U.S. patent application number 14/115236 was filed with the patent office on 2014-06-26 for method of treating cancer and bone cancer pain.
This patent application is currently assigned to Exelixis, Inc.. The applicant listed for this patent is Dana T. Aftab, Gisela Schwab. Invention is credited to Dana T. Aftab, Gisela Schwab.
Application Number | 20140179736 14/115236 |
Document ID | / |
Family ID | 46062768 |
Filed Date | 2014-06-26 |
United States Patent
Application |
20140179736 |
Kind Code |
A1 |
Schwab; Gisela ; et
al. |
June 26, 2014 |
Method of Treating Cancer and Bone Cancer Pain
Abstract
This invention is directed to the treatment of cancer,
particularly lung cancer, breast cancer, melanoma, renal cell
carcinoma, thyroid cancer that has metastasized to the bone. The
invention is also directed to a method for treating bone cancer
pain in an individual in need of such treatment comprising
administering to the individual an effective amount of a compound
of Formula I.
Inventors: |
Schwab; Gisela; (Hayward,
CA) ; Aftab; Dana T.; (San Rafael, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Schwab; Gisela
Aftab; Dana T. |
Hayward
San Rafael |
CA
CA |
US
US |
|
|
Assignee: |
Exelixis, Inc.
South San Francisco
CA
|
Family ID: |
46062768 |
Appl. No.: |
14/115236 |
Filed: |
May 2, 2012 |
PCT Filed: |
May 2, 2012 |
PCT NO: |
PCT/US2012/036191 |
371 Date: |
February 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61481682 |
May 2, 2011 |
|
|
|
61557366 |
Nov 8, 2011 |
|
|
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Current U.S.
Class: |
514/312 ;
546/153 |
Current CPC
Class: |
C07D 215/233 20130101;
A61P 25/04 20180101; A61P 35/04 20180101; A61K 31/536 20130101;
A61P 19/00 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/312 ;
546/153 |
International
Class: |
C07D 215/233 20060101
C07D215/233 |
Claims
1. A method for treating bone cancer associated with breast cancer,
melanoma, renal cell carcinoma, sarcoma, lung cancer, or thyroid
cancer, comprising administering to a patient in need of such
treatment a compound of Formula I: ##STR00012## or a
pharmaceutically acceptable salt thereof, wherein: R.sup.1 is halo;
R.sup.2 is halo; R.sup.3 is (C.sub.1-C.sub.6)alkyl; R.sup.4 is
(C.sub.1-C.sub.6)alkyl; and Q is CH or N.
2. The method of claim 1, wherein the dual MET and VEGF modulator
is a compound of Formula Ia ##STR00013## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is halo; R.sup.2 is halo;
and Q is CH or N.
3. The method of claims 1-2, wherein the compound of Formula I is
compound I: ##STR00014## or a pharmaceutically acceptable salt
thereof.
4. The compound of claim 3, which is
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
5. The method of claims 1-4, wherein the compound of Formula (I),
Formula I(a) and Compound 1 is the (L)- or (D)-malate salt.
6. The method of claims 1-5, wherein the compound of Formula (I) is
in the crystalline N-1 form of the (L) malate salt and/or the (D)
malate salt.
7. The method of claim 1, wherein the bone cancer is bone
metastases from lung cancer, breast cancer, melanoma, renal cell
carcinoma, or thyroid cancer.
8. A method for ameliorating abnormal deposition of unstructured
bone accompanied by increased skeletal fractures, spinal cord
compression, and severe bone pain of bone metastases, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound of claims 2-6,
optionally as a pharmaceutical composition.
9. A method for reducing or stabilizing metastatic bone lesions
associated with lung cancer, breast cancer, melanoma, renal cell
carcinoma, or thyroid cancer, comprising administering a
therapeutically effective amount of a compound claims 2-6,
optionally as a pharmaceutical composition, to a patient in need of
such treatment.
10. A method for reducing, treating or minimizing bone pain due to
metastatic bone lesions associated with lung cancer, breast cancer,
melanoma, renal cell carcinoma, or thyroid cancer, comprising
administering a therapeutically effective amount of a compound of
claims 2-6, optionally as a pharmaceutical composition, to a
patient in need of such treatment.
11. A method for preventing bone metastases associated with lung
cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid
cancer, comprising administering a therapeutically effective amount
of a pharmaceutical formulation comprising claims 2-6, optionally
as a pharmaceutical composition, to a patient in need of such
treatment.
12. A method for extending the overall survival in patients with
lung cancer, breast cancer, melanoma, renal cell carcinoma, or
thyroid cancer metastasized to bone, comprising administering a
therapeutically effective amount of claims 2-6, optionally as a
pharmaceutical composition, to a patient in need of such
treatment.
13. A method for treating bone cancer pain in an individual in need
of such treatment comprising administering to the individual an
effective amount of a compound of claims 2-6, optionally as a
pharmaceutical composition.
14. The method of claim 13, wherein the bone cancer pain is from
cancer originated in bone.
15. The method of claim 13, wherein the bone cancer pain is from
osteosarcoma.
16. The method of claim 13, wherein the bone cancer pain is from
cancer metastasized to bone.
17. The method of claim 13, wherein the bone cancer pain is from
breast cancer metastasized to bone.
18. The method of claim 17, wherein the bone cancer pain is from
lung cancer metastasized to bone.
19. The method of claim 13, wherein the bone cancer pain is from
sarcoma metastasized to bone.
20. The method of claim 13, wherein the bone cancer pain is from
renal cancer metastasized to bone.
21. The method of claim 13, wherein the bone cancer pain is from
thyroid cancer metastasized to bone.
22. The method of claim 13, wherein the bone cancer pain is from
melanoma metastasized to bone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of U.S.
Provisional Application No. 61/481,682, filed May 2, 2011, and U.S.
Provisional Application No. 61/557,366, filed Nov. 8, 2011, all of
which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention is directed to the treatment of cancer,
particularly to cancers where bone disease is common. These cancers
include breast cancer, melanoma, renal cell carcinoma, and thyroid
cancer, as well as others, using a compound of Formula I as
disclosed herein. In addition to treating these forms of cancer,
the compound of Formula I can be used to treat the pain associated
with bone metastases. The ability of the compound of Formula I to
treat these and other forms of cancer and the associated bone pain
can be monitored using imaging technologies, including magnetic
resonance imaging, among other methods.
BACKGROUND OF THE INVENTION
[0003] Bone disease is common in patients with prostate cancer,
lung cancer, breast cancer, melanoma, renal cell carcinoma, and
thyroid cancer. As an example, Castration-Resistant Prostate Cancer
(CRPC) is a leading cause of cancer-related death in men. Despite
progress in systemic therapy for CRPC, improvements in survival are
modest, and virtually all patients succumb to this disease with a
median survival of about 2 years. The primary cause of morbidity
and mortality in CRPC is metastasis to the bone, which occurs in
about 90% of cases.
[0004] Metastasis to bone is a complex process involving
interactions between the cancer cell and components of the bone
microenvironment including osteoblasts, osteoclasts, and
endothelial cells. Bone metastases cause local disruption of normal
bone remodeling, and lesions generally show a propensity for either
osteoblastic (bone-forming) or osteolytic (bone-resorbing)
activity. Although most CRPC patients with bone metastases display
features of both types of lesions, prostate cancer bone metastases
are often osteoblastic, with abnormal deposition of unstructured
bone accompanied by increased skeletal fractures, spinal cord
compression, and severe bone pain.
[0005] The receptor tyrosine kinase MET plays important roles in
cell motility, proliferation, and survival, and has been shown to
be a key factor in tumor angiogenesis, invasiveness, and
metastasis. Prominent expression of MET has been observed in
primary and metastatic prostate carcinomas, with evidence for
higher levels of expression in bone metastases compared to lymph
node metastases or primary tumors.
[0006] MET signaling can influence osteoblast and osteoclast
function. Strong immunohistochemical staining of MET has been
observed in osteoblasts in developing bone, while both HGF and MET
are expressed by osteoblasts and osteoclasts in vitro and regulate
cellular responses such as proliferation, migration and
differentiation. Secretion of HGF by osteoblasts has been proposed
as a key factor in osteoblast/osteoclast coupling and is thought to
promote the development of bone metastases by tumor cells that
express MET.
[0007] Vascular endothelial growth factor (VEGF) and its receptors
on endothelial cells are widely accepted as key mediators in the
process of tumor angiogenesis. In prostate cancer, elevated VEGF in
either plasma or urine is associated with shorter overall survival.
VEGF may also play a role in activating the MET pathway in tumor
cells by binding to neuropilin-1, which is frequently upregulated
in prostate cancer and appears to activate MET in a co-receptor
complex. Agents targeting the VEGF signaling pathway have
demonstrated some activity in patients with CRPC, as well as breast
cancer, melanoma, renal cell carcinoma, and thyroid cancer.
[0008] Like MET, the VEGF signaling pathway is strongly implicated
in bone formation and remodeling. Both osteoblasts and osteoclasts
express VEGF and VEGF receptors, which appear to be involved in
autocrine and/or paracrine feedback mechanisms regulating cell
proliferation, migration, differentiation and survival [62-66].
Experiments using genetically modified mice have shown that
angiogenesis and VEGF signaling in osteoblasts are both important
in bone development and repair.
[0009] A need remains for methods of treating cancer in human
patients with breast cancer, melanoma, renal cell carcinoma, and
thyroid cancer, and the bone metastases associated with these forms
of cancer. A need also remains for a method of treating bone cancer
or pain associated with bone metastases in individuals in need of
such treatment.
SUMMARY OF THE INVENTION
[0010] These and other needs are met by the present invention which
is directed to a method for treating bone cancer associated with
breast cancer, melanoma, renal cell carcinoma, lung cancer, and
thyroid cancer. The method comprises administering a
therapeutically effective amount of a compound that modulates both
MET and VEGF signaling to a patient in need of such treatment. In
some embodiments, the bone cancer is bone metastases associated
with breast cancer, melanoma, renal cell carcinoma, and thyroid
cancer.
[0011] In one aspect, the present invention is directed to a method
for treating bone metastases, lung cancer, breast cancer, melanoma,
renal cell carcinoma, or thyroid cancer, or bone metastases
associated with breast cancer, melanoma, renal cell carcinoma, or
thyroid cancer, comprising administering a therapeutically
effective amount of a compound that modulates both MET and VEGF
signaling to a patient in need of such treatment. In some
embodiments, the bone cancer or metastases is osteoblastic bone
cancer or bone metastases.
[0012] In one embodiment of this and other aspects, the dual acting
MET/VEGF inhibitor is a compound of Formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein:
[0013] R.sup.1 is halo;
[0014] R.sup.2 is halo;
[0015] R.sup.3 is (C.sub.1-C.sub.6)alkyl;
[0016] R.sup.4 is (C.sub.1-C.sub.6)alkyl; and
[0017] Q is CH or N.
[0018] In another embodiment, the compound of Formula I is compound
1:
##STR00002##
or a pharmaceutically acceptable salt thereof. Compound 1 is known
as
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
[0019] In another aspect, the invention provides a method for
treating bone metastases associated with lung cancer, breast
cancer, melanoma, renal cell carcinoma, or thyroid cancer,
comprising administering a therapeutically effective amount of a
pharmaceutical formulation to a patient in need of such treatment
comprising Compound of Formula I or the malate salt of Compound of
Formula I or another pharmaceutically acceptable salt of Compound
of Formula I, to a patient in need of such treatment.
[0020] In another aspect, the invention provides a method for
reducing or stabilizing metastatic bone lesions associated with
lung cancer, breast cancer, melanoma, renal cell carcinoma, or
thyroid cancer, comprising administering a therapeutically
effective amount of a pharmaceutical formulation to a patient in
need of such treatment comprising Compound of Formula I or the
malate salt of Compound of Formula I or another pharmaceutically
acceptable salt of Compound of Formula I, to a patient in need of
such treatment.
[0021] In another aspect, the invention provides a method for
reducing bone pain due to metastatic bone lesions associated with
lung cancer, breast cancer, melanoma, renal cell carcinoma, or
thyroid cancer, comprising administering a therapeutically
effective amount of a pharmaceutical formulation to a patient in
need of such treatment comprising Compound of Formula I or the
malate salt of Compound of Formula I or another pharmaceutically
acceptable salt of Compound of Formula I, to a patient in need of
such treatment.
[0022] In another aspect, the invention provides a method for
treating or minimizing bone pain due to metastatic bone lesions
associated with lung cancer, breast cancer, melanoma, renal cell
carcinoma, or thyroid cancer, comprising administering a
therapeutically effective amount of a pharmaceutical formulation to
a patient in need of such treatment comprising Compound of Formula
I or the malate salt of Compound of Formula I or another
pharmaceutically acceptable salt of Compound of Formula I, to a
patient in need of such treatment.
[0023] In another aspect, the invention provides a method for
preventing bone metastases associated with lung cancer, breast
cancer, melanoma, renal cell carcinoma, or thyroid cancer,
comprising administering a therapeutically effective amount of a
pharmaceutical formulation to a patient in need of such treatment
comprising Compound of Formula I or the malate salt of Compound of
Formula I or another pharmaceutically acceptable salt of Compound
of Formula I, to a patient in need of such treatment.
[0024] In another aspect, the invention provides a method for
preventing bone metastases in patients with lung cancer, breast
cancer, melanoma, renal cell carcinoma, or thyroid cancer, who have
not yet advanced to metastatic disease, comprising administering a
therapeutically effective amount of a pharmaceutical formulation to
a patient in need of such treatment comprising Compound of Formula
I or the malate salt of Compound of Formula I or another
pharmaceutically acceptable salt of Compound of Formula I, to a
patient in need of such treatment.
[0025] In another aspect, the invention provides a method for
extending the overall survival in patients with lung cancer, breast
cancer, melanoma, renal cell carcinoma, or thyroid cancer,
comprising administering a therapeutically effective amount of a
pharmaceutical formulation to a patient in need of such treatment
comprising Compound of Formula I or the malate salt of Compound of
Formula I or another pharmaceutically acceptable salt of Compound
of Formula I, to a patient in need of such treatment.
[0026] In another aspect, the invention provides a method for
treating bone cancer pain in an individual comprising administering
to the individual an effective amount of a Compound of Formula I or
the malate salt of Compound of Formula I or another
pharmaceutically acceptable salt of Compound of Formula I, to a
patient in need of such treatment. In a specific embodiment, the
Compound of Formula I is Compound 1. In this aspect, the bone
cancer pain can originate from bone cancer, osteosarcoma, as well
as from cancer metastasized to bone. Thus, in this aspect, the bone
cancer pain can be from the list including but not limited to bone
metastases from lung cancer, breast cancer, sarcoma, or renal
cancer.
[0027] In these and other aspects, the ability of the compound of
Formula I to treat, ameliorate, or reduce the severity of bone
metastases can be determined both qualitatively and quantitatively
using various physiological markers, such as circulating biomarkers
of bone turnover (ie bALP, CTx, and NTx), circulating tumor cell
(CTC) counts, and imaging technologies. The imaging technologies
include positron emission tomography (PET) or computerized
tomography (CT) and magnetic resonance imaging. By using these
imaging techniques, it is possible to monitor and quantify the
reduction in tumor size and the reduction in the number and size of
bone lesions in response to treatment with the compound of Formula
I.
[0028] In these and other aspects, shrinkage of soft tissue and
visceral lesions has been observed to result when the compound of
Formula I is administered to patients with CRPC. Moreover,
administration of the compound of Formula I leads to increases in
hemoglobin concentration in patients CRPC patients with anemia.
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIGS. 1A-C show the bone scan (FIG. 1A), bone scan response
(FIG. 1B), and CT scan data (FIG. 1C) for Patient 1 having
CRPC.
[0030] FIGS. 2A-C show the bone scan (FIG. 2A), bone scan response
(FIG. 2B), and CT scan data (FIG. 2C) for Patient 2 having
CRPC.
[0031] FIGS. 3A-B show the bone scan (FIG. 3A), bone scan response
(FIG. 3B) for Patient 3 having CRPC.
[0032] FIGS. 4A and B shows the bone scan (FIG. 4A), bone scan
response (FIG. 4B) for a Patient having renal cell carcinoma with
bone metastases.
[0033] FIGS. 5A and 5B shows the bone scan (FIG. 5A), bone scan
response (FIG. 5B) for a Patient having melanoma with bone
metastases.
[0034] FIG. 6 shows a CT scan of a bone metastasis from a patient
with differentiated thyroid cancer before (FIG. 6A) and after (FIG.
6B) treatment.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0035] The following abbreviations and terms have the indicated
meanings throughout:
TABLE-US-00001 Abbreviation Meaning Ac Acetyl bALP Bone-specific
alkaline phosphatase Br Broad .degree. C. Degrees Celsius c- Cyclo
CBZ CarboBenZoxy = benzyloxycarbonyl CTx Cross-linked C-terminal
telopeptides of type-1 collagen d Doublet dd Doublet of doublet dt
Doublet of triplet DCM Dichloromethane DME 1,2-dimethoxyethane DMF
N,N-Dimethylformamide DMSO dimethyl sulfoxide Dppf
1,1'-bis(diphenylphosphano)ferrocene EI Electron Impact ionization
G Gram(s) h or hr Hour(s) HPLC High pressure liquid chromatography
L Liter(s) M Molar or molarity m Multiplet Mg Milligram(s) MHz
Megahertz (frequency) Min Minute(s) mL Milliliter(s) .mu.L
Microliter(s) .mu.M Micromole(s) or micromolar mM Millimolar Mmol
Millimole(s) Mol Mole(s) MS Mass spectral analysis N Normal or
normality nM Nanomolar NMR Nuclear magnetic resonance spectroscopy
NTx Cross-linked N-terminal telopeptides of type-1 collagen q
Quartet RT Room temperature s Singlet t or tr Triplet TFA
Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer
chromatography
[0036] The symbol "--" means a single bond, "=" means a double
bond.
[0037] When chemical structures are depicted or described, unless
explicitly stated otherwise, all carbons are assumed to have
hydrogen substitution to conform to a valence of four. For example,
in the structure on the left-hand side of the schematic below there
are nine hydrogens implied. The nine hydrogens are depicted in the
right-hand structure. Sometimes a particular atom in a structure is
described in textual formula as having a hydrogen or hydrogens as
substitution (expressly defined hydrogen), for example,
--CH.sub.1CH.sub.2--. It is understood by one of ordinary skill in
the art that the aforementioned descriptive techniques are common
in the chemical arts to provide brevity and simplicity to
description of otherwise complex structures.
##STR00003##
[0038] If a group "R" is depicted as "floating" on a ring system,
as for example in the formula:
##STR00004##
then, unless otherwise defined, a substituent "R" may reside on any
atom of the ring system, assuming replacement of a depicted,
implied, or expressly defined hydrogen from one of the ring atoms,
so long as a stable structure is formed.
[0039] If a group "R" is depicted as floating on a fused ring
system, as for example in the formulae:
##STR00005##
then, unless otherwise defined, a substituent "R" may reside on any
atom of the fused ring system, assuming replacement of a depicted
hydrogen (for example the --NH-- in the formula above), implied
hydrogen (for example as in the formula above, where the hydrogens
are not shown but understood to be present), or expressly defined
hydrogen (for example where in the formula above, "Z" equals
.dbd.CH--) from one of the ring atoms, so long as a stable
structure is formed. In the example depicted, the "R" group may
reside on either the 5-membered or the 6-membered ring of the fused
ring system. When a group "R" is depicted as existing on a ring
system containing saturated carbons, as for example in the
formula:
##STR00006##
where, in this example, "y" can be more than one, assuming each
replaces a currently depicted, implied, or expressly defined
hydrogen on the ring; then, unless otherwise defined, where the
resulting structure is stable, two "R's" may reside on the same
carbon. A simple example is when R is a methyl group; there can
exist a geminal dimethyl on a carbon of the depicted ring (an
"annular" carbon). In another example, two R's on the same carbon,
including that carbon, may form a ring, thus creating a spirocyclic
ring (a "spirocyclyl" group) structure with the depicted ring as
for example in the formula:
##STR00007##
[0040] "Halogen" or "halo" refers to fluorine, chlorine, bromine or
iodine.
[0041] "Yield" for each of the reactions described herein is
expressed as a percentage of the theoretical yield.
[0042] "Patient" for the purposes of the present invention includes
humans and other animals, particularly mammals, and other
organisms. Thus the methods are applicable to both human therapy
and veterinary applications. In another embodiment the patient is a
mammal, and in another embodiment the patient is human.
[0043] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. It is
understood that the pharmaceutically acceptable salts are
non-toxic. Additional information on suitable pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17.sup.th ed., Mack Publishing Company, Easton, Pa.,
1985, which is incorporated herein by reference or S. M. Berge, et
al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 both of
which are incorporated herein by reference.
[0044] Examples of pharmaceutically acceptable acid addition salts
include those formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric
acid, and the like; as well as organic acids such as acetic acid,
trifluoroacetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, oxalic acid, maleic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, malic acid, citric acid, benzoic acid,
cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
p-toluenesulfonic acid, and salicylic acid and the like.
[0045] "Prodrug" refers to compounds that are transformed
(typically rapidly) in vivo to yield the parent compound of the
above formulae, for example, by hydrolysis in blood. Common
examples include, but are not limited to, ester and amide forms of
a compound having an active form bearing a carboxylic acid moiety.
Examples of pharmaceutically acceptable esters of the compounds of
this invention include, but are not limited to, alkyl esters (for
example with between about one and about six carbons) the alkyl
group is a straight or branched chain. Acceptable esters also
include cycloalkyl esters and arylalkyl esters such as, but not
limited to benzyl. Examples of pharmaceutically acceptable amides
of the compounds of this invention include, but are not limited to,
primary amides, and secondary and tertiary alkyl amides (for
example with between about one and about six carbons). Amides and
esters of the compounds of the present invention may be prepared
according to conventional methods. A thorough discussion of
prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as
Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and
in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference for all purposes.
[0046] "Therapeutically effective amount" is an amount of a
compound of the invention, that when administered to a patient,
ameliorates a symptom of the disease. A therapeutically effective
amount is intended to include an amount of a compound alone or in
combination with other active ingredients effective to modulate
c-Met, and/or VEGFR2, or effective to treat or prevent cancer. The
amount of a compound of the invention which constitutes a
"therapeutically effective amount" will vary depending on the
compound, the disease state and its severity, the age of the
patient to be treated, and the like. The therapeutically effective
amount can be determined by one of ordinary skill in the art having
regard to their knowledge and to this disclosure.
[0047] "Treating" or "treatment" of a disease, disorder, or
syndrome, as used herein, includes (i) preventing the disease,
disorder, or syndrome from occurring in a human, i.e. causing the
clinical symptoms of the disease, disorder, or syndrome not to
develop in an animal that may be exposed to or predisposed to the
disease, disorder, or syndrome but does not yet experience or
display symptoms of the disease, disorder, or syndrome; (ii)
inhibiting the disease, disorder, or syndrome, i.e., arresting its
development; and (iii) relieving the disease, disorder, or
syndrome, i.e., causing regression of the disease, disorder, or
syndrome. As is known in the art, adjustments for systemic versus
localized delivery, age, body weight, general health, sex, diet,
time of administration, drug interaction and the severity of the
condition may be necessary, and will be ascertainable with routine
experience.
Embodiments
[0048] In one embodiment the compound of Formula I is the compound
of Formula Ia:
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein:
[0049] R.sup.1 is halo;
[0050] R.sup.2 is halo; and
[0051] Q is CH or N.
[0052] In another embodiment, the compound of Formula I is Compound
1:
##STR00009##
or a pharmaceutically acceptable salt thereof. As indicated
previously, compound I is referred to herein as
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide. WO 2005/030140 discloses Compound 1
and describes how it is made (Example 12, 37, 38, and 48) and also
discloses the therapeutic activity of this compound 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.
[0053] In other embodiments, the compound of Formula I, Ia, or
Compound 1, or a pharmaceutically acceptable salt thereof, is
administered as a pharmaceutical composition, wherein the
pharmaceutical composition additionally comprises a
pharmaceutically acceptable carrier, excipient, or diluent. In a
specific embodiment, the Compound of Formula I is Compound 1.
[0054] The compound of Formula I, Formula Ia, and Compound I, as
described herein, includes both the recited compounds as well as
individual isomers and mixtures of isomers. In each instance, the
compound of Formula I includes the pharmaceutically acceptable
salts, hydrates, and/or solvates of the recited compounds and any
individual isomers or mixture of isomers thereof.
[0055] In other embodiments, the compound of Formula I, Ia, or
Compound 1 can be the malate salt. The malate salt of the Compound
of Formula I and of Compound 1 is disclosed in PCT/US2010/021194
and 61/325,095.
[0056] In other embodiments, the compound of Formula I, Ia, or 1
can be the (D)-malate salt.
[0057] In other embodiments, the compound of Formula I, Ia, or 1
can be malate salt.
[0058] In other embodiments, the compound of Formula I, Ia, or 1
can be the (L)-malate salt.
[0059] In other embodiments, Compound 1 can be (D)-malate salt.
[0060] In other embodiments, Compound 1 can be the (L)-malate
salt.
[0061] In another embodiment, the malate salt of Compound 1 is in
the crystalline N-1 form of the (L) malate salt and/or the (D)
malate salt of the Compound 1 as disclosed in U.S. patent
Application Ser. No. 61/325,095. Also see WO 2008/083319 for the
properties of crystalline enantiomers, including the N-1 and/or the
N-2 crystalline forms of the malate salt of Compound 1. Methods of
making and characterizing such forms are fully described in
PCT/US10/21194, which is incorporated herein by reference in its
entirety.
[0062] In another embodiment, the invention is directed to a method
for ameliorating the symptoms of bone metastases, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound of Formula I in any
of the embodiments disclosed herein. In a specific embodiment, the
Compound of Formula I is Compound 1.
[0063] In another embodiment, the invention is directed to a method
for treating pain associated with bone metastases, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound of Formula I in any
of the embodiments disclosed herein. In a specific embodiment, the
Compound of Formula I is Compound 1.
[0064] In another embodiment, the compound of Formula I is
administered post-taxotere treatment. In a specific embodiment, the
Compound of Formula I is Compound 1.
[0065] In another embodiment, the compound of Formula I is as
effective or more effective than mitoxantrone plus prednisone. In a
specific embodiment, the Compound of Formula I is Compound 1.
[0066] In another embodiment, the Compound of Formula I, Ia, or
Compound 1 or a pharmaceutically acceptable salt thereof is
administered orally once daily as a tablet or capsule.
[0067] In another embodiment, Compound 1 is administered orally as
its free base or malate salt as a capsule or tablet.
[0068] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing up to 100 mg of Compound 1.
[0069] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 100 mg of Compound 1.
[0070] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 95 mg of Compound 1.
[0071] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 90 mg of Compound 1.
[0072] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 85 mg of Compound 1.
[0073] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 80 mg of Compound 1.
[0074] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 75 mg of Compound 1.
[0075] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 70 mg of Compound 1.
[0076] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 65 mg of Compound 1.
[0077] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 60 mg of Compound 1.
[0078] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 55 mg of Compound 1.
[0079] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 50 mg of Compound 1.
[0080] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 45 mg of Compound 1.
[0081] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 40 mg of Compound 1.
[0082] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 30 mg of Compound 1.
[0083] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 25 mg of Compound 1.
[0084] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 20 mg of Compound 1.
[0085] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 15 mg of Compound 1.
[0086] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 10 mg of Compound 1.
[0087] In another embodiment, Compound 1 is administered orally
once daily as its free base or as the malate salt as a capsule or
tablet containing 5 mg of Compound 1.
[0088] In another embodiment, Compound 1 is administered as its
free base or malate salt orally once daily as a tablet as provided
in the following table.
TABLE-US-00002 Ingredient (% w/w) Compound 1 31.68 Microcrystalline
Cellulose 38.85 Lactose anhydrous 19.42 Hydroxypropyl Cellulose
3.00 Croscarmellose Sodium 3.00 Total Intra-granular 95.95 Silicon
dioxide, Colloidal 0.30 Croscarmellose Sodium 3.00 Magnesium
Stearate 0.75 Total 100.00
[0089] In another embodiment, Compound 1 is administered orally as
its free base or malate salt once daily as a tablet as provided in
the following table.
TABLE-US-00003 Ingredient (% w/w) Compound 1 25.0-33.3
Microcrystalline Cellulose q.s Hydroxypropyl Cellulose 3 Poloxamer
0-3 Croscarmellose Sodium 6.0 Colloidal Silicon Dioxide 0.5
Magnesium Stearate 0.5-1.0 Total 100
[0090] In another embodiment, Compound 1 is administered orally as
its free base or malate salt once daily as a tablet as provided in
the following table.
TABLE-US-00004 Theoretical Quantity (mg/unit Ingredient dose)
Compound 1 100.0 Microcrystalline Cellulose PH- 155.4 102 Lactose
Anhydrous 60M 77.7 Hydroxypropyl Cellulose, EXF 12.0 Croscarmellose
Sodium 24 Colloidal Silicon Dioxide 1.2 Magnesium Stearate (Non-
3.0 Bovine) Opadry Yellow 16.0 Total 416
[0091] Any of the tablet formulations provided above can be
adjusted according to the dose of Compound 1 desired. Thus, the
amount of each of the formulation ingredients can be proportionally
adjusted to provide a table formulation containing various amounts
of Compound 1 as provided in the previous paragraphs. In another
embodiment, the formulations can contain 20, 40, 60, or 80 mg of
Compound 1.
Administration
[0092] Administration of the compound of Formula I, Formula Ia, or
Compound 1, or a pharmaceutically acceptable salt thereof, 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 dosages (which can be in capsules or
tablets), powders, solutions, suspensions, or aerosols, or the
like, specifically in unit dosage forms suitable for simple
administration of precise dosages.
[0093] The compositions will include a conventional pharmaceutical
carrier or excipient and a compound of Formula I as the/an active
agent, and, in addition, may include carriers and adjuvants,
etc.
[0094] Adjuvants include 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. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the use of
agents delaying absorption, for example, aluminum monostearate and
gelatin.
[0095] If desired, a pharmaceutical composition of the compound of
Formula I may also contain minor amounts of auxiliary substances
such as wetting or emulsifying agents, pH buffering agents,
antioxidants, and the like, such as, for example, citric acid,
sorbitan monolaurate, triethanolamine oleate, butylated
hydroxytoluene, etc.
[0096] The choice of composition depends on various factors such as
the mode of drug administration (e.g., for oral administration,
compositions in the form of tablets, pills or capsules) and the
bioavailability of the drug substance. Recently, pharmaceutical
compositions have been developed especially for drugs that show
poor bioavailability based upon the principle that bioavailability
can be increased by increasing the surface area i.e., decreasing
particle size. For example, U.S. Pat. No. 4,107,288 describes a
pharmaceutical composition having particles in the size range from
10 to 1,000 nm in which the active material is supported on a
crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684
describes the production of a pharmaceutical composition in which
the drug substance is pulverized to nanoparticles (average particle
size of 400 nm) in the presence of a surface modifier and then
dispersed in a liquid medium to give a pharmaceutical composition
that exhibits remarkably high bioavailability.
[0097] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0098] One specific route of administration is oral, using a
convenient daily dosage regimen that can be adjusted according to
the degree of severity of the disease-state to be treated.
[0099] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is admixed with at least one inert customary
excipient (or carrier) 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, alignates, 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.
[0100] 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.
[0101] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. Such dosage forms are prepared, for example,
by dissolving, dispersing, etc., the compound of Formula I, or a
pharmaceutically acceptable salt thereof, and optional
pharmaceutical adjuvants in a carrier, such as, for example, water,
saline, aqueous dextrose, glycerol, ethanol and the like;
solubilizing agents and emulsifiers, as for example, ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,
dimethylformamide; oils, in particular, cottonseed oil, groundnut
oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol,
tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid
esters of sorbitan; or mixtures of these substances, and the like,
to thereby form a solution or suspension.
[0102] 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.
[0103] Compositions for rectal administration are, for example,
suppositories that can be prepared by mixing the compound of
Formula I 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.
[0104] Dosage forms for topical administration of the compound of
Formula I include ointments, powders, sprays, and inhalants. The
active component is admixed under sterile conditions with a
physiologically acceptable carrier and any preservatives, buffers,
or propellants as may be required. Ophthalmic compositions, eye
ointments, powders, and solutions are also contemplated as being
within the scope of this disclosure.
[0105] Compressed gases may be used to disperse the compound of
Formula I in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0106] Generally, depending on the intended mode of administration,
the pharmaceutically acceptable compositions will contain about 1%
to about 99% by weight of a compound(s) of Formula I, or a
pharmaceutically acceptable salt thereof, 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 a
compound(s) of Formula I, Formula Ia, or Compound 1, or a
pharmaceutically acceptable salt thereof, with the rest being
suitable pharmaceutical excipients.
[0107] Actual methods of preparing such dosage forms are known or
will be apparent to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing
Company, Easton, Pa., 1990). The composition to be administered
will, in any event, contain a therapeutically effective amount of a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, for treatment of a disease-state in accordance with the
teachings of this disclosure.
[0108] The compounds of this disclosure, or their pharmaceutically
acceptable salts or solvates, are administered in a therapeutically
effective amount which will vary depending upon a variety of
factors including the activity of the specific compound employed,
the metabolic stability and length of action of the compound, the
age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular disease-states, and the host undergoing therapy.
The compound of Formula I, Formula Ia, or Compound 1, can be
administered to a patient at dosage levels in the range of about
0.1 to about 1,000 mg per day. For a normal human adult having a
body weight of about 70 kilograms, a dosage in the range of about
0.01 to about 100 mg per kilogram of body weight per day is an
example. The specific dosage used, however, can vary. For example,
the dosage can depend on a number of factors including the
requirements of the patient, the severity of the condition being
treated, and the pharmacological activity of the compound being
used. The determination of optimum dosages for a particular patient
is well known to one of ordinary skill in the art.
[0109] In other embodiments, the compound of Formula I, Formula Ia,
or Compound 1, can be administered to the patient concurrently with
other cancer treatments. Such treatments include other cancer
chemotherapeutics, hormone replacement therapy, radiation therapy,
or immunotherapy, among others. The choice of other therapy will
depend on a number of factors including the metabolic stability and
length of action of the compound, the age, body weight, general
health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular
disease-states, and the host undergoing therapy.
Preparation of Compound 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
[0110] 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.
##STR00010##
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0111] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (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 less than 2 percent of the
starting material remained (in process high-performance liquid
chromotography [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 percent 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).
Preparation of 6,7-Dimethyl-4-(4-nitro-phenoxy)-quinoline
[0112] 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 (less than 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).
Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0113] 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 percent 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 (less
than 2 percent starting material remaining, typically 1.5-15
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 percent
AUC).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic
acid
[0114] Triethylamine (8.0 kg) was added to a cooled (approximately
4.degree. C.) solution of commercially available
cyclopropane-1,1-dicarboxylic acid (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).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
[0115] 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.
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide
[0116] 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 (approximately 10 minutes), water
(74.0 kg) was added. The mixture was stirred at 15 to 30.degree. C.
for approximately 10 hours, which resulted in the precipitation of
the product. The product was recovered by filtration, washed with a
pre made 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.
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, (L) malate salt
[0117] 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). The
reaction mixture 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 the
title compound (5.0 kg).
[0118] An alternative route that for the preparation of Compound 1
is depicted in Scheme 2.
##STR00011##
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0119] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg).
The resulting mixture was heated to approximately 60.degree. C. and
phosphorus oxychloride (POCl.sub.3, 130.6 kg) was added. After the
addition of POCl.sub.3, the temperature of the reaction mixture was
raised to approximately 77.degree. C. The reaction was deemed
complete (approximately 13 hours) when less than 3 percent of the
starting material remained (in-process high-performance liquid
chromatography [HPLC] analysis). The reaction mixture was cooled to
approximately 2 to 7.degree. C. and then quenched into a chilled
solution of dichloromethane (DCM, 482.8 kg), 26 percent NH.sub.4OH
(251.3 kg), and water (900 L). The resulting mixture was warmed to
approximately 20 to 25.degree. C., and phases were separated. The
organic phase was filtered through a bed of AW hyflo super-cel NF
(Celite; 5.4 kg), and the filter bed was washed with DCM (118.9
kg). The combined organic phase was washed with brine (282.9 kg)
and mixed with water (120 L). The phases were separated and the
organic phase was concentrated by vacuum distillation with the
removal of solvent (approximately 95 L residual volume). DCM (686.5
kg) was charged to the reactor containing organic phase and
concentrated by vacuum distillation with the removal of solvent
(approximately 90 L residual volume). Methyl t-butyl ether (MTBE,
226.0 kg) was then charged and the temperature of the mixture was
adjusted to -20 to 25.degree. C. and held for 2.5 hours. This
resulted in solid precipitate, which was then filtered, washed with
n-heptane (92.0 kg), and dried on a filter at approximately
25.degree. C. under nitrogen to afford the title compound. (35.6
kg).
Preparation of
4-(6,7-Dimethoxy-1-quinoline-4-yloxy)-phenylamine
[0120] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide
(DMA, 184.3 kg) was charged to a reactor containing
4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide, (21.4
kg) and DMA (167.2 kg) at 20 to 25.degree. C. This mixture was then
heated to 100 to 105.degree. C. for approximately 13 hours. After
the reaction was deemed complete as determined using in-process
HPLC analysis (less than 2 percent starting material remaining),
the reactor contents were cooled at 15 to 20.degree. C. and water
(pre-cooled, 2 to 7.degree. C., 587 L) charged at a rate to
maintain 15 to 30.degree. C. temperature. The resulting solid
precipitate was filtered, washed with a mixture of water (47 L) and
DMA (89.1 kg) and finally with water (214 L). The filter cake was
then dried at approximately 25.degree. C. on filter to yield crude
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6
kg dry calculated based on LOD). Crude
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed
(approximately 75.degree. C.) in a mixture of tetrahydrofuran (THF,
211.4 kg) and DMA (108.8 kg) for approximately 1 hour and then
cooled to 0 to 5.degree. C. and aged for approximately 1 hour after
which time the solid was filtered, washed with THF (147.6 kg), and
dried on a filter under vacuum at approximately 25.degree. C. to
yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0
kg).
Alternative Preparation of
4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0121] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-Aminophenol
(30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35
wt percent in THF) were charged to a reactor, followed by
N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated
to 105 to 115.degree. C. for approximately 9 hours. After the
reaction was deemed complete as determined using in-process HPLC
analysis (less than 2 percent starting material remaining), the
reactor contents were cooled at 15 to 25.degree. C., and water (315
kg) was added over a two hour period while maintaining the
temperature between 20 and 30.degree. C. The reaction mixture was
then agitated for an additional hour at 20 to 25.degree. C. The
crude product was collected by filtration and washed with a mixture
of water (88 kg) and DMA (82.1 kg), followed by water (175 kg). The
product was dried on a filter drier for 53 hours. The LOD showed
less than 1 percent weight/weight (w/w).
[0122] In an alternative procedure, 1.6 equivalents of sodium
tert-pentoxide were used, and the reaction temperature was
increased from 110 to 120.degree. C. In addition, the cool down
temperature was increased to 35 to 40.degree. C., and the starting
temperature of the water addition was adjusted to 35 to 40.degree.
C., with an allowed exotherm to 45.degree. C.
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic
acid
[0123] Triethylamine (19.5 kg) was added to a cooled (approximately
5.degree. C.) solution of cyclopropane-1,1-dicarboxylic acid (24.7
kg) in THF (89.6 kg) at a rate such that the batch temperature did
not exceed 5.degree. C. The solution was stirred for approximately
1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping
the batch temperature below 10.degree. C. When the addition was
complete, the solution was stirred for approximately 4 hours
keeping the temperature below 10.degree. C. A solution of
4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate
such that the batch temperature did not exceed 10.degree. C. The
mixture was stirred for approximately 10 hours, after which the
reaction was deemed complete. The reaction mixture was then diluted
with isopropyl acetate (218.1 kg). This solution was washed
sequentially with aqueous sodium hydroxide (10.4 kg, 50% dissolved
in 119 L of water), further diluted with water (415 L), then with
water (100 L), and finally with aqueous sodium chloride (20.0 kg
dissolved in 100 L of water). The organic solution was concentrated
by vacuum distillation (100 L residual volume) below 40.degree. C.,
followed by the addition of n-heptane (171.4 kg), which resulted in
the precipitation of solid. The solid was recovered by filtration
and washed with n-Heptane (102.4 kg), resulting in wet crude,
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg).
The crude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
was dissolved in methanol (139.7 kg) at approximately 25.degree.
C., followed by the addition of water (320 L), resulting in slurry
which was recovered by filtration, washed sequentially with water
(20 L) and n-heptane (103.1 kg), and then dried on the filter at
approximately 25.degree. C. under nitrogen to afford the title
compound (25.4 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
[0124] Oxalyl chloride (12.6 kg) was added to a solution of
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg)
in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23
kg) at a rate such that the batch temperature did not exceed
25.degree. C. This solution was used in the next step without
further processing.
Alternative Preparation of
1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
[0125] A reactor was charged with
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg),
DMF (344 g), and THF (175 kg). The reaction mixture was adjusted to
12 to 17.degree. C., and then to the reaction mixture was charged
19.9 kg of oxalyl chloride over a period of 1 hour. The reaction
mixture was left stirring at 12 to 17.degree. C. for 3 to 8 hours.
This solution was used in the next step without further
processing.
Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide
[0126] The solution from the previous step containing
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was
added to a mixture of compound
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and
potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L)
at a rate such that the batch temperature did not exceed 30.degree.
C. When the reaction was complete (in approximately 20 minutes),
water (653 L) was added. The mixture was stirred at 20 to
25.degree. C. for approximately 10 hours, which resulted in the
precipitation of the product. The product was recovered by
filtration, washed with a pre-made solution of THF (68.6 kg) and
water (256 L), and dried first on a filter under nitrogen at
approximately 25.degree. C. and then dried at approximately
45.degree. C. under vacuum to afford the title compound (41.0 kg,
38.1 kg, calculated based on LOD).
Alternative Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinolone-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide
[0127] A reactor was charged with
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1
equivalent), followed by THF (412.9 kg). To the reaction mixture
was charged a solution of K.sub.2CO.sub.3 (48.3 g) in water (169
kg). The acid chloride solution described in the Alternative
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride above was transferred to the reactor containing
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine while maintaining
the temperature between 20 to 30.degree. C. over a minimum of two
hours. The reaction mixture was stirred at 20 to 25.degree. C. for
a minimum of three hours. The reaction temperature was then
adjusted to 30 to 25.degree. C., and the mixture was agitated. The
agitation was stopped and the phases of the mixture were allowed to
separate. The lower aqueous phase was removed and discarded. Water
(804 kg) was added to the remaining upper organic phase. The
reaction was left stirring at 15 to 25.degree. C. for a minimum of
16 hours.
[0128] The product precipitated. The product was filtered and
washed with a mixture of water (179 kg) and THF (157.9 kg) in two
portions. The crude product was dried under a vacuum for at least
two hours. The dried product was then taken up in THF (285.1 kg).
The resulting suspension was transferred to reaction vessel and
agitated until the suspension became a clear (dissolved) solution,
which required heating to 30 to 35.degree. C. for approximately 30
minutes. Water (456 kg) was then added to the solution, as well as
SDAG-1 (20 kg) ethanol (ethanol denatured with methanol over two
hours). The mixture was agitated at 15-25.degree. C. for at least
16 hours. The product was filtered and washed with a mixture of
water (143 kg) and THF (126.7 kg) in two portions. The product was
dried at a maximum temperature set point of 40.degree. C.
[0129] In an alternative procedure, the reaction temperature during
acid chloride formation was adjusted to 10 to 15.degree. C. The
recrystallization temperature was changed from 15 to 25.degree. C.
to 45 to 50.degree. C. for 1 hour and then cooled to 15 to
25.degree. C. over 2 hours.
Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide, (L) malate salt
[0130] Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl
ethyl ketone (MEK; 188.6 kg), and water (37.3 kg) were charged to a
reactor, and the mixture was heated to reflux (approximately
74.degree. C.) for approximately 2 hours. The reactor temperature
was reduced to 50 to 55.degree. C., and the reactor contents were
filtered. These sequential steps described above were repeated two
more times starting with similar amounts of
cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide (13.3 kg), L-Malic acid (4.96 kg), MEK
(198.6 kg), and water (37.2 kg). The combined filtrate was
azeotropically dried at atmospheric pressure using MEK (1133.2 kg)
(approximate residual volume 711 L; KF.ltoreq.0.5 w/w) at
approximately 74.degree. C. The temperature of the reactor contents
was reduced to 20 to 25.degree. C. and held for approximately 4
hours, resulting in solid precipitate which was filtered, washed
with MEK (448 kg), and dried under vacuum at 50.degree. C. to
afford the title compound (45.5 kg).
Alternative Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide, (L) malate salt
[0131] Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg
methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a
reactor, and the mixture was heated 50 to 55.degree. C. for
approximately 1 to 3 hours, and then at 55 to 60.degree. C. for an
additional 4 to 5 hours. The mixture was clarified by filtration
through a 1 .mu.m cartridge. The reactor temperature was adjusted
to 20 to 25.degree. C. and vacuum distilled with a vacuum at
150-200 mm Hg with a maximum jacket temperature of 55.degree. C. to
the volume range of 558-731 L.
[0132] The vacuum distillation was performed two more times with
the charge of 380 kg and 380.2 kg methyl ethyl ketone,
respectively. After the third distillation, the volume of the batch
was adjusted to 18 volume/weight (v/w) of
cyclopropane-,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide by charging methyl ethyl ketone (159.9 kg)
to give a total volume of 880 L. An additional vacuum distillation
was carried out by adjusting methyl ethyl ketone (245.7 kg). The
reaction mixture was left with moderate agitation at 20 to
25.degree. C. for at least 24 hours. The product was filtered and
washed with methyl ethyl ketone (415.1 kg) in three portions. The
product was dried under a vacuum with the jacket temperature set
point at 45.degree. C.
[0133] In an alternative procedure, the order of addition was
changes so that a solution of L-malic acid (17.7 kg) dissolved in
water (129.9 kg) was added to cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide
(4-fluoro-phenyl)-amide (48.7 kg) in methyl ethyl ketone (673.3
kg).
Use of a Compound of Formula I to Treat Cancer
[0134] The MET and VEGF signaling pathways appear to play important
roles in osteoblast and osteoclast function. Strong
immunohistochemical staining of MET has been observed in both cell
types in developing bone. HGF and MET are expressed by osteoblasts
and osteoclasts in vitro and mediate cellular responses such as
proliferation, migration, and expression of ALP. Secretion of HGF
by osteoblasts has been proposed as a key factor in
osteoblast/osteoclast coupling, and in the development of bone
metastases by tumor cells that express MET. Osteoblasts and
osteoclasts also express VEGF and its receptors, and VEGF signaling
in these cells is involved in potential autocrine and/or paracrine
feedback mechanisms regulating cell migration, differentiation, and
survival.
[0135] Compound 1 is an orally bioavailable multitargeted tyrosine
kinase inhibitor with potent activity against MET and VEGFR2.
Compound 1 suppresses MET and VEGFR2 signaling, rapidly induces
apoptosis of endothelial cells and tumor cells, and causes tumor
regression in xenograft tumor models. Compound 1 also significantly
reduces tumor invasiveness and metastasis and substantially
improves overall survival in a murine pancreatic neuroendocrine
tumor model. In a phase 1 clinical study, Compound 1 was generally
well-tolerated, with fatigue, diarrhea, anorexia, rash, and
palmar-plantar erythrodysesthesia being the most commonly observed
adverse events.
Case Study 1
[0136] Compound 1 is an orally bioavailable multitargeted tyrosine
kinase inhibitor with potent activity against MET and VEGFR2.
Compound 1 suppresses MET and VEGFR2 signaling, rapidly induces
apoptosis of endothelial cells and tumor cells, and causes tumor
regression in xenograft tumor models. Compound 1 also significantly
reduces tumor invasiveness and metastasis and substantially
improves overall survival in a murine pancreatic neuroendocrine
tumor model. In a phase 1 clinical study, Compound 1 was generally
well-tolerated, with fatigue, diarrhea, anorexia, rash, and
palmar-plantar erythrodysesthesia being the most commonly observed
adverse events.
[0137] Based on target rationale and observed antitumor activity in
clinical studies, an adaptive phase 2 trial was undertaken in
multiple indications including CRPC
(http://clinicaltrials.gov/ct2/results?term=NCT00940225 for Study
NCT00940225 last visited Sep. 20, 2011)), in which Compound 1 was
administered as a 100 mg dose to patients. The findings in the
first three CRPC patients with evidence of bone metastases on bone
scan enrolled to this study are described in the following Case
Studies.
[0138] Baseline characteristics for patients 1-3 are summarized in
Table 1.
TABLE-US-00005 TABLE 1 Summary of Baseline Characteristics and
Preliminary Best Responses for CRPC Patients Treated with Compound
1. Patient 1 Patient 2 Patient 3 Baseline Characteristics Age
(years) 77 73 66 Diagnosis 1993 2009 2009 ECOG 1 0 1 performance
status Disease location(s) Lung, LN, bone Liver, LN, bone LN, bone
Prior cancer Radical Radiation to CAB, therapies prostatectomy,
pubic ramus and docetaxel radiation to acetabulum, prostate bed,
CAB CAB, DES, docetaxel Bisphophonates No No Yes Narcotics Yes No
No Pain Yes Yes Yes PSA (ng/mL) 430.4 14.7 2.8 tALP (U/L) 689 108
869 Hemoglobin (g/dL) 13.5 13.3 10.2 Summary of Best Responses
Tumor response -41% -20% -51% Bone scan Complete Improvement Near
resolution resolution Pain Improvement Pain-free Pain-free PSA -78%
+61% -57% tALP -77% -6% -77% Hemoglobin (g/dL) +1.4 +1.8 +2.2 ADT,
androgen-deprivation therapy; CAB, combined androgen blockade
(leuprolide + bicalutamide); DES, diethylstilbestrol; LN, lymph
node; PSA, prostate-specific antigen; tALP, total alkaline
phosphatase.
[0139] Patient 1 was diagnosed with localized prostate cancer in
1993 and treated with radical prostatectomy (Gleason score
unavailable; PSA, 0.99 ng/mL). In 2000, local disease recurrence
was treated with radiation therapy. In 2001, combined androgen
blockade (CAB) with leuprolide and bicalutamide was initiated for
rising PSA (3.5 ng/mL). In 2006, diethystillbestrol (DES) was
administered briefly. In 2007, 6 cycles of docetaxel were given for
new lung metastases. Rising PSA was unresponsive to antiandrogen
withdrawal. Androgen ablation therapy was continued until clinical
progression. In October 2009, bone metastasis to the spine
associated with impingement on the spinal cord and back pain, was
treated with radiation therapy (37.5 Gy). In February 2010, a bone
scan was performed due to increasing bone pain and showed diffuse
uptake of radiotracer in the axial and appendicular skeleton. A CT
scan revealed new pulmonary and mediastinal lymph node metastases.
PSA was 430.4 ng/mL.
[0140] Patient 2 was diagnosed in April of 2009 after presenting
with a pathologic fracture (Gleason score, 4+5=9; PSA, 45.34
ng/mL). Bone scan showed uptake of radiotracer in the left iliac
wing, left sacroiliac joint, femoral head, and the pubic symphysis.
Biopsy of the left pubic ramus confirmed metastatic adenocarcinoma
with mixed lytic and blastic lesions. CAB with leuprolide and
bicalutamide and radiation therapy (8 Gy) to the left pubic ramus
and acetabulum resulted in bone pain relief and PSA normalization.
Rising PSA in November 2009 (16 ng/mL) was unresponsive to
antiandrogen withdrawal. In February 2010, bone scan showed
multiple foci throughout the axial and appendicular skeleton. A CT
scan revealed retroperitoneal lymph node enlargement and liver
metastases (PSA, 28.1 ng/mL). Further progression of disease was
marked by recurrent bone pain, new lung and hepatic metastases.
[0141] Patient 3 was diagnosed in April 2009 after presenting with
right hip pain (Gleason score, 4+5=9; PSA, 2.6 ng/mL). Bone scan
showed uptake of radiotracer at multiple sites throughout the axial
and appendicular skeleton. A CT scan revealed retroperitoneal,
common iliac, and supraclavicular adenopathy. CAB with leuprolide
and bicalutamide was initiated. The patient received 6 cycles of
docetaxel through December 2009. Following treatment, a bone scan
showed no changes. A CT scan revealed near resolution of the
retroperitoneal and common iliac adenopathy. In March 2010, PSA
began to rise, and bone pain worsened. A repeat bone scan showed
new foci, and a CT scan showed an increase in the retroperitoneal,
para-aortic, and bilateral common iliac adenopathy. Rising PSA in
April 2010 (2.8 ng/mL) and increasing bone pain were unresponsive
to antiandrogen withdrawal.
Results
[0142] All patients provided informed consent before study
screening.
[0143] Patient 1 started Compound 1 on Feb. 12, 2010. Four weeks
later, significant reduction in bone pain was reported. At Week 6,
bone scan showed a dramatic decrease in radiotracer uptake by bone
metastases (FIG. 1A). A CT scan showed a partial response (PR) with
a 33% decrease in measurable target lesions (FIG. 1C). At Week 12,
near complete resolution of bone lesions and a 44% decrease in
target lesions was observed and was stable through Week 18.
Corresponding with the bone scan response, after an initial rise,
serum tALP levels decreased from 689 U/L at baseline to 159 U/L at
Week 18 (FIG. 1B and Table 1). In addition, there was an increase
in hemoglobin of 1.4 g/dL at Week 2 compared with baseline (Table
1). PSA decreased from 430 ng/mL at baseline to 93.5 ng/mL at Week
18 (FIG. 1B and Table 1). The patient was on open-label treatment
through Week 18 when he withdrew after developing Grade 3
diarrhea.
[0144] Patient 2 started Compound 1 on Mar. 31, 2010. At Week 4,
reduction in bone pain was reported. At Week 6, bone scan showed a
slight flair in radiotracer uptake by bone lesions (FIG. 2A), and a
CT scan showed a 13% decrease in target lesions (FIG. 2C). At Week
12, a substantial reduction of radiotracer uptake (FIG. 2A) and a
20% decrease in measurable disease were observed (Table 1). After
randomization to placebo at Week 12 the patient developed severe
bone pain and sacral nerve root impingement. Radiation to the spine
was administered, and the patient crossed over to open-label
Compound 1 treatment at Week 15. Serum tALP levels were within the
normal range (101-144 U/L) (FIG. 2B). Hemoglobin increased by 1.8
g/dL at Week 12 compared with baseline (Table 1). PSA peaked at
close to 6-fold of baseline by Week 16, but then decreased to
2-fold of baseline by Week 18 subsequent to crossing over to
Compound 1 from placebo (FIG. 2B and Table 1). The patient
continues on Compound 1 treatment as of September 2010.
[0145] Patient 3 started Compound 1 on Apr. 26, 2010. After three
weeks a complete resolution of pain was reported. At Week 6, bone
scan showed a dramatic reduction in radiotracer uptake (FIG. 3A),
and a CT scan showed a PR with a 43% decrease in measurable target
lesions. At Week 12 a complete resolution of bone lesions on bone
scan (FIG. 3A) and a 51% decrease in measurable disease were
observed (Table 1 and FIG. 3B)). After an initial rise, serum tALP
levels steadily decreased, with tALP at 869 U/L at baseline and 197
U/L at Week 18 (FIG. 3B and Table 1). Hemoglobin increased 2.2 g/dL
at Week 2 compared with baseline (Table 1). PSA decreased from 2.4
ng/mL at screening to 1.2 ng/mL at Week 18 (FIG. 3B and Table 1).
The patient continues on Compound 1 treatment as of September
2010.
Discussion
[0146] All three patients experienced a striking decrease in uptake
of radiotracer on bone scan upon treatment with Compound 1. These
findings were accompanied by substantial reductions in bone pain
and evidence of response or stabilization in soft tissue lesions
during therapy with Compound 1. The onset of the effect was very
rapid in two of the patients, with substantial improvement or near
resolution of bone scan and improvement in pain occurring in the
first 6 weeks. In the third patient, an apparent flare in the bone
scan was observed at 6 weeks, followed by improvement by 12 weeks.
To our knowledge, such a comprehensive and rapid impact on both
osseous and soft tissue disease has not been observed in this
patient population.
[0147] Uptake of radiotracer in bone depends on both local blood
flow and osteoblastic activity, both of which may be pathologically
modulated by the tumor cells associated with the bone lesion.
Resolving uptake may therefore be attributable to either
interruption of local blood flow, direct modulation of osteoblastic
activity, a direct effect on the tumor cells in bone, or a
combination of these processes. However, decreased uptake on bone
scan in men with CRPC has only been rarely noted with VEGF/VEGFR
targeted therapy, despite numerous trials with such agents.
Similarly, observations of decreased uptake on bone scan in CRPC
patients have only been reported rarely for abiraterone, which
targets the cancer cells directly, and for dasatinib, which targets
both cancer cells and osteoclasts. Thus, targeting angiogenesis
alone, or selectively targeting the tumor cells and/or osteoclasts,
has not resulted in effects similar to those observed in the
patients treated with Compound 1.
[0148] These results indicate a potential critical role for the MET
and VEGF signaling pathways in the progression of CRPC and point to
the promise that simultaneously targeting these pathways may hold
in reducing morbidity and mortality in this patient population.
Case Study 2
[0149] In a phase 2 adaptive randomized discontinuation trial
(RDT), Compound 1 resulted in resolution or stabilization of
metastatic bone lesions on bone scan in 82 of 108 (76 percent)
patients evaluable by this method. The majority of patients treated
with Compound 1 reported reduced bone pain and reduced reliance
upon narcotic pain medication. A total of 83 patients had bone
metastases and bone pain reported at baseline, and at least one
post-baseline assessment of pain status. Of these patients, 56
(68%) had pain improvement at either Week 6 or 12. Narcotic
analgesic medication was required at baseline for control of bone
pain in 67 patients assessable for post-baseline review of narcotic
consumption. Of these 67 patients, 47 (70%) were able to decrease
or discontinue narcotic medication for bone pain. Data on bone pain
and narcotic use, as assessed by the investigator, were collected
retrospectively. These results suggest that Compound 1 can be used
to treat and ameliorate bone and/or ameliorate bone metastases and
pain due to other forms of cancer.
[0150] Patients with partial or complete resolution of metastatic
bone lesions by bone scan were more likely to remain free of
disease progression at month 6, experience pain relief, reduce or
eliminate their use of narcotic analgesics, achieve tumor
regression, and experience marked declines in markers of bone
turnover when compared to those who did not achieve bone scan
resolution.
[0151] Updated progression-free survival (PFS) data show that
Compound 1 results in median PFS that appear to be similar in
docetaxel-naive and pretreated patients, and compare favorably to
population matched historical controls. In the randomized
discontinuation phase of this study, significant improvement in
median PFS was observed in patients randomized to Compound 1.
Despite only 31 patients randomized at week 12, the results were
highly statistically significant, suggestive of a sizable treatment
effect over placebo. Durable increases in hemoglobin levels in
anemic patients were also observed.
[0152] In the randomized discontinuation phase, a total of 31
patients with SD at week 12 were randomized to either placebo or
Compound 1. From week 12 onward, the investigator-assessed median
PFS is 6 weeks (95% Confidence Interval [CI]: 5, 12 weeks) for the
placebo group (n=17), and 21 weeks (95% CI: 11 weeks, upper limit
not yet reached) for the Compound 1 group (n=14). The hazard ratio
(HR) of 0.13 (95% CI 0.03, 0.50) strongly favored the Compound 1
arm and corresponded to an 87% reduction in the risk of progression
for patients treated with Compound 1 compared with placebo. These
results were statistically significant (p=0.0007).
[0153] Excluding those randomized to placebo, the median PFS was 29
weeks for the overall population (n=154). Median PFS in the subsets
of docetaxel-naive and -pretreated patients were 24 weeks (95% CI
24, upper limit not yet reached) and 29 weeks (95% CI 18, 33),
respectively. These data indicate that Compound 1 treatment results
in durable disease control in both docetaxel-naive and pretreated
populations.
[0154] Effects on bone scan were further assessed by an independent
reviewer in a larger subset (n=108) of patients with bone
metastases. Partial or complete resolution of bone scan was
observed in 82 (76%) subjects. Twenty-three patients (21%) had
stable disease (SD) on bone scan, and only three patients (3%) had
progressive disease in bone as their best assessment.
[0155] Based on a post hoc analysis, patients with bone scan
resolution (either complete or partial) were more likely to be free
of disease progression at month 6 (61% vs. 35%), experience pain
relief (83% vs. 43%), reduce or eliminate their need for narcotic
analgesics (68% vs. 33%), achieve tumor regression (78% vs. 58%),
and experience marked declines in markers of bone turnover (60% vs.
43%), as compared to those who did not achieve bone scan resolution
(stable or progressing bone scan).
[0156] Of 55 patients who had baseline bone pain, 42 had complete
(n=10) or partial (n=32) resolution and 13 had stabilization of
disease by bone scan evaluation. Of these patients, 80%, 84%, and
38%, respectively, reported improvements in bone pain. These
findings are the first to show an association between changes in
bone scan imaging and improvement in clinical symptoms of
disease.
[0157] Compound 1, an inhibitor of tumor growth, metastasis and
angiogenesis, simultaneously targets MET and VEGFR2, key kinases
involved in the development and progression of many cancers.
Prominent expression of MET has been observed in primary and
metastatic prostate carcinomas, with evidence for higher levels of
expression in bone metastases. Overexpression of hepatocyte growth
factor (HGF), the ligand for MET, has also been observed in
prostate carcinoma, and increased plasma levels of HGF are
associated with decreased overall survival in CRPC. Data from
preclinical studies also suggest that both HGF and MET are
regulated by the androgen signaling pathway in prostate cancer,
where upregulation of MET signaling is associated with the
transition to androgen-independent tumor growth. Additionally, both
the MET and VEGFR signaling pathways also appear to play important
roles in the function of osteoblasts and osteoclasts--cells in the
bone microenvironment that are often dysregulated during the
establishment and progression of bone metastases.
[0158] The primary cause of morbidity and mortality in patients
with CRPC is metastasis to the bone, which occurs in about 90% of
cases. Bone metastases cause local disruption of normal bone
remodeling, with lesions generally showing a propensity for an
osteoblastic (bone-forming) phenotype on imaging. These lesions
often lead to increased skeletal fractures, spinal cord
compression, and severe bone pain. Osteoblastic lesions are
typically visualized in CRPC patients by bone scan, which detects
rapid incorporation of 99 mTc-labeled methylene-diphosphonate
radiotracer into newly forming bone. In addition, increased blood
levels of ALP and CTx, markers for osteoblast and osteoclast
activity, respectively, are often observed in CRPC patients with
bone metastases, and are associated with shorter overall
survival.
Case Study 4: Renal Cell Carcinoma with Bone Metastases
[0159] In a Phase I trial of patients with renal cell carcinoma
with bone metastases, tumor shrinkage was observed in a patient
based bone scan analysis (FIG. 4). This patient showing resolution
of bone lesions on bone scan also substantially reduced narcotic
use by seven weeks to control pain and continued on reduced
narcotic use until week 25. A second patient with renal cell
carcinoma with bone metastases and pain at baseline (pain score 5
on a scale of 10) reported complete resolution of pain by four
weeks and remained pain-free as of week 73 of the study.
Case Study 5: Melanoma with Bone Metastases
[0160] In a randomized discontinuation study of 65 patients with
melanoma with bone metastases, tumor shrinkage was observed in 39
of 65 patients (60 percent) based bone scan analysis (FIG. 5).
Case Study 6: Breast Cancer with Bone Metastases
[0161] In a randomized discontinuation study of 44 patients with
breast cancer, 10 were found to be evaluable for bone scan
resolution. Tumor shrinkage was observed in 4 (forty percent)
patients based bone scan analysis.
Case Study 7: Differentiated Thyroid Cancer with Bone
Metastasis.
[0162] In a Phase 1 drug-drug trial, 15 patients with
differentiated thyroid cancer were enrolled, one of whom had a bone
metastasis to the skull. This lesion showed a dramatic response
after 9 weeks of cabozantinib treatment as judged by MRI (FIG.
6).
[0163] Study 8: Effect of Compound 1 Administration on CT.sup.x
Plasma Concentration
[0164] The effects of Compound 1 treatment on osteoclast activity
was also investigated based on the measurement of changes in plasma
concentration of Cross-linked C-terminal telopeptides of type-1
collagen (CT.sup.x) concentration in bisphosphonate treated and
bisphosphonate naive patients with ovarian cancer that exhibited
bone metastases (N=27). CT.sup.x levels dropped in the majority of
patients relative to baseline based on plasma samples analyzed by
ELISA at weeks 6 and 12 of the study. The results indicate the
ability of Compound 1 to inhibit bone resorption.
Other Embodiments
[0165] 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.
[0166] 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.
* * * * *
References