Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
A NOVEL LACTIC ACID FORMULATION OF MK-0457 USEFUL FOR THE TREATMENT
OF CANCER
BACKGROUND OF THE INVENTION
The Aurora A, B, and C family of serine/threonine kinases is essential for
entry
into and progression through mitosis.. Aurora A regulates initiation of
mitosis and plays a critical
role in centrosome maturation, the establishment of bipolar spindles during
cell division, and the
attachment of chromosomes to the spindle. Aurora B is a chromosomal passenger
protein with a
more critical role in the latter stages of mitosis, being required for
chromosome alignment, the
mitotic checkpoint and cytokinesis. The function of Aurora C remains unclear.
MK-0457 is a potent and highly selective Aurora kinase inhibitor that is being
developed for the treatment of cancer. MK-0457 causes delayed entry and
progression through
mitosis, exit from mitosis without cytokinesis, and induction of apoptosis. MK-
0457 has potent
activity in vitro and in vivo against a variety of solid tumors, leukemias,
and lymphomas.
MK-0457 was initially formulated as a lyophilized sulfate salt product for
Phase I
studies. The solubility of the initially prepared MK-0457 as a sulfate salt
was 30 mg/mL.
However, during manufacture, a more thermodynamically stable polymorph was
discovered and
generated, which had a solubility of only 1 mg/mL. A salt screen was conducted
to determine a.
more soluble formulation of MK-0457, which returned several crystalline
pharmaceutically
relevant salts, including but not limited to, phosphate, succinate, citrate,
toysalate and besylate,
all with a maximum solubility of approximately 2 mg/mL. Surprisingly, a novel
formulation of
MK-0457 utilizing lactic acid was identified having a solubility of 20 mg/mL.
MK-0457 is currently in Phase II clinical oncology studies.
It is an object of this invention to provide a novel lactic acid formulation
and
process thereof of MK-0457 which is characterized by properties that offer
advantages in the
delivery of MK-0457 to a patient in need of cancer treatment.
SUMMARY OF THE INVENTION
A lactic acid fonnulation, and a process to prepare that formulation, of MK-
0457
is disclosed:
Me
NH
HN `N
H
yY
~N fLN N~SJ~ O
Me N MK-0457
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Such a formulation is useful in the treatment of cancer. _
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the lactic acid formulation of MK-0457:
Me
X'NH
HN
N
\N ~
11 H
O
N I N~S ~ I
~J
M9 N MK-0457
It has been surprisingly discovered that a lactic acid formulation of MK-0457
provided improved solubility (20 mg/mL).
The instant invention is also directed to the process for the preparation of
the
lactic acid formulation of MK-0457 which comprises the steps of: combining a
lactic acid
solution with an amount of MK-0457; and adding a sugar.
In an embodiment of the instant process, the process further comprises the
step of
mixing until all contents are dissolved.
In another embodiment of the instant process, the process further comprises
the
step of adjusting the pH.
In another embodiment of the instant process, the lactic acid solution has a
concentration range from I mg/mL to 100 mg/mL.
In another embodiment of the instant process, the lactic acid solution has a
concentration range from 5 mg/mL to 50 mg/mL.
In another embodiment of the instant process, the lactic acid solution has a
concentration of 20 mg/mL.
In another embodiment of the instant process, the lactic acid solution has a
concentration of 10 mg/mL.
In another embodiment of the instant process, the amount of MK-0457 ranges
from 1 mg to 2000 mg.
In another embodiment of the instant process, the amount of MK-0457 ranges
from 2 mg to 1000 mg.
In another embodiment of the instant process, the amount of MK-0457 ranges
from 5 mg to 500 mg.
In another embodiment of the instant process, the amount of MK-0457 ranges
from 100 mg to 500 mg.
In another embodiment of the instant process, the amount of MK-0457 is 200 mg.
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In another embodiment of the instant process, the sugar is selected from
mannitol
or dextrose.
In another embodiment of the instant process, the sugar is added to reach
tonicity.
In another embodiment of the instant process, the pH is adjusted to a range of
about 2.5 to 4.5.
In another embodiment of the instant process, the pH is adjusted to a range of
about 3 to 3.5.
The lactic acid formulation of MK-0457 may additionally comprise
pharmaceutically acceptable carriers, excipients or diluents. In this regard,
see, e.g. Remington's
Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Company, edited by
Osol et al. Such
compositions may include proteins, such as serum proteins, for example, human
serum albumin,
and the like. Suitable diluents for reconstituting the lyophilized formulation
prior to
administration may include, for example, sterile water, isotonic saline,
dilute aqueous dextrose, a
polyhydric alcohol or mixtures of such alcohols, for example, glycerin,
propylene glycol,
polyethylene glycol and the like. As used, "pharmaceutically acceptable"
refers to those agents
which are useful in the treatment or diagnosis of a warm-blooded animal
including, for example,
a human, equine, porcine, bovine, murine, canine, feline, or other manunal, as
well as an avian or
other warm-blooded animal. The preferred mode of administration of the
reconstituted
formulation is parenterally, particularly by the intravenous, intramuscular,
subcutaneous,
intraperitoneal, or intralymphatic route.
As used herein, the terms "composition" and "formulation" are intended to
encompass a product comprising the specified ingredients, as well as any
product which results,
directly or indirectly, from combination of the specific ingredients.
The formulation of the instant invention may also be administered in
combination
with another anti-cancer agent(s).
For intravenous administration, the composition preferably will be prepared so
that the amount administered to the patient will be from about 0.Olg to about
lg of MK-0457.
Preferably, the amount administered will be in the range of about 0.2g to
about 1 g of 1VIK-0457.
The salt of the invention is effective over a wide dosage range depending on
factors such as the
disease state to be treated or the biological effect to be modified, the
manner in which the salt is
administered, the age, weight and condition of the patient as well as other
factors to be
determined by the treating physician. Thus, the amount administered to any
given patient must
be determined on an individual basis.
One skilled in the art will appreciate that although specific reagents and
reaction
conditions are outlined in the following examples, modification can be made
and are meant to be
encompassed by the spirit and scope of the invention. The following
preparations and examples,
therefore, are provided to further illustrate the invention, and are not
limiting.
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UTILITY
The formulations and methods provided herein are particularly deemed useful
for
the treatment of cancer. Cancers that may be treated by the formulations and
methods of the
invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma,
fibrosarcoma,
rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and
teratoma;
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell,
undifferentiated large
cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,
sarcoma,
lymphoma, chondromatous hamartoma, mesothelioma, non small cell;
Gastrointestinal:
esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),
stomach
(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,
insulinoma,
glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel
(adenocarcinoma, lymphoma,
carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma,
neurofibroma, fibroma),
large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,
leiomyoma),
colon, colorectal, rectal ; Genitourinartract: kidney (adenocarcinoma, Wihn's
tumor
[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell
carcinoma,
transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma,
sarcoma), testis
(seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,
sarcoma,
interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,
lipoma); Liver:
hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,
angiosarcoma,
hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma),
fibrosarcoma,
malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant
lymphoma
(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor
chordoma,
osteochronfroma (osteocartilaginous exostoses), benign chondroma,
chondroblastoma,
chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system:
skull (osteoma,
hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,
meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma,
ependymoma,
germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma,
glioma, sarcoma);
Gvnecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-
tumor cervical
dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous
cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors,
Sertoli-Leydig cell
tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,
intraepithelial
carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell
carcinoma, squamous
cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes
(carcinoma),
breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute
lymphoblastic
leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple
myeloma,
myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma
[malignant
lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell
carcinoma,
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Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,
keloids, psoriasis;
and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided
herein, includes
a cell afflicted by any one of the above-identified conditions.
Cancers that may be treated by the formulations and methods of the invention
include, but are not limited to: breast, prostate, colon, colorectal, lung,
brain, testicular, stomach,
ovarian, pancrease, skin, small intestine, large intestine, throat, head and
neck, oral, bone, liver,
bladder, kidney, thyroid and blood.
Cancers that may be treated by the formulations and methods of the invention
include: breast, prostate, colon, ovarian, colorectal and lung.
Cancers that may be treated by the formulations and methods of the invention
include: breast, colon, (colorectal) and lung (non small cell lung cancer).
Cancers that may be treated by the formulations and methods of the invention
include: lymphoma and leukemia.
Cancers that may be treated by the formulations and methods of the invention
include: myeloid leukemia [acute and chronic], acute lymphoblastic leukemia,
chronic
lymphocytic leukemia, myeloproliferative diseases, multiple myeloma,
myelodysplastic
syndrome, Hodgkin's disease, non-Hodglcin's lymphoma [malignant lymphoma].
Cancers that may be treated by the formulations and methods of the invention
include: myeloid leukemia [acute and.chronic], acute lymphoblastic leukemia,
myeloproliferative
diseases.
Cancers that may be treated by the formulations and methods of the invention
include: chronic myeloid leukemia (CML) and acute lymphoblastic leukemia
(ALL).
Cancers that may be treated by the formulations and methods of the invention
include: chronic myeloid leukemia (CML).
The formulations of the invention are also useful in preparing a medicament
that
is useful in treating cancer.
MK-0457 may be synthesized according to the General Scheme and Examples
herein (see also WO 04/000833, which is incorporated herein by reference).
Additionally, MK-
0457 may be synthesized by methods known to skilled practitioners.
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General Scheme:
cl cl
H
N
+ N O (-' C (
CI N~S% MeHCI NS O
0 O C
Me Me
N ~ \N
HN ~I/ HN H
~L- ^ N 1~ H
N ~ ~ j ~ N
I
CI N~S ' \ I C N \NS \ 0
~
D Me/-N J 1
EXAMPLES
Examples 1-4 refer to the General Scheme above.
Example 1
4,6-Dichloropyrimidine-2-methylsulfone (A): Prepared by methods substantially
similar to those
set forth in Koppell et al, JOC, 26, 1961, 792, in the following manner. To a
stirred solution of
4,6-dichloro-2-(methylthio)pyrimidine (50 g, 0.26 mol) in dichloromethane (1
L) at 0 C was
added meta-chloroperoxybenzoic acid (143.6 g, 0.64 mol) over a period of 20
minutes. The
solution was allowed to warm to room temperature and was stirred for 4 hours.
The mixture was
diluted with dichloromethane (1.5 L) and then treated sequentially with 50%
Na2S2O3 / NaHCO3
solution (2 x 200 ml), sat. NaHCO3 solution (4 x 300 ml), and brine (200 ml)
then dried
(MgSO4)= The solvent was removed in vacuo to afford an off-white solid, which
was redissolved
in EtOAc (1L) and treated sequentially with sat. NaHCO3 solution (3 x 300 ml),
and brine (100
ml) then dried (MgSO4). The solvent was removed in vacuo to afford the title
compound (A) as
a white solid (55.6 g, 96% yield). ' H NMR CDC13 5 3.40 (3H, s, CH3), 7.75 (1
H. s. ArH).
Example 2
Cyclopropane carboxylic acid [4-(4,6-dichloro-pyrimidin-2-ylsulphanyl)-phenyl]-
amide (C): A
suspension of compound A(lOg, 44.04 mmol) and cyclopropane carboxylic acid (4-
mercapto-
phenyl)-amide (B, 8.51 g, 44.04 nunol) in t-butanol (300 ml) was degassed by
evacuation, then
flushing with nitrogen. The mixture was stirred at 90 C under nitrogen
atmosphere for 1 hour
then the solvent was removed in vacuo. The residue was dissolved in ethyl
acetate (600 ml) and
washed with an aqueous solution of potassium carbonate and sodium chloride.
The organic
extract was dried over magnesium sulphate, concentrated to a low volume and
allowed to
crystallize. The product C was collected as colourless crystals, (11.15 e.
74%). IH-NMR
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DMSO-d6, S 0.82-0.89 (4H, m), 1.80-1.88 (IH, m), 7.55 (2H, d), 7.70-7.76 (3H,
m), 10.49 (IH,
s); M+H, 340.
ExamQle 3
Cyclopropane carboxylic acid{4-[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-
pyrimidin-2-
ylsulphanyl]-phenyl} amide (D): A mixture of compound C (1.0 g, 2.94 mmol)and
3-amino-5-
methylpyrazole (314 mg, 3.23 mmol) in dimethylformamide (6 ml) was treated
with
diisopropylethylamine (0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3.53
mmol). The
mixture was stirred under nitrogen at 85 for 4 hours, cooled to room
temperature and diluted
with ethyl acetate. The solution was washed with water (x 4), dried over
magnesium sulphate
and concentrated to 5 ml to afford, upon crystallization and harvesting of
colourless crystals, the
title compound D (920 mg, 78%). 'H-NMR DMSO-d6, S 0.80-0.87 (4H, m), 1.77-1.85
(1H, m),
1.92 (1 H, s), 5.24 (IH, br s), 6.47 (1 H, br s), 7.55 (2H, d), 7.70-7.80 (2H,
m), 10.24 (1 H, s),
10.47 (1H, s), 11.92 (1H, s).
Example 4
Cyclopropane carboxylic acid {4-[4-(4-methyl-piperazin-1-yl)-6-(5-methyl-2H-
pyrazol-3-
ylamino)-pyrimidin-2-ylsulphanyl]-phenyl}-amide (I): Compound D (2.373 g, 5.92
mmol) was
treated with N-methylpiperazine (10 ml) and the mixture stirred at 110 for 2
hours. The excess
N-methylpiperazine was removed in vacuo then the residue was dissolved in
ethyl acetate,
washed with aqueous sodium bicarbonate solution, dried over magnesium
sulphate, and
concentrated. The residue was crystallised from methanol to give colourless
crystals of desired
product I(MK-0457) (1.82 g, 66%), 'H-NMR DMSO-d6, S 0.81 (4H, d), 1.79 (1H,
m), 2.01 (3H,
s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.42 (1H, s), 6.02 (1H,
br s), 7.47 (2H, d),
7.69 (2H, d), 9.22 (IH, s), 10.39 (1 H, s), 11.69 (1 H, s).
The formulations of this invention may be administered to mammals, including
humans, either alone or, in combination with pharmaceutically acceptable
carriers, excipients or
diluents, in a pharmaceutical composition, according to standard
pharmaceutical practice. The
compounds can be administered orally or parenterally, including the
intravenous, intramuscular,
intraperitoneal, and subcutaneous routes of administration.
The pharmaceutical compositions containing the active ingredient may be in a
form suitable for oral use, for example, as tablets, troches, lozenges,
aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules, or syrups
or elixirs.
Compositions intended for oral use may be prepared according to any method
known to the art
for the manufacture of pharmaceutical compositions and such compositions may
contain one or
more agents selected from the group consisting of sweetening agents, flavoring
agents, coloring
agents and preserving agents in order to provide pharmaceutically elegant and
palatable
preparations. Tablets contain the active ingredient in admixture with non-
toxic pharmaceutically
acceptable excipients which are suitable for the manufacture of tablets. These
excipients may be
for example, inert diluents/fillers, such as calcium carbonate, sodium
carbonate, lactose,
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mannitol, sucrose, starch, kaolin, dicalcium phosphate or sodium phosphate;
granulating and
disintegrating agents, for example, microcrystalline cellulose, sodium
crosscarmellose, corn
starch, crospovidone, sodium starch glycolate, or alginic acid; binding
agents, for example
starch, cellulose polymers (hydroxypropyl cellulose, HPMC, hydroxyethyl
cellulose, methyl
cellulose), gelatin, polyvinyl-pyrrolidone or synthetic gums (acacia, guar
gum, xanthan gum,
pectin, sodium alginate, carageenan) and lubricating agents, for example,
magnesium stearate,
stearic acid, sodium stearyl fumarate, colloidal silicon dioxide or talc. The
tablets may. be
uncoated or they may be coated by known techniques to mask the unpleasant
taste of the drug,
improve physical appearance, or delay disintegration and absorption in the
gastrointestinal tract
and thereby provide a sustained action over a longer period. For example, any
water soluble
taste masking material such as but not limited to hydroxypropylmethyl-
cellulose, shellac,
Eudragit, cellulose acetate phthalate, or hydroxypropylcellulose, or a time
delay material such as
ethyl cellulose, cellulose acetate buryrate, cellulose acetate, or Eudragits
may be employed.
Formulations for oral use may also be presented as hard gelatin capsules
wherein
the active ingredient is mixed with an inert solid diluent, for example,
calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed
with water soluble carrier such as polyethyleneglycol or an oil medium, for
example peanut oil,
liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such excipients are
suspending agents, for
example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-
cellulose,
sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting
agents may be a naturally-occurring phosphatide, for example lecithin, or
condensation products
of an alkylene oxide with fatty acids, for example polyoxyethylene stearate,
or condensation
products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethylene-
oxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example
polyethylene sorbitan monooleate or nonionic surfactants (tween or TPGS) or
others such as
sodium lauryl sulfate, docusate sodium, polyethylene-polypropylene block co-
polymers
(poloxamer). The aqueous suspensions may also contain one or more
preservatives, for example
ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents,
and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil,
or in mineral oil such
as liquid paraffin. The oily suspensions may contain a thickening agent, for
example beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring
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agents may be added to provide a palatable.oral preparation. These
compositions may be
preserved by the addition of an anti-oxidant such as butylated hydroxyanisol
or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in admixture
with a dispersing
or wetting agent, suspending agent and one or more preservatives. Suitable
dispersing or wetting
agents and suspending agents are exemplified by those already mentioned above.
Additional
excipients, for example sweetening, flavoring and coloring agents, may also be
present. These
compositions may be preserved by the addition of an anti-oxidant such as
ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of an
oil-in-water emulsion. The oily phase may be a vegetable oil, for example
olive oil or arachis
oil, or a mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying
agents may be naturally-occurring phosphatides, for example soy bean lecithin,
and esters or
partial esters derived from fatty acids and hexitol anhydrides, for example
sorbitan monooleate,
and condensation products of the said partial esters with ethylene oxide, for
example
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening, flavouring
agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also
contain a demulcent,
a preservative, flavoring and coloring agents and antioxidant.
The pharmaceutical compositions may be in the form of sterile injectable
aqueous
solutions. Among the acceptable vehicles and solvents that may be employed are
water, Ringer's
solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-
water
microemulsion where the active ingredient is dissolved in the oily phase. For
example, the
active ingredient may be first dissolved in a mixture of soybean oil and
lecithin. The oil solution
then introduced into a water and glycerol mixture and processed to form a
microemulsion.
The injectable solutions or microemulsions may be introduced into a patient's
blood-stream by local bolus injection. Alternatively, it may be advantageous
to administer the
solution or microemulsion in such a way as to maintain a constant circulating
concentration of
the instant compound. In order to maintain such a constant concentration, a
continuous
intravenous delivery device may be utilized. An example of such a device is
the Deltec CADD-
PLUSTM model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable
aqueous or oleagenous suspension for intramuscular and subcutaneous
administration. This
suspensioin may be formulated according to the known art using those suitable
dispersing or
wetting agents and suspending agents which have been mentioned above. The
sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-
toxic parenterally-
acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
In addition, sterile,
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fixed oils.are conventionally employed as a solvent or suspending medium. For
this purpose any
bland fixed oil composed of different chain length triglycerides (e.g. soybean
oil, coconut oil,
and safflower oil) may be employed including synthetic mono- or diglycerides.
In addition, fatty
acids such as oleic acid, linoleic acid, palmitic acid, stearic acid fmd use
in the preparation of
injectables.
When a composition according to this invention is administered into a human
subject, the daily dosage will normally be determined by the prescribing
physician with the
dosage generally varying according to the age, weight, and response of the
individual patient, as
well as the severity of the patient's symptoms.
The dosage regimen utilizing the formulations of the instant invention can be
selected in accordance with a variety of factors including type, species, age,
weight, sex and the
type of cancer being treated; the severity (i.e., stage) of the cancer to be
treated; the route of
administration; the renal and hepatic function of the patient; and the
particular compound or salt
thereof employed. An ordinarily skilled physician or veterinarian can readily
determine and
prescribe the effective amount of the drug required to treat, for example, to
prevent, inhibit (fully
or partially) or arrest the progress of the disease. For example, formulations
of the instant
invention can be administered in a total daily dose of up to 1000 mg.
Formulations of the instant
invention can be administered once daily (QD), or divided into multiple daily
doses such as twice
daily (BID), and three times daily (TID). Formulations of the instant
invention can be
administered at a total daily dosage of up to 1000 mg, e.g., 200 mg, 300 mg,
400 mg, 600 mg,
800 mg or 1000 mg, which can be administered in one daily dose or can be
divided into multiple
daily doses as described above.
In addition, the administration can be continuous, i.e., every day, or
intermittently.
The terms "intemzittent" or "intermittently" as used herein means stopping and
starting at either
regular or irregular intervals. For example, intermittent administration of a
formulation of the
instant invention may be administration one to six days per week or it may
mean administration
in cycles (e.g. daily administration for two to eight consecutive weeks, then
a rest period with no
administration for up to one week) or it may mean administration on alternate
days.
In addition, the formulations of the instant invention may be administered
according to any of the schedules described above, consecutively for a few
weeks, followed by a
rest period. For example, the formulations of the instant invention may be
administered
according to any one of the schedules described above from two to eight weeks,
followed by a
rest period of one week, or twice daily at a dose of 100 - 500 mg for three to
five days a week. In
another particular embodiment, the formulations of the instant invention may
be administered
three times daily for two consecutive weeks, followed by one week of rest.
In another embodiment, the formulations of the instant invention can be
administered intravenously for a 5-day continuous infusion at 24-64 mg/m2/hr
with a cycle
duration every 14-28 days. In another embodiment, the formulation can be
administered
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intravenously for a 5-day continuous infusion at 6-12 mg/m2/hr with a cycle
duration every 14-28
days. In another embodiment, the formulation can be administered intravenously
for a 5-day
continuous infusion at 8-10 mg/m2/hr with a cycle duration every 14-28 days.
In another
embodiment, the formulation can be administered intravenously for a 24 hr
infusion every 14-21
days at 32-200 mg/m2/hr. In another embodiment, the formulation can be
administered
intravenously for a 24 hr infusion every 14-21 days at 32-64 mg/m2/hr. In
another embodiment,
the formulation can be administered intravenously for a 48 hr infusion every
21-28 days at 8-12
mg/mZ/hr. In another embodiment, the formulation can be administered
intravenously for a 6 hr
infusion every 14-21 days at 32-200 mg/m2/hr. In another embodiment, the
formulation can be
administered intravenously for a 6 hr infusion every 14-21 days at 32-64
mg/mZ/hr. In another
embodiment, the formulation can be administered intravenously for a 3 hr
infusion every 14-21
days at 32-200 mg/m2/hr. In another embodiment, the formulation can be
administered
intravenously for a 3 hr infusion every 14-21 days at 32-64 mg/m2/hr.
In another embodiment, the formulation can be administered intravenously for a
5-day continuous infusion at 24-64 mg/m2/hr with a cycle duration every 14-28
days. In another
embodiment, the formulation can be administered intravenously for a 5-day
continuous infusion
at 8-10 mg/m2/hr with a cycle duration every 21 days. In another embodiment,
the formulation
can be administered intravenously for a 24 hr infusion every 21 days at 64-96
mg/m2/hr. In
another embodiment, the formulation can be administered intravenously for a 24
hr infusion
every 21 days at 32-64 mg/m2/hr. In another embodiment, the formulation can be
administered
intravenously for a 6 hr infusion every 14-21 days at 32-200 mg/m2/hr. In
another embodiment,
the formulation can be administered intravenously for a 3 hr infusion every 14-
21 days at 32-200
mg/m2/hr.
Any one or more of the specific dosages and dosage schedules of the
formulations
of the instant invention, may also be applicable to any one or more of the
therapeutic agents to be
used in the combination treatinent (hereinafter refered to as the "second
therapeutic agent").
Moreover, the specific dosage and dosage schedule of this second therapeutic
agent can further vary, and the optimal dose, dosing schedule and route of
administration will be
determined based upon the specific second therapeutic agent that is being
used.
Of course, the route of administration of the formulations of the instant
invention
is independent of the route of administration of the second therapeutic agent.
In an embodiment,
the administration for a formulation of the instant invention is oral
administration. In another
embodiment, the administration for a formulation of the instant invention is
intravenous
administration. Thus, in accordance with these embodiments, a formulation of
the instant
invention is administered orally or intravenously, and the second therapeutic
agent can be
administered orally, parenterally, intraperitoneally, intravenously,
intraarterially, transdermally,
sublingually, intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation,
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vaginally, intraoccularly, via local delivery by catheter or stent,
subcutaneously, intraadiposally,
intraarticularly, intrathecally, or in a slow release dosage form.
In addition, a formulation of the instant invention and second therapeutic
agent
may be administered by the same mode of administration, i.e. both agents
administered e.g.
orally, by IV. However; it is also within the scope of the present invention
to administer a
formulation of the instant invention by one mode of administration, e.g. IV,
and to administer the
second therapeutic agent by another mode of administration, e.g. oral or any
other ones of the
administration modes described hereinabove.
The first treatment procedure, administration of afonnulation of the instant
invention, can take place prior to the second treatment procedure, i.e., the
second therapeutic
agent, after the treatment with the second therapeutic agent, at the same time
as the treatment
with the second therapeutic agent, or a combination thereof. For example, a
total treatment
period can be decided for a formulation of the instant invention. The second
therapeutic agent
can be administered prior to onset of treatment with a fonnulation of the
instant invention or
following treatment with a formulation of the instant invention. In addition,
anti-cancer
treatment can be administered during the period of administration of a
formulation of the instant
invention but does not need to occur over the entire treatment period of a
formulation of the
instant invention.
The instant formulations are also useful in combination with therapeutic,
chemotherapeutic and anti-cancer agents. Combinations of the presently
disclosed formulations
with therapeutic, chemotherapeutic and anti-cancer agents are within the scope
of the invention.
Examples of such agents can be found in Cancer Principles and Practice of
Oncology by V.T.
Devita and S. Hellman (editors), 6h edition (February 15, 2001), Lippincott
Williams & Wilkins
Publishers. A person of ordinary skill in the art would be able to discern
which combinations of
agents would be useful based on the particular characteristics of the drugs
and the cancer
involved. Such agents include the following: estrogen receptor modulators,
androgen receptor
modulators, retinoid receptor modulators, cytotoxic/cytostatic agents,
antiproliferative agents,
prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other
angiogenesis
inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors,
inhibitors of cell proliferation
and survival signaling, bisphosphonates, aromatase inhibitors, siRNA
therapeutics, -y-secretase
inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and
agents that interfere
with cell cycle checkpoints. The instant compounds are particularly useful
when co-administered
with radiation therapy.
"Estrogen receptor modulators" refers to compounds that interfere with or
inhibit
the binding of estrogen to the receptor, regardless of mechanism. Examples of
estrogen receptor
modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene,
LY353381,
LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-
[4-[2-(1-
-12-
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piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-
dimethylpropanoate, 4,4'-
dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
"Androgen receptor modulators" refers to compounds which interfere or inhibit
the binding of androgens to the receptor, regardless of mechanism. Examples of
androgen
receptor modulators include finasteride and other 5ac reductase inhibitors,
nilutamide, flutamide,
bicalutamide, liarozole, and abiraterone acetate.
"Retinoid receptor modulators" refers to compounds which interfere or inhibit
the
binding of retinoids to the receptor, regardless of mechanism. Examples of
such retinoid
receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-
retinoic acid, a-
. 10 difluoromethylomithine, ILX23-7553, trans-N-(4'-hydroxyphenyl)
retinamide, and N-4-
carboxyphenyl retinamide.
"Cytotoxic%ytostatic agents" refer to compounds which cause cell death or
inhibit
cell proliferation primarily by interfering directly with the cell's
functioning or inhibit or interfere
with cell myosis, including alkylating agents, tumor necrosis factors,
intercalators, hypoxia
activatable compounds, microtubule inhibitors/microtubule-stabilizing agents,
inhibitors of
mitotic kinesins,histone deacetylase inhibitors, inhibitors of kinases
involved in mitotic
progression, inhibitors of kinases involved in growth factor and cytokine
signal transduction
pathways, antimetabolites, biological response modifiers, hormonal/anti-
hormonal therapeutic
agents, haematopoietic growth factors, monoclonal antibody targeted
therapeutic agents,
topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors,
and aurora kinase
inhibitors.
Examples of cytotoxic/cytostatic agents include, but are not limited to,
sertenef,
cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,
prednimustine,
dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin,
temozolomide, heptaplatin,
estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium
chloride, pumitepa,
lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide,
cis-aminedichloro(2-
methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans,
trans)-bis-mu-
(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum
(II)]tetrachloride,
diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-
3,7-
dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene,
mitoxantrone, pirarubicin,
pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-
deoxo-10-
hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4-demethoxy-
3-deamino-
3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032), Raf kinase
inhibitors (such as
Bay43-9006) and mTOR inhibitors (such as Wyeth's CCI-779).
An example of a hypoxia activatable compound is tirapazamine.
Examples of proteosome inhibitors include but are not limited to lactacystin
and
MLN-341 (Velcade).
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Examples of microtubule inhibitors/microtubule-stabilising agents include.
paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-
norvincaleukoblastine, docetaxol,
rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,
BMS 184476,
vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)
benzene
sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-
L-prolyl-L-
proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos.
6,284,781 and
6,288,237) and BMS 188797. In an embodiment the epothilones are not included
in the
microtubule inhibitors/microtubule-stabilising agents.
Some examples of topoisomerase inhibitors are topotecan, hycaptamine,
irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin,
9-methoxy-N,N-
dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-
ethyl=5-fluoro-2,3-
dihydro-9-hydroxy-4-methyl-1 H,12H-benzo[de]pyrano[3',4':b,7]-indolizino[
1,2b]quinoline-
10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-
(20S)camptothecin, BNP1350,
BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-.
dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-
5,6-
dimethyl-6H-pyrido[4,3-b]carbazole-I-carboxamide, asulacrine, (5a, 5aB,
8aa,9b)-9-[2-[N-[2-
(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro0xy-3,5-dimethoxyphenyl]-
5,5a,6,8,8a,9-hexohydrofiuo(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6-one, 2,3-
(methylenedioxy)-5-
methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-
aminoethyl)amino]benzo[g]isoguinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-
dihydroxy-2-
(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1-
[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-
ylmethyl]formamide, N-(2-
(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-
3-hydroxy-
7H-indeno[2,1-c] quinolin-7-one, and dimesna.
Examples of inhibitors of mitotic kinesins, and in particular the human
mitotic
kinesin KSP, are described in Publications W003/039460, W003/050064,
W003/050122, -
W003/049527, W003/049679, W003/049678, W004/039774, W003/079973, W003/09921 1,
W003/105855, W003/106417, W004/037171, W004/058148; W004/058700, W004/126699,
W005/018638, W005/019206, W005/019205, W005/018547, W005/017190,
US2005/0176776. In an embodiment inhibitors of mitotic kinesins include, but
are not limited to
inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of
MCAK and
inhibitors of Rab6-KIFL.
Examples of "histone deacetylase inhibitors" include, but are not limited to,
SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Further reference to other
histone
deacetylase inhibitors may be found in the following manuscript; Miller, T.A.
et al. J. Med.
Chem. 46(24):5097-5116 (2003).
"Inhibitors of kinases involved in mitotic progression" include, but are not
limited
to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in
particular inhibitors of
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PLK-1), inhibitors of bub-1 and inhibitors of bub-Rl. An example of an "aurora
kinase
inhibitor" is VX-680.
."Antiproliferative agents" includes antisense RNA and DNA oligonucleotides
such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such
as
enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate,
fludarabine, capecitabine,
galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,
paltitrexid, emitefur,
tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-
methylidenecytidine, 2'-
fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-
(3,4-
dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-
tetradecadienoyl]glycylamino]-L-glycero-B-
L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-
amino-4-oxo-
4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][ 1,4]thiazin-6-yl-(S)-ethyl]-2,5-
thienoyl-L-glutamic
acid, aminopterin, 5-flurouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-
4-formyl-6-
methoxy-14-oxa-1,11-diazatetracyclo(7.4.1Ø0)-tetradeca-2,4,6-trien-9-yl
acetic acid ester,
swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-
palmitoyl-l-B-D-
arabino furanosyl cytosine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
and
trastuzumab.
Examples of monoclonal antibody targeted therapeutic agents include those
therapeutic agents which have cytotoxic agents or radioisotopes attached to a
cancer cell specific
or target cell specific monoclonal antibody. Examples include Bexxar.
"HMG-CoA rediuctase inhibitors" refers to inhibitors of 3-hydroxy-3-
methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that
may be used
include but are not limited to lovastatin (MEVACOR ; see U.S. Patent Nos.
4,231,938,
4,294,926 and 4,319,039), simvastatin (ZOCOR ; see U.S. Patent Nos. 4,444,784,
4,820,850
and 4,916,239), pravastatin (PRAVACHOL ; see U.S. Patent Nos.
4,346,227,4,537,859,
4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL ; see U.S. Patent
Nos. 5,354,772,
4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896),
atorvastatin (LIPITOR ;
see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) and
cerivastatin (also
known as rivastatin and BAYCHOL ; see US Patent No. 5,177,080). The structural
formulas of
these and additional HMG-CoA reductase inhibitors that may be used in the
instant methods are
described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry &
Industry, pp.
85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314. The term
HMG-CoA
reductase inhibitor as used herein includes all pharmaceutically acceptable
lactone and open-acid
forms (i.e., where the lactone ring is opened to form the free acid) as well
as salt and ester forms
of compounds which have HMG-CoA reductase inhibitory activity, and therefor
the use of such
salts, esters, open-acid and lactone forms is included within the scope of
this invention.
"Prenyl-protein transferase inhibitor" refers to a compound which inhibits any
one
or any combination of the prenyl-protein transferase enzymes, including
famesyl-protein
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transferase (FPTase), geranylgeranyl-protein transferase type I(GGPTase-I),
and geranylgeranyl-
protein transferase type-H (GGPTase-II, also called Rab GGPTase).
Examples of prenyl-protein transferase inhibitors can be found in the
following
publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478,
WO
97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245,
U.S. Patent
No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S.
Patent No. 5,589,485,
U.S. Patent No. 5,602,098, European Patent Publ. 0 618 221, European Patent
Publ. 0 675 112,
European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357,
WO
95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Patent No.
5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO
96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO
96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736,
U.S.
Patent No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO
96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477,
WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785,
WO
97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO
98/02436, and U.S. Patent No. 5,532,359. For an example of the role of a
prenyl-protein
transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No.
9, pp.1394-1401
(1999).
"Angiogenesis inhibitors" refers to compounds that inhibit the formation of
new
blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors
include, but are
not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine
kinase receptors Flt-1
(VEGFRI) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-
derived, or
platelet derived growth factors, MMP (matrix metalloprotease) inhibitors,
integrin blockers,
interferon-a, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors,
including
nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well
as selective
cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p.
7384 (1992); JNCI,
Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec.,
Vol. 238, p. 68
(1994); FEBSLetters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76
(1995); J. Mol.
Endocrinol., Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105
(1997); CancerRes.,
Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med.,
Vol. 2, p. 715 (1998); J.
Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as
corticosteroids,
mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred,
betamethasone),
carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-
carbonyl)-fumagillol,
thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see
Fernandez et al., J. Lab.
Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature
Biotechnology, Vol. 17,
pp.963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO
00/44777; and WO
00/61186).
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Other.therapeutic agents that modulate or inhibit angiogenesis and may also be
used in combination with the formulations of the instant invention include
agents that modulate
or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem.
La. Med. 38:679-
692 (2000)). Examples of such agents that modulate or inhibit the coagulation
and fibrinolysis
pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-
23 (1998)), low
molecular weight heparins and carboxypeptidase U inhibitors (also known as
inhibitors of active
thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res.
101:329-354 (2001)).
TAFIa inhibitors have been described in U.S. Ser. Nos. 60/310,927 (filed
August 8, 2001) and
60/349,925 (filed January 18, 2002).
"Agents that interfere with cell cycle checkpoints" refer to compounds that
inhibit
protein kinases that transduce cell cycle checkpoint signals, thereby
sensitizing the cancer cell to
DNA damaging agents. Such agents include inhibitors of ATR, ATM, the CHKI and
CHK2
kinases and cdk and cdc kinase inhibitors and are specifically exemplified by
7-
hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
"Agents that interfere with'receptor tyrosine kinases (RTKs)" refer to
compounds
that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor
progression.
Such agents include inhibitors of c-Kit, Eph, PDGF, F1t3 and c-Met. Further
agents include
inhibitors of RTKs as described by Bume-Jensen and Hunter, Nature, 411:355-
365, 2001.
."Inhibitors of cell proliferation and survival signalling pathway" refer to
compounds that inhibit signal transduction cascades downstream of cell surface
receptors. Such
agents include inhibitors of serine/threonine kinases (including but not
limited to inhibitors of
Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-
0116432,
WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO
03/084473, WO 03/086403, WO 2004/04 1 1 62, WO 2004/096131, WO 2004/096129, WO
2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 2005/029941,
US
2005/44294, US 2005/43361, 60/734188, 60/652737, 60/670469), inhibitors of Raf
kinase (for
example BAY-43-9006 ), inhibitors of MEK (for example CI-1040 and PD-098059),
inhibitors
of mTOR (for example Wyeth CCI-779), and inhibitors of P13K (for example
LY294002).
As described above, the combinations with NSAID's are directed to the use of
NSAID's which are potent COX-2 inhibiting agents. For purposes of this
specification an
NSAID is potent if it possesses an IC50 for the inhibition of COX-2 of 1 M or
less as measured
by cell or microsomal assays.
The invention also encompasses combinations with NSAID's which are selective
COX-2 inhibitors. For purposes of this specification NSAID's which are
selective inhibitors of
COX-2 are defined as those which possess a specificity for inhibiting COX-2
over COX-1 of at
least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1
evaluated by
cell or microsomal assays. Such compounds include, but are not limited to
those disclosed in
U.S. Patent 5,474,995, U.S. Patent 5,861,419, U.S. Patent 6,001,843, U.S.
Patent 6,020,343, U.S.
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Patent 5,409,944, U.S. Patent 5,436,265, U.S. Patent 5,536,752, U.S. Patent
5,550,142, U.S.
Patent 5,604,260, U.S. 5,698,584, U.S. Patent 5,710,140, WO 94/15932, U.S.
Patent 5,344,991,
U.S. Patent 5,134,142, U.S. Patent 5,380,738, U.S. Patent 5,393,790, U.S.
Patent 5,466,823, U.S.
Patent 5,633,272 and U.S. Patent 5,932,598, all of which are hereby
incorporated by reference.
Inhibitors of COX-2 that are particularly useful in the instant method of
treatment
are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a
pharmaceutically
acceptable salt thereof.
Compounds that have been described as specific inhibitors of COX-2 and are
therefore useful in the present invention include, but are not limited to, the
following: parecoxib,
BEXTRA and CELEBREX or a pharmaceutically acceptable salt thereof.
Other examples of angiogenesis inhibitors include, but are not limited to,
endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-
butenyl)oxiranyl]-
1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-
[[3,5-dichloro-4-(4-
chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101,
squalamine,
combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-
(carbonyl-
bi s[imino-N-methyl-4,2-pyrrolocarbonylimino [N-methyl-4,2-pyrrole]-
carbonylimino]-bi s-(1, 3-
naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-
indolinone (SU5416).
As used above, "integrin blockers" refers to compounds which selectively
antagonize, inhibit or counteract binding of a physiological ligand to the
av[i3 integrin, to
compounds which selectively antagonize, inhibit or counteract binding of a
physiological ligand
to the av(35 integrin, to compounds which antagonize, inhibit or counteract
binding of a
physiological ligand to both the av(33 integrin and the a05 integrin, and to
compounds which
antagonize, inhibit or counteract the activity of the particular integrin(s)
expressed on capillary
endothelial cells. The term also refers to antagonists of the avR6, avR8,
aiRl, a201, a01,
a6(31 and a6[34 integrins. The term also refers to antagonists of any
combination of avR3,
a05, avR6, avP8, a1R1, a2R1, a5R1, a601 and a6[34 integrins.
Some specific examples of tyrosine kinase inhibitors include N-
(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-
5-
yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-
chloro-4-
fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-
ethynylphenyl)-
6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-
10-
(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1 H-diindolo[ 1,2,3-fg:3',2',1'-
kl]pyrrolo[3,4-
i][1,6]benzodiazocin-l-one, SH268, genistein, ST1571, CEP2563, 4-(3-
chlorophenylamino)-5,6-
dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-
hydroxyphenyl)amino-
6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,
SU6668,
STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and
EMD121974.
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. Combinations with compounds other than anti-cancer compounds are also
encompassed in the instant methods. For example, combinations of the instantly
claimed
formulations with PPAR-y (i.e., PPAR-gamma) agonists and PPAR-S (i.e., PPAR-
delta) agonists
are useful in the treatment of certain malingnancies. PPAR-y and PPAR-S are
the nuclear
peroxisome proliferator-activated receptors y and S. The expression of PPAR-y
on endothelial
cells and its involvement in angiogenesis has been reported in the. literature
(see J. Cardiovasc.
Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999;274.:9116-9121; Invest.
Ophthalmol Vis. Sci.
2000; 41:2309-2317). More recently, PPAR-y agonists have been shown to inhibit
the
angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone
maleate inhibit the
development of retinal neovascularization in mice. (Arch. Ophthamol. 2001;
119:709-717).
Examples of PPAR-y agonists and PPAR- y/a agonists include, but are not
limited to,
thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and
pioglitazone),
fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501,
MCC-555,
GW2331, GW409544, NN2344, KRP297, NPOI 10, DRF4158, NN622, G1262570,
PNU182716,
DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-
methylpropionic
acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chloro-4-(4-
fluorophenoxy)
phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in USSN
60/235,708 and
60/244,697).
Another embodiment of the instant invention is the use of the presently
disclosed
fonnulations in combination with gene therapy for the treatment of cancer. For
an overview of
genetic strategies to treating cancer see Hall et al (Am. J. Hum. Genet.
61:785-789, 1997) and
Kufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000).
Gene therapy
can be used to deliver any tumor suppressing gene. Examples of such genes
include, but are not
limited to, p53, which can be delivered via recombinant virus-mediated gene
transfer (see U.S.
Patent No. 6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-
Mediated Delivery of
a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and
Dissemination
in Mice," Gene Therapy, August 1998;5(8):1105-13), and interferon gamma (J.
Immunol.
2000;164:217-222).
The formulation of the instant invention may also be administered in
combination
with an inhibitor of inherent multidrug resistance (MDR), in particular MDR
associated with
high levels of expression of transporter proteins. Such MDR inhibitors include
inhibitors of p-
glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and
PSC833
(valspodar).
A formulation of the present invention may be employed in conjunction with
anti-
emetic agents to treat nausea or emesis, including acute, delayed, late-phase,
and anticipatory
emesis, which may result from the use of a formulation of the present
invention, alone or with
radiation therapy. For the prevention or treatment of emesis, a formulation of
the present
invention may be used in conjunction with other anti-emetic agents, especially
neurokinin-1
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WO 2008/013807 PCT/US2007/016637
receptor antagonists, 5HT3 receptor antagonists, such as.ondansetron,
granisetron, xropisetron,
and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid
such as Decadron
(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others
such as disclosed
in U.S.Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768,
3,996,359, 3,928,326
and 3,749,712, an antidopaminergic, such as the phenothiazines (for example
prochlorperazine,
fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In
another
embodiment, conjunctive therapy with an anti-emesis agent selected from a
neurokinin-1
receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is
disclosed for the treatment
or prevention of emesis that may result upon administration of the instant
compounds.
Neurokinin-1 receptor antagonists of use in conjunction with the formulations
of
the present invention are fully described, for example, in U.S. Patent Nos.
5,162,339, 5,232,929,
5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699,
5,719,147;
European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429
366, 0 430 771, 0
436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0
514 273, 0 514
274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528
495, 0 532 456, 0
533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394,0 585 913,0 590 152, 0 599
538, 0 610
793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707
006, 0 708 101, 0
709 375, 0 709 376,0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT
International Patent
Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688,
92/06079, 92/1215 1,
92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,
93/00331, 93/01159,
93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084,
93/14113, 93/18023,
93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402,
94/02461, 94/02595,
94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997,
94/10165, 94/10167,
94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903,
94/19320; 94/19323,
94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042,
95/06645, 95/07886,
95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382,
95/18124, 95/18129,
95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,
95/30674, 95/30687,
95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562,
96/16939, 96/18643,
96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214,
96/32385, 96/37489,
97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206,
97/19084, 97/19942
and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931, 2
269 170, 2 269
590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The
preparation of such
compounds is fully described in the aforementioned patents and publications,
which are
incorporated herein by reference.
In an embodiment, the neurokinin-1 receptor antagonist for use in conjunction
with the formulations of the present invention is selected from: 2-(R)-(1-(R)-
(3,5-
bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxb-1 H,4H-
1,2,4-
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WO 2008/013807 PCT/US2007/016637
triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof,
which is described in
U.S. Patent No. 5,719,147.
A formulation of the instant invention may also be administered with an agent
useful in the treatment of anemia. Such an anemia treatment agent is, for
example, a continuous
erythropoiesis receptor activator (such as epoetin alfa).
A formulation of the instant invention may also be administered with an agent
useful in the treatment of neutropenia. Such a neutropenia treatment agent is,
for example, a
hematopoietic growth factor which regulates the production and function of
neutrophils such as a
human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF
include
filgrastim.
A formulation of the instant invention may also be administered with an
immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
A formulation of the instant invention may also be useful for treating or
preventing cancer in combination with P450 inhibitors including: xenobiotics,
quinidine,
tyrarnine, ketoconazole, testosterone, quinine, methyrapone, caffeine,
phenelzine, doxorubicin,
troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafyline,
cimetidine,
dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine,
verapamil, cortisol,
itraconazole, mibefradil, nefazodone and nelfinavir.
A formulation of the instant invention may also be useful for treating or
preventing cancer in combination with Pgp and/or BCRP inhibitors including:
cyclosporin A,
PSC833, GF120918, cremophorEL, fumitremorgin C, Ko132, Ko134, Iressa, Imatnib
mesylate,
EKI-785, C11033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-
710, tryprostatin A,
flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine,
verapamil, terfenadine,
ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir,
cortisol,
testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and
talinolol.
A formulation of the instant invention may also be useful for treating or
preventing cancer, including bone cancer, in combination with bisphosphonates
(understood to
include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic
acids).
Examples of bisphosphonates include but are not limited to: etidronate
(Didronel), pamidronate
(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa),
ibandronate
(Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate,
neridronate,
piridronate and tiludronate including any and all pharmaceutically acceptable
salts, derivatives,
hydrates and mixtures thereof.
A formulation of the instant invention may also be useful for treating or
preventing breast cancer in combination with aromatase inhibitors. Examples of
aromatase
inhibitors include but are not limited to: anastrozole, letrozole and
exemestane.
A formulation of the instant invention may also be useful for treating or.
preventing cancer in combination with siRNA therapeutics.
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The formulations of the instant invention may also be administered in
combination with ry-secretase inhibitors and/or inhibitors of NOTCH signaling.
Such inhibitors
include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO
03/013506,
WO 02/36555, WO 03/093252, WO 03/093264; WO 03/09325 1, WO 03/093253, WO.
2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, USSN 10/957,251,
WO
2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO
2004/03 1 1 39, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671
(including LY-450139).
A formulation of the instant invention may also be useful for treating or
preventing cancer in combination with PARP inhibitors.
A formulation of the instant invention may also be useful for treating cancer
in
combination with the following therapeutic agents: abarelix (Plenaxis
depot(&); aldesleukin
(Prokine ); Aldesleukin (Proleukin(&); Alemtuzumabb (Campath ); alitretinoin
(Panretin );
allopurinol (Zyloprim ); altretamine (Hexalen ); amifostine (Ethyol );
anastrozole
(Arimidex ); arsenic trioxide (Trisenox ); asparaginase (Elspar ); azacitidine
(Vidaza );
bevacuzimab (Avastin ); bexarotene capsules (Targretin ); bexarotene gel
(Targretin );
bleomycin (Blenoxane ); bortezomib (Velcade ); busulfan intravenous (Busulfex
); busulfan
oral (Myleran(&); calusterone (Methosarb ); capecitabine (Xeloda );
carboplatin (Paraplatin(&);
carmustine (BCNU , BiCNU(&); carmustine (Gliadel ); carmustine with
Polifeprosan 20
Implant (Gliadel Wafer ); celecoxib (Celebrex(D); cetuximab (Erbitux );
chlorambucil
(Leukeran ); cisplatin (Platinol ); cladribine (Leustatin , 2-CdA );
clofarabine (Clolar );
cyclophosphamide (Cytoxan , Neosar ); cyclophosphamide (Cytoxan Injection );
cyclophosphamide (Cytoxan Tablet ); cytarabine (Cytosar-U ); cytarabine
liposomal
(DepoCyt(D); dacarbazine (DTIC-Dome ); dactinomycin, actinomycin D (Cosmegen
);
Darbepoetin alfa (Aranesp(&); daunorubicin liposomal (DanuoXome );
daunorubicin,
daunomycin (Daunorubicin ); daunorubicin, daunomycin (Cerubidine ); Denileukin
difftitox
(Ontak ); dexrazoxane (Zinecard ); docetaxel (Taxotere ); doxorubicin
(Adriamycin PFS );
doxorubicin (Adriamycin , Rubex ); doxorubicin (Adriamycin PFS Injection );
doxorubicin
liposomal (Doxil ); dromostanolone propionate (dromostanolone );
dromostanolone
propionate (masterone injection ); Elliott's B Solution (Elliott's B Solution
); epirubicin
(Ellence ); Epoetin alfa (epogen ); erlotinib (Tarceva ); estramustine (Emcyt
); etoposide
phosphate (Etopophos ); etoposide, VP-16 (Vepesid ); exemestane (Aromasin );
Filgrastim
(Neupogen ); floxuridine (intraarterial) (FUDR ); fludarabine (Fludara(&);
fluorouracil, 5-FU
(Adrucil ); fulvestrant (Faslodex ); gefitinib (Iressa ); gemcitabine (Gemzar
); gemtuzumab
ozogamicin (Mylotarg ); goserelin acetate (Zoladex Implant ); goserelin
acetate (Zoladex );
histrelin acetate (Histrelin implant ); hydroxyurea (Hydrea ); Ibritumomab
Tiuxetan
(Zevalin ); idarubicin (Idamycin ); ifosfamide (IFEX ); imatinib mesylate
(Gleevec );
interferon alfa 2a (Roferon A ); Interferon alfa-2b (Intron A ); irinotecan
(Camptosar );
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lenalidomide (Revlimid ); letrozole (Femara ); leucovorin (Wellcovorin(D,
Leucovorin );
Leuprolide Acetate (Eligard ); levamisole (Ergamisol ); lomustine, CCNU (CeeBU
);
meclorethamine, nitrogen mustard (Mustargen ); megestrol acetate (Megace );
melphalan, L-
PAM (Alkeran ); mercaptopurine, 6-MP (Purinethol ); mesna (Mesnex(D); mesna
(Mesnex
tabs ); methotrexate (Methotrexate ); methoxsalen (Uvadex ); mitomycin
C(Mutamycin );
mitotane (Lysodren ); mitoxantrone (Novantrone ); nandrolone phenpropionate
(Durabolin-
50 ); nelarabine (Arranon ); Nofetumomab (Verluma(D); Oprelvekin (Neumega );
oxaliplatin
(Eloxatin ); paclitaxel (Paxene(g); paclitaxel (Taxol ); paclitaxel protein-
bound particles
(Abraxane(D); palifermin (Kepivance ); pamidronate (Aredia(D); pegademase
(Adagen
(Pegademase Bovine) ); pegaspargase (Oncaspar ); Pegfilgrastim (Neulasta );
pemetrexed
disodium (Alimta ); pentostatin (Nipent ); pipobroman (Vercyte ); plicamycin,
mithramycin
(Mithracin ); porfimer sodium (Photofrin ); procarbazine (Matulane );
quinacrine
(Atabrine ); Rasburicase (Elitek ); Rituximab (Rituxan ); sargramostim
(Leukine(&);
Sargramostim (Prokine ); sorafenib (Nexavar ); streptozocin (Zanosar );
sunitinib maleate
(Sutent ); talc (Sclerosol ); tamoxifen (Nolvadex ); temozolomide (Temodar );
teniposide,
VM-26 (Vumon ); testolactone (Teslac(&); thioguanine, 6-TG (Thioguanine );
thiotepa
(Thioplex ); topotecan (Hycanitin ); toremifene (Fareston ); Tositumomab
(Bexxar(&);
Tositumomab/I-131 tositumomab (Bexxar ); Trastuzumab (Herceptin ); tretinoin,
ATRA
(Vesanoid ); Uracil Mustard (Uracil Mustard Capsules ); valrubicin (Valstar );
vinblastine
(Velban ); vincristine (Oncovin(D); vinorelbine (Navelbine ); vorinostat
(Zolinza ) and
zoledronate (Zometa ).
In another embodiment, the formulation may also be useful for treating cancer
in
combination with dasatinib or nilotinib.
In another embodiment, the formulation may be useful for treating cancer in
combination with radioactive iodine (usually 1131) and thyroid hormone
(levothyroxine and/or
triiodothyronin).
In another embodiment, the formulation may be useful for treating cancer in
combination with somatostatin analogs (e.g. sandostatin and octreotide).
In another embodiment, the formulation may be useful for treating cancer in
combination with radiolabeled CEA antibodies.
Thus, the scope of the instant invention encompasses the use of the instantly
claimed formulations in combination with a second compound selected from: an
estrogen
receptor modulator, an androgen receptor modulator, a retinoid receptor
modulator, a
cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein
transferase inhibitor, an
HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse
transcriptase inhibitor, an
angiogenesis inhibitor, PPAR-y agonists, PPAR-8 agonists, an inhibitor of
inherent multidrug
resistance, an anti-emetic agent, an agent useful in the treatment of anemia,
an agent useful in the
treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell
proliferation and
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survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA
therapeutic, -i-secretase
and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases
(RTKs), an agent
that interferes with a cell cycle checkpoint, and any of the therapeutic
agents listed above.
In an embodiment, the angiogenesis inhibitor to be used as the second compound
is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-
derived growth factor, an
inhibitor of fibroblast-derived growth factor, an inhibitor of platelet
derived growth factor, an
1VIMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-a,
interleukin-12,
pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole,
combretastatin A-4,
squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,
troponin-1, or an
antibody to VEGF. In an embodiment, the estrogen receptor modulator is
tamoxifen or
raloxifene.
The term "administration" and variants thereof (e.g., "administering" a
compound)
in reference to a formulation of the invention means introducing the
formulation or a prodrug of
the formulation into the system of the animal in need of treatment. When a
formulation of the
invention or prodrug thereof is provided in combination with one or more other
active agents
(e.g., a cytotoxic agent, etc.), "administration" and its variants are each
understood to include
concurrent and sequential introduction of the formulation or prodrug thereof
and other agents.
As used herein, the term "composition" or "formulation" is intended to
encompass
a product comprising the specified ingredients in the specified amounts, as
well as any product
which results, directly or indirectly, from combination of the specified
ingredients in the
specified amounts.
The term "therapeutically effective amount" as used herein means that amount
of
active compound or pharmaceutical agent in the insant formulation that elicits
the biological or
medicinal response in a tissue, system, animal or human that is being sought
by a researcher,
veterinarian, medical doctor or other clinician.
The term "treating cancer" or "treatment of cancer" refers to administration
to a
mammal afflicted with a cancerous condition and refers to an effect that
alleviates the cancerous
condition by killing the cancerous cells, but also to an effect that results
in the inhibition of
growth and/or metastasis of the cancer.
Also included in the scope of the claims is a method of treating cancer that
comprises administering a therapeutically effective amount of a formulation of
the instant
invention in combination with radiation therapy and/or in combination with a
second compound
selected from: an estrogen receptor modulator, an androgen receptor modulator,
a retinoid
receptor modulator, a cytotoxiccytostatic agent, an antiproliferative agent, a
prenyl-protein
transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease
inhibitor, a reverse
transcriptase inhibitor, an angiogenesis inhibitor, PPAR-y agonists, PPAR-S
agonists, an
inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent
useful in the treatment
of anemia, an agent useful in the treatment of neutropenia, an immunologic-
enhancing drug, an
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inhibitor of cell proliferation and survival signaling, a bisphosphonate, an
aromatase inhibitor, an
siRNA therapeutic, -t-secretase and/or NOTCH inhibitors, agents that interfere
with receptor
tyrosine kinases (RTKs), an agent that interferes with a cell cycle
checkpoint, and any of the
therapeutic agents listed above.
And yet another embodiment of the invention is a method of treating cancer
that
comprises administering a therapeutically effective amount of a formulation of
the instant
invention in combination with paclitaxel or trastuzumab.
The invention further encompasses a method of treating or preventing cancer
that
comprises administering a therapeutically effective amount of a formulation of
the instant
invention in combination with a COX-2 inhibitor.
The instant invention also includes a pharmaceutical composition useful for
treating or preventing cancer that comprises a therapeutically effective
amount of a formulation
of the instant invention and a second compound selected from: an estrogen
receptor modulator,
an androgen receptor modulator, a retinoid receptor modulator, a
cytotoxic/cytostatic agent, an
antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA
reductase inhibitor,
an HN protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis
inhibitor, a PPAR-y
agonist, a PPAR-S agonist, an inhibitor of cell proliferation and survival
signaling, a
bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, -)-secretase
and/or NOTCH
inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an
agent that interferes
with a cell cycle checkpoint, and any of the therapeutic agents listed above.
EXAMPLE 1
Lactic Acid Formulation (20mg/mL) of MK-0457
Prepare a 20mg/mL concentration of lactic acid in water by weighing 2.Og of
lactic acid (either, L-lactic acid, D-lactic acid or a racemic mixture) into a
100mL volumetric
flask. Next, weigh out 200mg of MK-0457 into a lOmL volumetric flask. Next,
add
approximately 8mL of the 20mg/mL lactic acid solution to the l OmL volumetric
flask. Next, add
the appropriate amount of sugar (for example, 15mg/mL, 50mg/mL and 100mg/mL,
depending
on the desired tonicity). Stir the solution until all the drug contents are
dissolved. Qs'd the
solution to l OmL with the 20mg/mL lactic acid solution and adjust the pH as
needed to aid in
solublization.
EXAMPLE 2
Lactic Acid Formulation (20mg/mL) of MK-0457 (large scale manufacture)
Add water for injection equal to 80 percent of batch weight to a suitable
mixing
vessel. Add the necessary amount of compendial lactic acid (either, L-lactic
acid, D-lactic acid
or a racemic mixture) equaling to 20mg/mL and mix to insure homogeneity. Add
MK-0457
equal to 20mg/mL free base to the vessel and mix to dissolve. Add the
appropriate amount of
sugar (for example, 15mg/mL, 50mg/mI, and 100mg/mL, depending on the desired
tonicity) to
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WO 2008/013807 PCT/US2007/016637
the vessel and mix to dissolve. Adjust the pH as needed. Qs'd the batch to
final weight with
water for injection. Sterile filter and collect the filtered formulation in an
appropriate sterile
receiving vessel. Fill and stopper the formulation in appropriate vials using
aseptic technique in
a properly classified area. Cap and terminally sterilize product as required.
Store the
formulation at the appropriate temperature conditions.
EXAMPLE 3
Lactic Acid Formulation (20mg/mL) of MK-0457 (large scale manufacture)
In another embodiment, a 20mg/mL lactic acid formulation of Compound I (large
scale manufacture) may be prepared according to the following steps: Add water
for injection
equal to 80 percent of batch weight to a suitable mixing vessel. Add the
necessary amount of
compendial lactic acid (either L-lactic acid, D-lactic acid.or a racemic
mixture) equaling to
20mg/mL and mix to insure homogeneity. Add MK-0457 equal to 20mg/mL free base
to the
vessel and mix to dissolve. Add the appropriate amount of sugar (for example,
15mg/mL,
50mg/mL or 100mg/mL, depending on the desired tonicity) and 0.05mg/ml EDTA
(edetate
disodium dihydrate) to the vessel and mix to dissolve. Adjust the pH as
needed. Qs'd the batch
to final weight with water for injection. Sterile filter and collect the
filtered fonmulation in an
appropriate sterile receiving vessel. Fill and stopper the formulation in
appropriate vials using
aseptic technique in a properly classified area. Cap and terminally sterilize
product as required.
Store the formulation at the appropriate temperature conditions.
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