM 2:1),
and evaporated to yield a dark black solid, which was purified in 4
batches:
[0380] Batch 1: 28 g was dissolved in Toluene/Ethanol/Ammonia
80:20:2 (100 mL) and purified by column chromatography (1.5 kg
silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to
give the title compound as an off-white solid (14.78 g).
[0381] Batch 2: 30 g was dissolved in methanol and mixed with
Fluorisil. The solvent was then removed by evaporation and the
solid purified by column chromatography (1.5 kg silica column,
solid sample injection module), eluting with
Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as an
off-white solid (9.44 g).
[0382] Batch 3: 31 g was dissolved in Toluene/Ethanol/Ammonia
80:20:2 (100 mL) and purified by column chromatography (1.5 kg
silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to
give the title compound as an off-white solid (17 g).
[0383] Batch 4: 29 g was dissolved in Toluene/Ethanol/Ammonia
80:20:2 (100 mL) and purified by column chromatography (1.5 kg
silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to
give the title compound as an off-white solid (21 g).
[0384] The mixed fractions from the 4 columns were combined and
evaporated to yield 19 g which was dissolved in 200 mL of
Toluene/Ethanol/Ammonia 80:20:2 (+additional 4 ml of 0.88 NH3 to
help solubility) then purified by column chromatography (1.5 kg
silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to
give the title compound as an off-white solid (6.1 g).
[0385] All pure batches were combined (68 g) and recrystallised
from ethanol (1200 mL). The suspension was heated to reflux and a
solution formed. The resulting solution was then cooled to room
temperature overnight. The resulting solid was then collected by
filtration, washed sparingly with ethanol and dried under vacuum to
give the title compound as an off-white solid (56 g). This material
was recrystallised again from ethanol (1100 mL). The suspension was
heated to reflux and a solution formed. The resulting solution was
then cooled to room temperature overnight with stirring. The
resulting solid was collected by filtration and washed sparingly
with ethanol. The solid was dried in vacuo at 60.degree. C. for 5
hrs to give the title compound as an off-white solid (45.51 g).
[0386] LCMS (Method A): Rt 0.61 mins, MH.sup.+ 513.
[0387] The filtrate from the two recrystallisations was evaporated
to yield .about.23 g of a solid residue that was dissolved in 200
mL of Toluene/Ethanol/Ammonia 80:20:2 (+additional 4 ml of 0.88 NH3
to help solubility) then purified by column chromatography (1.5 kg
silica column), eluting with Toluene/Ethanol/Ammonia 80:20:2 to
give a further crop of the title compound as an off-white solid
(18.5 g). This solid was then recrystallised from ethanol (370 mL).
The suspension was heated to reflux then the resulting solution
stirred for 20 mins before being allowed to cool to room
temperature naturally overnight. The solid was then dried in vacuo
at 65.degree. C. overnight to give the title compound as an
off-white solid (11.90 g).
[0388] LCMS (Method A): Rt 0.62 mins, MH.sup.+ 513.
[0389] Method C
[0390] 10M Sodium hydroxide solution (0.70 ml) was added to a
stirred suspension of
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfo-
namide (1.17 g) in water (5.8 ml). The resulting mixture was
stirred at room temperature for 3.75 hours and was then washed with
ethyl acetate (2.times.6 ml). The layers were separated and the
aqueous phase was acidified to pH 6 with 2M hydrochloric acid (0.8
ml). The acidified aqueous layer was extracted twice with ethyl
acetate (11 ml then 5 ml). The combined ethyl acetate extracts were
dried by azeotropic distillation and diluted with further ethyl
acetate (11 ml). The mixture was stirred at room temperature for
112 hours. The slurry was seeded and then stirred at room
temperature for 48 hours. The resultant suspension was filtered,
washed with ethyl acetate (2.times.2 ml) and the solid dried under
vacuum at 40.degree. C. to give the title compound as a pale yellow
solid (0.58 g).
[0391] LCMS (Method B): Rt 1.86 min, MH.sup.+ 513.
[0392] Method D
[0393] To a suspension of
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfo-
namide (596.5 g, 0.91 mol) in water (3.8 L) is added 5M sodium
hydroxide (715 ml, 3.56 mol) over 20 mins at <25.degree. C. The
mixture is stirred at 20.+-.3.degree. C. for 2 h 45 min then washed
with EtCN (3 L). The pH of the basic aqueous phase is adjusted to
pH 6.6 using 2M hydrochloric acid (1.4 L), maintaining the
temperature below 30.degree. C. The mixture is then extracted with
MeTHF (2.times.4.8 L), and the combined MeTHF extracts are washed
with water (1.2 L). The mixture is concentrated to approx 2.4 L and
EtOAc (3 L) is added. This put and take distillation is repeated a
further 3 times. The mixture is adjusted to 60.+-.3.degree. C. and
seeded twice (2.times.3 g) 35 mins apart. The resultant is aged for
1 h 10 mins then cooled over 2 h to 20-25.degree. C., and aged for
a further 15 h 50 min. The slurry is filtered, washed with EtOAc
(2.times.1 0.2 L) and dried in vacuo at 45.+-.5.degree. C. for
approx 3 day to give the title compound.
Preparation of Polymorphs of Compound A
[0394] Form (II)
[0395] Ethyl acetate (15 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (2.1
g) and was stirred at ambient conditions overnight. The resultant
slurry was filtered and dried under vacuum at 50.degree. C. to give
a new solid state form (91% w/w).
[0396] .sup.1H NMR (400 MHz, DMSO d6) d=13.49 (br s, 1H), 9.39 (s,
1H), 8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H),
7.93 (d, J=1.2 Hz, 1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H),
3.74 (s, 2H), 3.58 (m, 2H), 3.11 (s, 3H), 2.80 (d, J=10.3 Hz, 2H),
1.78 (t, J=10.3 Hz, 2H), 1.05 (d, J=6.4 Hz, 6H)
[0397] Form (III)
[0398] Methanol (4 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.3
g) followed by fumaric acid (0.0764 g) in methanol (2 ml). The
resultant suspension was diluted further with methanol (3 ml) and
stirred overnight at ambient conditions. The suspension was
filtered, washed with methanol and air dried to give a new solid
state form (64% w/w).
[0399] .sup.1H NMR (400 MHz, DMSO d6) d=13.50 (br s, 1H), 9.39 (s,
1H), 8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H),
7.93 (d, J=1.2 Hz, 1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H),
3.74 (s, 2H), 3.58 (m, 2H), 3.11 (s, 3H), 2.80 (d, J=10.3 Hz, 2H),
1.78 (t, J=10.5 Hz, 2H), 1.05 (d, J=6.4 Hz, 6H)
[0400] Form (IV)
[0401] Tetrahydrofuran was saturated with
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide at
room temperature and heated. The suspension was cooled to room
temperature and solids filtered, washed with THF and dried under
vacuum at 30.degree. C. to give a new solid state form.
[0402] .sup.1H NMR (400 MHz, DMSO d6) d=13.50 (br s, 1H), 9.39 (s,
1H), 8.58 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H),
7.93 (d, J=0.7 Hz, 1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H),
3.74 (s, 2H), 3.58 (m, 2.4H), 3.11 (s, 3H), 2.80 (d, J=10.5 Hz,
2H), 1.78 (t, J=10.5 Hz, 2.4H), 1.05 (d, J=6.1 Hz, 6H)
[0403] Sample contains 0.2 molar equivalents tetrahydrofuran
[0404] X-Ray Powder Diffraction (XRPD) for Forms (II) to (IV)
[0405] The data were acquired on a PANalytical X'Pert Pro powder
diffractometer, model PW3040/60 using an X'Celerator detector. The
acquisition conditions were: radiation: Cu K.alpha., generator
tension: 40 kV, generator current: 45 mA, start angle: 2.0.degree.
2.theta., end angle: 40.0.degree. 2.theta., step size:
0.0167.degree. 2.theta., time per step: 31.75 seconds. The sample
was prepared by mounting a few milligrams of sample on a silicon
wafer (zero background) plate, resulting in a thin layer of
powder.
[0406] Form (Ill) was lightly ground with pestle and mortar to
reduce preferred orientation.
[0407] Form (II)
[0408] The XRPD data are shown in FIG. 1.
[0409] Characteristic XRPD angles and d-spacings for the solid
state form are summarised in Table 1. Peak positions were measured
using Highscore software.
TABLE-US-00005 TABLE 1 2.theta./.degree. d-spacing/.ANG. 4.6 19.1
9.2 9.6 11.4 7.8 12.1 7.3 12.7 7.0 13.7 6.5 14.0 6.3 16.0 5.5 17.1
5.2 17.9 5.0 18.5 4.8 18.8 4.7 22.3 4.0 20.8 4.3 23.8 3.7 25.9
3.4
[0410] Form (III)
[0411] The XRPD data are shown in FIG. 2.
[0412] Characteristic XRPD angles and d-spacings for the solid
state form are summarised in Table 2. Peak positions were measured
using Highscore software.
TABLE-US-00006 TABLE 2 2.theta./.degree. d-spacing/.ANG. 6.7 13.2
8.2 10.8 8.8 10.0 9.7 9.1 11.1 8.0 12.6 7.0 13.6 6.5 14.4 6.1 17.0
5.2 17.7 5.0 18.8 4.7 20.9 4.2 21.3 4.2 22.8 3.9 24.4 3.6 25.3
3.5
[0413] Form (IV)
[0414] The XRPD data are shown in FIG. 3.
[0415] Characteristic XRPD angles and d-spacings for the solid
state form are summarised in Table 3. Peak positions were measured
using Highscore software.
TABLE-US-00007 TABLE 3 2.theta./.degree. d-spacing/.ANG. 5.8 15.2
11.1 8.0 11.6 7.6 14.0 6.3 17.5 5.1 19.3 4.6 22.3 4.0 25.7 3.5
Preparation of Salts of Compound A
[0416] Sodium Salt
[0417] Methanol (2 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.3
g) followed by aqueous sodium hydroxide (0.129 ml) to give a
solution. Tert-butylmethylether (4 ml) was added to the solution
followed by seed crystals of the sodium salt and this suspension
was stirred overnight at ambient conditions. The suspension was
filtered, washed with tert-butylmethylether (2 ml) and air dried to
give the sodium salt (0.2312 g) as a hydrate.
[0418] NMR: Consistent with salt formation
[0419] .sup.1H NMR (400 MHz, DMSO d6) d=13.35 (br s, 1H), 8.53 (s,
1H), 7.90 (d, J=1.2 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J=2.5 Hz, 1H),
7.62 (d, J=2.2 Hz, 1H), 7.33 (s, 1H), 4.00 (s, 3H), 3.80 (s, 3H),
3.59 (m, 2H), 2.83 (d, J=10.3, 2H), 2.61 (s, 3H), 1.78 (t, J=10.5
Hz, 2H), 1.05 (d, J=6.1 Hz, 6H)
[0420] Tosylate Salt
[0421] A solution of
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.3
g) in tetrahydrofuran (3 ml) was added to p-toluenesulfonic acid
(0.1224 g) to give initially a solution. A suspension formed on
stirring and was diluted with tetrahydrofuran (2 ml) and stirred
overnight at ambient conditions. The suspension was filtered,
washed with tetrahydrofuran (2 ml) and air dried to give the
tosylate (0.3759 g).
[0422] NMR: Consistent with mono tosylate formation
[0423] .sup.1H NMR (400 MHz, DMSO d6) d=13.56 (br s, 1H), 10.38 (br
s, 1H), 9.43 (s, 1H), 8.69 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.03
(s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.46
(d, J=7.8 Hz, 2H), 7.11 (d, J=7.8 Hz, 2H), 4.69 (br s, 2H), 4.00
(s, 3H), 3.80 (br s, 2H), 3.50 (br s, 2H), 3.11 (s, 3H), 2.80 (br
s, 2H), 2.28 (s, 3H), 1.05 (d, J=6.1 Hz, 6H) Sample contains 0.5
molar equivalents tetrahydrofuran NMR signals 3.60 (m, 2H), 1.76
(m, 2H)
[0424] Maleate Salt
[0425] Methanol (4 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.3
g) followed by maleic acid (0.0749 g) in methanol (2 ml). The
solution was allowed to crystallise overnight at ambient
conditions. The resultant suspension was filtered, washed with
methanol (1 ml) and air dried to give the maleate (0.1441 g).
[0426] NMR: Consistent with mono maleate formation
[0427] .sup.1H NMR (400 MHz, DMSO d6) d=13.53 (br s, 1H), 9.41 (s,
1H), 8.63 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H),
7.98 (d, J=1.2 Hz, 1H), 7.92 (s, 1H), 7.51 (s, 1H), 6.16 (s, 2H),
4.16 (br s, 2H), 4.00 (s, 3H), 3.69 (br s, 2H)*, 3.11 (s+br s,
3H+2H), 2.22 (br s, 2H), 1.10 (d, J=6.4 Hz, 6H)
[0428] *Partial increase in integral due to overlap with broad HOD
peak
[0429] Hemi Pamoate Salt
[0430] Tetrahydrofuran (1 ml) was added to pamoic acid (0.0759 g)
to give a suspension. This suspension was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.2
g). Further tetrahydrofuran (7 ml) and water (12 ml) were added
before the solution was reduced in volume by ca. 10% under a
nitrogen flow. The resultant suspension was sonicated and stirred
at ambient conditions overnight. The suspension was filtered,
washed with water and dried under vacuum at 50.degree. C. to give
the hemi pamoate (0.092 g) containing 5% w/w water.
[0431] NMR: Consistent with hemi pamoate formation
[0432] .sup.1H NMR (400 MHz, DMSO d6) d=13.51 (br s, 1H), 9.40 (s,
1H), 8.60 (s, 1H), 8.42 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 7.99 (d,
J=2.2 Hz, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=8.0 Hz, 1H),
7.42 (s, 1H), 7.33 (t, J=7.3 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.78
(s, 1H), 4.00 (s, 3H), 3.92 (br s, 2H), 3.63 (m, 2H), 3.11 (s, 3H),
2.95 (d, J=11.0 Hz, 2H), 1.97 (m, 2H), 1.07 (d, J=6.4 Hz, 6H)
[0433] Hemi Naphthalenedisulfonate Salt
[0434] Isopropylacetate (12 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.2
g) followed by naphthalenedisulfonic acid (0.0703 g) in
isopropylacetate (2 ml). The suspension was stirred at ambient
temperature for 9 days prior to filtration and dried under vacuum
at 40.degree. C. for 3 hrs to give the hemi
napthalenedisulfonate.
[0435] NMR Consistent with hemi naphthalenedisulfonate
formation
[0436] .sup.1H NMR (400 MHz, DMSO d6) d=13.56 (br s, 1H), 10.38 (br
s, 1H), 9.42 (s, 1H), 8.85 (d, J=8.8 Hz, 1H), 8.69 (s, 1H), 8.43
(d, J=2.5, 1H), 8.03 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.96 (s, 1H),
7.93 (d, J=7.1 Hz, 1H), 7.69 (br s, 1H), 7.40 (t, J=7.8 Hz, 1H),
4.68 (br s, 2H), 4.00 (s, 3H), 3.80 (br s, 2H), 3.50 (br s, 2H),
3.11 (s, 3H), 2.80 (br s, 2H), 1.15 (d, J=6.1 Hz, 6H)
[0437] Integrals at 4.68 and 2.80 are only at 1.6H not the expected
2H
[0438] Extra peaks due to ca. 0.1 eq isopropylacetate.
[0439] Raman: Not consistent with freebase forms known
[0440] Mesitylenesulfonate Salt
[0441] A solution of mesitylenesulfonic acid dihydrate (0.0698 g,
0.295 mmol, 1.0 eq) in tetrahydrofuran (0.5 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(0.1505 g, 0.294 mmol) and sonicated to give a clear solution.
After stirring at ambient temperature for ca. 2 mins the solution
had formed a very thick suspension. This was held at ambient
temperature overnight. The solids were collected by filtration and
washed with tetrahydrofuran (1-2 ml) before being dried in vacuo at
50.degree. C. overnight to give the mesitylenesulfonate salt
(0.1399 g, 66.8% th).
[0442] NMR: consistent with salt formation
[0443] NMR (400 MHz, DMSO d6) d=13.56 (s, 1H), 10.39 (bs, 1H), 9.42
(s, 1H), 8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.99
(d, J=2.2 Hz, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 6.73 (s, 2H), 4.69
(bs, 2H), 4.01 (s, 3H), 3.81 (bs, 2H), 3.49 (bs, 4H), 3.11 (s, 3H),
2.79 (bs, 2H), 2.16 (s, 3H), 1.15 (d, J=6.1 Hz, 6H).
[0444] Two methyl groups from mesitylenesulfonic acid are not seen
as they overlap with resonance from d.sub.5H-DMSO.
[0445] Hemi Biphenyldisulfonate
[0446] A solution of biphenyldisulfonic acid (0.0465 g, 0.148 mmol,
0.5 eq) in tetrahydrofuran (0.2 ml) and water (0.2 ml) was added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(0.1506 g, 0.294 mmol) and sonicated to give a solution which was
stirred at ambient temperature overnight. After this time the
solution set solid due to a precipitate. These solids were
collected by filtration and washed with tetrahydrofuran (1-2 ml)
before being dried in vacuo at 50.degree. C. overnight to give the
hemi-biphenyldisulfonate salt (0.117 g, 59.5% th)
[0447] NMR: consistent with salt formation
[0448] NMR (400 MHz, DMSO d6) d=13.55 (s, 1H), 10.37 (bs, 1H), 9.42
(s, 1H), 8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.99
(d, J=2.2 Hz, 1H), 7.96 (s, 1H), 7.66 (s+d, J=8.1 Hz, 1H+2H), 7.61
(d, J=8.3 Hz, 2H), 4.69 (bs, 2H), 4.01 (s, 3H), 3.81 (bs, 2H), 3.50
(bs, 4H), 3.11 (s, 3H), 2.79 (bs, 2H), 1.16 (d, J=6.1 Hz, 6H).
[0449] 2-Naphthalenesulfonate (Napsylate)
[0450]
N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol--
2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(0.200 g, 0.390 mmol) was dissolved in tetrahydrofuran (3.2 ml) and
water (0.8 ml). Separately, 2-naphthalenesulfonic acid (0.081 mg,
0.390 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.8 ml) and
added to the
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
solution. This was seeded with a previous napsylate salt, however
these seeds dissolved. The solution was allowed to evaporate at
ambient temperature for 2 days. The white solid formed was
triturated in water and sonicated before being filtered and washed
with water. The damp solids were dried further in vacuo at
40-50.degree. C. for 5 days to give the napsylate salt (254.8 mg,
91% th).
[0451] NMR: consistent with salt formation
[0452] NMR (400 MHz, DMSO d6) d=13.56 (s, 1H), 10.38 (bs, 1H), 9.42
(s, 1H), 8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 8.03
(s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.96 (m, 2H), 7.86 (m, 2H), 7.71
(m, 2H), 7.53 (m, 2H), 4.68 (bs, 2H), 4.01 (s, 3H), 3.79 (bs, 2H),
3.50 (bs, 2H), 3.11 (s, 3H), 2.78 (bs, 2H), 1.14 (d, J=6.1 Hz,
6H).
[0453] NMR also shows some unidentified low level impurities and
residual tetrahydrofuran (0.1 molar equivalents).
[0454] Hemi Cinnamate
[0455] Method A
[0456]
N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol--
2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(0.02505 g, 0.049 mmol) was treated with trans-cinnamic acid
(0.01453 g, 0.098 mmol, 2.0 eq) in methanol (0.5 ml). This was
heated with a hot air gun until dissolution occurred then allowed
to cool to room temperature. Solids precipitated on returning to
room temperature and were allowed to stir overnight. The solids
were filtered and solvent removed by pulling vacuum through the
cake to give the salt.
[0457] Method B
[0458]
N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol--
2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(80 g, 0.156 mol) and trans-cinnamic acid (58.66 g, 0.396 mol, 2.5
eq) were dissolved in methanol (3.2 L) by heating to 65.degree. C.
The solution was cooled to 60.degree. C. and seeded with
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
hemi-cinnamate (0.0802 g), these dissolved so the solution was
cooled further to 50.degree. C. and reseeded with
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
hemi-cinnamate. This was stirred for 1 hr at 50.degree. C. and then
cooled at .about.0.167.degree. C./min to 20.degree. C. After 2 hrs
a sample was taken and proved to be Form 3 by Raman analysis. The
slurry was heated back to reflux to give a solution and extra
methanol (100 ml) was added to make up for solvent losses incurred
during the extended high temperature process. The solution was
cooled to 25.degree. C. and sample taken which was seeded with
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
hemi-cinnamate. This seeded sample was aged for 20 mins and then
used to seed the bulk solution. This was allowed to stir at
25.degree. C. for 16 hrs. The slurry was filtered and sucked dry
before being dried in vacuo at 50.degree. C. to give the salt (75.4
g, 82.5% th).
[0459] NMR: consistent with salt formation
[0460] NMR (400 MHz, DMSO d6) d=13.49 (bs, 1H), 9.40 (bs, 1H), 8.58
(s, 1H), 8.42 (d, J=2.5 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.94 (s,
1H), 7.88 (s, 1H), 7.68 (m, 1H), 7.57 (d, J=16.1 Hz, 0.5H), 7.42
(m, 1.5H), 7.35 (s, 1H), 6.55 (d, J=15.9 Hz, 0.5H), 4.01 (s, 3H),
3.74 (s, 2H), 3.58 (m, 2H), 3.12 (s, 3H), 2.80 (d, J=10.5, 2H),
1.78 (t, J=10.5, 2H), 1.05 (d, J=6.1 Hz, 6H).
[0461] NMR also shows residual methanol (signal 3.18 ppm) at
<0.1 molar equivalents.
[0462] Hemi Sebacate
[0463] A solution of sebacic acid (118.6 mg, 0.586 mmol, 2.0 eq) in
THF (2 ml) was made up and added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(150.6 mg, 0.294 mmol) and heated to give a clear solution. The
solution was allowed to cool to room temperature with stirring and
after 2 hrs solids were present. A further aliquot of THF was added
at this point and the suspension stirred overnight at ambient
temperature. The solids were isolated by filtration and dried in
vacuo at 50.degree. C. overnight to give the hemi-sebacate
salt.
[0464] NMR: consistent with salt formation
[0465] NMR (400 MHz, DMSO d6) d=13.49 (s, 1H), 11.94 (bs, 1H),
10.38 (bs, 1H), 9.38 (s, 1H), 8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H),
7.99 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.35 (s, 1H),
4.00 (s, 3H), 3.74 (s, 2H), 3.11 (s, 3H), 2.80 (d, J=10.5, 2H),
2.18 (t, J=7.3 Hz, 2H), 1.48 (t, J=6.8 Hz, 2H), 1.25 (s, 4H), 1.05
(d, J=6.1 Hz, 6H). Sample contains 0.85 molar equivalents
tetrahydrofuran--NMR signals 3.60 ppm (m, 3.3H) and 1.76 ppm (m,
3.4H).
[0466] Hemi Pyromellitate
[0467] A solution of pyromellitic acid (0.0546 g, 0.215 mmol, 0.55
eq) was made up in tetrahydrofuran (1 ml) and added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(0.1999 g, 0.390 mmol) followed by further tetrahydrofuran (1 ml).
This suspension was sonicated at which point the solids changed
physical character and set solid. A further aliquot of
tetrahydrofuran (2 ml) was added and the solution was heated and
sonicated, however dissolution was not observed. The suspension was
allowed to cool and stir overnight at room temperature. The solids
were collected by filtration and washed with tetrahydrofuran (2 ml)
before drying in vacuo overnight at 50.degree. C. to give the
hemi-pyromellitate salt as a tetrahydrofuran solvate.
[0468] NMR: consistent with salt formation
[0469] NMR (400 MHz, DMSO d6) d=13.52 (s, 1H), 9.39 (s, 1H), 8.61
(s, 1H), 8.42 (d, J=2.2 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J=2.2 Hz,
1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.45 (s, 1H), 4.01 (s, 5H), 3.60
(m, 6H), 3.11 (s, 3H), 3.02 (d, J=10.8 Hz, 2H), 2.06 (bs, 2H), 1.76
(m, 4H), 1.05 (d, J=6.1 Hz, 6H).
[0470] Tetrahydrofuran signals are 3.60 ppm (m, 4H) and 1.76 ppm
(M, 4H) corresponding to 1 molar equivalent.
[0471] Hemi Benzenediacrylate
[0472] 1,4-Benzenediacrylic acid (0.0431 g, 0.197 mmol, 0.5 eq) was
dissolved in dimethylsulfoxide (0.5 ml) with heating, this was
added to
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)--
1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
(0.2003 g, 0.391 mmol) and heated to give a solution.
Tetrahydrofuran (1 ml) was added to the solution and it was then
heated and sonicated before being allowed to stir at room
temperature overnight. The solids were isolated by filtration and
washed with tetrahydrofuran before being dried in vacuo at
65.degree. C. overnight to give the hemi-benzenediacrylate salt
(0.1385 g, 57% th).
[0473] NMR: consistent with salt formation
[0474] NMR (400 MHz, DMSO d6) d=13.49 (bs, 1H), 12.40 (bs, 1H),
9.38 (bs, 1H), 8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2
Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.73 (s, 2H), 7.58 (d, J=16.1
Hz, 1H), 7.35 (s, 1H), 6.62 (d, J=16.1 Hz, 1H), 4.00 (s, 3H), 3.74
(s, 2H), 3.11 (s, 3H), 2.80 (d, J=10.5 Hz, 2H), 1.05 (d, J=6.4 Hz,
6H).
[0475] Tetrahydrofuran signals are 3.60 ppm (m, 2.7H) and 1.78 ppm
(m, 2.7H) corresponding to 0.68 molar equivalent. Dimethylsulfoxide
signal is 2.54 ppm (s, 0.7H) corresponding to 0.12 molar
equivalents.
* * * * *