NZ716805B2 - Method of treating cancer and bone cancer pain - Google Patents
Method of treating cancer and bone cancer pain Download PDFInfo
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- NZ716805B2 NZ716805B2 NZ716805A NZ71680512A NZ716805B2 NZ 716805 B2 NZ716805 B2 NZ 716805B2 NZ 716805 A NZ716805 A NZ 716805A NZ 71680512 A NZ71680512 A NZ 71680512A NZ 716805 B2 NZ716805 B2 NZ 716805B2
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- compound
- bone
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Abstract
Provided is the use of quinolone derivative compounds of general formula I, where the variables are as defined in the specification, for the treatment of cancer. A preferred compound for use is N-(4-{[6,7-bis(methyloxy)quinolin-4-yl}oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. A preferred cancer to be treated is renal cell carcinoma metastasised to bone. eferred cancer to be treated is renal cell carcinoma metastasised to bone.
Description
Method of Treating Cancer and Bone Cancer Pain
Cross-Reference to Related Applications
This application is a divisional application of New Zealand patent application
617508, which is the national phase entry in New Zealand of PCT international application
(published as ), and 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 November 8, 2011, all of which are incorporated herein by
reference.
Field of the Invention
Described is 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
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.
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.
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.
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.
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.
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.
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.
[0009a] An object of the present invention is to meet at least one of these needs through
use of a compound defined herein in the preparation of a medicament for extending the
overall survival of patients with renal cell carcinoma metastasized to bone; and/or to at least
provide the public with a useful choice.
[0009b] In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
[0009c] In the description in this specification reference may be made to subject matter
that is not within the scope of the claims of the current application. That subject matter
should be readily identifiable by a person skilled in the art and may assist in putting into
practice the invention as defined in the claims of this application.
Summary of the Invention
[0009d] The present invention relates to the use of Compound 1
CH O
H C O N
Compound 1
or the malate salt thereof, in the preparation of a medicament containing 60, 40 or 20 mg of
Compound 1 for extending the overall survival of patients with renal cell carcinoma
metastasized to bone, wherein the treatment comprises once daily administration of the
medicament.
Brief Description of the Invention
Described is 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.
Also described is 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.
In one embodiment described, the dual acting MET/VEGF inhibitor is a
compound of Formula I:
0- 5
0- 4
R O N
or a pharmaceutically acceptable salt thereof, wherein:
R is halo;
R is halo;
R is (C -C )alkyl;
R is (C -C )alkyl; and
Q is CH or N.
In another embodiment, the compound of Formula I is compound 1:
CH F
H C O N
Compound 1
or a pharmaceutically acceptable salt thereof. Compound 1 is known as N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide.
Also described is 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.
Also described is 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.
Also described is 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.
Also described is 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.
Also described is 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.
Also described is 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.
Also described is 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.
Also described is 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. The bone cancer pain can originate from bone
cancer, osteosarcoma, as well as from cancer metastasized to bone. Thus, 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.
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.
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
Figures 1A-C show the bone scan (Figure 1A), bone scan response (Figure 1B),
and CT scan data (Figure 1C) for Patient 1 having CRPC.
Figures 2A-C show the bone scan (Figure 2A), bone scan response (Figure 2B),
and CT scan data (Figure 2C) for Patient 2 having CRPC.
Figures 3A-B show the bone scan (Figure 3A), bone scan response (Figure 3B) for
Patient 3 having CRPC.
Figure 4A and B shows the bone scan (Figure 4A), bone scan response (Figure
4B) for a Patient having renal cell carcinoma with bone metastases.
Figure 5A and 5B shows the bone scan (Figure 5A), bone scan response (Figure
5B) for a Patient having melanoma with bone metastases.
Figure 6 shows a CT scan of a bone metastasis from a patient with differentiated
thyroid cancer before (Figure 6A) and after (Figure 6B) treatment.
Detailed Description of the Invention
Abbreviations and Definitions
The following abbreviations and terms have the indicated meanings throughout:
Abbreviation Meaning
Ac Acetyl
bALP Bone-specific alkaline phosphatase
Br Broad
Abbreviation Meaning
°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)
µL Microliter(s)
µM Micromole(s) or micromolar
mM Millimolar
Mmol Millimole(s)
Mol Mole(s)
MS Mass spectral analysis
Abbreviation Meaning
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
The symbol “-” means a single bond, “=” means a double bond.
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 CH -. 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.
H H H
Br Br
If a group “R” is depicted as “floating” on a ring system, as for example in the
formula:
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.
If a group “R” is depicted as floating on a fused ring system, as for example in the
formulae:
, or , or
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 =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:
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:
“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.
“Yield” for each of the reactions described herein is expressed as a percentage of
the theoretical yield.
“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.
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 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.
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-hydroxyenecarboxylic 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.
“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 useful in 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.
“Therapeutically effective amount” is an amount of a compound useful in 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 useful in 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.
“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.
[0042a] The term “comprising” as used in this specification and claims means “consisting
at least in part of”. When interpreting statements in this specification, and claims which
include the term “comprising”, it is to be understood that other features that are additional to
the features prefaced by this term in each statement or claim may also be present. Related
terms such as “comprise” and “comprised” are to be interpreted in similar manner.
Embodiments
In one embodiment the compound of Formula I is the compound of Formula Ia:
Formula Ia
or a pharmaceutically acceptable salt thereof, wherein:
R is halo;
R is halo; and
Q is CH or N.
In another embodiment, the compound of Formula I is Compound 1:
H C O N
Compound 1
or a pharmaceutically acceptable salt thereof. As indicated previously, compound 1 is
referred to herein as N-(4-{[6,7-bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide. 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.
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.
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.
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 and 61/325095.
In other embodiments, the compound of Formula I, Ia, or 1 can be the (D)-malate
salt.
In other embodiments, the compound of Formula I, Ia, or 1 can be malate salt.
In other embodiments, the compound of Formula I, Ia, or 1 can be the (L)-malate
salt.
In other embodiments, Compound 1 can be (D)-malate salt.
In other embodiments, Compound 1 can be the (L)-malate salt.
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
United States patent Application Ser. No. 61/325095. Also see 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.
Also described is 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.
Also described is 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.
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.
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.
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.
In another embodiment, Compound 1 is administered orally as its free base or
malate salt as a capsule or tablet.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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
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.
Ingredient Theoretical
Quantity (mg/unit
dose)
Compound 1 100.0
Microcrystalline Cellulose PH- 155.4
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
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
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.
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.
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.
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, butylalted hydroxytoluene, etc.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide and the (L)-malate salt thereof.
The synthetic route used for the preparation of N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 1.
Scheme 1
POCl3/CH3CN
2,6-Lutidine
Pd/C
HCO H, HCO K
K CO ,H O, THF
2 3 2 F
EtOH
(L)-Malic acid
Acetone
O N O O THF
Cl N
Oxalyl chloride
1) SO Cl ,Et N
2 2 3
F O O
O O THF
.C H O
HO OH
4 6 5
HO N
Compound (I)
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
A reactor was charged sequentially with 6,7-dimethoxy-quinolineol (10.0 kg)
and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 °C and
phosphorus oxychloride (POCl , 50.0 kg) was added. After the addition of POCl , the
temperature of the reaction mixture was raised to approximately 80°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 °C and then quenched into a chilled solution
of dichloromethane (DCM, 238.0 kg), 30 percent NH OH (135.0 kg), and ice (440.0 kg).
The resulting mixture was warmed to approximately 14 °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 °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 °C to afford the title compound (8.0 kg).
Preparation of 6,7-Dimethyl(4-nitro-phenoxy)-quinoline
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 °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 °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 °C for approximately 12
hours to afford the title compound (4.0 kg).
Preparation of 4-(6,7-Dimethoxy-quinolineyloxy)-phenylamine
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-nitro-phenoxy)-quinoline (4.0 kg),
% palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had
been heated to approximately 60 °C. The addition was carried out such that the temperature
of the reaction mixture remained approximately 60 °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 °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 °C to afford the
title compound (3.0 kg; 97 percent AUC).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
Triethylamine (8.0 kg) was added to a cooled (approximately 4°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 °C. The solution was stirred for
approximately 30 minutes, and then thionyl chloride (9.0 kg) was added, keeping the batch
temperature below 10 °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
°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 °C under vacuum to
afford the title compound (10.0 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
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
°C. This solution was used in the next step without further processing.
Preparation of N-(4-{[6,7-bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide
The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-
cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline
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 °C. When the reaction
was complete (approximately 10 minutes), water (74.0 kg) was added. The mixture was
stirred at 15 to 30 °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 °C under vacuum for
approximately 12 hours to afford the title compound (free base, 5.0 kg). H NMR (400 MHz,
d -DMSO): δ 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)quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (L) malate salt
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-quinolineyloxy)-phenyl]-amide (4-
fluoro-phenyl)-amide free base (1 5, 5.0 kg) in ethanol, maintaining a batch temperature of
approximately 25 °C. Carbon (0.5 kg) and thiol silica (0.1 kg) were then added, and the
resulting mixture was heated to approximately 78 °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 °C. The product was
recovered by filtration and washed with isopropanol (20.0 kg) and dried at approximately 65
°C to afford the title compound (5.0 kg).
An alternative route that for the preparation of Compound 1 is depicted in Scheme
Scheme 2
Preparation of 4–Chloro–6,7–dimethoxy–quinoline
A reactor was charged sequentially with 6,7-dimethoxy-quinolineol (47.0 kg)
and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and
phosphorus oxychloride (POCl , 130.6 kg) was added. After the addition of POCl , the
temperature of the reaction mixture was raised to approximately 77 °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 °C and then quenched into a chilled
solution of dichloromethane (DCM, 482.8 kg), 26 percent NH OH (251.3 kg), and water (900
L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were
separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite;
.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 ºC 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 °C under nitrogen to afford the title compound.
(35.6 kg).
Preparation of 4–(6, 7 –Dimethoxy–quinoline–4–yloxy)–phenylamine
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 ºC. This mixture was then heated to 100
to 105 ºC 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 ºC and water (pre-cooled, 2 to 7 ºC, 587 L) charged at a rate
to maintain 15 to 30 ºC 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 ºC on filter to yield crude 4-(6,7-dimethoxy-quinoline
yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-
dimethoxy-quinolineyloxy)-phenylamine was refluxed (approximately 75 ºC) 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 ºC 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 ºC to
yield 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine (34.0 kg).
Alternative Preparation of 4-(6,7-Dimethoxy-quinolineyloxy)-phenylamine
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 ºC 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 ºC, and water (315 kg) was added
over a two hour period while maintaining the temperature between 20 and 30 ºC. The
reaction mixture was then agitated for an additional hour at 20 to 25 ºC. The crude product
was collected by filtration and washed with a mixture of water (88kg) 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).
In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used,
and the reaction temperature was increased from 110 to 120 °C. In addition , the cool down
temperature was increased to 35 to 40 °C, and the starting temperature of the water addition
was adjusted to 35 to 40 °C, with an allowed exotherm to 45 °C.
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
Triethylamine (19.5 kg) was added to a cooled (approximately 5 °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 °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 °C. When
the addition was complete, the solution was stirred for approximately 4 hours keeping the
temperature below 10 °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 °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 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 ºC, 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 ºC under nitrogen to afford the title compound
(25.4 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
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 °C. This solution was used in the next step without further processing.
Alternative Preparation of 1–(4–Fluoro–phenylcarbamoyl)–cyclopropanecarbonyl
chloride
A reactor was charged with 1-(4-fluoro-phenylcarbamoyl)-
cyclopropanecarboxylic acid (35 kg), DMF (344 g), and THF (175kg). The reaction mixture
was adjusted to 12 to 17 °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 °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
yloxy)-phenyl]-amide (4-fluoro–phenyl)-amide
The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-
cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-
quinolineyloxy)-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 °C. When
the reaction was complete (in approximately 20 minutes), water (653 L) was added. The
mixture was stirred at 20 to 25 °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 ºC and then dried at approximately 45 ºC 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-
quinoloneyloxy)-phenyl]-amide (4-fluoro-phenyl)-amide
A reactor was charged with 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine
(35.7 kg, 1 equivalent), followed by THF (412.9 kg). To the reaction mixture was charged a
solution of K CO (48.3g) 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-quinolineyloxy)-
phenylamine while maintaining the temperature between 20 to 30 °C over a minimum of two
hours. The reaction mixture was stirred at 20 to 25 °C for a minimum of three hours. The
reaction temperature was then adjusted to 30 to 25 °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 °C for a minimum of 16 hours.
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 °C for approximately
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-
°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 °C.
In an alternative procedure, the reaction temperature during acid chloride
formation was adjusted to 10 to 15 °C. The recrystallization temperature was changed from
to 25 °C to 45 to 50 °C for 1 hour and then cooled to 15 to 25 °C over 2 hours.
Preparation of Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline
yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L) malate salt
Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolineyloxy)-
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 ºC) for approximately 2 hours. The reactor temperature
was reduced to 50 to 55 ºC, 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-quinolineyloxy)-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 < 0.5 % w/w) at approximately 74 ºC.
The temperature of the reactor contents was reduced to 20 to 25 ºC and held for
approximately 4 hours, resulting in solid precipitate which was filtered, washed with MEK
(448 kg), and dried under vacuum at 50 ºC 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
Cyclopropane–1,1–dicarboxylic acid [4-(6,7-dimethoxy-quinolineyloxy)-
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 °C for approximately 1 to 3 hours, and then at 55 to 60 °C for an additional 4 to 5
hours. The mixture was clarified by filtration through a 1 μm cartridge. The reactor
temperature was adjusted to 20 to 25 ºC and vacuum distilled with a vacuum at 150-200 mm
Hg with a maximum jacket temperature of 55 °C to the volume range of 558-731 L.
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-quinolineyloxy)-phenyl]-amide (4-fluoro-phenyl)-amide by charging methyl
ethyl ketone (159.9 kg) to give a total volume of 880L. An addition al 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 ºC 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 ºC.
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-quinolineyloxy)-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
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.
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
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.
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
September 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.
Baseline characteristics for patients 1-3 are summarized in Table 1.
Table 1.
Summary of Baseline Characteristics and Preliminary Best Responses for CRPC
Patients Treated with Compound 1.
Baseline Characteristics Patient 1 Patient 2 Patient 3
Age (years) 77 73 66
Diagnosis 1993 2009 2009
ECOG performance status 1 0 1
Disease location(s) Lung, LN, bone Liver, LN, bone LN, bone
Prior cancer therapies Radical
prostatectomy, Radiation to
radiation to pubic ramus and CAB, docetaxel
prostate bed, acetabulum,
CAB, DES, CAB
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%
Complete
Bone scan 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;
Baseline Characteristics Patient 1 Patient 2 Patient 3
tALP, total alkaline phosphatase.
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.
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.
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
All patients provided informed consent before study screening.
Patient 1 started Compound 1 on February 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 (Figure 1A). A CT scan showed a partial response
(PR) with a 33% decrease in measurable target lesions (Figure 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 (Figure 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 (Figure 1B and Table 1). The patient was on open-label treatment through Week
18 when he withdrew after developing Grade 3 diarrhea.
Patient 2 started Compound 1 on March 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 (Figure 2A), and a CT scan showed a 13% decrease in target lesions (Figure 2C). At
Week 12, a substantial reduction of radiotracer uptake (Figure 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
. Serum tALP levels were within the normal range (101-144 U/L) (Figure 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 (Figure 2B and Table 1).
The patient continues on Compound 1 treatment as of September 2010.
Patient 3 started Compound 1 on April 26, 2010. After three weeks a complete
resolution of pain was reported. At Week 6, bone scan showed a dramatic reduction in
radiotracer uptake (Figure 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
(Figure 3A) and a 51% decrease in measurable disease were observed (Table 1 and Figure
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 (Figure 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 (Figure 3B and Table 1). The patient continues on Compound 1 treatment
as of September 2010.
Discussion
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.
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.
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
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.
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.
Updated progression-free survival (PFS) data show that Compound 1 results in
median PFS that appear to be similar in docetaxel-naïve 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.
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).
Excluding those randomized to placebo, the median PFS was 29 weeks for the
overall population (n=154). Median PFS in the subsets of docetaxel-naïve 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-naïve and pretreated populations.
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.
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).
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.
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.
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 99mTc-
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
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 (Figure 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
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 (Figure 5).
Case Study 6: Breast Cancer with Bone Metastases
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.
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 (Figure 6).
Study 8: Effect of Compound 1 Administration on CT Plasma Concentration
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 ) concentration in bisphosphonate treated and
bisphosphonate naïve patients with ovarian cancer that exhibited bone metastases (N=27).
CT 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
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.
Claims (8)
1. Use of Compound 1 CH O H C O N Compound 1 or the malate salt thereof, in the preparation of a medicament containing 60, 40 or 20 mg of Compound 1 for extending the overall survival of patients with renal cell carcinoma metastasized to bone, wherein the treatment comprises once daily administration of the medicament.
2. The use of claim 1, wherein the Compound 1, malate salt is the Compound 1, L-malate salt or Compound 1, D-malate salt.
3. The use of claim 2, wherein the Compound 1, malate salt is the Compound 1, L-malate salt.
4. The use of claim 2, wherein the Compound 1, malate salt is the Compound 1, D-malate salt.
5. The use of any one of claims 1-4, wherein the medicament is in the form of a tablet.
6. The use of any one of claims 1-5, wherein the medicament is in the form of a tablet pharmaceutical composition as provided in the following table: Ingredient (% w/w) Compound 1, malate salt 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
7. The use of any one of claims 1-6, wherein the patient is a human patient.
8. The use as claimed in any one of claims 1 to 7, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US201161481682P | 2011-05-02 | 2011-05-02 | |
US61/481,682 | 2011-05-02 | ||
US201161557366P | 2011-11-08 | 2011-11-08 | |
US61/557,366 | 2011-11-08 | ||
NZ617508A NZ617508B2 (en) | 2011-05-02 | 2012-05-02 | Method of treating cancer and bone cancer pain |
Publications (2)
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NZ716805A NZ716805A (en) | 2017-11-24 |
NZ716805B2 true NZ716805B2 (en) | 2018-02-27 |
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