Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION OF AN INDAZOLYLAMINOPYRROLOTRIAZINE AND TAXANE
FOR CANCER TREATMENT
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119(e) to U.S.
Provisional
Application No. 61/159,404, filed March 11, 2009, the disclosure of which is
incorporated
herein by reference in its entirety.
FIELD
[0002] Provided herein are methods of treating a proliferative disease in a
subject,
comprising administering to the subject a therapeutically effective amount of
an
indazolylaminopyrrolotriazine and a taxane. Also provided herein are
pharmaceutical
compositions which comprise an indazolylaminopyrrolotriazine and taxane, in
combination
with one or more pharmaceutically acceptable excipients.
BACKGROUND
[0003] The Her family of receptor tyrosine kinase is comprised of Her 1 (also
known
as EGFR or ErbB-1), Her2 (ErbB-2), Her3 (ErbB-3), and Her4 (ErbB-4). The
activation or
overexpression of its members, such as Herl or Her2, is implicated in human
malignancies
that include breast cancer, ovarian cancer, endometrial cancer, cervical
cancer, esophageal
cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer,
non-small cell
lung cancer (NSCLC), bladder cancer, head and neck cancer, and glioma
including
glioblastoma. Currently marketed anti-EGFR therapies include the small
molecules gefitinib
(IRESSA ), which was approved for the treatment of NSCLC, and erlotinib
(TARCEVA ),
which was approved for the treatment of NSCLC and pancreatic cancer. Currently
marketed
monoclonal antibody therapies include cetuximab (ERBITUX ), an anti-EGFR
antibody that
was approved for the treatment of colorectal cancer, and trastuzumab
(HERCEPTIN ), an
anti-Her2 antibody that was approved for the treatment of Her2-positive breast
cancer.
Lapatinib (TYKERB ), which is a small molecule inhibitor with dual anti-
EGFR/Her2
activity, was most recently approved for the treatment of Her2-positive breast
cancer.
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[00041 The taxanes are a powerful class of chemotherapeutics that may be
isolated
from the plant genus Taxus or further derivatized as a synthetic analog. The
taxanes that
comprise this class share the same chemical scaffold and similar mechanism of
action and
they have been found to have similar preclinical activity and clinical
activity. See,
Eisenhauer et al., Drugs 1998, 55, 5-30; Huizing et al., Cancer Investigation
1995, 13, 381-
404; and Von Hoff et al., Seminars in Oncology, 1997, 24, S13-3- S13-10. The
first taxane,
paclitaxel (TAXOL ), which is 5 (3,20-epoxy-1,2a,4,713, 10(3, 13 a-
hexahydroxytax-11-en-9-one
4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine,
was isolated in
1971 from the Pacific yew (Taxus brevifolia), but may also be prepared using a
semi-
synthetic process from the European yew (Taxus baccata). Another well known
taxane,
docetaxel (TAXOTERE ), which is (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-
butyl ester,
13-ester with 513-20-epoxy- 1,2a,4,713, 10(3, 13a-hexahydroxytax-11-en-9-one 4-
acetate 2-
benzoate, trihydrate, is also prepared from a semi-synthetic process from
Taxus baccata. The
taxanes belong to the subclass of antimitotics and exert their effect by
promoting the
polymerization of tubulin to the extent of interfering with the normal dynamic
process of
tubulin assembly and disassembly during cell cycling. This microtubule
dysfunction leads to
cell death. Despite these advances in anticancer therapy, there exists a long-
felt need for
effective therapies for proliferative diseases, in one embodiment, for cancers
that are
refractory to existing therapies.
SUMMARY OF THE DISCLOSURE
[00051 Provided herein is a method of treating a proliferative disease in a
subject,
comprising administering to the subject a therapeutically effective amount of
(i) a taxane; and
(ii) an indazolylaminopyrrolotriazine of Formula I:
rR
N,
,N
R1 HN
-N
HN
~( N.N
X O
R2
(I)
or an enantiomer, a mixture of enantiomers, or a mixture of two or more
diastereomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof;
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wherein:
R is C6_14 aryl, heteroaryl, or heterocyclyl;
RI is C1.6 alkyl;
R2 is hydrogen, C1.6 alkyl, C3_10 cycloalkyl, C6.14 aryl, C7_20 aralkyl,
heteroaryl, or
heterocyclyl;
X is a bond, -0-, -S-, -C(R3R4)-, or -N(R3)-; and
each R3 and R4 is independently hydrogen, C1.6 alkyl, C6_14 aryl, C7-2o
aralkyl,
heteroaryl, or heterocyclyl;
wherein each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally
substituted with one or more substituents Q selected from the group consisting
of (a) cyano,
halo, and nitro; (b) C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3_10 cycloalkyl,
C6.14 aryl,
heteroaryl, and heterocyclyl; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbR , -
C(=NRa)NRbRc,
-ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbR , -OC(=NRa)NRbRc, -OS(O)Ra, -OS(O)2Ra,
-OS(O)NRbR , -OS(O)2NRbR , -NR aRd, -NR aC(O)Rb, -NR aC(O)ORb, -NR aC(O)NRbRc,
-NR aC(=NRd)NRbRc, -NR aS(O)Rb, -NR aS(O)2Rb, -NR aS(O)NRbRc, -NR aS(O)2NRbRc,
-SRa, -S(O)Ra, and -S(O)2Ra; wherein each Ra, Rb, Rc, and Rd is independently
(i) hydrogen,
C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_10 cycloalkyl, C6_14 aryl,
heteroaryl, or heterocyclyl;
or (ii) Rb and Rc together with the N atom to which they are attached form
heterocyclyl or
heteroaryl.
[00061 In one embodiment, the taxane and the indazolylaminopyrrolotriazine
described herein, e.g., a compound of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; are administered
accordingly to a dosing
schedule provided herein.
[00071 Also provided herein is a method of inhibiting the growth of a cell,
comprising
contacting the cell with an effective amount of a taxane and an
indazolylaminopyrrolotriazine
described herein, e.g., a compound of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[00081 Further provided herein is a pharmaceutical composition, comprising (i)
a
taxane; and (ii) an indazolylaminopyrrolotriazine described herein, e.g., a
compound of
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Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof; in combination with one or more pharmaceutically acceptable
excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows the synergetic effect of AC480 in combination with
paclitaxel
on MX-1 human breast carcinoma as determined by tumor size. The animals were
treated
according to the dosing schedules as shown in Table 1.
[0010] FIG. 2 shows the synergetic effect of AC480 in combination with
paclitaxel
on MX-1 human breast carcinoma as measured by the percentage of complete
regression.
The animals were treated according to the dosing schedules as shown in Table
1.
[0011] FIG. 3 shows the synergetic effect of AC480 in combination with
paclitaxel
on MX-1 human breast carcinoma as measured by the percentage of survival after
treatment.
The animals were treated according to the dosing schedules as shown in Table
1.
[0012] FIG. 4 shows the synergetic effect of AC480 in combination with
paclitaxel
on MX-1 human breast carcinoma as measured by the percentage of complete
regression.
The animals were treated according to the dosing schedules as shown in Table
2.
DETAILED DESCRIPTION
[0013] To facilitate understanding of the disclosure set forth herein, a
number of
terms are defined below.
[0014] Generally, the nomenclature used herein and the laboratory procedures
in
organic chemistry, medicinal chemistry, biochemistry, biology, pharmacology,
and others
described herein are those well known and commonly employed in the art. Unless
defined
otherwise, all technical and scientific terms used herein generally have the
same meaning as
commonly understood by one of ordinary skill in the art to which this
disclosure belongs.
[0015] The term "tumor," "neoplasm," and "neoplastic disorder or disease" are
used
interchangeably herein and are meant to refer to unwanted cell proliferation
of one or more
subset of cells in a multicellular organism resulting in harm (i.e.,
discomfort or decreased life
expectancy) to the multicellular organisms. In certain embodiments, a tumor
can be benign
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(non-invasive) or malignant (invasive).
[0016] The term "cancer" is meant to refer to a malignant neoplasm, which is
characterized by uncontrolled cell proliferation where cells have lost their
normal regulatory
controls that would otherwise govern the rate of cell growth. These
unregulated, dividing
cells can spread throughout the body and invade normal tissues in a process
referred to as
"metastasis."
[0017] The term "naturally occurring" or "native" when used in connection with
biological materials such as nucleic acid molecules, polypeptides, host cells,
and the like,
refers to materials which are found in nature and are not manipulated by man.
Similarly,
"non-naturally occurring" or "non-native" refers to a material that is not
found in nature or
that has been structurally modified or synthesized by man.
[0018] The terms "HER1," "epidermal growth factor receptor," "EGFR," and
"ErbB 1" are used interchangeably herein and refer to an EGFR receptor protein
or variant
thereof, as described, for example, in Carpenter et al., Ann. Rev. Biochem.
1987, 56, 881-914.
HER2 variants include proteins substantially homologous to a native EGFR,
i.e., proteins
having one or more naturally or non-naturally occurring amino acid deletions,
insertions or
substitutions (e.g., EGFR derivatives, homologs and fragments), as compared to
the amino
acid sequence of a native EGFR. The amino acid sequence of an HER2 variant is
at least
about 80% identical, at least about 90% identical, or at least about 95%
identical to a native
EGFR. An example of naturally occurring mutant forms of a native EGFR, i.e. a
deletion
mutant EGFR, is described in Humphrey et al., Proc. Natl. Acad. Sci. USA 1990,
87, 4207-
4211.
[0019] The terms "HER2" and "ErbB2" are used interchangeably herein and refer
to a
HER2 receptor protein or variant thereof. For example, a human HER2 protein is
described
in Semba et al., Proc. Natl. Acad. Sci. USA 1985, 82, 6497-6501 and Yamamoto
et al. Nature
1986, 319, 230-234 (Genebank accession number X03363). HER2 variants include
proteins
substantially homologous to a native HER2, i.e., proteins having one or more
naturally or
non-naturally occurring amino acid deletions, insertions or substitutions
(e.g., HER2
derivatives, homologs and fragments), as compared to the amino acid sequence
of a native
HER2. The amino acid sequence of a HER2 variant is at least about 80%
identical, at least
about 90% identical, or at least about 95% identical to a native HER2.
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[00201 The term "overexpress" or "overexpression" is meant that a cell
associated
with a disease, disorder, or condition comprises a detectably higher level of
a protein, such as
HER1 or HER2, than an otherwise identical cell that is not associated with a
disease, disorder
or condition.
[00211 The term "subject" refers to an animal, including, but not limited to,
a primate
(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
The terms
"subject" and "patient" are used interchangeably herein in reference, for
example, to a
mammalian subject, such as a human subject, in one embodiment, a human.
[00221 The terms "treat," "treating," and "treatment" are meant to include
alleviating
or abrogating a disorder, disease, or condition, or one or more of the
symptoms associated
with the disorder, disease, or condition; or alleviating or eradicating the
cause(s) of the
disorder, disease, or condition itself.
[00231 The term "contacting" or "contact" is meant to refer to bringing
together of a
therapeutic agent and cell or tissue such that a physiological and/or chemical
effect takes
place as a result of such contact. Contacting can take place in vitro, ex
vivo, or in vivo. In
one embodiment, a therapeutic agent is contacted with a cell in cell culture
(in vitro) to
determine the effect of the therapeutic agent on the cell. In another
embodiment, the
contacting of a therapeutic agent with a cell or tissue includes the
administration of a
therapeutic agent to a subject having the cell or tissue to be contacted.
[00241 The term "therapeutically effective amount" are meant to include the
amount
of a compound that, when administered, is sufficient to prevent development
of, or alleviate
to some extent, one or more of the symptoms of the disorder, disease, or
condition being
treated. The term "therapeutically effective amount" also refers to the amount
of a compound
that is sufficient to elicit the biological or medical response of a
biological molecule (e.g., a
protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which
is being
sought by a researcher, veterinarian, medical doctor, or clinician.
[00251 The term "pharmaceutically acceptable carrier," "pharmaceutically
acceptable
excipient," "physiologically acceptable carrier," or "physiologically
acceptable excipient"
refers to a pharmaceutically-acceptable material, composition, or vehicle,
such as a liquid or
solid filler, diluent, solvent, or encapsulating material. In one embodiment,
each component
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is "pharmaceutically acceptable" in the sense of being compatible with the
other ingredients
of a pharmaceutical formulation, and suitable for use in contact with the
tissue or organ of
humans and animals without excessive toxicity, irritation, allergic response,
immunogenicity,
or other problems or complications, commensurate with a reasonable
benefit/risk ratio. See,
Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott
Williams &
Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th
Edition, Rowe
et al., Eds., The Pharmaceutical Press and the American Pharmaceutical
Association: 2005;
and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower
Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd
Edition,
Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.
[00261 The term "about" or "approximately" means an acceptable error for a
particular value as determined by one of ordinary skill in the art, which
depends in part on
how the value is measured or determined. In certain embodiments, the term
"about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In certain
embodiments, the
term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%,
6%, 5%,
4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[00271 The terms "active ingredient" and "active substance" refer to a
compound,
which is administered, alone or in combination with one or more
pharmaceutically acceptable
excipients, to a subject for treating, preventing, or ameliorating one or more
symptoms of a
condition, disorder, or disease. As used herein, "active ingredient" and
"active substance"
may be an optically active isomer of a compound described herein.
[00281 The terms "drug," "therapeutic agent," and "chemotherapeutic agent"
refer to
a compound, or a pharmaceutical composition thereof, which is administered to
a subject for
treating, preventing, or ameliorating one or more symptoms of a condition,
disorder, or
disease.
[00291 The term "alkyl" refers to a linear or branched saturated monovalent
hydrocarbon radical, wherein the alkylene may optionally be substituted as
described herein.
The term "alkyl" also encompasses both linear and branched alkyl, unless
otherwise
specified. In certain embodiments, the alkyl is a linear saturated monovalent
hydrocarbon
radical that has 1 to 20 (C1 20), 1 to 15 (C1 15), 1 to 10 (C1_10), or 1 to 6
(C1.6) carbon atoms, or
branched saturated monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15
(C3_15), 3 to 10
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(C3_10), or 3 to 6 (C3.6) carbon atoms. As used herein, linear C1_6 and
branched C3.6 alkyl
groups are also referred as "lower alkyl." Examples of alkyl groups include,
but are not
limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl,
isopropyl, butyl
(including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl
(including all
isomeric forms), and hexyl (including all isomeric forms). For example, C1.6
alkyl refers to a
linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a
branched
saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
[00301 The term "alkenyl" refers to a linear or branched monovalent
hydrocarbon
radical, which contains one or more, in one embodiment, one to five, carbon-
carbon double
bonds. The alkenyl may be optionally substituted as described herein. The term
"alkenyl"
also embraces radicals having "cis" and "trans" configurations, or
alternatively, "Z" and "E"
configurations, as appreciated by those of ordinary skill in the art. As used
herein, the term
"alkenyl" encompasses both linear and branched alkenyl, unless otherwise
specified. For
example, C2.6 alkenyl refers to a linear unsaturated monovalent hydrocarbon
radical of 2 to 6
carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to
6 carbon
atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon
radical of 2
to 20 (C2_20), 2 to 15 (C2_15), 2 to 10 (C2_10), or 2 to 6 (C2.6) carbon
atoms, or a branched
monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C3_15), 3 to 10
(C3_10), or 3 to 6
(C3.6) carbon atoms. Examples of alkenyl groups include, but are not limited
to, ethenyl,
propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
[00311 The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon
radical, which contains one or more, in one embodiment, one to five, carbon-
carbon triple
bonds. The alkynyl may be optionally substituted as described herein. The term
"alkynyl"
also encompasses both linear and branched alkynyl, unless otherwise specified.
In certain
embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20
(C2_20), 2 to
15 (C2_15), 2 to 10 (C2_10), or 2 to 6 (C2.6) carbon atoms, or a branched
monovalent
hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C3_15), 3 to 10 (C3_10), or 3
to 6 (C3.6) carbon
atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C-
-CH) and
propargyl (-CH2C CH). For example, C2.6 alkynyl refers to a linear unsaturated
monovalent
hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated
monovalent
hydrocarbon radical of 3 to 6 carbon atoms.
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[0032] The term "cycloalkyl" refers to a cyclic saturated bridged and/or non-
bridged
monovalent hydrocarbon radical, which may be optionally substituted as
described herein. In
certain embodiments, the cycloalkyl has from 3 to 20 (C3_20), from 3 to 15
(C3_15), from 3 to
(C3_10), or from 3 to 7 (C3.7) carbon atoms. Examples of cycloalkyl groups
include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
[0033] The term "aryl" refers to a monocyclic aromatic group and/or
multicyclic
monovalent aromatic group that contain at least one aromatic hydrocarbon ring.
In certain
embodiments, the aryl has from 6 to 20 (C6_20), from 6 to 15 (C6_15), or from
6 to 10 (C6.10)
ring atoms. Examples of aryl groups include, but are not limited to, phenyl,
naphthyl,
fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
Aryl also refers
to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and
the others of
which may be saturated, partially unsaturated, or aromatic, for example,
dihydronaphthyl,
indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,
aryl may be
optionally substituted as described herein.
[0034] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group
substituted with one or more aryl groups. In certain embodiments, the aralkyl
has from 7 to
30 (C7_30), from 7 to 20 (C7_20), or from 7 to 16 (C7_16) carbon atoms.
Examples of aralkyl
groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-
phenylpropyl. In certain
embodiments, aralkyl may also be optionally substituted as described herein.
[0035] The term "heteroaryl" refers to a monocyclic aromatic group and/or
multicyclic aromatic group that contain at least one aromatic ring, wherein at
least one
aromatic ring contains one or more heteroatoms independently selected from 0,
S, and N.
Each ring of a heteroaryl group can contain one or two 0 atoms, one or two S
atoms, and/or
one to four N atoms, provided that the total number of heteroatoms in each
ring is four or less
and each ring contains at least one carbon atom. In certain embodiments, the
heteroaryl has
from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic
heteroaryl
groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl,
isoxazolyl,
oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridyl, pyrimidinyl,
pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and
triazolyl. Examples of
bicyclic heteroaryl groups include, but are not limited to, benzofuranyl,
benzimidazolyl,
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benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,
benzothienyl,
benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,
imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,
isobenzothienyl,
isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl,
phthalazinyl,
pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl,
quinazolinyl,
thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl
groups include, but
are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl,
perimidinyl,
phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxazinyl,
and xanthenyl. In certain embodiments, heteroaryl may also be optionally
substituted as
described herein.
[00361 The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-
aromatic
ring system and/or multicyclic ring system that contains at least one non-
aromatic ring,
wherein one or more of the non-aromatic ring atoms are heteroatoms
independently selected
from 0, S, or N; and the remaining ring atoms are carbon atoms. In certain
embodiments, the
heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to
10, from 3 to 8,
from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the
heterocyclyl is a
monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include
a fused or
bridged ring system, and in which the nitrogen or sulfur atoms may be
optionally oxidized,
the nitrogen atoms may be optionally quaternized, and some rings may be
partially or fully
saturated, or aromatic. The heterocyclyl may be attached to the main structure
at any
heteroatom or carbon atom which results in the creation of a stable compound.
Examples of
such heterocyclic radicals include, but are not limited to, azepinyl,
benzodioxanyl,
benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,
benzotetrahydrofuranyl,
benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, (3-carbolinyl,
chromanyl,
chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,
dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,
dihydropyrazolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl,
dioxolanyl, 1,4-
dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,
isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl,
isothiazolidinyl,
isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,
oxazolidinonyl,
oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,
pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl,
tetrahydroisoquinolinyl,
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tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl,
tetrahydroquinolinyl,
and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be
optionally substituted
as described herein.
[00371 The term "halogen", "halide" or "halo" refers to fluorine, chlorine,
bromine,
and/or iodine.
[00381 The term "optionally substituted" is intended to mean that a group,
such as an
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or alkoxy
group, may be
substituted with one or more substituents independently selected from, e.g.,
(a) alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl, each
optionally substituted
with one or more, in one embodiment, one, two, three, or four, substituents Q;
and (b) halo,
cyano (-CN), nitro (-NO2), -C(O)Ra, -C(O)ORa, -C(O)NRbRC, -C(NRa)NRbRc, -OR',
-OC(O)Ra, -OC(O)ORa, -OC(O)NRbRC, -OC(=NRa)NRbRc, -OS(O)Ra, -OS(O)2Ra,
-OS(O)NRbRC, -OS(O)2NRbRe, -NR bRC, -NR aC(O)Rd, -NR aC(O)ORd, -NR aC(O)NRbRc,
-NR aC(=NRd)NRbRc, -NR aS(O)Rd, -NR aS(O)2Rd, -NR aS(O)NRbRc, -NR aS(O)2NRbRe,
-SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRC, and -S(O)2NRbRe, wherein each Ra, Rb, Rc,
and Rd is
independently (i) hydrogen; (ii) C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3_7
cycloalkyl, C6-14
aryl, 07.15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted
with one or more,
in one embodiment, one, two, three, or four, substituents Q; or (iii) Rb and
Rc together with
the N atom to which they are attached form heteroaryl or heterocyclyl,
optionally substituted
with one or more, in one embodiment, one, two, three, or four, substituents Q.
As used
herein, all groups that can be substituted are "optionally substituted,"
unless otherwise
specified.
[00391 In one embodiment, each Q is independently selected from the group
consisting of (a) cyano, halo, and nitro; and (b) C1.6 alkyl, C2.6 alkenyl,
C2.6 alkynyl, C3_7
cycloalkyl, C6_14 aryl, 07.15 aralkyl, heteroaryl, and heterocyclyl; and (c) -
C(O)Re, -C(O)ORe,
-C(O)NRfRg, -C(NRe)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg,
-OC(=NRe)NRfRg, -OS(O)Re, _OS(O)2R e, -OS(O)NRfRg, -OS(0)2NRfRg, -NRfRg,
-NReC(O)Rh, -NReC(O)ORh, -NReC(O)NRfRg, -NReC(=NR)NRfRg, -NReS(O)Rh,
-NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -
S(O)NRfRg,
and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i)
hydrogen; (ii) C1.6
alkyl, C2.6 alkenyl, C2.6 alkynyl, C3_7 cycloalkyl, C6_14 aryl, 07.15 aralkyl,
heteroaryl, or
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heterocyclyl; or (iii) Rf and R9 together with the N atom to which they are
attached form
heteroaryl or heterocyclyl.
[00401 In certain embodiments, "optically active" and "enantiomerically
active" refer
to a collection of molecules, which has an enantiomeric excess of no less than
about 50%, no
less than about 70%, no less than about 80%, no less than about 90%, no less
than about 91%,
no less than about 92%, no less than about 93%, no less than about 94%, no
less than about
95%, no less than about 96%, no less than about 97%, no less than about 98%,
no less than
about 99%, no less than about 99.5%, or no less than about 99.8%. In certain
embodiments,
the compound comprises about 95% or more of the desired enantiomer and about
5% or less
of the less preferred enantiomer based on the total weight of the racemate in
question.
[00411 In describing an optically active compound, the prefixes R and S are
used to
denote the absolute configuration of the molecule about its chiral center(s).
The (+) and (-)
are used to denote the optical rotation of the compound, that is, the
direction in which a plane
of polarized light is rotated by the optically active compound. The (-) prefix
indicates that
the compound is levorotatory, that is, the compound rotates the plane of
polarized light to the
left or counterclockwise. The (+) prefix indicates that the compound is
dextrorotatory, that
is, the compound rotates the plane of polarized light to the right or
clockwise. However, the
sign of optical rotation, (+) and (-), is not related to the absolute
configuration of the
molecule, R and S.
[00421 The term "solvate" refers to a compound provided herein or a salt
thereof,
which further includes a stoichiometric or non-stoichiometric amount of
solvent bound by
non-covalent intermolecular forces. Where the solvent is water, the solvate is
a hydrate.
Indazolylaminopyrrolotriazines
[00431 In one embodiment, the indazolylaminopyrrolotriazine described herein
has
the structure of Formula I:
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rR
N
,N
R1 HN \
__N
HN
~( N.N
X O
R2
(I)
and enantiomers, mixtures of enantiomers, and mixtures of two or more
diastereomers
thereof; and pharmaceutically acceptable salts, solvates, hydrates, and
prodrugs thereof;
wherein:
R is C6_14 aryl, heteroaryl, or heterocyclyl;
R1 is C1.6 alkyl;
R2 is hydrogen, C1.6 alkyl, C3_10 cycloalkyl, C6.14 aryl, C7_20 aralkyl,
heteroaryl, or
heterocyclyl;
X is a bond, -0-, -S-, -C(R3R4)-, or -N(R3)-; and
each R3 and R4 is independently hydrogen, C1.6 alkyl, C6_14 aryl, C7-2o
aralkyl,
heteroaryl, or heterocyclyl;
wherein each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally
substituted with one or more substituents Q selected from the group consisting
of (a) cyano,
halo, and nitro; (b) C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3_10 cycloalkyl,
C6.14 aryl,
heteroaryl, and heterocyclyl; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbR , -
C(=NRa)NRbRc,
-ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbR , -OC(=NRa)NRbRc, -OS(O)Ra, -OS(O)2Ra,
-OS(O)NRbR , -OS(O)2NRbR , -NR aRd, -NR aC(O)Rb, -NR aC(O)ORb, -NR aC(O)NRbRc,
-NR aC(=NRd)NRbRc, -NR aS(O)Rb, -NR aS(O)2Rb, -NR aS(O)NRbRc, -NR aS(O)2NRbRc,
-SRa, -S(O)Ra, and -S(O)2Ra; wherein each Ra, Rb, Rc, and Rd is independently
(i) hydrogen,
C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3_10 cycloalkyl, C6.14 aryl,
heteroaryl, or heterocyclyl;
or (ii) Rb and Rc together with the N atom to which they are attached form
heterocyclyl or
heteroaryl.
[00441 In one embodiment, in the indazolylaminopyrrolotriazine of Formula I, R
is
C6_14 aryl, RI is C14 alkyl, each optionally substituted with one or more
substituents Q. in one
embodiment, one, two, or three substituents Q.
[00451 In another embodiment, in the indazolylaminopyrrolotriazine of Formula
I, X
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is 0, and R2 is C3_10 cycloalkyl, heteroaryl, or heterocyclyl, each optionally
substituted with
one or more substituents Q, in one embodiment, one, two, or three substituents
Q.
[0046] In another embodiment, the indazolylaminopyrrolotriazine is selected
from the
group consisting of:
115 -ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
115 -ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (2R)-2-pyrrolidinylmethyl ester;
115 -ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (2S)-2-pyrrolidinylmethyl ester;
[5-ethyl-4-[[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (3R)-3-morpholinylmethyl ester;
115 -ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, 3-[(3S)-3-hydroxy-l-pyrrolidinyl]propyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, 3-[(3S)-3-hydroxy-l-piperidinyl]propyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (3R)-3-pyrrolidinylmethyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, 3-[(3R)-3-hydroxy-l-pyrrolidinyl]propyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, [(2S)-1-methyl-2-pyrrolidinyl]methyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (2S)-2-morpholinylmethyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-pyrrolidinylmethyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (2R)-2-morpholinylmethyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, [(3R)-1-methyl-3-pyrrolidinyl]methyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, trans-4-aminocyclohexyl ester;
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[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (3R)-3-piperidinyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-piperidinyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, cis-4-aminocyclohexyl;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (2R,4R)-2-(hydroxymethyl)-4-piperidinyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, (2S)-2-(hydroxymethyl)-4-piperidinyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, cis-4-(aminomethyl)cyclohexyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, cis-4-amino-4-methylcyclohexyl ester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, [(2R,4R)-4-(hydroxy-2-piperidinyl]methylester;
[5-ethyl-4- [[(1-phenylmethyl)-1H-indazol-5-yl] amino]pyrrolo[2,1-f] [
1,2,4]triazin-6-yl]-
carbamic acid, trans-4-(aminomethyl)cyclohexyl ester;
[5-ethyl-4-[[1-(2-oxazolylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,
4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-(2-thienylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4
]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-(4-thiazolylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-(3-thienylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-(2-pyridinylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-(2-thiazolylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[1-(3-pyridinylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f]
[1,2,4]triazin-6-yl]-
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carbamic acid, (3S)-3-morpholinylmethyl ester;
[5-ethyl-4-[[ 1-(pyrazinylmethyl)-1H-indazol-5-yl] amino]pyrrolo [2,1-f] [
l,2,4]triazin-6-yl]-
carbamic acid, (3S)-3-morpholinylmethyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, trans-4-aminocyclohexyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (2R,4R)-2-(hydroxymethyl)-4-piperidinyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (2S,4S)-2-(hydroxymethyl)-4-piperidinyl ester;
[4-[[-1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[ 1,2,4]-
triazin-6-yl]-carbamic acid, cis-4-aminocyclohexyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, cis-4-amino-4-methyl-cyclohexyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (2R)-2-aminopropyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (2S)-2-aminopropyl ester;
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (3R)-3-morpholinylmethyl ester;
[4-[[ 1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[ 1,2,4]triazin-
6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester;
[4-[[ 1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[ 1,2,4]triazin-
6-yl]-carbamic acid, (3R)-3-piperidinyl ester;
[4-[[ 1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[ 1,2,4]triazin-
6-yl]-carbamic acid, (3S)-3-piperidinyl ester;
3-[[[[[4-[[1[(3 -fluorophenyl)methyll - 1H-indazol-5 -yl] amino] -5-
methylpyrrolo[2,1-f] [ 1,2,4]-
triazin-6-yl]amino] carbonyl] oxy]methyl]-4-morpholinecarboxylic acid, (3S)-
1,1-
dimethylethyl ester;
[4-[[ 1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[ 1,2,4]triazin-
6-yl]-carbamic acid, 3-morpholinylmethyl ester; and
[4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f]
[1,2,4]triazin-
6-yl]-carbamic acid, (3R)-3-morpholinylmethyl ester;
and pharmaceutically acceptable salts, solvates, hydrates, or prodrugs
thereof.
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[00471 In yet another embodiment, the indazolylaminopyrrolotriazine has the
structure of Formula II: r-Q N F
/N
HN
N
HN
O O~ \ N'N
O
NH
(II)
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00481 The compound of Formula II is also known as AC480 or BMS-599626.
[00491 Further examples of indazolylaminopyrrolotriazines that are suitable
for use in
the pharmaceutical compositions and methods provided herein are illustrated in
U.S. Pat.
Nos. 6,916,815; 7,102,001; and 7,148,220; and U.S. Pat. Pub. Nos. 2005/0209454
and
2006/0014741, each of which is incorporated herein by reference in its
entirety.
[00501 The compound of Formula I can be prepared according to the methods as
described in U.S. Pat. Nos. 6,916,815; 7,102,001; and 7,148,220; and U.S. Pat.
Pub. No.
2005/0209454 and 2006/0014741. The compound can be also synthesized according
to other
methods apparent to those of skill in the art based upon the teaching herein.
[00511 In one embodiment, the indazolylaminopyrrolotriazine is a compound of
Formula I, or a pharmaceutically acceptable solvate or hydrate thereof. In one
embodiment,
the compound of Formula I is a solid. In another embodiment, the compound of
Formula I is
a solid in an amorphous form. In yet another embodiment, the compound of
Formula I is a
solid in a crystalline form. In yet another embodiment, the compound of
Formula I is a
solvate. In yet another embodiment, the compound of Formula I is a hydrate. In
yet another
embodiment, the compound of Formula I is a monohydrate. In still another
embodiment, the
compound of Formula I is a monohydrate in a crystalline form.
[00521 In another embodiment, the indazolylaminopyrrolotriazine used in the
methods provided herein is a free base of the compound of Formula II, or a
pharmaceutically
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acceptable solvate or hydrate thereof. In one embodiment, the free base is a
solid. In another
embodiment, the free base is a solid in an amorphous form. In yet another
embodiment, the
free base is a solid in a crystalline form, including, but not limited to, the
N-2 form. In yet
another embodiment, the free base is a solid in the N-2 form. In yet another
embodiment, the
compound is a solvate. In yet another embodiment, the compound is a hydrate.
In yet
another embodiment, the compound is a monohydrate. In still another
embodiment, the
compound is a monohydrate in the H-1 form. The compound of Formula II in solid
forms
can be prepared according to the method described in U.S. Pat. Pub. No.
2006/0014741,
which is incorporated herein by reference in its entirety; or using other
suitable methods
known in the art.
[00531 The compounds provided herein are intended to encompass all possible
stereoisomers, unless a particular stereochemistry is specified. Where the
indazolylaminopyrrolotriazine provided herein contains an alkenyl or
alkenylene group, the
compound may exist as one or a mixture of geometric cisltrans (or Z/E)
isomers. Where
structural isomers are interconvertible via a low energy barrier, the
indazolylaminopyrrolotriazine may exist as a single tautomer or a mixture of
tautomers. This
can take the form of proton tautomerism in the indazolylaminopyrrolotriazine
that contains,
for example, an imino, keto, or oxime group; or so-called valence tautomerism
in the
compound that contain an aromatic moiety. It follows that a single
indazolylaminopyrrolotriazine may exhibit more than one type of isomerism.
[00541 The indazolylaminopyrrolotriazines provided herein may be
enantiomerically
pure, such as a single enantiomer or a single diastereomer, or be
stereoisomeric mixtures,
such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers;
or a mixture of
two or more diastereomers. As such, one of skill in the art will recognize
that administration
of a compound in its (R) form is equivalent, for compounds that undergo
epimerization in
vivo, to administration of the compound in its (S) form. Conventional
techniques for the
preparation/isolation of individual enantiomers include synthesis from a
suitable optically
pure precursor, asymmetric synthesis from achiral starting materials, or
resolution of an
enantiomeric mixture, for example, chiral chromatography, recrystallization,
resolution,
diastereomeric salt formation, or derivatization into diastereomeric adducts
followed by
separation.
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[00551 When the indazolylaminopyrrolotriazines provided herein contains an
acidic
or basic moiety, it may also be provided as a pharmaceutically acceptable salt
(See, Berge et
al., J. Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts,
Properties, and
Use," Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).
[00561 Suitable acids for use in the preparation of pharmaceutically
acceptable salts
include, but are not limited to, acetic acid, 2,2-dichloroacetic acid,
acylated amino acids,
adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid,
4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-
camphor-l0-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic
acid, citric acid,
cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-
disulfonic acid,
ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric
acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-
glutamic acid,
a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid,
hydrochloric acid,
hydroiodic acid, (+)-L-lactic acid, ( )-DL-lactic acid, lactobionic acid,
lauric acid, maleic
acid, (-)-L-malic acid, malonic acid, ( )-DL-mandelic acid, methanesulfonic
acid,
naphthalene-2-sulfonic acid, naphthalene- 1,5-disulfonic acid, 1-hydroxy-2-
naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic
acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid,
salicylic acid, 4-amino-
salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid,
tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric
acid.
[00571 Suitable bases for use in the preparation of pharmaceutically
acceptable salts,
including, but not limited to, inorganic bases, such as magnesium hydroxide,
calcium
hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and
organic bases,
such as primary, secondary, tertiary, and quaternary, aliphatic, aromatic,
heteroaryl, and
heterocyclic amines, including L-arginine, benethamine, benzathine, choline,
deanol,
diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-
(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,
isopropylamine, N-
methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-
hydroxyethyl)-
morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-
(2-
hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline,
secondary amines,
triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-
2-
(hydroxymethyl)-1,3-propanediol, and tromethamine.
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[0058] In one embodiment, the compound suitable for use in the methods
provided
herein is a pharmaceutically acceptable salt of the compound of Formula II. In
one
embodiment, the salt is a solid. In another embodiment, the salt is a solid in
an amorphous
form. In yet another embodiment, the salt is a solid in a crystalline form,
including, but not
limited to, the N-1 form. In yet another embodiment, the salt is a solid in
the N-1 form. In
yet another embodiment, the salt is a hydrochloride salt. In yet another
embodiment, the
hydrochloride salt is in a crystalline form, including, but not limited to,
the N-1 form. In still
another embodiment, the hydrochloride salt is in the N-1 form. The
pharmaceutically
acceptable salt compound of Formula II in solid forms can be prepared
according to the
method described in U.S. Pat. Pub. No. 2006/0014741, which is incorporated
herein by
reference in its entirety; or using other suitable methods known in the art.
[0059] In certain embodiments, the salt is a sulfonic acid salt. See, e.g.,
U.S.
Provisional Application No. , filed on March 11, 2010, the disclosure of which
is
incorporated herein by reference in its entirety. In certain embodiments, the
sulfonic salt is in
an amorphous form. In certain embodiments, the sulfonic salt is in a
crystalline form.
[0060] In certain embodiments, the compound suitable for use in the methods
provided herein is an ethanesulfonic acid salt of (S)-morpholin-3-ylmethyl 4-
(1-(3-
fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2 J][1,2,4]triazin-6-
ylcarbamate, or
a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the
term
"ethanesulfonic acid salt" is used interchangeably with the term "esylate
salt."
[0061] In certain embodiments, the molar ratio of (S)-morpholin-3-ylmethyl 4-
(1-(3-
fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2 J][1,2,4]triazin-6-
ylcarbamate
versus ethanesulfonic acid in the salt provided herein, including hydrates and
pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to
about 3, from
about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments,
the molar ratio
of (S)-morpholin-3-ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-
methylpyrrolo[1,2 J][1,2,4]triazin-6-ylcarbamate versus ethanesulfonic acid in
the salt
provided herein, including hydrates and pharmaceutically acceptable solvates
thereof, is
about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1,
about 1.2, about 1.4,
about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6,
about 2.8, or about 3.
[0062] In one embodiment, the ethanesulfonic acid salt of (S)-morpholin-3-
ylmethyl
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4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-6-
ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof,
comprises about
one molar equivalent of (S)-morpholin-3-ylmethyl 4-(1-(3-fluorobenzyl)-1H-
indazol-5-
ylamino)-5-methylpyrrolo[1,2 f][1,2,4]triazin-6-ylcarbamate and about one
molar equivalent
of ethanesulfonic acid. In certain embodiments, the molar ratio of (S)-
morpholin-3-ylmethyl
4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-6-
ylcarbamate versus ethanesulfonic acid is determined based on its 1H NMR
spectrum.
[0063] In certain embodiments, the ethanesulfonic acid salt of (S)-morpholin-3-
ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-
6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof,
has a purity of at
least about 95%, at least about 96%, at least about 97%, at least about 98%,
at least about
98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at
least about 99.5%, at
least about 99.6%, at least about 99.7%, at least about 99.8%, or at least
about 99.9%. In
certain embodiments, the ethanesulfonic acid salt of (S)-morpholin-3-ylmethyl
4-(1-(3-
fluorobenzyl)- 1H-indazol-5-ylamino)-5-methylpyrrolo[1,2 f][1,2,4]triazin-6-
ylcarbamate, or
a hydrate or pharmaceutically acceptable solvate thereof, contains the
nitrosamine at a level
of no greater than about 5 ppm, no greater than about 4 ppm, no greater than
about 3 ppm, no
greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about
1 ppm, no
greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than
about 0.4 ppm, no
greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0064] In one embodiment, the ethanesulfonic acid salt of (S)-morpholin-3-
ylmethyl
4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-6-
ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is
in an amorphous
form. In another embodiment, the ethanesulfonic acid salt of (S)-morpholin-3-
ylmethyl 4-(1-
(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2 f][1,2,4]triazin-6-
ylcarbamate,
or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline.
In certain
embodiments, the ethanesulfonic acid salt has an endotherm with a peak
temperature of about
202 C and an onset temperature of 197 C in a DSC thermogram. In certain
embodiments,
the ethanesulfonic acid salt shows no greater than about 1%, no greater than
about 0.8%, no
greater than about 0.6%, no greater than about 0.4%, no greater than about
0.2%, no greater
than about 0.1%, no greater than about 0.09%, no greater than about 0.08%, no
greater than
about 0.07%, no greater than about 0.06%, or no greater than about 0.05%
weight loss
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between 25 C to 150 C in a thermogravimetric thermogram. In certain
embodiments, the
ethanesulfonic acid salt shows about 0.1% weight loss between 25 C to 150 C
in a
thermogravimetric thermogram.
[0065] In one embodiment, the ethanesulfonic acid salt of (S)-morpholin-3-
ylmethyl
4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-6-
ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is
in crystalline
Form II-A.
[0066] In another embodiment, the ethanesulfonic acid salt of (S)-morpholin-3-
ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-
6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is
in crystalline
Form II-B.
[0067] In yet another embodiment, the ethanesulfonic acid salt of (S)-
morpholin-3-
ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-
6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is
in crystalline
Form II-C.
[0068] In yet another embodiment, the ethanesulfonic acid salt of (S)-
morpholin-3-
ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-
6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is
in crystalline
Form II-D.
[0069] In still another embodiment, the ethanesulfonic acid salt of (S)-
morpholin-3-
ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo[1,2
f][1,2,4]triazin-
6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is
in crystalline
Form II-E.
[0070] The compound provided herein may also be provided as a prodrug, which
is a
functional derivative of the compound, for example, of Formula I or II and is
readily
convertible into the parent compound in vivo. Prodrugs are often useful
because, in some
situations, they may be easier to administer than the parent compound. They
may, for
instance, be bioavailable by oral administration whereas the parent compound
is not. The
prodrug may also have enhanced solubility in pharmaceutical compositions over
the parent
compound. A prodrug may be converted into the parent drug by various
mechanisms,
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including enzymatic processes and metabolic hydrolysis. See Harper, Progress
in Drug
Research 1962, 4, 221-294; Morozowich et al. in "Design of Biopharmaceutical
Properties
through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977;
"Bioreversible
Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA
Acad. Pharm.
Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al., Curr.
Pharm.
Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27,
235-256; Mizen
et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem.
1996, 671-
696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et
al., Ed.,
Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab.
Pharmacokinet. 1990, 15,
143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne,
Clin.
Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39;
Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug
Delivery
Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-
130; Fleisher et al.,
Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,
324-325;
Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and
Bundgaard, Eur. J.
Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs
Analogs, 1977,
409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker,
Adv. Drug
Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et
al., Adv. Drug
Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-
148;
Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and
Knaus, Adv.
Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin. Pharmac.
1989, 28, 497-
507.
Taxanes
[00711 As used herein, the term "taxane" includes both naturally derived and
chemically synthesized terpenes or derivatives thereof, including, but not
limited to,
paclitaxel (TAXOL ) and docetaxel (TAXOTERE ). Paclitaxel and its derivatives
are
described in U.S. Pat. Nos. 4,942,184; 5,440,056; 5,496,804; 5,641,803;
5,670,537; and
6,380,405; each of which is incorporated herein by reference in its entirety.
Docetaxel is
described in U.S. Pat. Nos. 4,814,470; 5,438,072; 5,698,582; and 5,714,512;
each of which is
incorporated herein by reference in its entirety.
[00721 In certain embodiments, the taxane is paclitaxel. In certain
embodiments, the
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taxane is albumin-bound paclitaxel (ABRAXANE ). In certain embodiments, the
taxane is
docetaxel.
Pharmaceutical Compositions
[0073] In one embodiment, provided herein are pharmaceutical compositions
comprising a taxane and an indazolylaminopyrrolotriazine provided herein,
e.g., a compound
of Formula I or II, including a single enantiomer, a mixture of enantiomers,
or a mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof, in combination with a pharmaceutically acceptable vehicle, carrier,
diluent, or
excipient, or a mixture thereof.
[0074] In another embodiment, provided herein are pharmaceutical compositions
comprising an indazolylaminopyrrolotriazine provided herein, e.g., a compound
of Formula I
or II, including a single enantiomer, a mixture of enantiomers, or a mixture
of diastereomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, in
combination with a pharmaceutically acceptable vehicle, carrier, diluent, or
excipient, or a
mixture thereof.
[0075] In yet another embodiment, provided herein are pharmaceutical
compositions
comprising an indazolylaminopyrrolotriazine provided herein, e.g., a compound
of Formula I
or II, including a single enantiomer, a mixture of enantiomers, or a mixture
of diastereomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, in
combination with hydroxypropyl-b-cyclodextrin, mannitol, water, or a mixture
thereof.
[0076] In yet another embodiment, provided herein are pharmaceutical
compositions
comprising [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-
pyrrolo[2,1-
f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester, or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, in combination with
hydroxypropyl-(3-
cyclodextrin, mannitol, water, or a mixture thereof.
[0077] In yet another embodiment, provided herein is a pharmaceutical
composition
comprising [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-
pyrrolo[2,1-
f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester,
ethanesulfonate, or a
pharmaceutically acceptable solvate or hydrate, thereof, in combination with
hydroxypropyl-
3-cyclodextrin, mannitol, water, or a mixture thereof.
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[0078] In yet another embodiment, provided herein is a pharmaceutical
composition
comprising about 15% by weight of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-
ylamino]-
5-methyl-pyrrolo[2,1-f][l,2,4]triazin-6-yl]-carbamic acid, (3S)-3-
morpholinylmethyl ester,
ethanesulfonate, about 75% by weight of hydroxypropyl-(3-cyclodextrin, and 10%
by weight
of mannitol.
[0079] In yet another embodiment, provided herein is a pharmaceutical
composition
in a unit-dosage, comprising about 363 mg of [4-[[1-(3-fluorophenyl)methyl]-1H-
indazol-5-
ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-
morpholinylmethyl ester, ethanesulfonate, about 1,800 mg of hydroxypropyl-(3-
cyclodextrin,
and 1,240 mg by weight of mannitol.
[0080] In certain embodiments, a pharmaceutical composition in a unit-dosage,
comprising about 363 mg of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-
ylamino]-5-
methyl-pyrrolo[2,1-f][l,2,4]triazin-6-yl]-carbamic acid, (3S)-3-
morpholinylmethyl ester,
ethanesulfonate in a crystalline form. In certain embodiments, a
pharmaceutical composition
in a unit-dosage, comprising about 363 mg of [4-[[1-(3-fluorophenyl)methyl]-1H-
indazol-5-
ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-
morpholinylmethyl ester, ethanesulfonate in crystalline Form II-B.
[0081] In yet another embodiment, provided herein are pharmaceutical
compositions
comprising a taxane and a pharmaceutically acceptable vehicle, carrier,
diluent, or excipient,
or a mixture thereof.
[0082] The taxane-containing compositions provided herein can also be
formulated as
known to those skilled in the art. Some examples of taxane-containing
pharmaceutical
compositions are described in U.S. Pat. Nos. 4,814,470; 4,942,184; 5,438,072;
5,440,056;
5,496,804; 5,641,803; 5,670,537; 5,698,582; 5,714,512; and 6,380,405; each of
which is
incorporated herein by reference in its entirety.
[0083] The pharmaceutical compositions provided herein can further comprise an
additional active agent provided herein. In one embodiment, the additional
active agent is
cisplatin, capecitabine, carboplatin, cetuximab, vinorelbine, gefitinib,
gemcitabine, etoposide,
irinotecan, lapatinib, trastuzumab, vinblastine, mitomycin, ifosfamide,
pemetrexed, erlotinib,
bevacizumab, or cetuximab.
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[00841 The pharmaceutical compositions provided herein may be formulated in
various dosage forms for oral, parenteral, and topical administration. The
pharmaceutical
compositions may also be formulated as modified release dosage forms,
including delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and
fast-, targeted-,
programmed-release, and gastric retention dosage forms. These dosage forms can
be
prepared according to conventional methods and techniques known to those
skilled in the art
(See, Remington: The Science and Practice of Pharmacy, supra; Modified-Release
Drug
Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical
Science, Marcel
Dekker, Inc.: New York, NY, 2003; Vol. 126).
[00851 In one embodiment, the pharmaceutical compositions provided herein are
formulated in a dosage form for oral administration. In another embodiment,
the
pharmaceutical compositions provided herein are formulated in a dosage form
for parenteral
administration. In yet another embodiment, the pharmaceutical compositions
provided herein
are formulated in a dosage form for topical administration.
[00861 The pharmaceutical compositions provided herein may be provided in a
unit-
dosage or multiple-dosage form. A unit-dosage form, as used herein, refers to
physically
discrete a unit suitable for administration to a subject, e.g., a human and
animal subject, and
packaged individually as is known in the art. Each unit-dose contains a
predetermined
quantity of an active ingredient(s) sufficient to produce the desired
therapeutic effect, in
association with the required pharmaceutical carriers or excipients. Examples
of a unit-
dosage form include an ampoule, syringe, and individually packaged tablet and
capsule. A
unit-dosage form may be administered in fractions or multiples thereof. A
multiple-dosage
form is a plurality of identical unit-dosage forms packaged in a single
container to be
administered in segregated unit-dosage form. Examples of a multiple-dosage
form include a
vial, bottle of tablets or capsules, or bottle of pints or gallons.
[00871 The pharmaceutical compositions provided herein may be administered at
once, or multiple times at intervals of time. It is understood that the
precise dosage and
duration of treatment may vary with the age, weight, and condition of the
patient being
treated, and may be determined empirically using known testing protocols or by
extrapolation
from in vivo or in vitro test or diagnostic data. It is further understood
that for any particular
individual, specific dosage regimens should be adjusted over time according to
the individual
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need and the professional judgment of the person administering or supervising
the
administration of the formulations.
A. Oral Administration
[00881 The pharmaceutical compositions provided herein for oral administration
can
be provided in solid, semisolid, or liquid dosage forms for oral
administration. As used
herein, oral administration also includes buccal, lingual, and sublingual
administration.
Suitable oral dosage forms include, but are not limited to, tablets,
fastmelts, chewable tablets,
capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets,
medicated chewing gum,
bulk powders, effervescent or non-effervescent powders or granules, oral
mists, solutions,
emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to
the active
ingredient(s), the pharmaceutical compositions can contain one or more
pharmaceutically
acceptable carriers or excipients, including, but not limited to, binders,
fillers, diluents,
disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-
migration inhibitors,
sweetening agents, flavoring agents, emulsifying agents, suspending and
dispersing agents,
preservatives, solvents, non-aqueous liquids, organic acids, and sources of
carbon dioxide.
[00891 Binders or granulators impart cohesiveness to a tablet to ensure the
tablet
remaining intact after compression. Suitable binders or granulators include,
but are not
limited to, starches, such as corn starch, potato starch, and pre-gelatinized
starch (e.g.,
STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses,
and lactose;
natural and synthetic gums, such as acacia, alginic acid, alginates, extract
of Irish moss,
panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose,
methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan,
powdered
tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose
acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl
cellulose,
hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl
methyl
cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-
PH-103,
AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures
thereof.
Suitable fillers include, but are not limited to, talc, calcium carbonate,
microcrystalline
cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid,
sorbitol, starch, pre-
gelatinized starch, and mixtures thereof. The amount of a binder or filler in
the
pharmaceutical compositions provided herein varies upon the type of
formulation, and is
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readily discernible to those of ordinary skill in the art. The binder or
filler may be present
from about 50 to about 99% by weight in the pharmaceutical compositions
provided herein.
[0090] Suitable diluents include, but are not limited to, dicalcium phosphate,
calcium
sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol,
sodium chloride, dry
starch, and powdered sugar. Certain diluents, such as mannitol, lactose,
sorbitol, sucrose, and
inositol, when present in sufficient quantity, can impart properties to some
compressed tablets
that permit disintegration in the mouth by chewing. Such compressed tablets
can be used as
chewable tablets. The amount of a diluent in the pharmaceutical compositions
provided
herein varies upon the type of formulation, and is readily discernible to
those of ordinary skill
in the art.
[0091] Suitable disintegrants include, but are not limited to, agar;
bentonite;
celluloses, such as methylcellulose and carboxymethylcellulose; wood products;
natural
sponge; cation-exchange resins; alginic acid; gums, such as guar gum and
Veegum HV; citrus
pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers,
such as
crospovidone; cross-linked starches; calcium carbonate; microcrystalline
cellulose, such as
sodium starch glycolate; polacrilin potassium; starches, such as corn starch,
potato starch,
tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures
thereof. The amount of
a disintegrant in the pharmaceutical compositions provided herein varies upon
the type of
formulation, and is readily discernible to those of ordinary skill in the art.
The amount of a
disintegrant in the pharmaceutical compositions provided herein varies upon
the type of
formulation, and is readily discernible to those of ordinary skill in the art.
The
pharmaceutical compositions provided herein may contain from about 0.5 to
about 15% or
from about 1 to about 5% by weight of a disintegrant.
[0092] Suitable lubricants include, but are not limited to, calcium stearate;
magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;
mannitol; glycols, such
as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium
lauryl sulfate; talc;
hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower
oil, sesame oil,
olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl
laureate; agar; starch;
lycopodium; silica or silica gels, such as AEROSIL 200 (W.R. Grace Co.,
Baltimore, MD)
and CAB-O-SIL (Cabot Co. of Boston, MA); and mixtures thereof. The
pharmaceutical
compositions provided herein may contain about 0.1 to about 5% by weight of a
lubricant.
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[00931 Suitable glidants include, but are not limited to, colloidal silicon
dioxide,
CAB-O-SIL (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable
coloring agents
include, but are not limited to, any of the approved, certified, water soluble
FD&C dyes, and
water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and
mixtures
thereof. A color lake is the combination by adsorption of a water-soluble dye
to a hydrous
oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable
flavoring agents
include, but are not limited to, natural flavors extracted from plants, such
as fruits, and
synthetic blends of compounds which produce a pleasant taste sensation, such
as peppermint
and methyl salicylate. Suitable sweetening agents include, but are not limited
to, sucrose,
lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as
saccharin and
aspartame. Suitable emulsifying agents include, but are not limited to,
gelatin, acacia,
tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan
monooleate
(TWEEN 20), polyoxyethylene sorbitan monooleate 80 (TWEEN 80), and
triethanolamine
oleate. Suitable suspending and dispersing agents include, but are not limited
to, sodium
carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium
carbomethylcellulose,
hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable
preservatives include,
but are not limited to, glycerin, methyl and propylparaben, benzoic add,
sodium benzoate and
alcohol. Suitable wetting agents include, but are not limited to, propylene
glycol
monostearate, sorbitan monooleate, diethylene glycol monolaurate, and
polyoxyethylene
lauryl ether. Suitable solvents include, but are not limited to, glycerin,
sorbitol, ethyl alcohol,
and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are
not limited to,
mineral oil and cottonseed oil. Suitable organic acids include, but are not
limited to, citric
and tartaric acid. Suitable sources of carbon dioxide include, but are not
limited to, sodium
bicarbonate and sodium carbonate.
[00941 It should be understood that many carriers and excipients may serve
several
functions, even within the same formulation.
[00951 The pharmaceutical compositions provided herein for oral administration
can
be provided as compressed tablets, tablet triturates, chewable lozenges,
rapidly dissolving
tablets, multiple compressed tablets, or enteric-coating tablets, sugar-
coated, or film-coated
tablets. Enteric-coated tablets are compressed tablets coated with substances
that resist the
action of stomach acid but dissolve or disintegrate in the intestine, thus
protecting the active
ingredients from the acidic environment of the stomach. Enteric-coatings
include, but are not
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limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated
shellac, and
cellulose acetate phthalates. Sugar-coated tablets are compressed tablets
surrounded by a
sugar coating, which may be beneficial in covering up objectionable tastes or
odors and in
protecting the tablets from oxidation. Film-coated tablets are compressed
tablets that are
covered with a thin layer or film of a water-soluble material. Film coatings
include, but are
not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose,
polyethylene glycol
4000, and cellulose acetate phthalate. Film coating imparts the same general
characteristics
as sugar coating. Multiple compressed tablets are compressed tablets made by
more than one
compression cycle, including layered tablets, and press-coated or dry-coated
tablets.
[00961 The tablet dosage forms can be prepared from the active ingredient in
powdered, crystalline, or granular forms, alone or in combination with one or
more carriers or
excipients described herein, including binders, disintegrants, controlled-
release polymers,
lubricants, diluents, and/or colorants. Flavoring and sweetening agents are
especially useful
in the formation of chewable tablets and lozenges.
[00971 The pharmaceutical compositions provided herein for oral administration
can
be provided as soft or hard capsules, which can be made from gelatin,
methylcellulose,
starch, or calcium alginate. The hard gelatin capsule, also known as the dry-
filled capsule
(DFC), consists of two sections, one slipping over the other, thus completely
enclosing the
active ingredient. The soft elastic capsule (SEC) is a soft, globular shell,
such as a gelatin
shell, which is plasticized by the addition of glycerin, sorbitol, or a
similar polyol. The soft
gelatin shells may contain a preservative to prevent the growth of
microorganisms. Suitable
preservatives are those as described herein, including methyl- and propyl-
parabens, and
sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may
be
encapsulated in a capsule. Suitable liquid and semisolid dosage forms include
solutions and
suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules
containing
such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245;
4,409,239; and
4,410,545. The capsules may also be coated as known by those of skill in the
art in order to
modify or sustain dissolution of the active ingredient.
[00981 The pharmaceutical compositions provided herein for oral administration
can
be provided in liquid and semisolid dosage forms, including emulsions,
solutions,
suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which
one liquid is
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dispersed in the form of small globules throughout another liquid, which can
be oil-in-water
or water-in-oil. Emulsions may include a pharmaceutically acceptable non-
aqueous liquid or
solvent, emulsifying agent, and preservative. Suspensions may include a
pharmaceutically
acceptable suspending agent and preservative. Aqueous alcoholic solutions may
include a
pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a
lower alkyl aldehyde,
e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or
more hydroxyl
groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened,
and
hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a
sugar, for example,
sucrose, and may also contain a preservative. For a liquid dosage form, for
example, a
solution in a polyethylene glycol may be diluted with a sufficient quantity of
a
pharmaceutically acceptable liquid carrier, e.g., water, to be measured
conveniently for
administration.
[0099] Other useful liquid and semisolid dosage forms include, but are not
limited to,
those containing the active ingredient(s) provided herein, and a dialkylated
mono- or poly-
alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme,
tetraglyme,
polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl
ether,
polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the
approximate
average molecular weight of the polyethylene glycol. These formulations can
further
comprise one or more antioxidants, such as butylated hydroxytoluene (BHT),
butylated
hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,
hydroxycoumarins,
ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol,
phosphoric acid, bisulfite,
sodium metabisulfite, thiodipropionic acid and its esters, and
dithiocarbamates.
[00100] The pharmaceutical compositions provided herein for oral
administration can
be also provided in the forms of liposomes, micelles, microspheres, or
nanosystems. Micellar
dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
[00101] The pharmaceutical compositions provided herein for oral
administration can
be provided as non-effervescent or effervescent, granules and powders, to be
reconstituted
into a liquid dosage form. Pharmaceutically acceptable carriers and excipients
used in the
non-effervescent granules or powders may include diluents, sweeteners, and
wetting agents.
Pharmaceutically acceptable carriers and excipients used in the effervescent
granules or
powders may include organic acids and a source of carbon dioxide.
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[001021 Coloring and flavoring agents can be used in all of the above dosage
forms.
[001031 The pharmaceutical compositions provided herein for oral
administration can
be formulated as immediate or modified release dosage forms, including delayed-
, sustained,
pulsed-, controlled, targeted-, and programmed-release forms.
B. Parenteral Administration
[001041 The pharmaceutical compositions provided herein can be administered
parenterally by injection, infusion, or implantation, for local or systemic
administration.
Parenteral administration, as used herein, include intravenous, intraarterial,
intraperitoneal,
intrathecal, intraventricular, intraurethral, intrasternal, intracranial,
intramuscular,
intrasynovial, intravesical, and subcutaneous administration.
[001051 The pharmaceutical compositions provided herein for parenteral
administration can be formulated in any dosage forms that are suitable for
parenteral
administration, including solutions, suspensions, emulsions, micelles,
liposomes,
microspheres, nanosystems, and solid forms suitable for solutions or
suspensions in liquid
prior to injection. Such dosage forms can be prepared according to
conventional methods
known to those skilled in the art of pharmaceutical science (see, Remington:
The Science and
Practice of Pharmacy, supra).
[001061 The pharmaceutical compositions intended for parenteral administration
can
include one or more pharmaceutically acceptable carriers and excipients,
including, but not
limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,
antimicrobial
agents or preservatives against the growth of microorganisms, stabilizers,
solubility
enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics,
suspending and
dispersing agents, wetting or emulsifying agents, complexing agents,
sequestering or
chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH
adjusting agents, and
inert gases.
[001071 Suitable aqueous vehicles include, but are not limited to, water,
saline,
physiological saline or phosphate buffered saline (PBS), sodium chloride
injection, Ringers
injection, isotonic dextrose injection, sterile water injection, dextrose and
lactated Ringers
injection. Suitable non-aqueous vehicles include, but are not limited to,
fixed oils of
vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil,
peppermint oil,
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safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils,
hydrogenated soybean oil,
and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable
water-miscible
vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid
polyethylene glycol
(e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol,
glycerin, N-
methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
[00108] Suitable antimicrobial agents or preservatives include, but are not
limited to,
phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl
p-
hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium
chloride), methyl-
and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but
are not limited to,
sodium chloride, glycerin, and dextrose. Suitable buffering agents include,
but are not
limited to, phosphate and citrate. Suitable antioxidants are those as
described herein,
including bisulfite and sodium metabisulfite. Suitable local anesthetics
include, but are not
limited to, procaine hydrochloride. Suitable suspending and dispersing agents
are those as
described herein, including sodium carboxymethylcelluose, hydroxypropyl
methylcellulose,
and polyvinylpyrrolidone. Suitable emulsifying agents are those described
herein, including
polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80,
and
triethanolamine oleate. Suitable sequestering or chelating agents include, but
are not limited
to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium
hydroxide,
hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents
include, but are not
limited to, cyclodextrins, including a-cyclodextrin, (3-cyclodextrin,
hydroxypropyl-(3-
cyclodextrin, sulfobutylether-(3-cyclodextrin, and sulfobutylether
7-(3-cyclodextrin (CAPTISOL , CyDex, Lenexa, KS).
[00109] When the pharmaceutical compositions provided herein are formulated
for
multiple dosage administration, the multiple dosage parenteral formulations
must contain an
antimicrobial agent at bacteriostatic or fungistatic concentrations. All
parenteral formulations
must be sterile, as known and practiced in the art.
[00110] In one embodiment, the pharmaceutical compositions for parenteral
administration are provided as ready-to-use sterile solutions. In another
embodiment, the
pharmaceutical compositions are provided as sterile dry soluble products,
including
lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle
prior to use.
In yet another embodiment, the pharmaceutical compositions are provided as
ready-to-use
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sterile suspensions. In yet another embodiment, the pharmaceutical
compositions are
provided as sterile dry insoluble products to be reconstituted with a vehicle
prior to use. In
still another embodiment, the pharmaceutical compositions are provided as
ready-to-use
sterile emulsions.
[00111] The pharmaceutical compositions provided herein for parenteral
administration can be formulated as immediate or modified release dosage
forms, including
delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release
forms.
[00112] The pharmaceutical compositions provided herein for parenteral
administration can be formulated as a suspension, solid, semi-solid, or
thixotropic liquid, for
administration as an implanted depot. In one embodiment, the pharmaceutical
compositions
provided herein are dispersed in a solid inner matrix, which is surrounded by
an outer
polymeric membrane that is insoluble in body fluids but allows the active
ingredient in the
pharmaceutical compositions diffuse through.
[00113] Suitable inner matrixes include, but are not limited to,
polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized
polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate,
natural rubber,
polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl
acetate
copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate
copolymers,
hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic
acid, collagen,
cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed
polyvinyl acetate.
[00114] Suitable outer polymeric membranes include but are not limited to,
polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl
acrylate
copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl
siloxanes,
neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride
copolymers with
vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer
polyethylene
terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol
copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol
copolymer.
C. Topical Administration
[00115] The pharmaceutical compositions provided herein can be administered
topically to the skin, orifices, or mucosa. The topical administration, as
used herein, includes
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(intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular,
transdermal,
nasal, vaginal, urethral, respiratory, and rectal administration.
[00116] The pharmaceutical compositions provided herein can be formulated in
any
dosage forms that are suitable for topical administration for local or
systemic effect, including
emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting
powders,
dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films,
aerosols, irrigations,
sprays, suppositories, bandages, and dermal patches. The topical formulation
of the
pharmaceutical compositions provided herein can also comprise liposomes,
micelles,
microspheres, nanosystems, and mixtures thereof.
[00117] Pharmaceutically acceptable carriers and excipients suitable for use
in the
topical formulations provided herein include, but are not limited to, aqueous
vehicles, water-
miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives
against the
growth of microorganisms, stabilizers, solubility enhancers, isotonic agents,
buffering agents,
antioxidants, local anesthetics, suspending and dispersing agents, wetting or
emulsifying
agents, complexing agents, sequestering or chelating agents, penetration
enhancers,
cryoprotectants, lyoprotectants, thickening agents, and inert gases.
[00118] The pharmaceutical compositions can also be administered topically by
electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or
needle-free
injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and BIOJECTTM
(Bioject Medical Technologies Inc., Tualatin, OR).
[00119] The pharmaceutical compositions provided herein can be provided in the
forms of ointments, creams, and gels. Suitable ointment vehicles include
oleaginous or
hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed
oil, and other
oils, white petrolatum; emulsifiable or absorption vehicles, such as
hydrophilic petrolatum,
hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such
as hydrophilic
ointment; water-soluble ointment vehicles, including polyethylene glycols of
varying
molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or
oil-in-water
(O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and
stearic acid
(see, Remington: The Science and Practice of Pharmacy, supra). These vehicles
are
emollient but generally require addition of antioxidants and preservatives.
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[001201 Suitable cream base can be oil-in-water or water-in-oil. Suitable
cream
vehicles may be water-washable, and contain an oil phase, an emulsifier, and
an aqueous
phase. The oil phase is also called the "internal" phase, which is generally
comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous
phase usually,
although not necessarily, exceeds the oil phase in volume, and generally
contains a
humectant. The emulsifier in a cream formulation may be a nonionic, anionic,
cationic, or
amphoteric surfactant.
[001211 Gels are semisolid, suspension-type systems. Single-phase gels contain
organic macromolecules distributed substantially uniformly throughout the
liquid carrier.
Suitable gelling agents include, but are not limited to, crosslinked acrylic
acid polymers, such
as carbomers, carboxypolyalkylenes, and CARBOPOL ; hydrophilic polymers, such
as
polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and
polyvinylalcohol;
cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxypropyl
methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose;
gums, such
as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to
prepare a uniform
gel, dispersing agents such as alcohol or glycerin can be added, or the
gelling agent can be
dispersed by trituration, mechanical mixing, and/or stirring.
[001221 The pharmaceutical compositions provided herein can be administered
rectally, urethrally, vaginally, or perivaginally in the forms of
suppositories, pessaries,
bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters,
contraceptives,
ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or
enemas.
These dosage forms can be manufactured using conventional processes as
described in
Remington: The Science and Practice of Pharmacy, supra.
[001231 Rectal, urethral, and vaginal suppositories are solid bodies for
insertion into
body orifices, which are solid at ordinary temperatures but melt or soften at
body temperature
to release the active ingredient(s) inside the orifices. Pharmaceutically
acceptable carriers
utilized in rectal and vaginal suppositories include bases or vehicles, such
as stiffening
agents, which produce a melting point in the proximity of body temperature,
when
formulated with the pharmaceutical compositions provided herein; and
antioxidants as
described herein, including bisulfite and sodium metabisulfite. Suitable
vehicles include, but
are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax
(polyoxyethylene
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glycol), spermaceti, paraffin, white and yellow wax, appropriate mixtures of
mono-, di- and
triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol,
hydroxyethyl methacrylate,
and polyacrylic acid. Combinations of the various vehicles can also be used.
Rectal and
vaginal suppositories may be prepared by compressing or molding. The typical
weight of a
rectal and vaginal suppository is about 2 to about 3 g.
[001241 The pharmaceutical compositions provided herein can be administered
ophthalmically in the forms of solutions, suspensions, ointments, emulsions,
gel-forming
solutions, powders for solutions, gels, ocular inserts, and implants.
[001251 The pharmaceutical compositions provided herein can be administered
intranasally or by inhalation to the respiratory tract. The pharmaceutical
compositions can be
provided in the form of an aerosol or solution for delivery using a
pressurized container,
pump, spray, atomizer, such as an atomizer using electrohydrodynamics to
produce a fine
mist, or nebulizer, alone or in combination with a suitable propellant, such
as 1,1,1,2-
tetrafluoroethane or 1, 1, 1,2,3,3,3-heptafluoropropane. The pharmaceutical
compositions can
also be provided as a dry powder for insufflation, alone or in combination
with an inert
carrier such as lactose or phospholipids; and nasal drops. For intranasal use,
the powder can
comprise a bioadhesive agent, including chitosan or cyclodextrin.
[001261 Solutions or suspensions for use in a pressurized container, pump,
spray,
atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol,
or a suitable
alternative agent for dispersing, solubilizing, or extending release of the
active ingredient
provided herein; a propellant as solvent; and/or a surfactant, such as
sorbitan trioleate, oleic
acid, or an oligolactic acid.
[001271 The pharmaceutical compositions provided herein can be micronized to a
size
suitable for delivery by inhalation, such as about 50 micrometers or less, or
about 10
micrometers or less. Particles of such sizes can be prepared using a
comminuting method
known to those skilled in the art, such as spiral jet milling, fluid bed jet
milling, supercritical
fluid processing to form nanoparticles, high pressure homogenization, or spray
drying.
[001281 Capsules, blisters, and cartridges for use in an inhaler or
insufflator can be
formulated to contain a powder mix of the pharmaceutical compositions provided
herein; a
suitable powder base, such as lactose or starch; and a performance modifier,
such as I-
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leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in
the form of
the monohydrate. Other suitable excipients or carriers include, but are not
limited to, dextran,
glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The
pharmaceutical
compositions provided herein for inhaled/intranasal administration can further
comprise a
suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as
saccharin and
saccharin sodium.
[001291 The pharmaceutical compositions provided herein for topical
administration
can be formulated to be immediate release or modified release, including
delayed-, sustained-
, pulsed-, controlled-, targeted, and programmed release.
D. Modified Release
[001301 The pharmaceutical compositions provided herein can be formulated as a
modified release dosage form. As used herein, the term "modified release"
refers to a dosage
form in which the rate or place of release of the active ingredient(s) is
different from that of
an immediate dosage form when administered by the same route. Modified release
dosage
forms include, but are not limited to, delayed-, extended-, prolonged-,
sustained-, pulsatile-,
controlled-, accelerated- and fast-, targeted-, programmed-release, and
gastric retention
dosage forms. The pharmaceutical compositions in modified release dosage forms
can be
prepared using a variety of modified release devices and methods known to
those skilled in
the art, including, but not limited to, matrix controlled release devices,
osmotic controlled
release devices, multiparticulate controlled release devices, ion-exchange
resins, enteric
coatings, multilayered coatings, microspheres, liposomes, and combinations
thereof. The
release rate of the active ingredient(s) can also be modified by varying the
particle sizes and
polymorphorism of the active ingredient(s).
[001311 Examples of modified release include, but are not limited to, those
described
in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;
5,674,533;
5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480;
5,733,566;
5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830;
6,087,324;
6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961;
6,589,548;
6,613,358; and 6,699,500.
1. Matrix Controlled Release Devices
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[001321 The pharmaceutical compositions provided herein in a modified release
dosage form can be fabricated using a matrix controlled release device known
to those skilled
in the art (see, Takada et al. in "Encyclopedia of Controlled Drug Delivery,"
Vol. 2,
Mathiowitz Ed., Wiley, 1999).
[001331 In certain embodiments, the pharmaceutical compositions provided
herein in a
modified release dosage form is formulated using an erodible matrix device,
which is water-
swellable, erodible, or soluble polymers, including, but not limited to,
synthetic polymers,
and naturally occurring polymers and derivatives, such as polysaccharides and
proteins.
[001341 Materials useful in forming an erodible matrix include, but are not
limited to,
chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya,
locust bean gum,
gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and
scleroglucan;
starches, such as dextrin and maltodextrin; hydrophilic colloids, such as
pectin; phosphatides,
such as lecithin; alginates; propylene glycol alginate; gelatin; collagen;
cellulosics, such as
ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose
(CMC), CMEC,
hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate
(CA),
cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate
(CAB), CAP,
CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl
methyl
cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose
(EHEC);
polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty
acid esters;
polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic
acid
(EUDRAGIT , Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-
methacrylate);
polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable
lactic acid-
glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic
acid
derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl
methacrylate, ethyl methacrylate, ethylacrylate, (2-
dimethylaminoethyl)methacrylate, and
(trimethylaminoethyl)methacrylate chloride.
[001351 In certain embodiments, the pharmaceutical compositions provided
herein are
formulated with a non-erodible matrix device. The active ingredient(s) is
dissolved or
dispersed in an inert matrix and is released primarily by diffusion through
the inert matrix
once administered. Materials suitable for use as a non-erodible matrix device
include, but are
not limited to, insoluble plastics, such as polyethylene, polypropylene,
polyisoprene,
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polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate,
chlorinated
polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate
copolymers, ethylene-
vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl
acrylate
copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride,
ethylene and
propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin
rubbers,
ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol
terpolymer,
ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon,
plasticized
polyethylene terephthalate, natural rubber, silicone rubbers,
polydimethylsiloxanes, and
silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose,
cellulose
acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl
acetate; and fatty
compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
[001361 In a matrix controlled release system, the desired release kinetics
can be
controlled, for example, via the polymer type employed, the polymer viscosity,
the particle
sizes of the polymer and/or the active ingredient(s), the ratio of the active
ingredient(s) versus
the polymer, and other excipients or carriers in the compositions.
[001371 The pharmaceutical compositions provided herein in a modified release
dosage form can be prepared by methods known to those skilled in the art,
including direct
compression, dry or wet granulation followed by compression, and melt-
granulation followed
by compression.
2. Osmotic Controlled Release Devices
[001381 The pharmaceutical compositions provided herein in a modified release
dosage form can be fabricated using an osmotic controlled release device,
including, but not
limited to, one-chamber system, two-chamber system, asymmetric membrane
technology
(AMT), and extruding core system (ECS). In general, such devices have at least
two
components: (a) a core which contains an active ingredient; and (b) a
semipermeable
membrane with at least one delivery port, which encapsulates the core. The
semipermeable
membrane controls the influx of water to the core from an aqueous environment
of use so as
to cause drug release by extrusion through the delivery port(s).
[001391 In addition to the active ingredient(s), the core of the osmotic
device
optionally includes an osmotic agent, which creates a driving force for
transport of water
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from the environment of use into the core of the device. One class of osmotic
agents is
water-swellable hydrophilic polymers, which are also referred to as
"osmopolymers" and
"hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents
include, but
are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides
such as calcium
alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene
glycol (PPG),
poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP
copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl
methacrylate
and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks,
sodium
croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl
cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and
carboxyethyl,
cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and
sodium starch
glycolate.
[001401 The other class of osmotic agents is osmogens, which are capable of
imbibing
water to affect an osmotic pressure gradient across the barrier of the
surrounding coating.
Suitable osmogens include, but are not limited to, inorganic salts, such as
magnesium sulfate,
magnesium chloride, calcium chloride, sodium chloride, lithium chloride,
potassium sulfate,
potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate,
potassium chloride,
and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol,
lactose, maltose,
mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,
such as ascorbic
acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid,
sorbic acid, adipic acid,
edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and
tartaric acid; urea; and
mixtures thereof.
[001411 Osmotic agents of different dissolution rates can be employed to
influence
how rapidly the active ingredient(s) is initially delivered from the dosage
form. For example,
amorphous sugars, such as MANNOGEMTM EZ (SPI Pharma, Lewes, DE) can be used to
provide faster delivery during the first couple of hours to promptly produce
the desired
therapeutic effect, and gradually and continually release of the remaining
amount to maintain
the desired level of therapeutic or prophylactic effect over an extended
period of time. In this
case, the active ingredient(s) is released at such a rate to replace the
amount of the active
ingredient metabolized and excreted.
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[001421 The core can also include a wide variety of other excipients and
carriers as
described herein to enhance the performance of the dosage form or to promote
stability or
processing.
[001431 Materials useful in forming the semipermeable membrane include various
grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic
derivatives that are
water-permeable and water-insoluble at physiologically relevant pHs, or are
susceptible to
being rendered water-insoluble by chemical alteration, such as crosslinking.
Examples of
suitable polymers useful in forming the coating, include plasticized,
unplasticized, and
reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate,
CA propionate,
cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP,
CA methyl
carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA
dimethylaminoacetate, CA
ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA
butyl
sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta
glucan acetate, beta
glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean
gum, hydroxylated
ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC,
CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-
(methacrylic) acids and esters and copolymers thereof, starch, dextran,
dextrin, chitosan,
collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,
polystyrenes,
polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic
waxes.
[001441 Semipermeable membrane can also be a hydrophobic microporous membrane,
wherein the pores are substantially filled with a gas and are not wetted by
the aqueous
medium but are permeable to water vapor, as disclosed in U.S. Pat. No.
5,798,119. Such
hydrophobic but water-vapor permeable membrane are typically composed of
hydrophobic
polymers such as polyalkenes, polyethylene, polypropylene,
polytetrafluoroethylene,
polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones,
polystyrenes,
polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers,
natural waxes, and
synthetic waxes.
[001451 The delivery port(s) on the semipermeable membrane can be formed post-
coating by mechanical or laser drilling. Delivery port(s) can also be formed
in situ by erosion
of a plug of water-soluble material or by rupture of a thinner portion of the
membrane over an
indentation in the core. In addition, delivery ports can be formed during
coating process, as
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in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat.
Nos.
5,612,059 and 5,698,220.
[001461 The total amount of the active ingredient(s) released and the release
rate can
substantially by modulated via the thickness and porosity of the semipermeable
membrane,
the composition of the core, and the number, size, and position of the
delivery ports.
[001471 The pharmaceutical compositions in an osmotic controlled-release
dosage
form can further comprise additional conventional excipients or carriers as
described herein
to promote performance or processing of the formulation.
[001481 The osmotic controlled-release dosage forms can be prepared according
to
conventional methods and techniques known to those skilled in the art (see,
Remington: The
Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled
Release 1995, 35,
1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-
708; Verma et
al., J. Controlled Release 2002, 79, 7-27).
[001491 In certain embodiments, the pharmaceutical compositions provided
herein are
formulated as AMT controlled-release dosage form, which comprises an
asymmetric osmotic
membrane that coats a core comprising the active ingredient(s) and other
pharmaceutically
acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and WO
2002/17918. The
AMT controlled-release dosage forms can be prepared according to conventional
methods
and techniques known to those skilled in the art, including direct
compression, dry
granulation, wet granulation, and a dip-coating method.
[001501 In certain embodiments, the pharmaceutical compositions provided
herein are
formulated as ESC controlled-release dosage form, which comprises an osmotic
membrane
that coats a core comprising the active ingredient(s), a hydroxylethyl
cellulose, and other
pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[001511 The pharmaceutical compositions provided herein in a modified release
dosage form can be fabricated as a multiparticulate controlled release device,
which
comprises a multiplicity of particles, granules, or pellets, ranging from
about 10 m to about
3 mm, about 50 m to about 2.5 mm, or from about 100 m to about 1 mm in
diameter. Such
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multiparticulates can be made by the processes known to those skilled in the
art, including
wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-
congealing, and
by spray-coating seed cores. See, for example, Multiparticulate Oral Drug
Delivery; Marcel
Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker:
1989.
[001521 Other excipients or carriers as described herein can be blended with
the
pharmaceutical compositions to aid in processing and forming the
multiparticulates. The
resulting particles can themselves constitute the multiparticulate device or
can be coated by
various film-forming materials, such as enteric polymers, water-swellable, and
water-soluble
polymers. The multiparticulates can be further processed as a capsule or a
tablet.
4. Targeted Delivery
[001531 The pharmaceutical compositions provided herein can also be formulated
to be
targeted to a particular tissue, receptor, or other area of the body of the
subject to be treated,
including liposome-, resealed erythrocyte-, and antibody-based delivery
systems. Examples
include, but are not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;
6,274,552;
6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;
6,048,736;
6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542;
and
5,709,874.
Methods of Use
[001541 In one embodiment, provided herein is a method of treating a
proliferative
disease in a subject, comprising administering to the subject a
therapeutically effective
amount of (i) a taxane; and (ii) an indazolylaminopyrrolotriazine provided
herein, e.g., a
compound of Formula I or II, including a single enantiomer, a mixture of
enantiomers, or a
mixture of diastereomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or
prodrug thereof. In certain embodiments, the combination of the taxane and
indazolylaminopyrrolotriazine has a synergetic effect when compared to the
administration of
the taxane or indazolylaminopyrrolotriazine alone.
[001551 In another embodiment, the method further comprises administering to
the
subject a therapeutically effective amount of a platinum agent. In certain
embodiments, the
platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216),
or CI-973. In
certain embodiments, the platinum agent is carboplatin. In certain
embodiments, the
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combination of the taxane, platinum agent, and indazolylaminopyrrolotriazine
has a
synergetic effect when compared to the administration of the combination of
taxane and
platinum agent, or indazolylaminopyrrolotriazine alone.
[001561 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered once a
day. In certain
embodiments, the indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a mixture of
enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically
acceptable salt,
solvate, hydrate, or prodrug thereof; is administered once a day with food. In
certain
embodiments, the indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a mixture of
enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically
acceptable salt,
solvate, hydrate, or prodrug thereof; is administered twice a day. In certain
embodiments, the
indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of
Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof; is administered twice a day with food.
[001571 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein is
administered to the subject in the amount ranging from about 0.01 to about
1,000 mg/kg,
from about 0.1 to about 500 mg/kg, from about 0.1 to about 250 mg/kg, or from
about 0.1 to
about 100 mg/kg.
[001581 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein is
administered to the subject in the amount ranging from about 0.01 to about
1,000 mg/kg/day,
from about 0.1 to about 500 mg/kg/day, from about 0.1 to about 250 mg/kg/day,
or from
about 0.1 to about 100 mg/kg/day. In certain embodiments, the
indazolylaminopyrrolotriazine provided herein is administered to the subject
in the amount of
about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about
9, about 10, about
15, about 20, about 25, about 30, about 35, about 40 about 50, about 60, about
70, about 75,
about 80, about 90, about 100, about 105, about 120, about 130, about 140,
about 150, about
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160, about 170, about 180, about 190, about 200, about 300, about 400, about
500, about 600,
about 700, about 750, about 800, about 900, or about 1,000 mg/kg/day.
[001591 The administered dose of the indazolylaminopyrrolotriazine provided
herein
can also be expressed in units other than the unit "mg/kg/day." For example,
doses for
parenteral administration can be expressed as mg/m2/day. One of ordinary skill
in the art
would readily know how to convert doses from mg/kg/day to mg/m2/day to given
either the
height or weight of a subject or both (See,
www.fda.gov/cder/cancer/animalframe.htm). For
example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38
mg/m2/day.
[001601 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein is
administered to the subject in the amount ranging from about 1 to about 1,500
mg/m2/day,
about 1 to about 1,000 mg/m2/day, from about 10 to about 500 mg/m2/day, from
about 10 to
about 300 mg/m2/day, or from about 20 to about 200 mg/m2/day. In certain
embodiments,
the indazolylaminopyrrolotriazine provided herein is administered to the
subject in the
amount of about 10, about 20, about 30, about 40, about 50, about 60, about
70, about 80,
about 90, about 100, about 110, about 120, about 130, about 134, about 140,
about 150,
about 160, about 170, about 180, about 190, about 200, about 210, about 220,
about 230,
about 240, about 250, about 260, about 270, about 280, about 290, or about 300
mg/m2/day.
[001611 In one embodiment, the indazolylaminopyrrolotriazine provided herein,
e.g.,
an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a mixture
of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically
acceptable salt,
solvate, hydrate, or prodrug thereof; is administered daily in a single dose
or divided doses,
where the total daily dose ranges from about 1 mg to about 2,000 mg, from
about 10 mg to
about 1,600 mg, from about 100 mg to about 1,200 mg, from about 200 mg to
about 1,200
mg, from about 200 mg to about 1,100 mg, from about 300 mg to about 1,100 mg,
from
about 300 mg to about 1,000 mg, from about 300 mg to about 800 mg, from about
320 to
about 800 mg, from about 320 to about 700 mg, from about 325 to about 650 mg,
from about
325 mg to about 600 mg, or from about 350 mg to about 600 mg.
[001621 In another embodiment, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered daily
in a single dose or
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divided doses for a total daily dose of at least 200 mg, at least 250 mg, at
least 300 mg, at
least 320 mg, at least 325 mg, at least 350 mg, or at least 400 mg.
[001631 In yet another embodiment, the indazolylaminopyrrolotriazine provided
herein, e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a
single
enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof;
or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is
administered daily in
a single dose or divided doses (e.g., BID) for a total daily dose of about 10
mg, about 30 mg,
about 65 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 320
mg,
about 400 mg, about 480 mg, about 500 mg, about 600 mg, about 660 mg, about
700 mg,
about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, or
about
1,600 mg.
[001641 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered daily
in a single dose or
divided doses for a total daily dose sufficient to achieve a plasma
concentration of the
compound at steady state ranging from about 0.5 M to about 40 M, from about
1 M to
about 30 M, from about 5 M to about 25 M or from about 10 M to about 20
M; in one
embodiment, about 1 M, about 2 M, about 5 M, about 10 M, about 15 M,
about 30
M, about 40 M, or about 50 M. As used herein, the term "plasma concentration
at steady
state" is the concentration reached after a period of administration of a
compound. Once
steady state is reached, there are minor peaks and troughs on the time
dependent curve of the
plasma concentration of the compound.
[001651 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered daily
in a single dose or
divided doses for a total daily dose calculated to achieve a plasma
concentration of the
compound at steady state ranging from about 0.5 M to about 40 M, from about
1 M to
about 30 M, from about 5 M to about 25 M or from about 10 M to about 20
M; in one
embodiment, about 1 M, about 2 M, about 5 M, about 10 M, about 15 M,
about 30
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M, about 40 M, or about 50 M.
[001661 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose sufficient to achieve a Cmax from about
0.1 to about 100
M, about 0.2 to about 50 M, about 0.4 to about 40 M, about 0.5 to about 10
M, about 5
to about 40 M, from about 10 to about 40 M, from about 0.4 to about 4.5 M,
or from
about 3.5 to about 6 M; in one embodiment, about 0.1 M, 0.2 M, about 0.3
M, about 0.4
M, about 0.5 M, 0.6 M, about 0.7 M, 0.8 M, about 0.9 M, about 1 M, about
2 M,
about 3 M, about 4 M, about 5 M, about 6 M, 7 M, about 8 M, 9 M, about
10 M,
about 15 M, about 20 M, about 30 M, about 40 M, about 50 M.
[001671 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose calculated to achieve a Cmax from about
0.1 to about 100
M, about 0.2 to about 50 M, about 0.4 to about 40 M, about 0.5 to about 10
M, about 5
to about 40 M, from about 10 to about 40 M, from about 0.4 to about 4.5 M,
or from
about 3.5 to about 6 M; in one embodiment, about 0.1 M, 0.2 M, about 0.3
M, about 0.4
M, about 0.5 M, 0.6 M, about 0.7 M, 0.8 M, about 0.9 M, about 1 M, about
2 M,
about 3 M, about 4 M, about 5 M, about 6 M, 7 M, about 8 M, 9 M, about
10 M,
about 15 M, about 20 M, about 30 M, about 40 M, about 50 M.
[001681 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose sufficient to achieve a Cmax of about 0.1
to about 50
g/mL, about 0.2 to about 40 g/mL, about 2 to about 20 g/mL, about 1.5 to
about 3.2
g/mL, or about 0.2 to about 2.2 g/mL.
[001691 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
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e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose calculated to achieve a Cmax of about 0.1
to about 50
g/mL, about 0.2 to about 40 g/mL, about 2 to about 20 g/mL, about 1.5 to
about 3.2
g/mL, or about 0.2 to about 2.2 g/mL.
[001701 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose sufficient to achieve an AUC from about 1
to about 500,
from about 5 to about 400, from about 60 to about 500, from about 125 to about
500, from
about 125 to about 300, from 125 to about 200, from about 4 to about 35, or
from about 40 to
about 55 pg*hr/mL.
[001711 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose calculated to achieve an AUC from about 1
to about 500,
from about 5 to about 400, from about 60 to about 500, from about 125 to about
500, from
about 125 to about 300, from 125 to about 200, from about 4 to about 35, or
from about 40 to
about 55 pg*hr/mL.
[001721 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose sufficient to achieve an AUC from about 5
to about 1,000,
from about 125 to about 1,000, from about 250 to about 500, from about 80 to
about 110, or
from about 5 to about 65 M*hr.
[001731 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
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mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a
single dose or
divided doses for a total daily dose calculated to achieve an AUC from about 5
to about
1,000, from about 125 to about 1,000, from about 250 to about 500, from about
80 to about
110, or from about 5 to about 65 M*hr.
[001741 Depending on the disease to be treated and the subject's condition,
the
indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of
Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof; can be administered by oral, parenteral (e.g., intramuscular,
intraperitoneal,
intravenous, CIV, intracistemal injection or infusion, subcutaneous injection,
or implant),
inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal
or local) routes of
administration. The indazolylaminopyrrolotriazine provided herein may be
formulated, alone
or together, in suitable dosage unit with pharmaceutically acceptable
excipients, carriers,
adjuvants and vehicles, appropriate for each route of administration.
[001751 The indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a mixture of
enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically
acceptable salt,
solvate, hydrate, or prodrug thereof; can be delivered as a single dose such
as, e.g., a single
bolus injection, or oral tablets or pills; or over time such as, e.g.,
continuous infusion over
time or divided bolus doses over time.
[001761 The indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a mixture of
enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically
acceptable salt,
solvate, hydrate, or prodrug thereof; can be administered once daily (QD), or
divided into
multiple daily doses such as twice daily (BID), three times daily (TID), and
four times daily
(QID). In addition, the administration can be continuous, i.e., every day, or
intermittently.
The term "intermittent" or "intermittently" as used herein is intended to mean
stopping and
starting at either regular or irregular intervals. For example, intermittent
administration of the
compound provided herein is administration for one to six days per week,
administration in
cycles (e.g., daily administration for two to eight consecutive weeks, then a
rest period with
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no administration for up to one week), or administration on alternate days.
[001771 In certain embodiments, the frequency of administration of the
indazolylaminopyrrolotriazine is in the range of about a daily dose to about a
monthly dose.
In certain embodiments, the administration of indazolylaminopyrrolotriazine is
once a day,
twice a day, three times a day, four times a day, once every other day, twice
a week, once
every week, once every two weeks, once every three weeks, or once every four
weeks. In
one embodiment, the indazolylaminopyrrolotriazine provided herein is
administered once a
day. In another embodiment, the indazolylaminopyrrolotriazine provided herein
is
administered twice a day. In yet another embodiment, the
indazolylaminopyrrolotriazine
provided herein is administered three times a day. In still another
embodiment, the
indazolylaminopyrrolotriazine provided herein is administered four times a
day.
[001781 In certain embodiments, the indazolylaminopyrrolotriazine is
administered
every week. In certain embodiments, the indazolylaminopyrrolotriazine is
administered on
days 1, 8, and 15 in a 28 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine is administered on days 1, 8, and 15 in a 21 day
cycle. In
certain embodiments, the indazolylaminopyrrolotriazine is administered on days
2, 9, and 16
in a 28 day cycle. In certain embodiments, the indazolylaminopyrrolotriazine
is administered
on days 2, 9, and 16 in a 21 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine is administered on days 3, 10, and 17 in a 28
day cycle. In
certain embodiments, the indazolylaminopyrrolotriazine is administered on days
3, 10, and 17
in a 21 day cycle.
[001791 In certain embodiments, the indazolylaminopyrrolotriazine is
administered
twice a week. In certain embodiments, the indazolylaminopyrrolotriazine is
administered on
days 1, 2, 8, 9, 15, and 16 in a 21 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine is administered on days 1, 2, 8, 9, 15, and 16
in a 28 day cycle.
In certain embodiments, the indazolylaminopyrrolotriazine is administered on
days 2, 3, 9,
10, 16, and 17 in a 21 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine
is administered on days 2, 3, 9, 10, 16, and 17 in a 28 day cycle. In certain
embodiments, the
indazolylaminopyrrolotriazine is administered on days 4, 5, 11, 12, 18, and 19
in a 21 day
cycle. In certain embodiments, the indazolylaminopyrrolotriazine is
administered on days 4,
5, 11, 12, 18, and 19 in a 28 day cycle.
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[00180] In certain embodiments, the indazolylaminopyrrolotriazine is
administered for
7 days in a 21 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine is
administered for 7 days in a 28 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine is administered daily for three weeks, followed
by a one-week
rest in a 28 day cycle. In certain embodiments, the
indazolylaminopyrrolotriazine is
administered daily, uninterrupted for 4 weeks in a 28 day cycle. In certain
embodiments, the
indazolylaminopyrrolotriazine is administered on days 1 and 2 in a 21 day
cycle.
[00181] In certain embodiments, the taxane is administered every three weeks.
In
certain embodiments, the taxane is administered every two weeks. In certain
embodiments,
the taxane is administered every week. In certain embodiments, the taxane is
administered on
days 1, 8, and 15 in a 28 day cycle. In certain embodiments, the taxane is
administered on
days 1, 8, and 15 in a 21 day cycle. In certain embodiments, the taxane is
administered on
days 3, 10, and 17 in a 28 day cycle. In certain embodiments, the taxane is
administered on
days 3, 10, and 17 in a 21 day cycle. In certain embodiments, the taxane is
administered for 7
days in a 21 day cycle.
[00182] In certain embodiments, paclitaxel is administered every three weeks.
In
certain embodiments, paclitaxel is administered every two weeks. In certain
embodiments,
paclitaxel is administered every week. In certain embodiments, paclitaxel is
administered on
days 1, 8, and 15 in a 28 day cycle. In certain embodiments, paclitaxel is
administered on
days 1, 8, and 15 in a 21 day cycle. In certain embodiments, paclitaxel is
administered on
days 3, 10, and 17 in a 28 day cycle. In certain embodiments, paclitaxel is
administered on
days 3, 10, and 17 in a 21 day cycle. In certain embodiments, paclitaxel is
administered for
7 days in a 21 day cycle.
[00183] In certain embodiments, the taxane is administered intravenously over
1 hour.
In certain embodiments, the taxane is administered intravenously over 30
minutes. In certain
embodiments, the taxane is administered intravenously over 3 hours. In certain
embodiments, the taxane is administered intravenously over 24 hours. In
certain
embodiments, paclitaxel is administered intravenously over 3 hours. In certain
embodiments,
paclitaxel is administered intravenously over 24 hours. In certain
embodiments, docetaxel is
administered intravenously over 1 hour. In certain embodiments, carboplatin is
administered
intravenously over 30 minutes.
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[001841 In one embodiment, the intravenous administration of the compound of
formula I occurs before the intravenous administration of paclitaxel. In one
embodiment, the
intravenous administration of the compound of formula I occurs two days before
the
intravenous administration of paclitaxel. In one embodiment, the intravenous
administration
of the compound of formula I occurs a day before the intravenous
administration of
paclitaxel. In one embodiment, the intravenous administration of the compound
of formula I
occurs on the same day as the intravenous administration of paclitaxel.
[001851 In yet another embodiment, the intravenous administration of the
compound of
formula I occurs after the intravenous administration of paclitaxel. In yet
another
embodiment, the intravenous administration of the compound of formula I occurs
one day
after the intravenous administration of paclitaxel. In yet another embodiment,
the
intravenous administration of the compound of formula I occurs two days after
the
intravenous administration of paclitaxel.
[001861 In certain embodiments, the taxane provided herein is administered to
the
subject in a single dose or divided doses for a total daily dose ranging from
about 10 to about
1,000 mg/m2, from about 20 to about 500 mg/m2, from about 50 to 250 mg/m2,
from about
110 to about 200 mg/m2, from about 60 to about 175 mg/m2, from about 60 to
about 100
mg/m2, or from about 80 to about 90 mg/m2. In certain embodiments, the taxane
provided
herein is administered to the subject in a single dose or divided doses for a
total daily dose in
the amount of about 60, about 75, about 80, about 90, about 100, about 135,
about 150, about
175, about 250 mg/m2, or about 260 mg/m2.. In certain embodiments, the taxane
provided
herein is administered to the subject in a single dose or divided doses for a
total daily dose in
the amount of about 60, about 75, about 80, about 90, about 100, about 135,
about 150, about
170, about 175, about 200, about 210, about 225, about 250, 255, about 260,
about 275, about
280 or about 300 mg/m2.
[001871 In certain embodiments, paclitaxel is administered intravenously to
the subject
in the amount of 250 mg/m2 over 3 hours. In certain embodiments, paclitaxel is
administered
intravenously to the subject in the amount of 250 mg/m2 over 24 hours. In
certain
embodiments, paclitaxel is administered intravenously to the subject in the
amount of 175
mg/m2 over 3 hours. In certain embodiments, paclitaxel is administered
intravenously to the
subject in the amount of 175 mg/m2 over 24 hours. In certain embodiments,
paclitaxel is
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administered intravenously to the subject in the amount of 150 mg/m2 over 3
hours. In
certain embodiments, paclitaxel is administered intravenously to the subject
in the amount of
150 mg/m2 over 24 hours. In certain embodiments, paclitaxel is administered
intravenously
to the subject in the amount of 135 mg/m2 over 3 hours. In certain
embodiments, paclitaxel is
administered intravenously to the subject in the amount of 135 mg/m2 over 24
hours. In
certain embodiments, paclitaxel is administered intravenously to the subject
in the amount of
100 mg/m2 over 3 hours. In certain embodiments, paclitaxel is administered
intravenously to
the subject in the amount of 100 mg/m2 over 24 hours. In certain embodiments,
paclitaxel is
administered intravenously to the subject in the amount of 80 to 90 mg/m2 over
3 hours. In
certain embodiments, paclitaxel is administered intravenously to the subject
in the amount of
80 to 90 mg/m2 over 24 hours. In certain embodiments, paclitaxel is
administered
intravenously to the subject in the amount of 90 mg/m2 over 3 hours. In
certain
embodiments, paclitaxel is administered intravenously to the subject in the
amount of 90
mg/m2 over 24 hours. In certain embodiments, paclitaxel is administered
intravenously to the
subject in the amount of 80 mg/m2 over 3 hours. In certain embodiments,
paclitaxel is
administered intravenously to the subject in the amount of 80 mg/m2 over 24
hours.
[00188] In certain embodiments, paclitaxel is administered intravenously to
the subject
in the amount of 175 mg/m2 over 3 hours every three weeks. In certain
embodiments,
paclitaxel is administered intravenously to the subject in the amount of 100
mg/m2 over 3
hours every two weeks. In certain embodiments, paclitaxel is administered
intravenously to
the subject in the amount of 135 mg/m2 over 3 hours. In certain embodiments,
paclitaxel is
administered intravenously to the subject in the amount of 80 to 90 mg/m2
every week. In
certain embodiments, paclitaxel is administered intravenously to the subject
in the amount of
80 mg/m2 every week. In certain embodiments, paclitaxel is administered
intravenously to
the subject in the amount of 80 mg/m2 on days 1, 8, and 15 every 28 days.
[00189] In certain embodiments, paclitaxel is administered intravenously to
the subject
in the amount of 30 mg/m2 or 40 mg/m2 on five consecutive days.
[00190] In certain embodiments, albumin-bound paclitaxel is administered
intravenously to the subject in the amount of 100 mg/m2 every 28 days. In
certain
embodiments, albumin-bound paclitaxel is administered intravenously to the
subject in the
amount of 150 mg/m2 on days 1, 8, and 15 every 28 days. In certain
embodiments, albumin-
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bound paclitaxel is administered intravenously to the subject in the amount of
260 mg/m2
every 21 days. In certain embodiments, albumin-bound paclitaxel is
administered
intravenously to the subject in the amount of 110-200 mg/m2.
[00191] In certain embodiments, paclitaxel is administered intravenously over
1 hour.
In certain embodiments, paclitaxel is administered intravenously over 1 - 2
hours. In certain
embodiments, paclitaxel is administered intravenously over 2 hours. In certain
embodiments,
paclitaxel is administered intravenously over 6 hours. In certain embodiments,
paclitaxel is
administered intravenously over 24 hours.
[00192] In certain embodiments, docetaxel is administered intravenously to the
subject
over 1 hour. In certain embodiments, docetaxel is administered intravenously
to the subject
every three weeks. In certain embodiments, docetaxel is administered
intravenously to the
subject over 1 hour every three weeks. In certain embodiments, docetaxel is
administered
intravenously to the subject in the amount of 60 to 100 mg/m2. In certain
embodiments,
docetaxel is administered intravenously to the subject in the amount of 60 to
125 mg/m2. In
certain embodiments, docetaxel is administered intravenously to the subject in
the amount of
60 mg/m2. In certain embodiments, docetaxel is administered intravenously to
the subject in
the amount of 70 mg/m2. In certain embodiments, docetaxel is administered
intravenously to
the subject in the amount of 75 mg/m2. In certain embodiments, docetaxel is
administered
intravenously to the subject in the amount of 90 mg/m2. In certain
embodiments, docetaxel is
administered intravenously to the subject in the amount of 100 mg/m2. In
certain
embodiments, docetaxel is administered intravenously to the subject in the
amount of 115
mg/m2. In certain embodiments, docetaxel is administered intravenously to the
subject in the
amount of 125 mg/m2.
[00193] In certain embodiments, docetaxel is administered intravenously to the
subject
in the amount of 60, 70 or 75 mg/m2 once every three weeks. In certain
embodiments,
docetaxel is administered intravenously to the subject in the amount of 60, 70
or 75 mg/m2
once every two weeks. In certain embodiments, docetaxel is administered
intravenously to
the subject in the amount of 60, 70 or 75 mg/m2 once every week. In certain
embodiments,
docetaxel is administered on day 2 in a 21 day cycle.
[00194] In certain embodiments, the docetaxel is administered intravenously to
the
subject in the amount of 50 mg/m2 on days 1 and 8 every 21 days. In certain
embodiments,
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the docetaxel is administered intravenously to the subject in the amount of 50
mg/m2 on days
1 and 8 every 30 days. In certain embodiments, the docetaxel is administered
intravenously
to the subject in the amount of 50 mg/m2 on days 1 and 8 every month.
[00195] In certain embodiments, the docetaxel is administered intravenously to
the
subject in the amount of 14 mg/m2 for 5 consecutive days
[00196] In certain embodiments, the indazolylaminopyrrolotriazine is
administered
intravenously to the subject on days 1 and 2 every 21 days. In certain
embodiments, the
docetaxel is administered intravenously to the subject once on day 2 every 21
days. In
certain embodiments, the indazolylaminopyrrolotriazine is administered
intravenously to the
subject in the amount of about 20, about 30, about 40, about 80, about 134,
about 200, or
about 280 mg/m2/day on days 1 and 2 every 21 days. In certain embodiments, the
docetaxel
is administered intravenously to the subject in the amount of about 60 or
about 75 mg/m2/day
on day 2 every 21 days.
[00197] In certain embodiments, the indazolylaminopyrrolotriazine is
administered
intravenously to the subject on days 1 and 2, and the docetaxel is
administered intravenously
to the subject once on day 2, both administered every 21 days. In certain
embodiments, the
indazolylaminopyrrolotriazine is administered intravenously to the subject in
the amount of
about 20, about 30, about 40, about 80, about 134, about 200, or about 280
mg/m2/day on
days 1 and 2, and the docetaxel is administered intravenously to the subject
in the amount of
about 60 or about 75 mg/m2/day on day 2, both administered every 21 days.
[00198] In certain embodiments, docetaxel is administered intravenously over 1
hour.
In certain embodiments, docetaxel is administered intravenously over 1 - 2
hours. In certain
embodiments, docetaxel is administered intravenously over 2 hour. In certain
embodiments,
docetaxel is administered intravenously over 6 hours. In certain embodiments,
docetaxel is
administered intravenously over 24 hours. In certain embodiments, the
indazolylaminopyrrolotriazine is administered intravenously over 30 min. In
certain
embodiments, docetaxel is administered immediately after the
indazolylaminopyrrolotriazine
on day 2.
[00199] In one embodiment, the method comprises an oral administration of an
indazolylaminopyrrolotriazine provided herein according to a regimen selected
from:
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a. 600 mg/day for 21 days;
b. 600 mg/day for 28 days; and
c. 400 mg/day for 21 days;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 260 mg/m2 over 24 hours;
ii. 250 mg/m2 over 24 hours;
iii. 200 mg/m2 over 24 hours;
iv. 185 mg/m2 over 3 hours;
v. 185 mg/m2 over 24 hours;
vi. 175 mg/m2 over 3 hours;
vii. 175 mg/m2 over 24 hours;
viii. 150 mg/m2 over 3 hours;
ix. 150 mg/m2 over 24 hours;
X. 135 mg/m2 over 3 hours;
xi. 135 mg/m2 over 24 hours;
xii. 100 mg/m2 over 3 hours;
xiii. 80-90 mg/m2;
xiv. 80 mg/m2;
xv. 30 mg/m2; and
xvi. 20 mg/m2;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
[002001 In another embodiment, the method comprises an oral or intravenous
administration of an indazolylaminopyrrolotriazine provided herein according
to a regimen
selected from:
a. 600 mg/day for 21 days;
b. 600 mg/day for 28 days;
c. 400 mg/day for 21 days; and
d. 40 to 300 mg/m2/day;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 260 mg/m2 over 24 hours;
ii. 250 mg/m2 over 24 hours;
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iii. 200 mg/m2 over 24 hours;
xvii. 185 mg/m2 over 3 hours;
xviii. 185 mg/m2 over 24 hours;
xix. 175 mg/m2 over 3 hours;
xx. 175 mg/m2 over 24 hours;
xxi. 150 mg/m2 over 3 hours;
xxii. 150 mg/m2 over 24 hours;
xxiii. 135 mg/m2 over 3 hours;
xxiv. 135 mg/m2 over 24 hours;
xxv. 100 mg/m2 over 3 hours;
xxvi. 100 mg/m2 over 1 hour;
xxvii. 80-90 mg/m2;
xxviii. 80 mg/m2;
xxix. 30 mg/m2;
xxx. 20 mg/m2;
xxxi. 60 to 125 mg/m2/day; and
xxxii. 135 to 250 mg/m2/day;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
[002011 In yet another embodiment, the method comprises an intravenous
administration of an indazolylaminopyrrolotriazine provided herein according
to a regimen
selected from:
a. 20 mg/m2 on days 1 and 2;
b. 30 mg/m2 on days 1 and 2;
C. 40 mg/m2 on days 1 and 2;
d. 80 mg/m2 on days 1 and 2;
e. 100 mg/m2 on days 1 and 2;
f. 134 mg/m2 on days 1 and 2;
g. 135 mg/m2 on days 1 and 2;
h. 150 mg/m2 on days 1 and 2;
i. 200 mg/m2 on days 1 and 2;
j. 250 mg/m2 on days 1 and 2;
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k. 275 mg/m2 on days 1 and 2;
1. 280 mg/m2 on days 1 and 2;
M. 300 mg/m2 on days 1 and 2; and
n. 40 to 300 mg/m2/day;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 260 mg/m2 over 24 hours;
ii. 250 mg/m2 over 24 hours;
iii. 200 mg/m2 over 24 hours;
iv. 185 mg/m2 over 3 hours;
V. 185 mg/m2 over 24 hours;
vi. 175 mg/m2 over 3 hours;
vii. 175 mg/m2 over 24 hours;
viii. 150 mg/m2 over 3 hours;
ix. 150 mg/m2 over 24 hours;
X. 135 mg/m2 over 3 hours;
xi. 135 mg/m2 over 24 hours;
xii. 100 mg/m2 over 3 hours;
xiii. 100 mg/m2 over 1 hour;
xiv. 80-90 mg/m2;
xv. 80 mg/m2;
xvi. 75 mg/m2;
xvii. 70 mg/m2;
xviii. 65 mg/m2;
xix. 60 mg/m2;
xx. 50 mg/m2;
xxi. 30 mg/m2;
xxii. 20 mg/m2;
xxiii. 60 to 125 mg/m2/day; and
xxiv. 135 to 250 mg/m2/day;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
[002021 In yet another embodiment, the method comprises an administration of
an
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indazolylaminopyrrolotriazine provided herein according to a regimen selected
from:
a. a dose sufficient to achieve a Cmax of about 5 to about 40 M;
b. a dose sufficient to achieve a Cmax of about 10 to about 40 M;
c. a dose sufficient to achieve a Cmax of about 2 to about 20 g/mL;
d. a dose sufficient to achieve a Cmax of about 3.5 to about 6 M;
e. a dose sufficient to achieve a Cmax of about 0.4 to about 4.5 M;
f. a dose sufficient to achieve a Cmax of about 1.5 to about 3.2 g/mL;
and
g. a dose sufficient to achieve a Cmax of about 0.2 to about 2.2 g/mL;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 260 mg/m2 over 24 hours;
ii. 250 mg/m2 over 24 hours;
iii. 200 mg/m2 over 24 hours;
iv. 185 mg/m2 over 3 hours;
v. 185 mg/m2 over 24 hours;
vi. 175 mg/m2 over 3 hours;
vii. 175 mg/m2 over 24 hours;
viii. 150 mg/m2 over 3 hours;
ix. 150 mg/m2 over 24 hours;
X. 135 mg/m2 over 3 hours;
xi. 135 mg/m2 over 24 hours;
xii. 100 mg/m2 over 3 hours;
xiii. 80-90 mg/m2;
xiv. 80 mg/m2;
xv. 30 mg/m2;
xvi. 20 mg/m2; and
xvii. 60 to 100 mg/m2/day;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
[002031 In yet another embodiment, the method comprises an intravenous
administration of an indazolylaminopyrrolotriazine provided herein according
to a regimen
selected from:
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a. a dose sufficient to achieve an AUC of about 60 to about 500
pg*hr/mL;
b. a dose sufficient to achieve an AUC of about 125 to about 500
pg*hr/mL;
c. a dose sufficient to achieve an AUC of about 125 to about 300
pg*hr/mL;
d. a dose sufficient to achieve an AUC of about 125 to about 200
pg*hr/mL;
e. a dose sufficient to achieve an AUC of about 125 to about 1,000
M*hr;
f. a dose sufficient to achieve an AUC of about 250 to about 500 M*hr;
g. a dose sufficient to achieve an AUC of about 4 to about 35 pg*hr/mL;
and
h.. a dose sufficient to achieve an AUC of about 40 to about 55 pg*hr/mL;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 260 mg/m2 over 24 hours;
ii. 250 mg/m2 over 24 hours;
iii. 200 mg/m2 over 24 hours;
iv. 185 mg/m2 over 3 hours;
v. 185 mg/m2 over 24 hours;
vi. 175 mg/m2 over 3 hours;
vii. 175 mg/m2 over 24 hours;
viii. 150 mg/m2 over 3 hours;
ix. 150 mg/m2 over 24 hours;
X. 135 mg/m2 over 3 hours;
xi. 135 mg/m2 over 24 hours;
xii. 100 mg/m2 over 3 hours;
xiii. 80-90 mg/m2;
xiv. 80 mg/m2;
xv. 30 mg/m2; xvi.20 mg/m2; and
xvii. 60 to 100 mg/m2/day;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
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[002041 In yet another embodiment, the method comprises an administration of
an
indazolylaminopyrrolotriazine provided herein according to a regimen selected
from:
a. a dose sufficient to achieve a Cmax of about 5 to about 40 M;
b. a dose sufficient to achieve a Cmax of about 10 to about 40 M;
c. a dose sufficient to achieve a Cmax of about 2 to about 20 g/mL;
d. a dose sufficient to achieve a Cmax of about 3.5 to about 6 M;
e. a dose sufficient to achieve a Cmax of about 0.4 to about 4.5 M;
f. a dose sufficient to achieve a Cmax of about 1.5 to about 3.2 g/mL;
and
g. a dose sufficient to achieve a Cmax of about 0.2 to about 2.2 g/mL;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 20-100 mg/m2 ;
ii. 60 mg/m2;
iii. 75 mg/m2;
iv. 100 mg/m2;
v. 30 mg/m2;
vi. 20 mg/m2; and
vii. 60 to 100 mg/m2/day;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
[002051 In yet another embodiment, the method comprises an intravenous
administration of an indazolylaminopyrrolotriazine provided herein according
to a regimen
selected from:
a. a dose sufficient to achieve an AUC of about 60 to about 500
pg*hr/mL;
b. a dose sufficient to achieve an AUC of about 125 to about 500
pg*hr/mL;
c. a dose sufficient to achieve an AUC of about 125 to about 300
pg*hr/mL;
d. a dose sufficient to achieve an AUC of about 125 to about 200
pg*hr/mL;
e. a dose sufficient to achieve an AUC of about 125 to about 1,000
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M*hr;
f. a dose sufficient to achieve an AUC of about 250 to about 500 M*hr;
g.. a dose sufficient to achieve an AUC of about 4 to about 35 pg*hr/mL;
and
h.. a dose sufficient to achieve an AUC of about 40 to about 55 pg*hr/mL;
and an intravenous administration of a taxane according to a regimen selected
from:
i. 60-100 mg/m2 ;
ii. 60 mg/m2;
iii. 75 mg/m2; and
iv. 100 mg/m2;
wherein the indazolylaminopyrrolotriazine and taxane are administered
simultaneously,
concurrently, separately, or sequentially.
[002061 In yet another embodiment, the method provided herein further
comprises an
intravenous administration of carboplatin according to a regimen selected
from:
1. a dose sufficient to achieve an AUC of about 2 to about 8 mg*min/mL;
2. a dose sufficient to achieve an AUC of about 3 to about 8 mg*min/mL;
3. a dose sufficient to achieve an AUC of about 3 to about 7.5
mg*min/mL;
4. a dose sufficient to achieve an AUC of about 2 mg*min/mL;
5. a dose sufficient to achieve an AUC of about 3 mg*min/mL;
6. a dose sufficient to achieve an AUC of about 5 mg*min/mL;
7. a dose sufficient to achieve an AUC of about 6 mg*min/mL; and
8. a dose sufficient to achieve an AUC of about 7.5 mg*min/mL;
wherein the indazolylaminopyrrolotriazine , taxane, and carboplatin are
administered
simultaneously, concurrently, separately, or sequentially.
[002071 In still another embodiment, the method provided herein further
comprises an
intravenous administration of carboplatin according to a regimen selected
from:
1. a dose calculated to achieve an AUC of about 2 to about 8
mg*min/mL;
2. a dose calculated to achieve an AUC of about 3 to about 8
mg*min/mL;
3. a dose calculated to achieve an AUC of about 3 to about 7.5
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mg*min/mL;
4. a dose calculated to achieve an AUC of about 2 mg*min/mL;
5. a dose calculated to achieve an AUC of about 3 mg*min/mL;
6. a dose calculated to achieve an AUC of about 5 mg*min/mL;
7. a dose calculated to achieve an AUC of about 6 mg*min/mL; and
8. a dose calculated to achieve an AUC of about 7.5 mg*min/mL;
wherein the indazolylaminopyrrolotriazine , taxane, and carboplatin are
administered
simultaneously, concurrently, separately, or sequentially.
[002081 In certain embodiments, the subject is a mammal. In certain
embodiments, the
mammal is a human.
[002091 In one embodiment, the proliferative disease is a tumor. In another
embodiment, the proliferative disease is a solid tumor. In certain
embodiments, the solid
tumor is an advanced solid tumor. In certain embodiments, the solid tumor is a
metastatic
solid tumor. In yet another embodiment, the proliferative disease is cancer.
In yet another
embodiment, the proliferative disease is advanced cancer. In certain
embodiments, the solid
tumor is metastatic cancer.
[002101 In certain embodiments, the tumor overexpresses HER1 protein. In
certain
embodiments, the tumor overexpresses HER2 protein.
[002111 In certain embodiments, the cancer treatable with the methods provided
herein
includes, but is not limited to, (1) leukemias, including, but not limited to,
acute leukemia,
acute myeloid leukemia (AML), acute lymphocytic leukemia, acute myelocytic
leukemias
such as myeloblastic, promyelocytic, myelomonocytic, monocytic,
erythroleukemia
leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia,
thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia
(RA), RA
with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in
transformation
(RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic
leukemias, including, but not limited to, chronic myelocytic (granulocytic)
leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia (CML), and hairy cell leukemia;
(3)
polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's
disease and non-
Hodgkin's disease; (5) multiple myelomas, including, but not limited to,
smoldering multiple
myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia,
solitary
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plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's
macroglobulinemia;
(7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal
gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas,
including,
but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's
sarcoma,
malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal
sarcoma, soft-tissue
sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma,
leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers,
neurilemmoma,
rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not
limited to,
glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma,
nonglial tumor,
acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma,
pineocytoma,
pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but
not limited
to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma,
medullary breast
cancer, mucinous breast cancer, tubular breast cancer, papillary breast
cancer, primary
cancers, Paget's disease, and inflammatory breast cancer; (13) adrenal cancer,
including, but
not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid
cancer,
including, but not limited to, papillary or follicular thyroid cancer,
medullary thyroid cancer,
and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not
limited to,
insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and
carcinoid
or islet cell tumor; (16) pituitary cancer, including, but limited to,
Cushing's disease,
prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer,
including, but
not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and
cilliary
body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not
limited to,
squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer,
including, but
not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell
carcinoma,
sarcoma, and Paget's disease; (20) cervical cancers, including, but not
limited to, squamous
cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not
limited to,
endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but
not limited
to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and
stromal tumor; (23)
esophageal cancer, including, but not limited to, squamous cancer,
adenocarcinoma, adenoid
cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma,
melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell)
carcinoma; (24)
stomach cancer, including, but not limited to, adenocarcinoma, fungating
(polypoid),
ulcerating, superficial spreading, diffusely spreading, malignant lymphoma,
liposarcoma,
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fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27)
liver cancer,
including, but not limited to, hepatocellular carcinoma and hepatoblastoma;
(28) gallbladder
cancer, including, but not limited to, adenocarcinoma; (29)
cholangiocarcinomas, including,
but not limited to, pappillary, nodular, and diffuse; (30) lung cancer,
including, but not
limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid
carcinoma),
adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31)
testicular cancer,
including, but not limited to, germinal tumor, seminoma, anaplastic, classic
(typical),
spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and
choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not
limited to,
adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34)
oral
cancer, including, but not limited to, squamous cell carcinoma; (35) basal
cancer; (36)
salivary gland cancer, including, but not limited to, adenocarcinoma,
mucoepidermoid
carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but
not limited to,
squamous cell cancer and verrucous; (38) skin cancer, including, but not
limited to, basal cell
carcinoma, squamous cell carcinoma and melanoma, superficial spreading
melanoma,
nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma;
(39)
kidney cancer, including, but not limited to, renal cell cancer,
adenocarcinoma,
hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or
uterer); (40)
Wilms' tumor; (41) bladder cancer, including, but not limited to, transitional
cell carcinoma,
squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer,
including, not
limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio-
endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial
carcinoma,
cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous
gland
carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et
al., 1985,
Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997,
Informed
Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery,
Viking
Penguin, Penguin Books U.S.A., Inc., United States of America).
[002121 In certain embodiments, the cancer that is treatable with the methods
provided
herein includes, but is not limited to, bladder cancer, breast cancer,
cervical cancer, colon
cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer,
gastric cancer, glioma
(e.g., glioblastoma), head and neck cancer, liver cancer, lung cancer (e.g.,
small cell and non-
small cell lung cancers), melanoma, myeloma, neuroblastoma, ovarian cancer,
pancreatic
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cancer, prostate cancer, renal cancer, sarcoma (e.g., osteosarcoma), skin
cancer (e.g.,
squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer,
and uterine
cancer.
[002131 In certain embodiments, the cancer that is treatable with the methods
provided
herein includes, but is not limited to, bladder cancer, breast cancer,
cervical cancer, colon
cancer (e.g., colorectal cancer), endometrial cancer, gastric cancer, glioma
(e.g.,
glioblastoma), head and neck cancer, liver cancer, non-small cell lung cancer,
ovarian cancer,
pancreatic cancer, and prostate cancer.
[002141 In certain embodiments, the cancer is non-small cell lung cancer. In
certain
embodiments, the cancer is non-small cell lung cancer which overexpresses HER1
protein.
In certain embodiments, the cancer is non-small cell lung cancer which
overexpresses HER2
protein. In certain embodiments, the cancer is non-small cell lung cancer
which
overexpresses HER1 and HER2 proteins. In certain embodiments, the cancer is
metastatic
non-small cell lung cancer. In certain embodiments, the cancer is metastatic
non-small cell
lung cancer which overexpresses HER1 protein. In certain embodiments, the
cancer is
metastatic non-small cell lung cancer which overexpresses HER2 protein. In
certain
embodiments, the cancer is metastatic non-small cell lung cancer which
overexpresses HER1
and HER2 proteins.
[002151 In certain embodiments, the cancer is breast cancer. In certain
embodiments,
the cancer is breast cancer which overexpresses HER1 protein. In certain
embodiments, the
cancer is breast cancer which overexpresses HER2 protein. In certain
embodiments, the
cancer is breast cancer which overexpresses HER1 and HER2 proteins. In certain
embodiments, the cancer is metastatic breast cancer. In certain embodiments,
the cancer is
metastatic breast cancer which overexpresses HER1 protein. In certain
embodiments, the
cancer is metastatic breast cancer which overexpresses HER2 protein. In
certain
embodiments, the cancer is metastatic breast cancer which overexpresses HER1
and HER2
proteins.
[002161 In certain embodiments, the cancer is head and neck cancer. In certain
embodiments, the cancer is lung cancer. In certain embodiments, the cancer is
lung
adenocarcinoma. In certain embodiments, the cancer is esophogeal or upper GI
cancer.
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[002171 In certain embodiments, the subject to be treated with one of the
methods
provided herein has not been treated with anticancer therapy. In certain
embodiments, the
subject to be treated with one of the methods provided herein has been treated
with anticancer
therapy.
[002181 The methods provided herein encompass treating a subject regardless of
patient's age, although some diseases or disorders are more common in certain
age groups.
Further provided is a method for treating a subject who has undergone surgery
in an attempt
to treat the disease or condition at issue, as well as the one who have not.
Because the
subjects with cancer have heterogeneous clinical manifestations and varying
clinical
outcomes, the treatment given to a particular subject may vary, depending on
his/her
prognosis.
[002191 The combination regimen can be administered repetitively if necessary,
for
example, until the patient experiences stable disease or regression, or until
the patient
experiences disease progression or unacceptable toxicity. For example, stable
disease for
solid tumors generally means that the perpendicular diameter of measurable
lesions has not
increased by 25% or more from the last measurement. Response Evaluation
Criteria in Solid
Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 2000, 92,
205-216.
Stable disease or lack thereof is determined by methods known in the art such
as evaluation
of patient symptoms, physical examination, visualization of the tumor that has
been imaged
using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation
modalities.
[002201 In certain embodiments, the combination regimen is administered to the
subject over an extended period of time, ranging from 1 day to about 12
months, from 2 days
to about 6 months, from 3 days to about 5 months, from 3 days to about 4
months, from 3
days to about 12 weeks, from 3 days to about 10 weeks, from 3 days to about 8
weeks, from
3 days to about 6 weeks, from 3 days to about 5 weeks, from 3 days to about 4
weeks, from 3
days to about 3 weeks, from 3 days to about 2 weeks, or from 3 days to about
10 days.
[002211 In certain embodiments, the combination regimen is administered in a
21 day
cycle. In certain embodiments, the combination regimen is administered in a 28
day cycle.
In certain embodiments, the combination regimen is administered in a monthly
cycle.
[002221 In certain embodiments, the combination regimen is cyclically
administered to
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the subject. Cycling therapy involves the administration of the combination
regimen
provided herein for a period of time, followed by a rest for a period of time,
and repeating
this sequential administration. Cycling therapy can reduce the development of
resistance to
one or more of the therapies, avoid or reduce the side effects of one of the
therapies, and/or
improves the efficacy of the treatment.
[002231 Consequently, in one embodiment, the combination regimen provided
herein
is administered daily for one week, two weeks, three weeks, four weeks, five
weeks, six
weeks, eight weeks, ten weeks, fifteen weeks, or twenty weeks, followed by a
rest period of
about 1 day to about ten weeks. For example, the methods contemplate using
cycling of one
week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks,
ten weeks,
fifteen weeks, or twenty weeks. In another embodiment, the combination regimen
provided
herein is administered daily for one week, two weeks, three weeks, four weeks,
five weeks, or
six weeks with a rest period of 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26,
28, 29 or 30 days.
In certain embodiments, the rest period is 14 days. In certain embodiments,
the rest period is
28 days. In one embodiment, the rest period is a period that is sufficient for
bone marrow
recovery. The frequency, number and length of dosing cycles can be increased
or decreased.
[002241 As used herein, the term "combination regimen" includes the use of
more than
one therapies (e.g., one or more prophylactic and/or therapeutic agents).
However, the use of
the term "combination regimen" does not restrict the order in which therapies
(e.g.,
prophylactic and/or therapeutic agents) are administered to the subject. A
first therapy (e.g.,
a prophylactic or therapeutic agent such as an indazolylaminopyrrolotriazine
provided herein)
can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2
hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1
week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly
with, or
subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2
hours, 4 hours,
6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3
weeks, 4
weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a
second therapy
(e.g., a prophylactic or therapeutic agent such as the taxane described
herein) to the subject.
Triple therapy is also contemplated herein (e.g., a platinum agent as a third
therapy).
[002251 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
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mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered to the
subject prior to the
administration of the taxane. In certain embodiments, the
indazolylaminopyrrolotriazine
provided herein is administered to the subject about 2 days, about 1 day,
about 12 hrs, about 6
hrs, about 4 hrs, about 2 hrs, about 60 min, about 30 min, about 20 min, about
10 min before
the administration of the taxane. In certain embodiments, the
indazolylaminopyrrolotriazine
provided herein is administered to the subject about 2 days before the
administration of the
taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided
herein is
administered to the subject about 1 day before the administration of the
taxane. In certain
embodiments, the indazolylaminopyrrolotriazine provided herein is administered
to the
subject in the same day as the administration of the taxane.
[002261 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered to the
subject after the
administration of the taxane. In certain embodiments, the
indazolylaminopyrrolotriazine
provided herein is administered to the subject about 2 days, about 1 day,
about 12 hrs, about 6
hrs, about 4 hrs, about 2 hrs, about 60 min, about 30 min, about 20 min, about
10 min after
the administration of the taxane. In certain embodiments, the
indazolylaminopyrrolotriazine
provided herein is administered to the subject about 2 days after the
administration of the
taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided
herein is
administered to the subject about 1 day after the administration of the
taxane.
[002271 In certain embodiments, the indazolylaminopyrrolotriazine provided
herein,
e.g., an indazolylaminopyrrolotriazine of Formula I or II, including a single
enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; is administered to the
subject
concurrently with the administration of the taxane.
[002281 In each embodiment provided herein, the method may further comprise a
diagnostic step for determining the expression level of HER1 protein on the
cells of the
tumor. In one embodiment, the diagnostic step is carried out prior to the
administration of the
combination regimen provided herein. If the subject has a tumor with
overexpressed HER1,
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the combination regimen provided herein is then administered. In another
embodiment, the
diagnostic step is carried out during the course of the treatment.
[002291 In each embodiment provided herein, the method may further comprise a
diagnostic step for determining the expression level of HER2 protein on the
cells of the
tumor. In one embodiment, the diagnostic step is carried out prior to the
administration of the
compounds. In another embodiment, the diagnostic step is carried out during
the course of
the treatment.
[002301 The methods provided herein may further comprise administering other
therapeutic agents useful in the treatment and/or prevention of a disease
described herein.
[002311 In certain embodiments, each method provided herein may independently
further comprise the step of administering an additional therapeutic agent.
The additional
therapeutic agents that may be used in combination with the combination
regimen herein
include, but are not limited to, surgery, endocrine therapy, biologic response
modifiers (e.g.,
interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and
cryotherapy,
agents to attenuate any adverse effects (e.g., antiemetics), and other
approved
chemotherapeutic drugs, including, but not limited to, alkylating drugs
(mechlorethamine,
chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites
(cytarabine
(also known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine),
and
methotrexate), purine antagonists and pyrimidine antagonists (6-
mercaptopurine, 5-
fluorouracil, cytarbine, and gemcitabine), spindle poisons (vinblastine,
vincristine, and
vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan),
antibiotics
(daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas
(carmustine and
lomustine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide,
flutamide, and
megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a
more
comprehensive discussion of updated cancer therapies; See,
http://www.nci.nih.gov/, a list of
the FDA approved oncology drugs at
http://www.fda.gov/cder/cancer/druglistframe.htm, and
The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are
hereby
incorporated by reference.
[002321 In certain embodiments, the additional therapeutic agents that may be
used in
combination with the combination regimen herein include, but are not limited
to, vinorelbine,
vinblastine, erlotinib, gemcitabine, mitomycin, bevacizumab, etoposide,
ifosfamide,
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cetuximab, irinotecan, and pemetrexed.
[002331 In another embodiment, provided herein is a method of inhibiting the
growth
of a cell, comprising contacting the cell with an effective amount of a taxane
and an
indazolylaminopyrrolotriazine described herein, e.g., an
indazolylaminopyrrolotriazine of
Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof.
[002341 In certain embodiments, the cell is a mammalian cell. In certain
embodiments,
the mammal is a human cell. In certain embodiments, the cell is a tumor cell.
In certain
embodiments, the cell is mammalian tumor cell. In certain embodiments, the
cell is a human
tumor cell. In certain embodiments, the cell is a cancerous cell. In certain
embodiments, the
cell is mammalian cancerous cell. In certain embodiments, the cell is a human
cancerous
cell.
[002351 In certain embodiments, the tumor cell overexpresses HER1 protein. In
certain embodiments, the tumor cell overexpresses HER2 protein.
[002361 In certain embodiments, the cancerous cell that can be treated with
the
methods provided herein includes, but is not limited to, cells of bladder
cancer, breast cancer,
cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer,
esophageal cancer,
gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver
cancer, lung cancer
(e.g., small cell and non-small cell lung cancers), melanoma, myeloma,
neuroblastoma,
ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma
(e.g., osteosarcoma),
skin cancer (e.g., squamous cell carcinoma), stomach cancer, testicular
cancer, thyroid
cancer, and uterine cancer.
[002371 In certain embodiments, the cell is a cell of bladder cancer, breast
cancer,
cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer,
gastric cancer,
glioma (e.g., glioblastoma), head and neck cancer, liver cancer, non-small
cell lung cancer,
ovarian cancer, pancreatic cancer, or prostate cancer.
[002381 In certain embodiments, the cell is treated by contacting the cell
with the
indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of
Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
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diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof; prior to contacting the cell with the taxane. In certain embodiments,
the cell is
treated with the indazolylaminopyrrolotriazine provided herein, about 2 days,
about 1 day,
about 12 hrs, about 6 hrs, about 4 hrs, about 2 hrs, about 60 min, about 30
min, or about 10
min before contacting the cell with the taxane.
[002391 In certain embodiments, the cell is treated by contacting the cell
with the
indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of
Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof; concurrently by contacting the cell with the taxane.
[002401 In certain embodiments, the cell is treated by contacting the cell
with the
indazolylaminopyrrolotriazine provided herein, e.g., an
indazolylaminopyrrolotriazine of
Formula I or II, including a single enantiomer, a mixture of enantiomers, or a
mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug
thereof; after contacting the cell with the taxane. In certain embodiments,
the cell is treated
with the indazolylaminopyrrolotriazine provided herein, about 2 days, about 1
day, about 12
hrs, about 6 hrs, about 4 hrs, about 2 hrs, about 60 min, about 30 min, or
about 10 min after
contacting the cell with the taxane.
[002411 The inhibition of cell growth can be gauged by, e.g., counting the
number of
cells contacted with compounds of interest, comparing the cell proliferation
with otherwise
identical cells not contacted with the compounds, or determining the size of
the tumor that
encompasses the cells. The number of cells, as well as the size of the cells,
can be readily
assessed using any method known in the art (e.g., trypan blue exclusion and
cell counting,
measuring incorporation of 3H-thymidine into nascent DNA in a cell).
[002421 The combination regimes provided herein can also be provided as an
article of
manufacture using packaging materials well known to those of skill in the art.
See, e.g., U.S.
Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical
packaging
materials include, but are not limited to, blister packs, bottles, tubes,
inhalers, pumps, bags,
vials, containers, syringes, and any packaging material suitable for a
selected formulation and
intended mode of administration and treatment.
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[002431 Provided herein also are kits which, when used by the medical
practitioner,
can simplify the administration of appropriate amounts of active ingredients
to a subject. In
certain embodiments, the kit provided herein includes containers and dosage
forms of the
compounds in the combination regimens provided herein.
[002441 In certain embodiments, the kit includes a container comprising dosage
forms
of the compounds in the combination regimens provided herein, in one or more
containers.
[002451 Kits provided herein can further include devices that are used to
administer the
active ingredients. Examples of such devices include, but are not limited to,
syringes, needle-
less injectors drip bags, patches, and inhalers. The kits provided herein can
also include
condoms for administration of the active ingredients.
[002461 Kits provided herein can further include pharmaceutically acceptable
vehicles
that can be used to administer one or more active ingredients. For example, if
an active
ingredient is provided in a solid form that must be reconstituted for
parenteral administration,
the kit can comprise a sealed container of a suitable vehicle in which the
active ingredient can
be dissolved to form a particulate-free sterile solution that is suitable for
parenteral
administration. Examples of pharmaceutically acceptable vehicles include, but
are not
limited to: aqueous vehicles, including, but not limited to, Water for
Injection USP, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride
Injection, and Lactated Ringer's Injection; water-miscible vehicles,
including, but not limited
to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-
aqueous vehicles,
including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame
oil, ethyl oleate,
isopropyl myristate, and benzyl benzoate.
[002471 The disclosure will be further understood by the following non-
limiting
examples.
EXAMPLES
Example 1
MX- 1 Human Breast Carcinoma Mouse Xenograft Study
[002481 The human breast carcinoma cell line MX-1 was from frozen stock that
was
passed serially in vivo for no more than 10 continual passages.
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[002491 Nude mice (Taconic Labs) were inoculated with MX- 1 cells as trocar
fragments subcutaneously in the axillary region. The tumors were grown to
about 100 mg
size, which was measured by electronic caliper measurement through the skin),
and the mice
were then randomized among control and the various treatment groups, with
eight mice per
group in the efficacy arms. During the treatment period, the solid tumors were
measured
three times weekly. Body weights were also measured three times weekly.
[002501 AC480 (Ambit Biosciences, San Diego, CA) was formulated in aqueous 50%
propylene glycol at a concentration of 30 mg/ml, and administered orally (PO)
once daily
(QD). Paclitaxel (Hauser Pharmaceuticals, Denver, CO) was formulated in
aqueous 10%
ethanol/10% CREMOPHOR EL (Sigma, St. Louis, MO) at a concentration of 2
mg/ml, and
administered once daily (QD) by intraperitoneal injection (IP). The animals
were grouped
and dosed as shown in Table 1.
TABLE 1.
Group Compounds Dosing Schedule
1 Untreated control N/A
2 Vehicle treated control The vehicle (0.2 mL/20 g) of AC480 formulation was
administered PO/QD from Day 1 through 21.
3 Paclitaxel only Paclitaxel (35 mg/kg) was administered IP/QD at Day 3, 10, &
17.
4 AC480 only AC480 (300 mg/kg) was administered PO/QD at Day 1, 2, 8, 9,
15, & 16.
AC480 only AC480 (180 mg/kg) was administered PO/QD from Day 1
through 21
6 AC480 + Paclitaxel AC480 (300 mg/kg) was administered PO/QD at Day 1, 2, 8,
9,
15, & 16.
Paclitaxel (35 mg/kg) was administered IP/QD at Day 3, 10, &
17.
7 AC480 + Paclitaxel AC480 (180 mg/kg) was administered PO/QD at Day 1, 2, 8,
9,
15, & 16.
Paclitaxel (35 mg/kg) was administered IP/QD at Day 3, 10, &
17.
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8 Paclitaxel + AC480 Paclitaxel (35 mg/kg) was administered IP/QD at Day 3,
10, &
17.
AC480 (300 mg/kg) was administered PO/QD at Day 4, 5, 11,
12, 18, & 19.
9 Paclitaxel + AC480 Paclitaxel (35 mg/kg) was administered IP/QD at Day 3,
10, &
17.
AC480 (180 mg/kg) was administered PO/QD at Day 4, 5, 11,
12, 18, & 19.
AC480 + Paclitaxel AC480 (300 mg/kg) was administered PO/QD at Day 2, 3, 9,
10,
16, & 17.
Paclitaxel (35 mg/kg) was administered IP/QD at Day 3, 10, &
17.
11 AC480 + Paclitaxel AC480 (180 mg/kg) was administered PO/QD at Day 2, 3, 9,
10,
16, & 17.
Paclitaxel (35 mg/kg) was administered IP/QD at Day 3, 10, &
17.
12 Gefitinib + Paclitaxel Gefitinib (150 mg/kg) was administered PO/QD at Day
1, 2, 8, 9,
15, & 16.
Paclitaxel (35 mg/kg) was administered IP/QD at Day 3, 10, &
17.
[002511 The results of this study are summarized in FIGS. 1 to 3. The
combination of
AC480 and paclitaxel appears to be well tolerated.
Example 2
MX- 1 Human Breast Carcinoma Mouse Xenograft Study
[002521 A second mouse xenograft study was conducted to study alternative
dosage
combinations and schedules. The same protocol as described in Example 1 was
followed for
body weight and tumor size measurements. The same compound formulations were
also
used, but paclitaxel dose was adjusted down to 25 mg/kg and administered
intravenously (IV)
for this study.
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TABLE 2.
Group Compounds Dosing Schedule
2 Vehicle treated control The vehicle (0.2 mL/20 g) of AC480 formulation was
administered PO/QD from Day 1 through 21.
3 Paclitaxel only Paclitaxel (25 mg/kg) was administered IP/QD at Day 3, 10, &
17.
4 AC480 only AC480 (300 mg/kg) was administered PO/QD at Day 1, 2, 8, 9,
15, & 16.
AC480 + Paclitaxel AC480 (300 mg/kg) was administered PO/QD at Day 1, 2, 8, 9,
15, & 16.
Paclitaxel (25 mg/kg) was administered IP/QD at Day 3, 10, &
17.
6 AC480 + Paclitaxel AC480 (300 mg/kg) was administered PO/QD at Day 2, 3, 9,
10,
16, & 17.
Paclitaxel (25 mg/kg) was administered IP/QD at Day 3, 10, &
17.
7 AC480 + Paclitaxel AC480 (180 mg/kg) was administered PO/QD at Day 2, 3, 9,
10,
16, & 17.
Paclitaxel (25 mg/kg) was administered IP/QD at Day 3, 10, &
17.
AC480 + Paclitaxel AC480 (300 mg/kg) was administered PO/QD at Day 3, 10, &
17.
Paclitaxel (25 mg/kg) was administered IP/QD at Day 3, 10, &
17.
[00253] The results of this study are shown in FIG. 4.
Example 3
Synthesis of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-
pyrrolo[2,1-
f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (AC480)
[00254] The synthesis of AC480 is shown in Scheme 1. Compound 1 was
chlorinated,
followed by coupling with compound 2 to form compound 3. Saponification of
compound 3
afforded acid 4, which was first converted to an acyl azide and then underwent
Curtius
rearrangement in the present of compound 5 to form compound 6. Removal of Boc
(N-tert-
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butoxycarbonyl) group with hydrochloride acid, formation of a hydrochloride
salt, and
subsequent neutralization gave free base compound II, which was then purified
via
crystallization.
Scheme 1
O 1. POCI /DIPEA / N F
\ NH 3 HN \ I N _NaOH
__
EtO2C
i
N
N'N \ / 60,
. EtO2C
2
F N) 3
1 / I N
~N
HZN \
2
N F
HNXITI~ N F N
1. (PhO)2PON3/TEA HN
1N
HOC N 2. OOH O O~\(\ \ N. J
O
Z N~ 4 - N
Boc N 6
Boc
--Q
F
XN
HCI HN
O- N'N
HN 0N \
Y O II
H
Example 4
Synthesis of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-
pyrrolo[2,1-
f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester,
ethanesulfonate (AC480
esylate) in crystalline Form 11-B
[00255] A mixture of free base compound II and ethanesulfonic acid in ethanol
was
heated at 78 5 C for at least one hour. The reaction mixture was then
cooled to 20 5 C
and AC480 esylate precipated. After filtration, the filter caske was washed
with ethanol
cooled to 0 5 C. The resulting solid was then dried to constant weight in a
vacuum oven at
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< 30 C to yield AC480 esylate in crystalline Form 11 B, which has a melting
point of about
202 C.
TABLE 3. Stability of AC480 Esylate at 5 C
Parameter Initial 1 Month 3 Month
Appearance Conformed' Conformed' Conformed'
AC480 content (HPLC) 100% 102% 99%
Total impurities (HPLC) 0.3% 0.4% 0.33%
Nitrosamine (LC/MS/MS) 0 ppm 0 ppm 0 ppm
Moisture content (KF) 0.9% 0.9% 0.6%
a. AC480 esylate is white to pale-yellow or pale-pink powder, which may
contain
lumps.
TABLE 4. Stability of AC480 Esylate at 25 C/60%oRH
Parameter Initial 1 Month 3 Month
Appearance Conformed' Conformed' Conformed'
AC480 content (HPLC) 100% 101% 100%
Total impurities (HPLC) 0.3% 0.4% 0.33%
Nitrosamine (LC/MS/MS) 0 ppm 0 ppm 0 ppm
Moisture content (KF) 0.9% 0.8% 0.6%
a. AC480 esylate is white to pale-yellow or pale-pink powder, which may
contain
lumps.
[002561 The stability of AC480 esylate in crystalline Form II-B was determined
under
three different storage conditions: i) 5 C; ii) 25 C and 60% RH; and iii) 40
C and 75% RH.
Results are summarized in Tables 3 to 5.
Example 5
Preparation of a pharmaceutical formulation comprising AC480 esylate
[002571 A pharmaceutical formulation comprising AC480 esylate was prepared
through an aseptic lyophilization process. The composition of the
pharmaceutical
formulation and the amount water used in the preparation are summarized in
Table 6.
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TABLE 5. Stability of AC480 Esylate at 40 C/75%oRH
Parameter Initial 1 Month 3 Month
Appearance Conformed' Conformed' Conformed'
AC480 content (HPLC) 100% 102% 100%
Total impurities (HPLC) 0.3% 0.4% 0.33%
Nitrosamine (LC/MS/MS) 0 ppm 0 ppm 0 ppm
Moisture content (KF) 0.9% 0.9% 0.6%
a. AC480 esylate is white to pale-yellow or pale-pink powder, which may
contain
lumps.
[002581 In preparation of the pharmaceutical formulation, 75% of the required
amount
of sterile water for injection was added to a clean depyrogenated glass
vessel. The required
amounts of powdered mannitol (2% by weight), hydroxypropyl-(3-cyclodextrin
(HP(3CD)
(15% by weight), and AC480 esylate were added to the vessel, and mixed until
dissolved.
The solution was brought to its final batch weight with sterile water for
injection, that is, the
remaining 25%. The solution was then sterile filtered and filled into 30 cc
amber glass vials
at 12 mL/vial. The vials were partially stoppered, and lyophilized. Once
lyophilization was
completed, the vials were backfilled with sterile filtered nitrogen, and
stoppers were fully
inserted. The vials were then crimp sealed using 20 mm White Flip-Off Crimp
seals.
TABLE 6
Component Amount Composition per Amount for 12 L
(%) 300 mg Unit Dose (12,000 g) Batch
AC480 Esylate' 3.025% 363 mg 363 g
Hydroxypropyl-r-cyclodextrin 15% 1,800 mg 1,800 g
Mannitol 2% 240 mg 240 g
Water for injection USPb 79.975% 9,597 mg 9,597 g
a. AC480 Esylate (363 mg) contained 300 mg of AC480 free base.
b. Water was removed during lyophilization.
[002591 Before administration to a patient, each vial will be reconstituted
with water to
25 mg/mL of AC480 free base
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Example 6
Phase I Clinical Trial of AC480 Esylate in Combination with Docetaxel
[002601 AC480 esylate will be tested in a Phase I trial in human patients
having a
broad range of advanced solid malignancies. This Phase I study is an open-
label, dose
escalation study of 2-day pulsed IV administration of AC480 esylate given as
monotherapy,
then in combination with docetaxel once every 3 weeks in patients with
advanced solid
tumors. In this Phase I study, the safety and PK parameters of a 2-day pulse
of AC480
esylate as monotherapy and also in combination with docetaxel once every 3
weeks are
determined.
[002611 AC480 esylate is administered intravenously on days 1 and 2, and
docetaxel
on day 2 of each 21-day treatment cycle. Dose escalation is guided by careful
monitoring of
toxicities with pre-specified escalation and stopping rules. The study
population includes
adult subjects with metastatic or locally advanced solid cancers, whose
disease has
progressed on or following currently available standard therapies or for which
no standard
therapy exists. Subjects with tumors that are known or likely to be HER1
and/or HER2+
expressing, including head and neck, lung adenocarcinoma, upper GI/esophageal,
and breast
cancers, and that may respond and derive clinical benefit from treatment with
AC480 are
included.
[002621 Phase I is divided into three parts. Part 1: The safety and
tolerability of
AC480 esylate as monotherapy are established first, along with the
determination of the MTD
(MTD1) of a 2-day pulse of IV dosing of AC480 esylate. Part 2: The PK
parameters of
docetaxel monotherapy at a reduced dose of 60 mg/m2 (80% standard dose due to
potential
overlapping hepatic toxicity) are determined. Then, the safety and
tolerability of the
combination of AC480 esylate (administered on days 1 and 2) and docetaxel
(administered
immediately after AC480 esylate on day 2 at same reduced dose) are determined,
where the
starting dose of AC480 esylate is one dose level below MTD1 as determined in
Part 1. The
MTD of AC480 esylate in combination with reduced dose docetaxel (MTD2) is also
determined. Part 3: The MTD (MTD3) of the combination of AC480 esylate
(administered
on days 1 and 2) and docetaxel (administered immediately after AC480 esylate
on day 2 at
the standard full dose of 75 mg/m2) is determined.
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Part 1:
[00263] Based on preclinical monkey data, the starting IV dose of AC480
esylate in
Part 1 is 40 mg/m2 given over an approximately 30 minute period. During Part
1, patients
receive AC480 esylate as monotherapy on days 1 and 2. PK blood samples are
drawn at pre-
specified time points. Patients are then followed weekly for 21 days to
evaluate toxicity.
Efficacy is assessed after Cycle 1 and every two cycles (six weeks)
thereafter. The DLT
evaluation period for AC480 esylate monotherapy is the first 21 days.
[00264] Dose escalation utilizes an accelerated design for Part 1 and a
standard 3 + 3
cohort design for Parts 2 and 3. In the first two dose cohorts of Part 1,
there is only one
patient initially and there is an opportunity to dose escalate if the first
patient in each cohort
completes the first 21-day period without DLT. This applies only to the first
two dose-
escalation cohorts (40 and 80 mg/m2). Thus, if the first patient in the first
cohort (40 mg/m2)
completes the 21-day peroid with no DLT, the next patient begins the trial in
the second
cohort (80 mg/m2). For only these first two patients in their respective
cohorts, DLT is
defined as any Grade > 2 toxicity (based on National Cancer Institute Common
Toxicity
Criteria for Adverse Events Version 4.0 [CTCv4]) at any point during the first
21 days that is
considered related to study drug. If the first patient in the second cohort
(80 mg/m2) also
does not experience DLT in the 21-day period, then the next patient begins the
trial in the
third cohort (134 mg/m2), and a standard 3 + 3 cohort design is used
thereafter.
[00265] If either the first patient in the first or second cohort experiences
a DLT, dose
escalation is changed immediately to a standard 3 + 3 cohort design. If this
occurs in either
the first or second cohort, and for the third dose cohort and all subsequent
dose cohorts in
Part 1 and for all cohorts in Parts 2 and 3 of the study, AC480 esylate is
dose escalated in
standard 3 + 3 cohorts (explained below). For the 3 + 3 cohorts, if there is
CTCv4 non-
hematological Grade > 3 and/or hematological Grade > 4 (or Grade 3 neutropenic
fever)
toxicity at any point during the first 21 days that is considered related to
study drug, this is
defined as the DLT for AC480 esylate monotherapy. Further administration of
AC480IV is
permanently discontinued and the patient comes off study. Also, if the first
cohort becomes a
3 + 3 cohort and more than one of six patients has a DLT, then the dose is
reduced to the -1
dose level (Table 7). A similar approach is used if a dose reduction to the -2
dose level is
necessary.
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TABLE 7. Dose Escalation Schedule for Part 1, AC480 as Monotherapy
AC480 Esylate IV %Change from Starting Dose
Dose-Level Dose (mg/m2) (40 mg/m2)
-2 20 -50
-1 30 -25
1 (Start) 40 0
2 80 100
3 134 335
4 200 500
280 700
[002661 Dose escalation by dose cohort is done in a standard modified
Fibonacci
design for Phase 1 studies. Each dose level is increase by 100%-33%, employing
smaller
increments as dose increases. When the dose escalation proceeds to the
standard 3 + 3
cohort, at least 21 days of treatment and toxicity data must be available for
all three patients
in a single cohort before the next cohort can open at the next dose level. If
zero of three
patients in a cohort experience DLT, the next cohort is enrolled at the next
higher dose level.
If one of three patients experiences a DLT, the cohort is expanded to a total
of six patients. If
more than one of six patients has a DLT, then there is no further dose
escalation and the
current dose is defined as the Maximum Administered Dose (MAD). In that case,
the next
lower dose level is expanded to a total of six patients or an intermediate
dose level (between
MAD and the next lower level) is opened for evaluation. The highest dose level
in which
>five of six patients in the cohort tolerates the dose is defined as the MTD.
In Part 1, this is
referred to as MTD 1. Once MTD 1 is confirmed in six total patients, at least
an additional
three patients are enrolled at the MTD for additional PK data. Thus, the MTD
of AC480
esylate monotherapy is determined in a total of at least nine patients.
Part 2:
[002671 Part 2 begins with the administrate of a single dose of docetaxel 60
mg/m2
(80% of the standard dose, reduced in this part of study due to the potential
for overlapping
hepatic toxicity in combination with AC480 esylate) on day 1 of a 21-day
cycle. Blood
samples for docetaxel PK studies are drawn at pre-specified time points during
this cycle of
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docetaxel monotherapy (Cycle 1 of Part 2). The regimen for all cycles after
Cycle 1 consists
of infusions of AC480 esylate on days 1 and 2 in combination with docetaxel at
60 mg/m2 on
day 2, administered after AC480 esylate. Each cycle may be repeated every 3
weeks (21
days). The starting dose for AC480 esylate in Part 2 is the MTD from Part 1
minus one dose
level (MTD1 - 1). Patients continue on therapy as long as they are not
experiencing
intolerable toxicities and there is no evidence of disease progression. All
subsequent cycles
in Part 2 are identical to Cycle 2, but with no further PK assessments.
Efficacy is assessed
after Cycle 1 immediately prior to Cycle 2, and every two cycles (six weeks)
thereafter. The
DLT but with no further PK assessments. The DLT evaluation period for Part 2
is the first 21
days of combination therapy of AC480 esylate and docetaxel (Cycle 2).
[002681 The AC480 esylate IV dose may be escalated or reduced in Part 2
according to
Table 8; however, the maximum dose of AC480 esylate can be no higher than the
MTD
found in Part 1 (MTD1). As in Part 1, the AC480 esylate IV dose in Part 2 is
dose escalated
in cohorts of 3. If zero of three patients in a cohort experience DLT, then
the next cohort is
enrolled at the next higher dose level. If patients cannot tolerate the
assigned AC480 esylate
IV dose with the 60 mg/m2 docetaxel dose, the AC480 esylate IV dose is lowered
until > five
of six patients tolerate the dose. Dose levels for escalation or reduction of
AC480 esylate are
those used in Part 1. The highest dose level in which > five of six patients
in the cohort
tolerates the dose is defined as the MTD of combination therapy. In Part 2,
this is referred to
as MTD2. Once MTD2 is confirmed in six total patients, an additional three
patients are
enrolled at MTD2 for additional PK data.
TABLE 8. Dose Escalation Schedule for Part 2
Dose-Level AC480 Esylate IV Dose (mg/m2) Docetaxel Dose (mg/m2)
-2 MTD1-3 60
-1 MTD1-2 60
1 (Start) MTD1-1 60
2 MTD1 60
Part 3:
[002691 Once the MTD of AC480 esylate with 60 mg/m2 docetaxel is established
(MTD2), the MTD of AC480 esylate with a full standard dose of docetaxel (75
mg/m2) is to
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be determined (MTD3). The starting AC480 esylate IV dose in Part 3 is the MTD
from Part
2 minus one dose level (MTD2-1). The first dose level of docetaxel is 75
mg/m2. AC480
esylate is administered on days 1 and 2 of each cycle. Docetaxel is
administered immediately
following the AC480 esylate infusion on day 2. Each cycle is 21 days long. If
zero of three
patients experience DLT, the next cohort receives AC480 esylate at MTD2, and
the docetaxel
dose remains at 75 mg/m2. Patients continue on therapy as long as they are not
experiencing
intolerable toxicities and there is no evidence of disease progression. All
subsequent cycles
in Part 3 of the study are to Cycle 2, but without the PK assessments.
Efficacy is assessed
after Cycle 1 immediately prior to Cycle 2, and every two cycles (six weeks)
thereafter. The
DLT evaluation period for Part 3 is the first 21 days of combination therapy
of AC480 esylate
and docetaxel (Cycle 2).
[002701 The dose escalation and reduction schedule for Part 3 is similar to
Part 2 (see,
Table 9). Starting dose for AC480 esylate is MTD2-1 and starting dose for
docetaxel is 75
mg/m2. The dose of AC480 esylate is increased or decreased based on patient
tolerability;
the maximum dose of AC480 esylate, however, can be no higher than the MTD
found in Part
2 (MTD2). Dose levels for escalation or reduction of AC480IV are those used in
Part 1. The
dose of docetaxel remains fixed at 75 mg/m2.
TABLE 9. Dose Escalation Schedule for Part 3
Dose-Level AC480 Esylate IV Dose (mg/m2) Docetaxel Dose (mg/m)
-2 MTD2-3 75
-1 MTD2-2 75
1 (Start) MTD2-1 75
2 MTD2 75
[002711 The examples set forth above are provided to give those of ordinary
skill in the
art with a complete disclosure and description of how to make and use the
claimed
embodiments, and are not intended to limit the scope of what is disclosed
herein.
Modifications that are obvious to persons of skill in the art are intended to
be within the
scope of the following claims. All publications, patents, and patent
applications cited in this
specification are incorporated herein by reference as if each such
publication, patent or patent
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application were specifically and individually indicated to be incorporated
herein by
reference.
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