U.S. patent application number 15/618593 was filed with the patent office on 2018-02-08 for malate salt of n-(4-phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer.
The applicant listed for this patent is Exelixis,Inc.. Invention is credited to Adrian St. Clair Brown, William P. Gallagher, Peter Lamb.
Application Number | 20180037552 15/618593 |
Document ID | / |
Family ID | 41820137 |
Filed Date | 2018-02-08 |
United States Patent
Application |
20180037552 |
Kind Code |
A1 |
Brown; Adrian St. Clair ; et
al. |
February 8, 2018 |
Malate salt of
N-(4-phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and
crystalline forms thereof for the treatment of cancer
Abstract
Disclosed are malate salts of
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide, including a (L)-malate salt, a
(D)-malate salt, a (DL) malate salt, and mixtures thereof; and
crystalline and amorphous forms of the malate salts. Also disclosed
are pharmaceutical compositions comprising at least one malate
salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-cy-
clopropane-1,1-dicarboxamide; and methods of treating cancer
comprising administering at least one malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
Inventors: |
Brown; Adrian St. Clair;
(Ely, GB) ; Lamb; Peter; (Oakland, CA) ;
Gallagher; William P.; (Princeton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Exelixis,Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
41820137 |
Appl. No.: |
15/618593 |
Filed: |
June 9, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15617725 |
Jun 8, 2017 |
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15618593 |
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14340871 |
Jul 25, 2014 |
9809549 |
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15617725 |
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13145054 |
Oct 20, 2011 |
8877776 |
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PCT/US2010/021194 |
Jan 15, 2010 |
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14340871 |
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61145421 |
Jan 16, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 5/14 20180101; C07D
215/22 20130101; C07D 215/233 20130101; A61P 25/00 20180101; A61P
43/00 20180101; A61P 35/00 20180101 |
International
Class: |
C07D 215/22 20060101
C07D215/22; C07D 215/233 20060101 C07D215/233 |
Claims
1-15. (canceled)
16. A method of treating kidney cancer, comprising administering to
a patient in need of such treatment
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)
cyclopropane-1,1-dicarboxamide, malate salt, wherein said salt is
in crystalline Form N-2 and said Form N-2 is characterized by at
least one of the following: (i) a solid state .sup.13C NMR spectrum
with four or more peaks selected from 23.0, 25.9, 38.0, 41.7, 69.7,
102.0, 122.5, 177.3, 179.3, 180.0, and 180.3, .+-.0.2 ppm; (ii) a
powder x-ray diffraction pattern (CuK.alpha. .lamda.=1.5418 .ANG.)
comprising 2.theta. values at 20.9.+-.0.2.degree.2.theta. and
21.9.+-.0.2.degree.2.theta., and two or more 2.theta. values
selected from: 6.4.+-.0.2.degree.2.theta.,
9.1.+-.0.2.degree.2.theta., 12.0.+-.0.2.degree.2.theta.,
12.8.+-.0.2, 13.7.+-.0.2, 17.1.+-.0.2, 22.6.+-.0.2, 23.7.+-.0.2,
wherein measurement of the crystalline form is at room temperature;
and/or (iii) an x-ray powder diffraction (XRPD) pattern
substantially in accordance with the pattern shown in FIG. 8.
17. A method of treating kidney cancer, comprising administering to
a patient in need of such treatment a pharmaceutical composition
comprising
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)
cyclopropane-1,1-dicarboxamide, (L)-malate salt and a
pharmaceutically acceptable carrier, wherein said salt is in
crystalline Form N-2 and said Form N-2 is characterized by at least
one of the following: (i) a solid state .sup.13C NMR spectrum with
four or more peaks selected from 23.0, 25.9, 38.0, 41.7, 69.7,
102.0, 122.5, 177.3, 179.3, 180.0, and 180.3, .+-.0.2 ppm; (ii) a
powder x-ray diffraction pattern (CuK.alpha. .lamda.=1.5418 .ANG.)
comprising 2.theta. values at 20.9.+-.0.2.degree.2.theta. and
21.9.+-.0.2.degree.2.theta., and two or more 2.theta. values
selected from: 6.4.+-.0.2.degree.2.theta.,
9.1.+-.0.2.degree.2.theta., 12.0.+-.0.2.degree.2.theta.,
12.8.+-.0.2, 13.7.+-.0.2, 17.1.+-.0.2, 22.6.+-.0.2, 23.7.+-.0.2,
wherein measurement of the crystalline form is at room temperature;
and/or (iii) an x-ray powder diffraction (XRPD) pattern
substantially in accordance with the pattern shown in FIG. 8.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
15/617,725, filed Jun. 8, 2017, which is a continuation of U.S.
Ser. No. 14/340,871, filed Jul. 25, 2014, which is a divisional of
U.S. Ser. No. 13/145,054, filed Oct. 20, 2011, which is a 371
application of PCT/US2010/021194, filed Jan. 15, 2010, and claims
the benefit under 35 U.S.C. .sctn.119 to U.S. Provisional
Application No. 61/145,421, filed Jan. 16, 2009, the entire
contents of which are incorporated herein by reference.
TECHNICAL FIELD
[0002] This disclosure relates to malate salts of
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide and to crystalline and amorphous forms
of the malate salts of
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide. The malate salts of
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide include one of (1) the (L)-malate
salt, (2) the (D)-malate salt, (3) the (D,L)-malate salt, and (4)
mixtures thereof. The disclosure also relates to pharmaceutical
compositions comprising at least one malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-cy-
clopropane-1,1-dicarboxamide.
[0003] The disclosure also relates to pharmaceutical compositions
comprising a crystalline or an amorphous form of at least one
malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-
-cyclopropane-1,1-dicarboxamide.
[0004] The disclosure also relates to methods of treating cancer
comprising administering at least one malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
[0005] The disclosure further relates to methods of treating cancer
comprising administering a crystalline or an amorphous form of at
least one malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
BACKGROUND
[0006] Traditionally, dramatic improvements in the treatment of
cancer are associated with identification of therapeutic agents
acting through novel mechanisms. One mechanism that can be
exploited in cancer treatment is the modulation of protein kinase
activity because signal transduction through protein kinase
activation is responsible for many of the characteristics of tumor
cells. Protein kinase signal transduction is of particular
relevance in, for example, thyroid, gastric, head and neck, lung,
breast, prostate, and colorectal cancers, as well as in the growth
and proliferation of brain tumor cells.
[0007] Protein kinases can be categorized as receptor type or
non-receptor type. Receptor-type tyrosine kinases are comprised of
a large number of transmembrane receptors with diverse biological
activity. For a detailed discussion of the receptor-type tyrosine
kinases, see Plowman et al., DN&P 7(6): 334-339, 1994. Since
protein kinases and their ligands play critical roles in various
cellular activities, deregulation of protein kinase enzymatic
activity can lead to altered cellular properties, such as
uncontrolled cell growth associated with cancer. In addition to
oncological indications, altered kinase signaling is implicated in
numerous other pathological diseases, including, for example,
immunological disorders, cardiovascular diseases, inflammatory
diseases, and degenerative diseases. Therefore, protein kinases are
attractive targets for small molecule drug discovery. Particularly
attractive targets for small-molecule modulation with respect to
antiangiogenic and antiproliferative activity include receptor type
tyrosine kinases Ret, c-Met, and VEGFR2.
[0008] The kinase c-Met is the prototypic member of a subfamily of
heterodimeric receptor tyrosine kinases (RTKs) which include Met,
Ron and Sea. The endogenous ligand for c-Met is the hepatocyte
growth factor (HGF), a potent inducer of angiogenesis. Binding of
HGF to c-Met induces activation of the receptor via
autophosphorylation resulting in an increase of receptor dependent
signaling, which promotes cell growth and invasion. Anti-HGF
antibodies or HGF antagonists have been shown to inhibit tumor
metastasis in vivo (See: Maulik et al Cytokine & Growth Factor
Reviews 2002 13, 41-59). c-Met, VEGFR2 and/or Ret overexpression
has been demonstrated on a wide variety of tumor types including
breast, colon, renal, lung, squamous cell myeloid leukemia,
hemangiomas, melanomas, astrocytic tumor (which includes
glioblastoma, giant cell glioblastoma, gliosarcoma, and
glioblastoma with oligodendroglial components). The Ret protein is
a transmembrane receptor with tyrosine kinase activity. Ret is
mutated in most familial forms of medullary thyroid cancer. These
mutations activate the kinase function of Ret and convert it into
an oncogene product.
[0009] Inhibition of EGF, VEGF and ephrin signal transduction will
prevent cell proliferation and angiogenesis, two key cellular
processes needed for tumor growth and survival (Matter A. Drug
Disc. Technol. 2001 6, 1005-1024). Kinase KDR (refers to kinase
insert domain receptor tyrosine kinase) and fit-4 (fins-like
tyrosine kinase-4) are both vascular endothelial growth factor
(VEGF) receptors. Inhibition of EGF, VEGF and ephrin signal
transduction will prevent cell proliferation and angiogenesis, two
key cellular processes needed for tumor growth and survival (Matter
A. Drug Disc. Technol. 2001 6, 1005-1024). EGF and VEGF receptors
are desirable targets for small molecule inhibition.
[0010] Accordingly, small-molecule compounds that specifically
inhibit, regulate and/or modulate the signal transduction of
kinases, particularly including Ret, c-Met and VEGFR2 described
above, are particularly desirable as a means to treat or prevent
disease states associated with abnormal cell proliferation and
angiogenesis. One such small-molecule is
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, which has the chemical structure:
##STR00001##
WO 2005/030140 describes the synthesis of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide (Example 12, 37, 38, and 48) and also
discloses the therapeutic activity of this molecule to inhibit,
regulate and/or modulate the signal transduction of kinases,
(Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in
WO 2005/030140.
[0011] Besides therapeutic efficacy, the drug developer endeavors
to provide a suitable form of the therapeutic agent that has
properties relating to processing, manufacturing, storage
stability, and/or usefulness as a drug. Accordingly, the discovery
of a form that possesses some or all of these desired properties is
vital to drug development.
[0012] Applicants have found a salt form of the drug
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide that has suitable properties for use in
a pharmaceutical composition for the treatment of a proliferative
disease such as cancer. The novel salt form of the invention exists
in crystalline and amorphous forms
SUMMARY
[0013] This disclosure relates to malate salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as described herein, pharmaceutical
compositions thereof as described herein, and uses thereof as
described herein.
[0014] Another aspect relates to crystalline and amorphous forms of
the malate salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as described herein, pharmaceutical
compositions thereof as described herein, and uses thereof as
described herein.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 shows the experimental XRPD pattern for crystalline
Compound (I), Form N-1 at 25.degree. C.
[0016] FIG. 2 shows the solid state .sup.13C NMR spectrum of
crystalline Compound (I), Form N-1.
[0017] FIG. 3 shows the solid state .sup.15N NMR spectrum of
crystalline Compound (I), Form N-1.
[0018] FIG. 4 shows the solid state .sup.19F NMR spectrum of
crystalline Compound (I), Form N-1.
[0019] FIG. 5 shows the thermal gravimetric analysis (TGA) of
crystalline Compound (I), Form N-1.
[0020] FIG. 6 shows the differential scanning calorimetry (DSC) of
crystalline Compound (I), Form N-1.
[0021] FIG. 7 shows the moisture sorption of crystalline Compound
(I), Form N-1.
[0022] FIG. 8 shows the experimental XRPD pattern for crystalline
Compound (I), Form N-2 at 25.degree. C.
[0023] FIG. 9 shows the solid state .sup.13C NMR spectrum of
crystalline Compound (I), Form N-2.
[0024] FIG. 10 shows the solid state .sup.15N NMR spectrum of
crystalline Compound (I), Form N-2.
[0025] FIG. 11 shows the solid state .sup.19F NMR spectrum of
crystalline Compound (I), Form N-2.
[0026] FIG. 12 shows the thermal gravimetric analysis (TGA) of
crystalline Compound (I), Form N-2.
[0027] FIG. 13 shows the differential scanning calorimetry (DSC) of
crystalline Compound (I), Form N-2.
[0028] FIG. 14 shows the moisture sorption of crystalline Compound
(I), Form N-2.
[0029] FIG. 15 shows the experimental and simulated XRPD patterns
for crystalline Compound (III), Form N-1 at room temperature.
[0030] FIG. 16 shows the solid state .sup.13C NMR spectrum of
crystalline Compound (III), Form N-1.
[0031] FIG. 17 shows the solid state .sup.15N NMR spectrum of
crystalline Compound (III), Form N-1.
[0032] FIG. 18 shows the solid state .sup.19F NMR spectrum of
crystalline Compound (III), Form N-1.
[0033] FIG. 19 shows the thermal gravimetric analysis (TGA) of
crystalline Compound (III), Form N-1.
[0034] FIG. 20 shows the differential scanning calorimetry (DSC) of
crystalline Compound (III), Form N-1.
[0035] FIG. 21 shows the moisture sorption of crystalline Compound
(III), Form N-1.
[0036] FIG. 22 shows the XRPD pattern of amorphous Compound (I) at
room temperature.
[0037] FIG. 23 shows the solid state .sup.13C NMR spectrum of
amorphous Compound (I).
[0038] FIG. 24 shows the solid state .sup.15N NMR spectrum of
amorphous Compound (I).
[0039] FIG. 25 shows the solid state .sup.19F NMR spectrum of
amorphous Compound (I).
[0040] FIG. 26 shows the differential scanning calorimetry (DSC) of
amorphous Compound (I).
[0041] FIG. 27 shows the moisture sorption of amorphous Compound
(I).
DETAILED DESCRIPTION
[0042] This disclosure relates to improvements of the
physiochemical properties of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, whereby this compound may be suitable
for drug development. Disclosed herein are malate salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide. New solid state forms of those salts
are also disclosed. The malate salts as well as their crystalline
and amorphous forms disclosed herein each represent separate
aspects of the disclosure. Although the malate salts and their
solid state forms are described herein, the invention also relates
to novel compositions containing the disclosed salts and solid
state forms. Therapeutic uses of the salts and solid state forms
described as well as therapeutic compositions containing them
represent separate aspects of the disclosure. The techniques used
to characterize the salts and their solid state forms are described
in the examples below. These techniques, alone or in combination,
may be used to characterize the salts and their solid state forms
disclosed herein. The salts and their solid state forms may be also
characterized by reference to the disclosed figures.
[0043]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)-cyclopropane-1,1-dicarboxamide was found to have an enzyme Ret
IC.sub.50 value of about 5.2 nM (nanomolar) and an enzyme c-Met
IC.sub.50 value of about 1.3 nM (nanomolar). The assay that was
used to measure this c-Met activity is described in paragraph
[0458] in WO2005-030140.
[0044] RET biochemical activity was assessed using a
Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format as
described in WO2005-030140. Kinase activity was measured as the
percent ATP remaining following the kinase reaction. Remaining ATP
was detected by luciferase-luciferin-coupled chemiluminescence.
Specifically, the reaction was initiated by mixing test compounds,
2 .mu.M ATP, 1 .mu.M poly-EY and 15 nM RET (baculovirus expressed
human RET kinase domain M700-D1042 with a (His).sub.6 tag on the
N-terminus) in a 20 uL assay buffer (20 mM Tris-HCL pH 7.5, 10 mM
MgCl.sub.2, 0.01% Triton X-100, 1 mM DTT, 3 mM MnCl.sub.2). The
mixture was incubated at ambient temperature for 2 hours after
which 20 uL luciferase-luciferin mix was added and the
chemiluminescent signal read using a Wallac Victor.sup.2 reader.
The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5
ug/mL oxalic acid (pH 7.8), 5 mM DTT, 0.4% Triton X-100, 0.25 mg/mL
coenzyme A, 63 .mu.M AMP, 28 .mu.g/mL luciferin and 40,000 units of
light/mL luciferase.
Malate Salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide
[0045] This disclosure relates to malate salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide. These malate salts are a combination
of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide with malic acid which forms a 1:1
malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-
cyclopropane-1,1-dicarboxamide.
[0046] Malic acid has the following structure:
##STR00002##
Due to its chiral carbon, two enantiomers of malic acid exist,
(L)-malic acid and (D)-malic acid.
[0047] (L)-malic acid has the following structure:
##STR00003##
There are various names or designations for the (L)-malic acid that
are known in the art. These include butanedioic acid, hydroxy-,
(2S)-(9CI); butanedioic acid, hydroxy-, (S)-; malic acid, L-(8CI);
malic acid, 1-(3CI); (-)-(S)-malic acid; (-)-Hydroxysuccinic acid;
(-)-(L)-malic acid; (-)-malic acid; (2S)-2-hydroxybutanedioic acid;
(2S)-2-hydroxysuccinic acid; (S)-malic acid; apple acid;
L-(-)-malic acid; (L)-malic acid; NSC 9232; S-(-)-malic acid; and
S-2-hydroxybutanedioic acid.
[0048] (D) malic acid has the following structure:
##STR00004##
There are various names or designations for the (D)-malic acid that
are known in the art. These include butanedioic acid, 2-hydroxy-,
(2R)--, butanedioic acid, hydroxy-, (2R)-(9CI); butanedioic acid,
hydroxy-, (R)-; (+)-malic acid; (2R)-2-hydroxybutanedioic acid;
(2R)-malic acid; (R)-(+)-malic acid; (R)-malic acid;
D-(+)-2-hydroxysuccinic acid; D-(+)-malic acid; and D-malic
acid.
[0049] As discussed above, the chemical structure of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is
##STR00005##
There are no chiral carbons in its chemical structure. There are
various names for
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluoro-
phenyl)cyclopropane-1,1-dicarboxamide which are publicly known, and
some of these various names or designations include
1,1-cyclopropanedicarboxamide,
N'-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)-
and 1,1-cyclopropanedicarboxamide,
N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(4-fluorophenyl)-(9CI).
[0050]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide can be prepared according to any
of several different methodologies, either on a gram scale (<1
kg) or a kilogram scale (>1 kg). A gram-scale method is set
forth in WO 2005-030140, which describes the synthesis of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide (Examples 25, 37, 38, and 48), which is
hereby incorporated by reference. Alternatively,
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, including the active compound(s), can
be prepared on a kilogram scale using the procedure set forth in
Example 1 below.
[0051] This disclosure relate to malate salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide: [0052] the (L)-malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, (Compound (I)); [0053] the (D)-malate
salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, (Compound (II)); and [0054] the
(DL)-malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluoroph-
enyl)cyclopropane-1,1-dicarboxamide (Compound (III)). Each has
improved properties over
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and its other salts. The names used
herein to characterize a specific form, e.g. "N-2" etc., are not to
be limited so as to exclude any other substance possessing similar
or identical physical and chemical characteristics, but rather such
names are used as mere identifiers that are to be interpreted in
accordance with the characterization information presented
herein.
[0055] The malate salts of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, and particularly Compound (I), have a
preferred combination of pharmaceutical properties for development.
Under the conditions of 25.degree. C./60% relative humidity (RH)
and 40.degree. C./60% RH, Compound (I) showed no change in assay,
purity, moisture and dissolution. The DSC/TGA showed the Compound
(I) to be stable up to 185.degree. C. No solvent losses were
observed. The uptake of water by the (L)-malate salt was reversible
with a slight hysteresis. The amount of water taken up was
calculated at about 0.60 wt % at 90% RH. The (L)-malate salt was
synthesized with good yield and purity >90% and had sufficient
solubility for use in a pharmaceutical composition. The amount of
water associated with this salt was calculated at about 0.5 wt % by
Karl Fischer analysis and correlates with TGA and GVS analysis. The
(D)-malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide) will have the same properties as the
(L)-malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide).
[0056] The Compound (I) salt itself, and separately its crystalline
and amorphous forms, exhibit beneficial properties over the free
base and the other salts of the
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide. For example, the hydrochloride salt
of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide exhibits undesirable moisture
sensitivity, changing phase upon exposure to high humidity (75%
humidity) and high temperature (40.degree. C.). The maleate salt
had low solubility. The tartrate salt had low crystallinity and low
solubility. The phosphate salt exhibited an 8% weight gain due to
absorption of H.sub.2O--the highest among the salts tested.
[0057] The water solubility of the various salts was determined
using 10 mg solids per mL water. The salts were prepared in a salt
screen by reacting an acetone solution of the freebase with stock
tetrahydrofuran (THF) solutions of a range of acids in about a 1:1
molar ratio. Table 1 below summarizes the water solubility and
other data relating to the free base and each salt.
TABLE-US-00001 TABLE 1 Solubility (mg/ml) Free base <<0.001
very low solubility Propionate <<0.001 no salt formation;
mixture of free base and acid Acetate <<0.001 no salt
formation; mixture of free base and acid Succinate 0.010 no salt
formation; mixture of free base and acid Benzoate 0.005 no salt
formation; mixture of free base and acid L-Lactate 0.015 Amorphous,
salt Pyrroglutamate 0.44 Amorphous, salt Glycolate 0.016 Amorphous,
salt L-Ascorbate 0.053 low crystallinity Sulfate 0.004 Crystalline
salt, low solubility Tosylate 0.007 Crystalline salt, low
solubility Malonate 0.003 Crystalline salt, low solubility
2,5dihydroxybenzoate <<0.001 Crystalline Salt, low solubility
Fumarate 0.008 Crystalline Salt, low solubility Citrate 0.002
Crystalline Salt, low solubility Mesylate 0.175 Crystalline Salt;
possible sulfonic acid formation when made with alcohol Esylate
0.194 Crystalline Salt; possible sulfonic acid formation when made
with alcohol Benzenesulfonate 0.039 Crystalline Salt; possible
sulfonic acid formation when made with alcohol Chloride 0.070
Crystalline but Hygroscopic; possible hydrate formation. Change in
XRPD pattern upon exposure to humidity. Maleate 0.005 Crystalline
salt, possible hydrate formation; low solubility; different XRPD
pattern observed upon scale up (possible polymorphism issue)
Phosphate 0.026 Crystalline but Hygroscopic. L-Tartrate 0.014 Low
degree of crystallinity; Hygroscopic. (L)-Malate 0.059 Crystalline;
non-Hygroscopic with no indication of hydrate formation. Suitable
solubility, and chemical/physical stability.
[0058] Another aspect of this disclosure relates to crystalline
forms of Compound (I), which include the N-1 and/or the N-2
crystalline form of Compound (I) as described herein. Each of form
of Compound (I) is a separate aspect of the disclosure. Similarly,
another aspect of this disclosure relates to crystalline forms of
Compound (II), which include the N-1 and/or the N-2 crystalline
form of Compound (II) as described herein. Each of which is also a
separate aspect of the disclosure. As is known in the art, the
crystalline (D) malate salt will form the same crystalline form and
have the same properties as crystalline Compound (I). See WO
2008/083319, which discusses the properties of crystalline
enantiomers. Mixtures of the crystalline forms of Compounds (I) and
(II) are another aspect of the disclosure.
[0059] The crystalline N-1 forms of Compounds (I) and (II) as
described here may be characterized by at least one of the
following: [0060] (i) a solid state .sup.13C NMR spectrum with
peaks at 18.1, 42.9, 44.5, 70.4, 123.2, 156.2, 170.8, 175.7, and
182.1 ppm, .+-.0.2 ppm; [0061] (ii) a solid state .sup.13C NMR
spectrum substantially in accordance with the pattern shown in FIG.
2; [0062] (iii) an x-ray powder diffraction pattern (CuK.alpha.
.lamda.=1.5418 .ANG.) comprising four or more peaks selected from:
6.4, 9.0, 12.0, 12.8, 13.5, 16.9, 19.4, 21.5, 22.8, 25.1, and
27.6.degree.2.theta..+-.0.2.degree.2.theta., wherein measurement of
the crystalline form is at an ambient room temperature; [0063] (iv)
an x-ray powder diffraction (XRPD) spectrum substantially in
accordance with the pattern shown in FIG. 1; [0064] (v) a solid
state .sup.15N NMR spectrum with peaks at 118.6, 119.6, 120.7,
134.8, 167.1, 176.0, and 180 ppm, .+-.0.2 ppm; and/or [0065] (vi) a
solid state .sup.15N NMR spectrum substantially in accordance with
the pattern shown in FIG. 3.
[0066] Other solid state properties which may be used to
characterize the crystalline N-1 forms of Compounds (I) and (II)
are shown in the figures and discussed in the examples below. For
crystalline Compound (I), the solid state phase and the degree of
crystallinity remained unchanged after exposure to 75% RH at
40.degree. C. for 1 week.
[0067] The crystalline N-2 forms of Compounds (I) and (II) as
described here may be characterized by at least one of the
following: [0068] (i) a solid state .sup.13C NMR spectrum with
peaks at 23.0, 25.9, 38.0, 54.4, 56.11, 41.7, 69.7, 102.0, 122.5,
177.3, 179.3, 180.0, and 180.3, +0.2 ppm; [0069] (ii) a solid state
.sup.13C NMR spectrum substantially in accordance with the pattern
shown in FIG. 9; [0070] (ii) an x-ray powder diffraction pattern
(CuK.alpha. .lamda.=1.5418 .ANG.) comprising four or more peaks
selected from: 6.4, 9.1, 12.0, 12.8, 13.7, 17.1, 20.9, 21.9, 22.6,
and 23.7.degree. 2.theta.+0.2.degree.2.theta., wherein measurement
of the crystalline form is at an ambient room temperature; [0071]
(iv) an x-ray powder diffraction (XRPD) spectrum substantially in
accordance with the pattern shown in FIG. 8; [0072] (v) a solid
state .sup.15N NMR spectrum with peaks at 118.5, 120.8, 135.1,
167.3, and 180.1 ppm; and/or [0073] (vi) a solid state .sup.15N NMR
spectrum substantially in accordance with the pattern shown in FIG.
10. Other solid state properties which may be used to characterize
the crystalline N-2 forms of Compounds (I) and (II) are shown in
the figures and discussed in the examples below.
[0074] In another embodiment, the disclosure relates to a
crystalline form of Compound (I), as described herein in any of the
aspects and/or embodiments, is substantially pure N-1 form.
[0075] In another embodiment, the disclosure relates to a
crystalline form of Compound (I), as described herein in any of the
aspects and/or embodiments, is substantially pure N-2 form.
[0076] The disclosure also relates to amorphous forms of Compounds
(I) and (II). The preparation and solid state properties and
characteristics of the amorphous form of Compound (I) are described
in the examples below. The amorphous forms of Compounds (I) and
(II) represent another aspect of the disclosure.
[0077] One further aspect of the disclosure relates to mixtures of
Compound (I) and Compound (II). The mixtures may have from greater
than zero weight % to less than 100 weight % Compound (I) and from
less than 100 weight % to greater zero weight % Compound (II),
based on the total weight of Compound (I) and Compound (II). In
other embodiments, the mixture comprises from about 1 to about 99
weight % Compound (I) and from about 99 to about 1 weight %
Compound (II), based on the total weight of Compound (I) and
Compound (II) in said mixture. In a further embodiment, the mixture
comprises from about 90 weight % to less than 100 weight % Compound
(I) and from greater than zero weight % to about 10 weight %
Compound (II), based on the total weight of Compound (I) and
Compound (II). Accordingly, the mixture may have 1-10% by weight of
Compound (I); 11-20% by weight of Compound (I); 21-30% by weight of
Compound (I); 31-40% by weight of Compound (I); 41-50% by weight of
Compound (I); 51-60% by weight of Compound (I); 61-70% by weight of
Compound (I); 71-80% by weight of Compound (I); 81-90% by weight of
Compound (I); or 91-99% by weight of Compound (I) with the
remaining weight percentage of malate salt being that of Compound
(II).
[0078] Another aspect of this disclosure relates to crystalline
forms of (DL)-malate salt of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, Compound (III). The (DL)-malate salt
is prepared from racemic malic acid. The crystalline N-1 form of
Compound (III) as described here may be characterized by at least
one of the following: [0079] (i) a solid state .sup.13C NMR
spectrum with four or more peaks selected from 20.8, 26.2, 44.8,
55.7, 70.7, 100.4, 101.0, 114.7, 115.2, 116.0, 119.7, 120.4, 121.6,
124.4, 136.9, 138.9, 141.1, 145.7, 150.3, 156.5, 157.6, 159.6,
165.2, 167.4, 171.2, 176.3, 182.1 ppm, .+-.0.2 ppm; [0080] (ii) a
solid state .sup.13C NMR spectrum substantially in accordance with
the pattern shown in FIG. 16; [0081] (iii) a powder x-ray
diffraction pattern (CuK.alpha. .lamda.=1.5418 .ANG.) comprising
four or more 2.theta. values selected from: 12.8, 13.5, 16.9, 19.4,
21.5, 22.8, 25.1, and 27.6, .+-.0.2.degree.2.theta., wherein
measurement of the crystalline form is at temperature of room
temperature; [0082] (iv) an x-ray powder diffraction (XRPD)
spectrum substantially in accordance with the pattern shown in FIG.
15; [0083] (v) a solid state .sup.15N NMR spectrum with peaks at
119.6, 134.7, and 175.5 ppm, .+-.0.2 ppm; and/or [0084] (vi) a
solid state .sup.15N NMR spectrum substantially in accordance with
the pattern shown in FIG. 17. Other solid state properties which
may be used to characterize the crystalline N-1 form of Compound
(III) are shown in the figures and discussed in the examples below.
In one embodiment, the N-1 Form of Compound (III) is characterized
by unit cell parameters approximately equal to the following: Cell
dimensions: [0085] a=14.60 .ANG. [0086] b=5.20 .ANG. [0087] c=39.09
.ANG. [0088] .alpha.=90.0.degree. [0089] .beta.=90.4.degree. [0090]
.gamma.=90.00 Space group: P2.sub.1/n Molecules of Compound
(I)/unit cell: 4
Volume=2969 .ANG..sup.3
[0091] Density (calculated)=1.422 g/cm.sup.3 The unit cell
parameters of Form N-1 of Compound (III) were measured at a
temperature of approximately 25.degree. C., e.g., ambient or room
temperature.
[0092] Each of the N-1 and N-2 crystalline forms of Compounds (I)
and (II) and the crystalline form N-1 of Compound (III) have unique
characteristics that can distinguish them one from another. These
characteristics can be understood by comparing the physical
properties of the solid state forms which are presented in the
Examples below. For example, Table 2 lists characteristic XRPD peak
positions (.degree.2.theta..+-.0.2.degree.2.theta.) for crystalline
Compound (III), Form N-1 and Forms N-1 and N-2 of crystalline
Compound (I). Amorphous forms do not display reflection peaks in
their XRPD patterns.
TABLE-US-00002 TABLE 2 Characteristic diffraction peak positions
(degrees 2.theta. .+-. 0.2) @ RT, based on pattern collected with a
diffractometer (CuK.alpha.) with a spinning capillary. Compound (I)
Compound (I) Compound (III) Form N-1 Form N-2 Form N-1 6.4 6.4 6.4
9.0 9.1 9.1 12.0 12.0 12.1 12.8 12.8 12.8 13.5 13.7 13.6 16.9 17.1
17.1 19.4* 20.9* 19.3 21.5* 21.9* 21.4 22.8* 22.6 22.8 25.1* 23.7
25.1 27.6* -- 27.6 *unique reflections between Compound (I), Form
N-1 and Compound (I), Form N-2.
The unique reflections between Forms N-1 and N-2 of crystalline
Compound (II) are designated by an asterisk (*). As discussed
above, Compound (II) is an enantiomer of Compound (I) and thus,
Compound (II), Form N-1 will have the same characteristic
reflection pattern and unique peaks as those listed in Table 2 for
Compound (I), Form N-1. Likewise, Compound (II), Form N-2 will have
the same characteristic reflection pattern and unique peaks as
those listed in Table 2 for Compound (I), Form N-2. Compounds (I)
and (II) are distinct from one another based on their absolute
stereochemistry, i.e., the (L)-malate salt versus the (D)-malate
salt, respectively. Crystalline Compound (III), Form N-1, is
distinct as the (D,L)-malate salt.
[0093] The characteristic peaks from the solid state NMR may also
serve to distinguish the crystalline and amorphous forms disclosed
herein. For example, Table 3 lists characteristic solid state
.sup.13C NMR peaks for crystalline Compound (III), Form N-1;
crystalline Compound (I), Forms N-1 and N-2, and the amorphous form
of Compound (I).
TABLE-US-00003 TABLE 3 Solid State Carbon-13 NMR Resonances (ppm,
.+-.0.2 ppm) (I) (III), Form (I) Form N-1 (I), Form N-2 N-1
Amorphous 18.1 23.0 20.8 27.2 42.9 25.9 26.2 33.8 44.5 38.0 44.8
142.9 54.4 54.4 70.7 -- 56.1 56.1 114.7 -- 70.4 41.7 141.1 -- 123.2
69.7 145.7 -- 156.2 102.0 176.3 -- 170.8 122.5 182.1 -- 175.7 177.3
-- -- 182.1 179.3 -- -- -- 180.0 -- -- -- 180.3 -- --
The solid state .sup.19F and .sup.15N NMR spectra, discussed below,
provide data for similar comparison and characterization. As
discussed above, being an enantiomer of Compound (I), crystalline
Forms N-1 and N-2 and the amorphous form of Compound (II) will have
the same solid state NMR resonances, and unique peaks between them,
as those listed in Table 3 for Forms N-1 and N-2 of crystalline
Compound (I).
Pharmaceutical Compositions and Methods of Treatment
[0094] Another aspect of this disclosure relates to a
pharmaceutical composition comprising at least one of Compound (I),
Compound (II), Compound (III), or combinations thereof, and a
pharmaceutically acceptable excipient. The amount of Compound (I),
Compound (II), Compound (III), or the combinations thereof in the
pharmaceutical composition can be a therapeutically effective
amount. Compound (I), Compound (II), or Compound (III) may
individually be present in the pharmaceutical composition as one of
the solid state forms discussed above or combinations thereof. The
crystalline forms are preferred solid state forms. Accordingly
another aspect of this disclosure relates to a solid or dispersion
pharmaceutical composition comprising at least one of a
therapeutically effective amount of a crystalline form of Compound
(I), Compound (II), Compound (III), or combinations thereof, and a
pharmaceutically acceptable excipient.
[0095] Another aspect of this disclosure relates to a method of
treating cancer comprising administering to a subject in need
thereof at least one of Compound (I), Compound (II), Compound (III)
or combinations thereof. The amount of Compound (I), Compound (II),
or combinations thereof administered can be a therapeutically
effective amount. Compound (I), Compound (II), or Compound (III)
may be individually administered as one of the solid state forms
discussed above or combinations thereof. The crystalline forms are
preferred solid state forms, with crystalline Compound (I), Form
N-1 or N-2 being preferred. Accordingly another aspect of this
disclosure relates to a method of treating cancer comprising
administering to a subject in need thereof a therapeutically
effective amount of at least one of Compound (I), Compound (II),
Compound (III), or combinations thereof, wherein Compound (I),
Compound (II), or Compound (III) is present in a crystalline form.
In another aspect of this disclosure, the method of treatment may
be practiced by administering a pharmaceutical composition of at
least one of Compound (I), Compound (II), Compound (III) or
combinations thereof such as discussed above.
[0096] Another aspect of this disclosure relates to a method of
treating cancer, as discussed above, where the cancer treated is
stomach cancer, esophageal carcinoma, kidney cancer, liver cancer,
ovarian carcinoma, cervical carcinoma, large bowel cancer, small
bowel cancer, brain cancer (including astrocytic tumor, which
includes glioblastoma, giant cell glioblastoma, gliosarcoma, and
glioblastoma with oligodendroglial components), lung cancer
(including non-small cell lung cancer), bone cancer, prostate
carcinoma, pancreatic carcinoma, skin cancer, bone cancer,
lymphoma, solid tumors, Hodgkin's disease, non-Hodgkin's lymphoma
or thyroid cancer thyroid cancer (including medullary thyroid
cancer).
[0097] Tyrosine kinase inhibitors have also been used to treat
non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are
angiogenesis inhibitors that target receptors of an epidermal
growth factor called tyrosine kinase. Erlotinib and Gefitinib are
currently being used for treating NSCLC. Another aspect of this
disclosure relates to a method of treating non-small cell lung
cancer (NSCLC) in a subject, the method comprising administering to
the subject in need of the treatment a therapeutically effective
amount of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt
thereof, optionally in combination with Erlotinib or Gefitinib. In
another embodiment, the combination is with Erlotinib.
[0098] Another aspect of this disclosure relates to a method of
treating non-small cell lung cancer (NSCLC) in a subject, the
method comprising administering to the subject in need of the
treatment a therapeutically effective amount of Erlotinib or
Gefitinib in combination with at least one of Compound (I),
Compound (II), Compound (III) or combinations thereof. Compound
(I), Compound (II), or Compound (III) may be individually
administered as one of the solid state forms discussed above or
combinations thereof. The crystalline forms are preferred solid
state forms. Accordingly another aspect of this disclosure relates
to a method of treating a method of treating non-small cell lung
cancer (NSCLC) in a subject, the method comprising administering to
the subject in need of the treatment a therapeutically effective
amount of Erlotinib or Gefitinib in combination with at least one
of Compound (I), Compound (II), Compound (III), or combinations
thereof, wherein Compound (I), Compound (II), or Compound (III) is
present in a crystalline form. In another aspect of this
disclosure, this method of treatment may be practiced by
administering a pharmaceutical composition of at least one of
Compound (I), Compound (II), Compound (III) or combinations thereof
such as discussed above. In another embodiment, the combination
administered in this method is Erlotinib with at least one of
Compound (I), Compound (II), Compound (III), or combinations
thereof.
[0099] Another aspect of this disclosure relates to a method of
treating an astrocytic tumor (which includes glioblastoma, giant
cell glioblastoma, gliosarcoma, and glioblastoma with
oligodendroglial components in a subject) in a subject, the method
comprising administering to the subject in need of the treatment a
therapeutically effective amount of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
[0100] Another aspect of this disclosure relates to a method of
treating an astrocytic tumor (which includes glioblastoma, giant
cell glioblastoma, gliosarcoma, and glioblastoma with
oligodendroglial components in a subject) in a subject, the method
comprising administering to the subject in need of the treatment a
therapeutically effective amount of at least one of Compound (I),
Compound (II), Compound (III) or combinations thereof. Compound
(I), Compound (II), or Compound (III) may be individually
administered as one of the solid state forms discussed above or
combinations thereof. The crystalline forms are preferred solid
state forms. Accordingly another aspect of this disclosure relates
to a method of treating an astrocytic tumor comprising
administering to a subject in need thereof a therapeutically
effective amount of at least one of Compound (I), Compound (II),
Compound (III), or combinations thereof, wherein Compound (I),
Compound (II), or Compound (III) is present in a crystalline form.
In another aspect of this disclosure, this method of treatment may
be practiced by administering a pharmaceutical composition of at
least one of Compound (I), Compound (II), Compound (III) or
combinations thereof such as discussed above.
[0101] Another aspect of this disclosure relates to a method of
treating thyroid cancer (including medullary thyroid cancer) in a
subject, the method comprising administering to the subject in need
of the treatment
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt
thereof. The amount administered can be a therapeutically effective
amount.
[0102] Another aspect of this disclosure relates to a method of
treating thyroid cancer (including medullary thyroid cancer) in a
subject, the method comprising administering to the subject in need
of the treatment at least one of Compound (I), Compound (II),
Compound (III) or combinations thereof. Compound (I), Compound
(II), or Compound (III) may be individually administered as one of
the solid state forms discussed above or combinations thereof. The
crystalline forms are preferred solid state forms. Accordingly
another aspect of this disclosure relates to a method of treating
thyroid cancer comprising administering to a subject in need
thereof a therapeutically effective amount of at least one of
Compound (I), Compound (II), Compound (III), or combinations
thereof, wherein Compound (I), Compound (II), or Compound (III) is
present in a crystalline form. In another aspect of this
disclosure, this method of treatment may be practiced by
administering a pharmaceutical composition of at least one of
Compound (I), Compound (II), Compound (III) or combinations thereof
such as discussed above.
[0103] Another aspect of this disclosure relates to a method of
treating diseases or disorders associated with uncontrolled,
abnormal, and/or unwanted cellular activities. This method
administers, to a subject in need thereof, at least one of Compound
(I), Compound (II), Compound (III) or combinations thereof. The
amount of Compound (I), Compound (II), or combinations thereof
administered can be a therapeutically effective amount. Compound
(I), Compound (II), or Compound (III) may be individually
administered as one of the solid state forms discussed above or
combinations thereof. The crystalline forms are preferred solid
state forms.
[0104] Accordingly another aspect of this disclosure relates to a
method of treating diseases or disorders associated with
uncontrolled, abnormal, and/or unwanted cellular activities
comprising administering to a subject in need thereof a
therapeutically effective amount of at least one of Compound (I),
Compound (II), Compound (III), or combinations thereof, wherein
Compound (I), Compound (II), or Compound (III) is present in a
crystalline form. In another aspect of this disclosure, this method
of treatment may be practiced by administering a pharmaceutical
composition of at least one of Compound (I), Compound (II),
Compound (III) or combinations thereof such as discussed above.
Another aspect of this disclosure relates to a method of treating
diseases or disorders associated with uncontrolled, abnormal,
and/or unwanted cellular activities. This method administers, to a
subject in need thereof, a crystalline form of Compound (I),
Compound (II), or any combination of Compound (I) and (II). The
amount of Compound (I), Compound (II), or any combination of
Compound (I) and (II) administered can be a therapeutically
effective amount.
[0105] Another aspect of this disclosure relates to a use of the
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)
cyclopropane-1,1-dicarboxamide, malate salt according to any of the
above embodiments for the manufacture of a medicament for the
treatment of a disease or disorder discussed above. When dissolved,
a crystalline or amorphous form according to this disclosure loses
its solid state structure, and is therefore referred to as a
solution of, for example, Compound (I). At least one crystalline
form disclosed herein may be used to prepare at least one liquid
formulation in which at least one crystalline form according to the
disclosure is dissolved and/or suspended.
[0106] A pharmaceutical composition such as discussed above may be
any pharmaceutical form which contains active Compound (I),
Compound (II) and/or Compound (III), including the solid state
forms thereof (hereinafter referred to as active compound(s). The
pharmaceutical composition may be, for example, a tablet, capsule,
liquid suspension, injectable, topical, or transdermal. The
pharmaceutical compositions generally contain about 1% to about 99%
by weight of the active compound(s), or a crystalline form of the
active compound(s), and 99% to 1% by weight of a suitable
pharmaceutical excipient. In one example, the composition will be
between about 5% and about 75% by weight of active compound, with
the rest being suitable pharmaceutical excipients or other
adjuvants, as discussed below.
[0107] A "therapeutically effective amount of the active compounds,
or a crystalline or amorphous form of the active compound(s),
according to this disclosure to inhibit, regulate and/or modulate
the signal transduction of kinases (discussed here concerning the
pharmaceutical compositions) refers to an amount sufficient to
treat a patient suffering from any of a variety of cancers
associated with abnormal cell proliferation and angiogenesis. A
therapeutically effective amount according to this disclosure is an
amount therapeutically useful for the treatment or prevention of
the disease states and disorders discussed herein. Compounds (I),
(II), and/or (III) (including their solid state forms), possess
therapeutic activity to inhibit, regulate and/or modulate the
signal transduction of kinases such as described in WO2005-030140.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-cy-
clopropane-1,1-dicarboxamide.
[0108] The actual amount required for treatment of any particular
patient will depend upon a variety of factors including the disease
state being treated and its severity; the specific pharmaceutical
composition employed; the age, body weight, general health, sex and
diet of the patient; the mode of administration; the time of
administration; the route of administration; and the rate of
excretion of the active compound(s), or a crystalline form of the
active compound(s), according to this disclosure; the duration of
the treatment; any drugs used in combination or coincidental with
the specific compound employed; and other such factors well known
in the medical arts. These factors are discussed in Goodman and
Gilman's "The Pharmacological Basis of Therapeutics", Tenth
Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill
Press, 155-173, 2001, which is incorporated herein by reference.
The active compound(s), or a crystalline form of active
compound(s), according to this disclosure and pharmaceutical
compositions comprising them, may be used in combination with
anticancer or other agents that are generally administered to a
patient being treated for cancer. They may also be co-formulated
with one or more of such agents in a single pharmaceutical
composition.
[0109] Depending on the type of pharmaceutical composition, the
pharmaceutically acceptable carrier may be chosen from any one or a
combination of carriers known in the art. The choice of the
pharmaceutically acceptable carrier depends partly upon the desired
method of administration to be used. For a pharmaceutical
composition of this disclosure, that is, one of the active
compound(s), or a crystalline form of the active compound(s), of
this disclosure, a carrier should be chosen so as to substantially
maintain the particular form of the active compound(s), whether it
would be crystalline or not. In other words, the carrier should not
substantially alter the form the active compound(s) are. Nor should
the carrier be otherwise incompatible with the form of the active
compound(s), such as by producing any undesirable biological effect
or otherwise interacting in a deleterious manner with any other
component(s) of the pharmaceutical composition.
[0110] The pharmaceutical compositions of this disclosure may be
prepared by methods know in the pharmaceutical formulation art, for
example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack
Publishing Company, Easton, Pa., 1990). In a solid dosage forms
Compound (I) is admixed with at least one pharmaceutically
acceptable excipient such as sodium citrate or dicalcium phosphate
or (a) fillers or extenders, as for example, starches, lactose,
sucrose, glucose, mannitol, and silicic acid, (b) binders, as for
example, cellulose derivatives, starch, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as
for example, glycerol, (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, croscarmellose sodium, complex silicates, and sodium
carbonate, (e) solution retarders, as for example paraffin, (f)
absorption accelerators, as for example, quaternary ammonium
compounds, (g) wetting agents, as for example, cetyl alcohol, and
glycerol monostearate, magnesium stearate and the like (h)
adsorbents, as for example, kaolin and bentonite, and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, tablets, and pills, the
dosage forms may also comprise buffering agents.
[0111] Pharmaceutically acceptable adjuvants known in the
pharmaceutical formulation art may also be used in the
pharmaceutical compositions of this disclosure. These include, but
are not limited to, preserving, wetting, suspending, sweetening,
flavoring, perfuming, emulsifying, and dispensing agents.
Prevention of the action of microorganisms can be ensured by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride, and the like. If desired, a pharmaceutical composition of
this disclosure may also contain minor amounts of auxiliary
substances such as wetting or emulsifying agents, pH buffering
agents, and antioxidants, such as, for example, citric acid,
sorbitan monolaurate, triethanolamine oleate, and butylated
hydroxytoluene.
[0112] Solid dosage forms as described above can be prepared with
coatings and shells, such as enteric coatings and others well known
in the art. They may contain pacifying agents, and can also be of
such composition that they release the active compound or compounds
in a certain part of the intestinal tract in a delayed manner.
Examples of embedded compositions that can be used are polymeric
substances and waxes. The active compounds can also be in
microencapsulated form, if appropriate, with one or more of the
above-mentioned excipients.
[0113] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances, and the
like.
[0114] Compositions for rectal administrations are, for example,
suppositories that can be prepared by mixing the active
compound(s), or a crystalline form of the active compound(s), with,
for example, suitable non-irritating excipients or carriers such as
cocoa butter, polyethyleneglycol or a suppository wax, which are
solid at ordinary temperatures but liquid at body temperature and
therefore, melt while in a suitable body cavity and release the
active component therein.
[0115] Because the active compound(s), or a crystalline form of the
active compound(s), is maintained during their preparation, solid
dosage forms are preferred for the pharmaceutical composition of
this disclosure. Solid dosage forms for oral administration, which
includes capsules, tablets, pills, powders, and granules, are
particularly preferred. In such solid dosage forms, the active
compound(s) mixed with at least one inert, pharmaceutically
acceptable excipient (also known as a pharmaceutically acceptable
carrier). Administration of the active compound(s), or a
crystalline form of the active compound(s), in pure form or in an
appropriate pharmaceutical composition, can be carried out via any
of the accepted modes of administration or agents for serving
similar utilities. Thus, administration can be, for example,
orally, nasally, parenterally (intravenous, intramuscular, or
subcutaneous), topically, transdermally, intravaginally,
intravesically, intracistemally, or rectally, in the form of solid,
semi-solid, lyophilized powder, or liquid dosage forms, such as for
example, tablets, suppositories, pills, soft elastic and hard
gelatin capsules, powders, solutions, suspensions, or aerosols, or
the like, preferably in unit dosage forms suitable for simple
administration of precise dosages. One preferable route of
administration is oral administration, using a convenient dosage
regimen that can be adjusted according to the degree of severity of
the disease-state to be treated.
General Preparation Methods of Crystalline Forms
[0116] Crystalline forms may be prepared by a variety of methods
including, but not limited to, for example, crystallization or
recrystallization from a suitable solvent mixture; sublimation;
growth from a melt; solid state transformation from another phase;
crystallization from a supercritical fluid; and jet spraying.
Techniques for crystallization or recrystallization of crystalline
forms of a solvent mixture include, but are not limited to, for
example, evaporation of the solvent; decreasing the temperature of
the solvent mixture; crystal seeding of a supersaturated solvent
mixture of the compound and/or salt thereof; crystal seeding a
supersaturated solvent mixture of the compound and/or a salt from
thereof; freeze drying the solvent mixture; and adding antisolvents
(countersolvents) to the solvent mixture. High throughput
crystallization techniques may be employed to prepare crystalline
forms including polymorphs.
[0117] Crystals of drugs, including polymorphs, methods of
preparation, and characterization of drug crystals are discussed in
Solid-State Chemistry of Drugs, S. R. Bym, R. R. Pfeiffer, and J.
G. Stowell, 2.sup.nd Edition, SSCI, West Lafayette, Ind.
(1999).
[0118] In a crystallization technique in which solvent is employed,
the solvent(s) are typically chosen based on one or more factors
including, but not limited to, for example, solubility of the
compound; crystallization technique utilized; and vapor pressure of
the solvent. Combinations of solvents may be employed. For example,
the compound may be solubilized in a first solvent to afford a
solution to which antisolvent is then added to decrease the
solubility of the Compound (I)n the solution and precipitate the
formation of crystals. An antisolvent is a solvent in which a
compound has low solubility.
[0119] In one method that can be used in preparing crystals,
Compound (I), Compound (II) and/or Compound (III) can be suspended
and/or stirred in a suitable solvent to afford a slurry, which may
be heated to promote dissolution. The term "slurry", as used
herein, means a saturated solution of the compound, wherein such
solution may contain an additional amount of compound to afford a
heterogeneous mixture of compound and solvent at a given
temperature.
[0120] Seed crystals may be added to any crystallization mixture to
promote crystallization. Seeding may be employed to control growth
of a particular polymorph and/or to control the particle size
distribution of the crystalline product. Accordingly, calculation
of the amount of seeds needed depends on the size of the seed
available and the desired size of an average product particle as
described, for example, in Programmed Cooling Batch Crystallizers,"
J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26,
3690377. In general, seeds of small size are needed to effectively
control the growth of crystals in the batch. Seeds of small size
may be generated by sieving, milling, or micronizing large
crystals, or by microcrystallizing a solution. In the milling or
micronizing of crystals, care should be taken to avoid changing
crystallinity from the desired crystalline form (i.e., changing to
an amorphous or other polymorphic form).
[0121] A cooled crystallization mixture may be filtered under
vacuum and the isolated solid product washed with a suitable
solvent, such as, for example, cold recrystallization solvent.
After being washed, the product may be dried under a nitrogen purge
to afford the desired crystalline form. The product may be analyzed
by a suitable spectroscopic or analytical technique including, but
not limited to, for example, differential scanning calorimetry
(DSC); x-ray powder diffraction (XRPD); and thermogravimetric
analysis (TGA) to assure the crystalline form of the compound has
been formed. The resulting crystalline form may be produced in an
amount greater than about 70 wt. % isolated yield, based on the
weight of the compound originally employed in the crystallization
procedure, and preferably greater than about 90 wt. % isolated
yield. Optionally, the product may be delumped by being comilled or
passed through mesh screen.
[0122] The features and advantages of this disclosure may be more
readily understood by those of ordinary skill in the art upon
reading the following detailed description. It is to be appreciated
that certain features of the invention that are, for clarity
reasons, described above and below in the context of separate
embodiments, may also be combined to form a single embodiment.
Conversely, various features of this disclosure that are, for
brevity reasons, described in the context of a single embodiment,
may also be combined so as to form sub-combinations thereof. The
disclosure is further illustrated by the following examples, which
are not to be construed as limiting the disclosure in scope or
spirit to the specific procedures described in them.
[0123] The definitions set forth herein take precedence over
definitions set forth in any patent, patent application, and/or
patent application publication incorporated herein by reference.
All measurements are subject to experimental error and are within
the spirit of the invention.
[0124] As used herein, "amorphous" refers to a solid form of a
molecule and/or ion that is not crystalline. An amorphous solid
does not display a definitive X-ray diffraction pattern with sharp
maxima.
[0125] As used herein, the term "substantially pure" means the
crystalline form of Compound (I) referred to contains at least
about 90 wt. % based on the weight of such crystalline form. The
term "at least about 90 wt. %," while not intending to limit the
applicability of the doctrine of equivalents to the scope of the
claims, includes, but is not limited to, for example, about 90,
about 91, about 92, about 93, about 94, about 95, about 96, about
97, about 98, about 99 and about 100% wt. %, based on the weight of
the crystalline form referred to. The remainder of the crystalline
form of Compound (I) may comprise other Form(s) of Compound (I)
and/or reaction impurities and/or processing impurities that arise,
for example, when the crystalline form is prepared. The presence of
reaction impurities and/or processing impurities may be determined
by analytical techniques known in the art, such as, for example,
chromatography, nuclear magnetic resonance spectroscopy, mass
spectroscopy, and/or infrared spectroscopy.
PREPARATIVE EXAMPLES
Example 1: Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof
(Compound (I))
[0126] The synthetic route used for the preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof is
depicted in Scheme 1:
##STR00006##
[0127] The process shown in Scheme 1 is described in more detail
below.
1.1 Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0128] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (1 L, 10.0 kg) and acetonitrile (64.0
L). The resulting mixture was heated to approximately 65.degree. C.
and phosphorus oxychloride (POCl.sub.3, 50.0 kg) was added. After
the addition of POCl.sub.3, the temperature of the reaction mixture
was raised to approximately 80.degree. C. The reaction was deemed
complete (approximately 9.0 hours) when <2% of the starting
material remained (in process high-performance liquid
chromatography [HPLC] analysis). The reaction mixture was cooled to
approximately 10.degree. C. and then quenched into a chilled
solution of dichloromethane (DCM, 238.0 kg), 30% NH.sub.4OH (135.0
kg), and ice (440.0 kg). The resulting mixture was warmed to
approximately 14.degree. C., and phases were separated. The organic
phase was washed with water (40.0 kg) and concentrated by vacuum
distillation with the removal of solvent (approximately 190.0 kg).
Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and
the mixture was cooled to approximately 10.degree. C., during which
time the product crystallized out. The solids were recovered by
centrifugation, washed with n-heptane (20.0 kg), and dried at
approximately 40.degree. C. to afford the title compound (8.0
kg).
1.2 Preparation of 6,7-Dimethyl-4-(4-nitro-phenoxy)-quinoline
[0129] A reactor was sequentially charged with
4-chloro-6,7-dimethoxy-quinoline (8.0 kg), 4 nitrophenol (7.0 kg),
4 dimethylaminopyridine (0.9 kg), and 2,6 lutidine (40.0 kg). The
reactor contents were heated to approximately 147.degree. C. When
the reaction was complete (<5% starting material remaining as
determined by in process HPLC analysis, approximately 20 hours),
the reactor contents were allowed to cool to approximately
25.degree. C. Methanol (26.0 kg) was added, followed by potassium
carbonate (3.0 kg) dissolved in water (50.0 kg). The reactor
contents were stirred for approximately 2 hours. The resulting
solid precipitate was filtered, washed with water (67.0 kg), and
dried at 25.degree. C. for approximately 12 hours to afford the
title compound (4.0 kg).
1.3 Preparation of
4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0130] A solution containing potassium formate (5.0 kg), formic
acid (3.0 kg), and water (16.0 kg) was added to a mixture of
6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium
on carbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that
had been heated to approximately 60.degree. C. The addition was
carried out such that the temperature of the reaction mixture
remained approximately 60.degree. C. When the reaction was deemed
complete as determined using in-process HPLC analysis (<2%
starting material remaining, typically 1 5 hours), the reactor
contents were filtered. The filtrate was concentrated by vacuum
distillation at approximately 35.degree. C. to half of its original
volume, which resulted in the precipitation of the product. The
product was recovered by filtration, washed with water (12.0 kg),
and dried under vacuum at approximately 50.degree. C. to afford the
title compound (3.0 kg; 97% AUC).
1.4 Preparation of
1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
[0131] Triethylamine (8.0 kg) was added to a cooled (approximately
4.degree. C.) solution of commercially available
cyclopropane-1,1-dicarboxylic acid (2 1, 10.0 kg) in THF (63.0 kg)
at a rate such that the batch temperature did not exceed 10.degree.
C. The solution was stirred for approximately 30 minutes, and then
thionyl chloride (9.0 kg) was added, keeping the batch temperature
below 10.degree. C. When the addition was complete, a solution of
4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such
that the batch temperature did not exceed 10.degree. C. The mixture
was stirred for approximately 4 hours and then diluted with
isopropyl acetate (87.0 kg). This solution was washed sequentially
with aqueous sodium hydroxide (2.0 kg dissolved in 50.0 L of
water), water (40.0 L), and aqueous sodium chloride (10.0 kg
dissolved in 40.0 L of water). The organic solution was
concentrated by vacuum distillation followed by the addition of
heptane, which resulted in the precipitation of solid. The solid
was recovered by centrifugation and then dried at approximately
35.degree. C. under vacuum to afford the title compound. (10.0
kg).
1.5 Preparation of
1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
[0132] Oxalyl chloride (1.0 kg) was added to a solution of
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg)
in a mixture of THF (11 kg) and N, N-dimethylformamide (DMF; 0.02
kg) at a rate such that the batch temperature did not exceed
30.degree. C. This solution was used in the next step without
further processing.
1.6 Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide
[0133] The solution from the previous step containing
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was
added to a mixture of
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and
potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg)
at a rate such that the batch temperature did not exceed 30.degree.
C. When the reaction was complete (in typically 10 minutes), water
(74.0 kg) was added. The mixture was stirred at 15-30.degree. C.
for approximately 10 hours, which resulted in the precipitation of
the product. The product was recovered by filtration, washed with a
premade solution of THF (11.0 kg) and water (24.0 kg), and dried at
approximately 65.degree. C. under vacuum for approximately 12 hours
to afford the title compound (free base, 5.0 kg). .sup.1H NMR (400
MHz, d.sub.6-DMSO): .delta. 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s,
1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m,
2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS:
M+H=502.
1.7 Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, (L) malate salt (Compound (I))
[0134] A solution of (L)-malic acid (2.0 kg) in water (2.0 kg) was
added to a solution of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide free base (1 5, 5.0 kg) in ethanol,
maintaining a batch temperature of approximately 25.degree. C.
Carbon (0.5 kg) and thiol silica (0.1 kg) were then added, and the
resulting mixture was heated to approximately 78.degree. C., at
which point water (6.0 kg) was added. The reaction mixture was then
filtered, followed by the addition of isopropanol (38.0 kg), and
was allowed to cool to approximately 25.degree. C. The product was
recovered by filtration and washed with isopropanol (20.0 kg) and
dried at approximately 65.degree. C. to afford Compound (I) (5.0
kg).
Example 2: Preparation of Crystalline Compound (I), Form N-1
[0135] A solution was prepared by adding tetrahydrofuran (12
mL/g-bulk-LR (limiting reagent); 1.20 L) and
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide, (100 g; 1.00 equiv; 100.00 g) and
(L)-malic acid (1.2 equiv (molar); 32.08 g) to a 1 L reactor. Water
(0.5317 mL/g-bulk-LR; 53.17 mL) was added and the solution was
heated to 60.degree. C. and maintained at that temperature for one
hour until the solids were fully dissolved. The solution was passed
through a Polish Filter.
[0136] At 60.degree. C., acetonitrile (12 mL/g-bulk-LR; 1.20 L) was
added over a period of 8 hours. The solution was held at 60.degree.
C. for 10 hours. The solution was then cooled to 20.degree. C. and
held for 1 hour. The solids were filtered and washed with
acetonitrile (12 mL/g-bulk-LR; 1.20 L). The solids were dried at
60.degree. C. (25 mm Hg) for 6 hours to afford Compound (I), Form
N-1 (108 g; 0.85 equiv; 108.00 g; 85.22% yield) as a white
crystalline solid.
Example 3: Alternate Preparation of Crystalline Compound (I), Form
N-1
[0137] A solution was prepared with 190 mL tetrahydrofuran (110
mL), methyl isobutyl ketone, and 29 mL water. Next, 20 mL of this
solution were transferred into an amber bottle, and then saturated
by adding
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide, (L)-malate until a thick slurry
formed, and aging for at least 2 h with stirring at room
temperature. The solids were removed by filtration through a
Buchner funnel, rendering a clear saturated solution.
[0138] Separately, a powder blend was made with known amounts of
two batches of Compound (I): (1) 300 mg of batch 1, which contained
approximately 41% Compound (I), Form N-1 and 59% Compound (I), Form
N-2 by Raman spectroscopy analysis, and (2) 200 mg of batch 2,
which had a XPRD pattern similar to Compound (I), Form N-2.
[0139] The Compound (I), Form N-1 and Compound (I), Form N-2 powder
blend was added into the saturated solution, and the slurry was
aged under magnetic stirring at room temperature for 25 days. The
slurry was then sampled and filtered through a Buchner funnel to
obtain 162 mg of wet cake. The wet cake was dried in a vacuum oven
at 45.degree. C. to afford 128 mg of crystalline Compound (I) in
the N-1 form.
Example 4: Preparation of Crystalline Compound (I), Form N-2
4.1 Preparation of Crystalline Compound (I), Form N-2 Seed
Crystals
[0140] A solution was prepared by combining 20 ml of acetone and
300 mg of freebase
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorop-
henyl)cyclopropane-1,1-dicarboxamide in a 25 ml screw capped vial.
Next, 0.758 ml of a 0.79M (L)-malic acid stock solution was added
to the vial with magnetic stirring. The solution was then left
stirring for 24 hr at ambient temperature. The sample was then
suction filtered with 0.45 .mu.m PTFE filter cartridge and dried in
vacuo at ambient temperature overnight.
4.2 Preparation of Crystalline Compound (I), Form N-2
[0141] To a reactor were added
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide (48 g; 1.00 equiv; 48.00 g) and
tetrahydrofuran (16.5 mL/g-bulk-LR; 792.00 mL). The water content
was adjusted to 1 wt % water. The solution was heated to 60.degree.
C. Once dissolved, the solution was passed through a polish filter
to provide the first solution.
[0142] In a separate reactor, (L)-malic acid (1.2 equiv (molar);
15.40 g) was dissolved into methyl isobutyl ketone (10
mL/g-bulk-LR; 480.00 mL) and tetrahydrofuran (1 mL/g-bulk-LR; 48.00
mL). Next, 50 mL of the (L)-malic acid solution was added to the
first solution at 50.degree. C. Seed crystals were added (1%, 480
mg) and the malic acid solution was added at 50.degree. C. dropwise
via an addition funnel (1.3 ml/min (3 h)). The slurry was held at
50.degree. C. for 18 h and then was cooled to 25.degree. C. over 30
min. The solids were filtered, and washed with 20%
tetrahydrofuran/methyl isobutyl ketone (10V, 480 mL). The solids
were dried under vacuum at 60.degree. C. for 5 h to afford Compound
(I) (55.7 g; 0.92 equiv; 55.70 g; 91.56% yield) as an off-white
crystalline solid.
Example 5: Preparation of Crystalline Compound (III), Form N-1
[0143] A one ml aliquot (DL)-malic acid salt of
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide, slurried in tetrahydrofuran (THF),
was heated to 60.degree. C. on a hot-plate in a half-dram vial.
Next, tetrahydrofuran was added drop-wise until an almost clear
solution was obtained. The vial was capped, removed from the hot
plate and equilibrated at ambient temperature without agitation.
Crystallization was apparent after several hours and the solution
was allowed to stand overnight to allow completion. Several
droplets of the resulting slurry were placed on a glass slide for
microscopic analysis. The crystalline material consisted of many
elongated plates ranging up to 60 microns in the longest
dimension.
[0144] Alternate Preparation of Crystalline Compound (III), Form
N-1
[0145] To a reactor were added
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy-
clopropane-1,1-dicarboxamide (15 g; 1.00 equiv; 15.00 g) and
tetrahydrofuran (16.5 mL/g-bulk-LR; 792.00 mL). The water content
was adjusted to 1 wt % water. The solution was heated to 60.degree.
C. Once dissolved, the solution was passed through a polish filter
to provide the first solution.
[0146] In a separate reactor, (DL)-malic acid (1.2 equiv (molar);
4.53 g) was dissolved into methyl isobutyl ketone (8 mL/g-bulk-LR;
120.00 mL) and tetrahydrofuran (1 mL/g-bulk-LR; 15.00 mL). Next, 20
mL of the solution was added to the first solution at 50.degree. C.
The malic acid solution was added at 50.degree. C. dropwise via an
addition funnel (1.3 ml/min (3 h)). The slurry was held at
50.degree. C. for 18 h and then was cooled to 25.degree. C. over 30
min. The solids were filtered, and washed with 20% THF/MIBK (10V,
150 mL). The solids were dried under vacuum at 60.degree. C. for 5
h to afford Compound (III) (15.52 g; 86.68% yield) as an off-white
solid.
Example 6: Preparation of Amorphous Compound (I)
[0147] A solution was prepared with 5 g of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, (L)-malate and 250 mL of a 1:1 (v:v)
mixture of methanol and dichloromethane. The hazy solution was
filtered through a 0.45 micron filter to yield a clear, yellowish
solution. The solution was pumped through the spray dryer nozzle at
a rate of 12.9 cc/min, and was atomized by nitrogen gas fed at a
rate of 10.9 L/min. The temperature at the inlet of the cyclone was
set to 65.degree. C. to dry the wet droplets. Dry amorphous powder
(1.5 g) was collected (yield=30%).
CHARACTERIZATION EXAMPLES
[0148] I. NMR Spectra in Dimethyl Sulfoxide Solution
[0149] I.1 Compound (I), Form N-1
[0150] .sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta. 1.48 (s, 1H),
2.42-2.48 (m, 1H), 2.60-2.65 (m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30
(dd, 1H, J=5, 8 Hz), 6.44 (d, 1H, J=5 Hz, 1H), 7.12-7.19 (m, 2H),
7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.63-7.68 (m, 2H),
7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s, 1H), 10.21 (s,
1H).
[0151] .sup.13C NMR (d.sub.6-DMSO): 15.36, 31.55, 55.64, 55.67,
66.91, 99.03, 102.95, 107.66, 114.89, 115.07, 115.11, 121.17,
122.11, 122.32, 122.39, 135.15, 136.41, 146.25, 148.7, 149.28,
149.38, 152.54, 157.03, 159.42, 160.02, 168.07, 171.83, 174.68.
[0152] I.2 Compound (I), Form N-2
[0153] .sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta. 1.48 (s, 1H),
2.42-2.48 (m, 1H), 2.60-2.65 (m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30
(dd, 1H, J=5, 8 Hz), 6.44 (d, J=5 Hz, 1H), 7.12-7.19 (m, 2H),
7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.63-7.68 (m, 2H),
7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s, 1H), 10.21 (s,
1H).
[0154] .sup.13C NMR (d.sub.6-DMSO): 15.36, 31.55, 55.64, 55.67,
66.91, 99.03, 102.95, 107.66, 114.89, 115.07, 115.11, 121.17,
122.11, 122.32, 122.39, 135.15, 136.41, 146.25, 148.7, 149.28,
149.38, 152.54, 157.03, 159.42, 160.02, 168.07, 171.83, 174.68.
[0155] I.3 Compound (III), Form N-1
[0156] .sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta. 1.48 (s, 1H),
2.42-2.48 (m, 1H), 2.60-2.65 (m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30
(dd, 1H, J=5, 8 Hz), 6.44 (d, J=5 Hz, 1H), 7.12-7.19 (m, 2H),
7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.63-7.68 (m, 2H),
7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s, 1H), 10.21 (s,
1H).
[0157] .sup.13C NMR (d.sub.6-DMSO): 15.36, 31.55, 55.64, 55.67,
66.91, 99.03, 102.95, 107.66, 114.89, 115.07, 115.11, 121.17,
122.11, 122.32, 122.39, 135.15, 136.41, 146.25, 148.7, 149.28,
149.38, 152.54, 157.03, 159.42, 160.02, 168.07, 171.83, 174.68.
[0158] Characterization of Solid State Forms of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, malate
[0159] II. Powder X-Ray Diffraction (XRPD) Studies
[0160] X-Ray Powder Diffraction (XRPD) patterns were collected on a
Bruker AXS C2 GADDS diffractometer equipped with an automated XYZ
stage, laser video microscope for auto-sample positioning and a
HiStar 2-dimensional area detector. The radiation source used was
copper (Cu K.alpha.=1.5406 .ANG.), wherein the voltage was set at
40 kV and the current was set at 40 mA, X-ray optics consists of a
single Gobel multilayer mirror coupled with a pinhole collimator of
0.3 mm. The beam divergence, i.e. the effective size of the X-ray
beam on the sample, was approximately 4 mm. A .theta.-.theta.
continuous scan mode was employed with a sample--detector distance
of 20 cm which gives an effective 2.theta. range of
3.2.degree.-29.8.degree.. Samples run under ambient conditions
(from about 18.degree. C. to about 25.degree. C.) were prepared as
flat plate specimens using powder as received without grinding.
Approximately 1-2 mg of the sample was lightly pressed on a glass
slide to obtain a flat surface. Typically the sample would be
exposed to the X-ray beam for 120 seconds. Beam divergence (i.e.,
effective size of X-ray spot, gives a value of approximately 4 mm.
Alternatively, the powder samples were placed in sealed glass
capillaries of 1 mm or less in diameter; the capillary was rotated
during data collection at a sample-detector distance of 15 cm. Data
were collected for 3<20<35.degree. with a sample exposure
time of at least 2000 seconds. The resulting two-dimensional
diffraction arcs were integrated to create a traditional
1-dimensional XRPD pattern with a step size of 0.02.degree.
2.theta. in the range of 3 to 35.degree.
2.theta.+0.2.degree.2.theta.. The software used for data collection
was GADDS for WNT 4.1.16 and the data were analyzed and presented
using Diffrac Plus EVA v 9.0.0.2 or v 13.0.0.2.
[0161] II.1 Compound (I), Form N-1
[0162] FIG. 1 shows the experimental XRPD pattern of crystalline
Compound (I), Form N-1 acquired at room temperature (about
25.degree. C.). A list of the peaks are shown in Table 2, above.
The 2.theta. values at 19.4, 21.5, 22.8, 25.1, and 27.6
(+0.2.degree.2.theta.) are useful for characterizing crystalline
Compound (I), Form N-1. The entire list of peaks, or a subset
thereof, may be sufficient to characterize crystalline Compound
(I), Form N-1.
[0163] II.2 Compound (I), Form N-2
[0164] FIG. 8 shows the experimental XRPD pattern of crystalline
Compound (I), Form N-2 acquired at room temperature (about
25.degree. C.). A list of the peaks are shown in Table 2, above.
The 2.theta. values at 20.9 and 21.9 (+0.2.degree.2.theta.) are
useful for characterizing crystalline Compound (I), Form N-2. The
entire list of peaks, or a subset thereof, may be sufficient to
characterize crystalline Compound (I), Form N-2.
[0165] II.3 Compound (III), Form N-1
[0166] FIG. 15 shows the experimental and the simulated XRPD
pattern of crystalline Compound (III), Form N-1, acquired at
25.degree. C. using a spinning capillary sample. A list of the
peaks are shown in Table 2, above. The entire list of peaks, or a
subset thereof, may be sufficient to characterize crystalline
Compound (III), Form N-2.
[0167] II.4 Amorphous Compound (I)
[0168] FIG. 22 shows the experimental XRPD pattern of amorphous
Compound (I) acquired at room temperature (about 25.degree. C.).
The spectra is characterized a broad peak and the absence of sharp
peaks, which is consistent with an amorphous material.
[0169] III. Single Crystal X-Ray Study for Compound (III), Form
N-1
[0170] Data were collected on a Bruker-Nonius CAD4 serial
diffractometer. Unit cell parameters were obtained through
least-squares analysis of the experimental diffractometer settings
of 25 high-angle reflections. Intensities were measured using Cu
K.alpha. radiation (.lamda.=1.5418 .ANG.) at a constant temperature
with the .theta.-2.theta. variable scan technique and were
corrected only for Lorentz-polarization factors. Background counts
were collected at the extremes of the scan for half of the time of
the scan. Alternately, single crystal data were collected on a
Bruker-Nonius Kappa CCD 2000 system using Cu K.alpha. radiation
(.lamda.=1.5418 .ANG.). Indexing and processing of the measured
intensity data were carried out with the HKL2000 software package
(Otwinowski, Z. & Minor, W. (1997) in Macromolecular
Crystallography, eds. Carter, W. C. Jr & Sweet, R. M.
(Academic, NY), Vol. 276, pp. 307-326) in the Collect program suite
(Collect Data collection and processing user interface: Collect:
Data collection software, R. Hooft, Nonius B.V., 1998).
Alternately, single crystal data were collected on a Bruker-AXS
APEX2 CCD system using Cu Kc radiation (.lamda.=1.5418 .ANG.).
Indexing and processing of the measured intensity data were carried
out with the APEX2 software package/program suite (APEX2 Data
collection and processing user interface: APEX2 User Manual,
v1.27). When indicated, crystals were cooled in the cold stream of
an Oxford cryo system (Oxford Cryosystems Cryostream cooler: J.
Cosier and A. M. Glazer, J. Appl. Cryst., 1986, 19, 105) during
data collection.
[0171] The structures were solved by direct methods and refined on
the basis of observed reflections using either the SDP software
package (SDP, Structure Determination Package, Enraf-Nonius,
Bohemia N.Y. 11716. Scattering factors, including f' and f'', in
the SDP software were taken from the "International Tables for
Crystallography", Kynoch Press, Birmingham, England, 1974; Vol IV,
Tables 2.2A and 2.3.1) with minor local modifications or the
crystallographic packages MAXUS (maXus solution and refinement
software suite: S. Mackay, C. J. Gilmore, C. Edwards, M. Tremayne,
N. Stewart, K. Shankland. maXus: a computer program for the
solution and refinement of crystal structures from diffraction
data) or SHELXTL (APEX2 Data collection and processing user
interface: APEX2 User Manual, v1.27).
[0172] The derived atomic parameters (coordinates and temperature
factors) were refined through full matrix least-squares. The
function minimized in the refinements was
.SIGMA..sub.w(|F.sub.o|-|F.sub.c|).sup.2. R is defined as
.SIGMA..parallel.F.sub.o|-|F.sub.c.parallel./.SIGMA.|F.sub.o| while
R.sub.w=[.SIGMA..sub.w(|F.sub.o|-|F.sub.c|).sup.2/.SIGMA..sub.w|F.s-
ub.o|.sup.2].sup.1/2 where w is an appropriate weighting function
based on errors in the observed intensities. Difference maps were
examined at all stages of refinement. Hydrogens were introduced in
idealized positions with isotropic temperature factors, but no
hydrogen parameters were varied.
[0173] "Hybrid" simulated powder X-ray patterns were generated as
described in the literature (Yin. S.; Scaringe, R. P.; DiMarco, J.;
Galella, M. and Gougoutas, J. Z., American Pharmaceutical Review,
2003, 6, 2, 80). The room temperature cell parameters were obtained
by performing a cell refinement using the CellRefine.xls program.
Input to the program includes the 2-theta position of ca. 10
reflections, obtained from the experimental room temperature powder
pattern; the corresponding Miller indices, hkl, were assigned based
on the single-crystal data collected at low temperature. A new
(hybrid) XRPD was calculated (by either of the software programs,
Alex or LatticeView) by inserting the molecular structure
determined at low temperature into the room temperature cell
obtained in the first step of the procedure. The molecules are
inserted in a manner that retains the size and shape of the
molecule and the position of the molecules with respect to the cell
origin, but, allows intermolecular distances to expand with the
cell.
[0174] A single crystal, measuring 40.times.30.times.10 microns,
was selected from the slurry of crystals described in Example 5 for
single crystal diffraction analysis. The selected crystal was
affixed to a thin glass fiber with a small amount of a light
grease, and mounted at room temperature on a Bruker ApexII single
crystal diffractometer equipped with a rotating copper anode.
[0175] Crystalline Compound (III), From N-1 is characterized by
unit cell parameters approximately equal to those reported in Table
4. The unit cell parameters were measured at a temperature of about
25.degree. C.
TABLE-US-00004 TABLE 4 a = 14.60 .ANG. b = 5.20 .ANG. c = 39.09
.ANG. .alpha. = 90.0.degree. .beta. = 90.4.degree. .gamma. =
90.0.degree. Space group: P2.sub.1/n Molecules of Compound (I)/unit
cell: 4 Volume = 2969 .ANG..sup.3
[0176] Structure solution and refinement were routine in the
monoclinic space group, P2.sub.1/n, with four formula units in the
unit cell. The structure contains cations of
N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicar-
boxamide, protonated at the quinoline nitrogen atom, and singly
ionized malic acid anions, in a 1:1 ratio. Further, the crystal
contained a 1:1 ratio of (L)-malic acid ions to (D)-malic acid
ions. Table 5 fractional atomic coordinates for Compound (III),
Form N-1 calculated at a temperature of about 25.degree. C.
[0177] Based on the single crystal X-ray data, crystalline Compound
(III), Form N-1 may be characterized by a simulated powder x-ray
diffraction (XRPD) pattern substantially in accordance with the
simulated pattern shown in FIG. 15 and/or by an observed XRPD
pattern substantially in accordance with the experimental pattern
shown in FIG. 15.
TABLE-US-00005 TABLE 5 Fractional Atomic Coordinates for Compound
(III), Form N-1 Calculated at a Temperature of about 25.degree. C.
Atom X Y Z O1 0.30601 -0.52166 0.22875 O2 0.29518 0.12504 0.09391
O3 0.19041 -0.53232 0.18147 F5 -0.07307 2.12170 -0.08811 O6 0.18186
1.20500 -0.03241 O7 0.57137 0.22739 0.23473 O8 0.58700 -0.17911
0.24998 O9 0.41742 0.76377 -0.04319 N10 0.28649 0.82210 -0.01420
O11 0.87391 0.22086 0.31241 N12 0.46887 0.17029 0.17613 C13 0.29647
0.64886 0.01247 C14 0.31416 1.08187 -0.06304 C15 0.33900 -0.02207
0.14761 N16 0.20651 1.40640 -0.08267 C17 0.40079 -0.01723 0.17602
C18 0.29743 0.29956 0.06604 C19 0.00418 1.80556 -0.05680 C20
0.11925 1.73626 -0.11097 C21 0.22556 1.24019 -0.05791 C22 0.39150
-0.17467 0.20389 C23 0.22558 0.63870 0.03619 O24 0.62714 0.39565
0.29760 C25 0.34591 0.87438 -0.03961 C26 0.36467 -0.51389 0.25773
C27 0.26562 -0.20277 0.14859 C28 0.35380 0.15272 0.12054 C29
0.07365 1.60604 -0.05443 C30 0.04897 1.92890 -0.11212 C31 0.73841
0.04517 0.28641 C32 0.32089 -0.35160 0.20385 C33 0.36641 0.29052
0.04302 C34 0.42458 0.32272 0.12143 C35 0.11723 -0.54030 0.15742
C36 0.12933 1.59042 -0.08228 C37 -0.00344 1.93494 -0.08547 C38
0.36439 0.47245 0.01586 C39 0.59040 0.05797 0.25625 C40 0.25712
-0.35516 0.17574 C41 0.63543 0.13842 0.29041 C42 0.22703 0.46640
0.06306 C43 0.34559 1.01717 -0.10021 C44 0.39312 1.20834 -0.08137
C45 0.48224 0.32340 0.15059 O46 0.77400 0.04784 0.34652 C47 0.79349
0.09920 0.31966 H10 0.22646 0.91057 -0.01479 H16 0.24790 1.42164
-0.10317 H19 -0.04176 1.82973 -0.03893 H20 0.16347 1.73025 -0.13083
H22 0.43179 -0.17902 0.22447 H23 0.17093 0.73524 0.03244 H27
0.21953 -0.24212 0.12962 H29 0.07954 1.50390 -0.03492 H30 0.04671
2.05817 -0.13354 H33 0.41851 0.16255 0.04395 H34 0.43433 0.41859
0.10106 H38 0.41440 0.45648 -0.00227 H41 0.61062 0.02238 0.31086
H42 0.17752 0.45794 0.07911 H45 0.53033 0.44239 0.15049 H31a
0.76754 0.12071 0.26693 H31b 0.74726 -0.15247 0.28137 H43a 0.30237
1.06909 -0.12187 H43b 0.36868 0.85693 -0.10836 H44a 0.45563 1.18725
-0.07495 H44b 0.38932 1.39942 -0.08846 H26a 0.35958 -0.37184
0.27147 H26b 0.42813 -0.55605 0.25348 H26c 0.34954 -0.66814 0.27571
H35a 0.08189 -0.39941 0.15398 H35b 0.06671 -0.68838 0.16269 H35c
0.13276 -0.61095 0.13323 H11 0.88836 0.21926 0.28968 H12 0.50720
0.16494 0.19477 H24 0.61522 0.45898 0.27789
[0178] IV. Solid State Nuclear Magnetic Resonance (SSNMR)
[0179] All solid-state C-13 NMR measurements were made with a
Bruker DSX-400, 400 MHz NMR spectrometer. High resolution spectra
were obtained using high-power proton decoupling and the TPPM pulse
sequence and ramp amplitude cross-polarization (RAMP-CP) with
magic-angle spinning (MAS) at approximately 12 kHz (A. E. Bennett
et al, J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S. O.
Smith, J. Magn. Reson. A, 1994, 110, 219-227). Approximately 70 mg
of sample, packed into a canister-design zirconia rotor was used
for each experiment. Chemical shifts (.delta.) were referenced to
external adamantane with the high frequency resonance being set to
38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn. Reson., 1982,
48, 35-54).
[0180] IV.1 Compound (I), Form N-1
[0181] The solid state .sup.13C NMR spectrum of crystalline
Compound (I), Form N-1 is shown in FIG. 2. The entire list of
peaks, or a subset thereof, may be sufficient to characterize
crystalline Compound (I), Form N-1.
[0182] SS .sup.13C NMR Peaks: 18.1, 20.6, 26.0, 42.9, 44.5, 54.4,
55.4, 56.1, 70.4, 99.4, 100.1, 100.6, 114.4, 114.9, 115.8, 119.6,
120.1, 121.6, 123.2, 124.1, 136.4, 138.6, 140.6, 145.4, 150.1,
150.9, 156.2, 157.4, 159.4, 164.9, 167.1, 170.8, 175.7, and 182.1
ppm, .+-.0.2 ppm.
[0183] FIG. 3 shows the solid state .sup.15N NMR spectrum of
crystalline Compound (I), Form N-1. The spectrum shows peaks at
118.6, 119.6, 120.7, 134.8, 167.1, 176.0, and 180 ppm, .+-.0.2 ppm.
The entire list of peaks, or a subset thereof, may be sufficient to
characterize crystalline Compound (I), Form N-1.
[0184] FIG. 4 shows the solid state .sup.19F NMR spectrum of
crystalline Compound (I), Form N-1. The spectrum shows a peak at
-121.6, -120.8, and -118.0 ppm, .+-.0.2 ppm.
[0185] IV.2 Compound (I), Form N-2
[0186] The solid state .sup.13C NMR spectrum of crystalline
Compound (I), Form N-2 is shown in FIG. 9. The entire list of
peaks, or a subset thereof, may be sufficient to characterize
crystalline Compound (I), Form N-2.
[0187] SS .sup.13C NMR Peaks: 20.5, 21.8, 23.0, 25.9, 26.4, 38.0,
41.7, 54.7, 55.8, 56.2, 56.6, 69.7, 99.4, 100.0, 100.4, 100.8,
102.3, 114.5, 115.5, 116.7, 119.0, 120.2, 121.1, 121.2, 122.1,
122.9, 124.5, 136.0, 137.3, 138.1, 138.9, 139.5, 140.2, 144.9,
145.7, 146.1, 150.7, 156.7, 157.7, 159.6, 159.7, 165.1, 167.0,
168.0, 171.5, 177.3, 179.3, 180.0, and 180.3 ppm, .+-.0.2 ppm.
[0188] FIG. 10 shows the solid state .sup.15N NMR spectrum of
crystalline Compound (I), FormN-2. The spectrum shows peaks at
118.5, 120.8, 135.1, 167.3, and 180.1 ppm, .+-.0.2 ppm. The entire
list of peaks, or a subset thereof, may be sufficient to
characterize crystalline Compound (I), Form N-2.
[0189] FIG. 11 shows the solid state .sup.19F NMR spectrum of
crystalline Compound (I), Form N-2. The spectrum shows peaks at
-121.0 and -119.1 ppm, .+-.0.2 ppm. Those peaks, individually or
together, may be sufficient to characterize crystalline Compound
(I), Form N-2.
[0190] IV.3 Compound (III), Form N-1
[0191] The solid state .sup.13C NMR spectrum of crystalline
Compound (III), Form N-1 is shown in FIG. 16. The entire list of
peaks, or a subset thereof, may be sufficient to characterize
crystalline Compound (III), Form N-1.
[0192] SS .sup.13C NMR Peaks: 20.8, 26.2, 44.8, 55.7, 70.7, 100.4,
101.0, 114.7, 115.2, 116.0, 119.7, 120.4, 121.6, 124.4, 136.9,
138.9, 141.1, 145.7, 150.3, 156.5, 157.6, 159.6, 165.2, 167.4,
171.2, 176.3, and 182.1 ppm, .+-.0.2 ppm.
[0193] FIG. 17 shows the solid state .sup.15N NMR spectrum of
crystalline Compound (III), Form N-1. The spectrum shows peaks at
119.6, 134.7, and 175.5 ppm, .+-.0.2 ppm. The entire list of peaks,
or a subset thereof, may be sufficient to characterize crystalline
Compound (III), Form N-1.
[0194] FIG. 18 shows the solid state .sup.19F NMR spectrum of
crystalline Compound (III), Form N-1. The spectrum shows a peak at
-120.5 ppm, .+-.0.2 ppm.
[0195] IV.4 Compound (I), Amorphous
[0196] FIG. 23 shows the solid state .sup.13C NMR spectrum of
amorphous Compound (I). The entire list of peaks, or a subset
thereof, may be sufficient to characterize amorphous Compound
(I).
[0197] SS .sup.13C NMR Peaks (ppm): 12.2, 17.8, 20.3, 21.8, 27.2,
33.8, 41.7, 56.9, 69.9, 99.9, 102.2, 115.6, 122.2, 134.4, 137.8,
142.9, 149.1, 150.9, 157.3, 159.7, 167.0, 171.7, 173.1, 177.4, and
179.5 ppm, .+-.0.2 ppm.
[0198] FIG. 24 shows the solid state .sup.15N NMR spectrum of
amorphous Compound (I). The spectrum shows peaks at 120.8, 131.8,
174.7, and 178.3 ppm, .+-.0.2 ppm. The entire list of peaks, or a
subset thereof, may be sufficient to characterize amorphous
Compound (I).
[0199] FIG. 25 shows the solid state .sup.19F NMR spectrum of
amorphous Compound (I). The spectrum shows a peak at -118.9 ppm,
.+-.0.2 ppm.
[0200] V. Thermal Characterization Measurements
[0201] Thermal Gravimetric Analysis (TGA)
[0202] The TGA measurements were performed in a TA Instruments.TM.
model Q500 or 2950, employing an open pan setup. The sample (about
10-30 mg) was placed in a platinum pan previously tared. The weight
of the sample was measured accurately and recorded to a thousand of
a milligram by the instrument. The furnace was purged with nitrogen
gas at 100 mL/min. Data were collected between room temperature and
300.degree. C. at 10.degree. C./min heating rate.
[0203] Differential Scanning Calorimetry (DSC) Analysis
[0204] DSC measurements were performed in a TA Instruments.TM.
model Q2000, Q1000 or 2920, employing an open pan setup. The sample
(about 2-6 mg) was weighed in an aluminum pan and recorded
accurately recorded to a hundredth of a milligram, and transferred
to the DSC. The instrument was purged with nitrogen gas at 50
mL/min. Data were collected between room temperature and
300.degree. C. at 10.degree. C./min heating rate. The plot was made
with the endothermic peaks pointing down.
[0205] V.1 Compound (I), Form N-1
[0206] FIG. 5 shows the TGA thermogram for crystalline Compound
(I), Form N-1, which shows a weight loss of approximately 0.4
weight % at a temperature of 170.degree. C.
[0207] FIG. 6 shows the DSC thermogram for crystalline Compound
(I), Form N-1, which showed a melting point of approximately
187.degree. C.
[0208] V.2 Compound (I), Form N-2
[0209] FIG. 12 shows the TGA thermogram for crystalline Compound
(I), Form N-2, which shows a weight loss of approximately 0.1
weight % at a temperature of 170.degree. C.
[0210] FIG. 13 shows the DSC thermogram for crystalline Compound
(I), Form N-2, which showed a melting point of approximately
186.degree. C.
[0211] V.3 Compound (III), Form N-1
[0212] FIG. 19 shows the TGA thermogram for crystalline Compound
(III), Form N-1, which shows a weight loss of approximately 0.2
weight % at a temperature of 170.degree. C.
[0213] FIG. 20 shows the DSC thermogram for crystalline Compound
(III), Form N-1, which showed a melting point of approximately
186.degree. C.
[0214] V.2 Compound (I), Amorphous
[0215] FIG. 26 shows the DSC for crystalline Compound (I).
[0216] VI. Moisture Vapor Isotherm Measurements
[0217] Moisture sorption isotherms were collected in a VTI SGA-100
Symmetric Vapor Analyzer using approximately 10 mg of sample. The
sample was dried at 60.degree. C. until the loss rate of 0.0005 wt
%/min was obtained for 10 minutes. The sample was tested at
25.degree. C. and 3 or 4, 5, 15, 25, 35, 45, 50, 65, 75, 85, and
95% RH. Equilibration at each RH was reached when the rate of
0.0003 wt %/min for 35 minutes was achieved or a maximum of 600
minutes.
[0218] VI.1 Compound (I), Form N-1
[0219] FIG. 7 shows the moisture vapor isotherm of crystalline
Compound (I), Form N-1.
[0220] VI.2 Compound (I), Form N-1
[0221] FIG. 14 shows the moisture vapor isotherm of crystalline
Compound (I), Form N-2.
[0222] VI.3 Compound (III), Form N-1
[0223] FIG. 21 shows the moisture vapor isotherm of crystalline
Compound (III), Form N-1.
[0224] VI.4 Compound (I), Amorphous
[0225] FIG. 27 shows the moisture vapor isotherm of amorphous
Compound (I).
[0226] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. The invention has been described with reference to
various specific and preferred embodiments and techniques. However,
it should be understood that many variations and modifications can
be made while remaining within the spirit and scope of the
invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *