U.S. patent application number 13/438964 was filed with the patent office on 2012-10-04 for method of treating cancer.
This patent application is currently assigned to Exelixis, Inc.. Invention is credited to Dana T. Aftab, Frauke Schimmoller.
Application Number | 20120252840 13/438964 |
Document ID | / |
Family ID | 46928035 |
Filed Date | 2012-10-04 |
United States Patent
Application |
20120252840 |
Kind Code |
A1 |
Aftab; Dana T. ; et
al. |
October 4, 2012 |
Method of Treating Cancer
Abstract
This invention is directed to the treatment of cancer,
particularly ocular melanoma, with a dual inhibitor of MET and VEGF
such as Compound 1. ##STR00001##
Inventors: |
Aftab; Dana T.; (San Rafael,
CA) ; Schimmoller; Frauke; (Menlo Park, CA) |
Assignee: |
Exelixis, Inc.
South San Francisco
CA
|
Family ID: |
46928035 |
Appl. No.: |
13/438964 |
Filed: |
April 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61471367 |
Apr 4, 2011 |
|
|
|
Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61K 31/47 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/312 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method for treating melanoma, comprising administering to a
patient in need of such treatment a compound of Formula I:
##STR00015## or a pharmaceutically acceptable salt thereof,
wherein: R.sup.1 is halo; R.sup.2 is halo; R.sup.3 is
(C.sub.1-C.sub.6)alkyl; R.sup.4 is (C.sub.1-C.sub.6)alkyl; and Q is
CH or N.
2. The method of claim 1, wherein the melanoma is ocular
melanoma.
3. The method of claim 1, wherein the ocular melanoma is choroidal
or iris melanoma.
4. The method of claim 1, wherein, the dual MET and VEGF modulator
is a compound of Formula Ia: ##STR00016## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is halo; R.sup.2 is halo;
and Q is CH or N.
5. The method of claim 1, wherein the compound of Formula I is
Compound 1: ##STR00017## or a pharmaceutically acceptable salt
thereof.
6. The method of claim 5, wherein Compound 1 is the (L)- or
(D)-malate salt.
7. The method of claim 6, wherein Compound 1 is in the crystalline
N-1 form.
8. The method of claim 1, wherein the compound of Formula I, I(a),
or Compound 1, or a pharmaceutically acceptable salt thereof, is
administered as a pharmaceutical composition comprising a
pharmaceutically acceptable carrier, excipient, or diluent.
9. A method for treating ocular melanoma comprising administering
to a patient in need of such treatment Compound 1 or a
pharmaceutically acceptable salt thereof. ##STR00018##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
patent application Ser. No. 61/471,367, filed Apr. 4, 2011, which
is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention is directed to the treatment of cancer,
particularly uveal melanoma, with a dual inhibitor of MET and VEGF,
such as a Compound of Formula I as disclosed herein.
BACKGROUND OF THE INVENTION
[0003] Uveal, or ocular, melanoma, which includes choroidal and
iris melanomas, is the most common intraocular tumor found in
adults. Tumors arise from the pigment cells, or melanocytes, that
reside within the uvea that give color to the eye. Statistics
indicate that up to 2000 individuals in the United States are
diagnosed with ocular melanoma every year.
[0004] Once metastatic, ocular melanomas are highly fatal, and
patients rarely live for more than a year after diagnosis. Although
surgery and/or radiation therapy may be effective for treating
ocular melanoma that is localized to the area around the eye,
chemotherapy historically has been considered ineffective for
treating metastasized ocular melanoma.
[0005] Abdel-Rahman and coworkers (Invest. Ophthalmol. Vis. Sci.
51, 7, 3333-3339 (2010)) recently observed a high frequency of
overexpression of MET protein in ocular melanomas. MET plays
important roles in cell motility, proliferation, and survival, and
it has been shown to be a key factor in tumor angiogenesis,
invasiveness, and metastasis. Prominent expression of MET has been
observed in other tumor types. The high frequency of MET in ocular
melanoma supports its role in the pathogenesis of these tumors and
also suggests that MET is a potentially useful therapeutic target
for treating ocular melanoma.
[0006] Thus, a need remains for methods of treating ocular
melanoma, particularly by inhibiting MET.
SUMMARY OF THE INVENTION
[0007] These and other needs are met by the present invention,
which is directed to a method for treating melanoma. The melanoma
can be ocular melanoma, and more particularly choroidal melanoma or
iris melanoma. The method comprises administering to a patient in
need of such treatment a therapeutically effective amount of a
compound that modulates MET.
[0008] In one aspect, the present invention is directed to a method
for treating ocular melanoma comprising administering to a patient
in need of such treatment a compound of Formula I
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0009] R.sup.1 is halo;
[0010] R.sup.2 is halo;
[0011] R.sup.3 is (C.sub.1-C.sub.6)alkyl;
[0012] R.sup.4 is (C.sub.1-C.sub.6)alkyl; and
[0013] Q is CH or N.
[0014] In one embodiment, the compound of Formula I is a compound
of Formula I(a)
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0015] R.sup.1 is halo;
[0016] R.sup.2 is halo; and
[0017] Q is CH or N.
[0018] In another embodiment, the compound of Formula I is Compound
1:
##STR00004##
or a pharmaceutically acceptable salt thereof. Compound 1 is known
as
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide.
[0019] In another embodiment, the invention provides a method for
treating metastatic ocular melanoma, comprising administering to a
patient in need of such treatment a therapeutically effective
amount of a pharmaceutical formulation comprising Compound of
Formula I, Ia, or Compound 1 the malate salt of Compound of Formula
I, Ia, or Compound 1, or another pharmaceutically acceptable salt
of Compound of Formula I, Ia, or Compound 1.
[0020] Compound 1 is an orally bioavailable multitargeted tyrosine
kinase inhibitor with potent activity against MET and VEGFR2.
Compound 1 suppresses MET and VEGFR2 signaling, rapidly induces
apoptosis of endothelial cells and tumor cells, and causes tumor
regression in xenograft tumor models. Compound 1 also significantly
reduces tumor invasiveness and metastasis and substantially
improves overall survival in a murine pancreatic neuroendocrine
tumor model. In a phase 1 clinical study, Compound 1 was generally
well-tolerated, with fatigue, diarrhea, anorexia, rash, and
palmar-plantar erythrodysesthesia being the most commonly observed
adverse events.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 summarizes the results of a Phase 2 study using
Compound 1 in a cohort of patients with melanoma, including ocular
melanoma.
[0022] FIG. 2 summarizes the baseline mutation status of the ocular
melanoma patients.
[0023] FIG. 3 summarizes the treatment status of the ocular
melanoma patients.
[0024] FIG. 4 provides an overview of the patients with the best
response of SD or PR.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0025] The following abbreviations and terms have the indicated
meanings throughout:
TABLE-US-00001 Abbreviation Meaning Ac Acetyl Br Broad .degree. C.
degrees Celsius c- Cyclo CBZ CarboBenZoxy = benzyloxycarbonyl d
Doublet dd doublet of doublet dt doublet of triplet DCM
Dichloromethane DME 1,2-dimethoxyethane DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphano)ferrocene
EI Electron Impact ionization G gram(s) h or hr hour(s) HPLC high
pressure liquid chromatography L liter(s) M molar or molarity m
Multiplet Mg milligram(s) MHz megahertz (frequency) Min minute(s)
mL milliliter(s) .mu.L microliter(s) .mu.M Micromole(s) or
micromolar mM Millimolar Mmol millimole(s) Mol mole(s) MS mass
spectral analysis N normal or normality nM Nanomolar NMR nuclear
magnetic resonance spectroscopy q Quartet RT Room temperature s
Singlet t or tr Triplet TFA trifluoroacetic acid THF
Tetrahydrofuran TLC thin layer chromatography The symbol "-" means
a single bond, and "=" means a double bond.
[0026] When chemical structures are depicted or described, unless
explicitly stated otherwise, all carbons are assumed to have
hydrogen substitution to conform to a valence of four. For example,
in the structure on the left-hand side of the schematic below there
are nine hydrogens implied. The nine hydrogens are depicted in the
right-hand structure. Sometimes a particular atom in a structure is
described in textual formula as having a hydrogen or hydrogens as
substitution (expressly defined hydrogen), for example,
--CH.sub.2CH.sub.2--. It is understood by one of ordinary skill in
the art that the aforementioned descriptive techniques are common
in the chemical arts to provide brevity and simplicity to
description of otherwise complex structures.
##STR00005##
[0027] If a group "R" is depicted as "floating" on a ring system,
as for example in the formula:
##STR00006##
then, unless otherwise defined, a substituent "R" may reside on any
atom of the ring system, assuming replacement of a depicted,
implied, or expressly defined hydrogen from one of the ring atoms,
so long as a stable structure is formed.
[0028] If a group "R" is depicted as floating on a fused ring
system, as for example in the formulae:
##STR00007##
then, unless otherwise defined, a substituent "R" may reside on any
atom of the fused ring system, assuming replacement of a depicted
hydrogen (for example the --NH-- in the formula above), implied
hydrogen (for example, in the formula above, where the hydrogens
are not shown but understood to be present), or expressly defined
hydrogen (for example where in the formula above, "Z" equals
.dbd.CH--) from one of the ring atoms, so long as a stable
structure is formed. In the example depicted, the "R" group may
reside on either the 5-membered or the 6-membered ring of the fused
ring system.
[0029] When a group "R" is depicted as existing on a ring system
containing saturated carbons, as for example in the formula:
##STR00008##
where, in this example, "y" can be more than one, assuming each
replaces a currently depicted, implied, or expressly defined
hydrogen on the ring; then, unless otherwise defined, where the
resulting structure is stable, two "R's" may reside on the same
carbon. A simple example is when R is a methyl group; there can
exist a geminal dimethyl on a carbon of the depicted ring (an
"annular" carbon). In another example, two R's on the same carbon,
including that carbon, may form a ring, thus creating a spirocyclic
ring (a "spirocyclyl" group) structure with the depicted ring as
for example in the formula:
##STR00009##
[0030] "Halogen" or "halo" refers to fluorine, chlorine, bromine,
or iodine.
[0031] "Yield" for each of the reactions described herein is
expressed as a percentage of the theoretical yield.
[0032] "Patient," for the purposes of the present invention,
includes humans and other animals, particularly mammals, and other
organisms. Thus the methods are applicable to both human therapy
and veterinary applications. In one embodiment, the patient is a
mammal, and in another embodiment, the patient is human.
[0033] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. It is
understood that the pharmaceutically acceptable salts are
non-toxic. Additional information on suitable pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17.sup.th ed., Mack Publishing Company, Easton, Pa.,
1985, or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm.
Sci., 1977; 66:1-19, both of which are incorporated herein by
reference.
[0034] Examples of pharmaceutically acceptable acid addition salts
include those formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric
acid, and the like; as well as organic acids such as acetic acid,
trifluoroacetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, oxalic acid, maleic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, malic acid, citric acid, benzoic acid,
cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
p-toluenesulfonic acid, and salicylic acid, and the like.
[0035] "Prodrug" refers to compounds that are transformed, (usually
rapidly), in vivo to yield an active compound, for example, by
hydrolysis in blood. Common examples include, but are not limited
to, ester and amide forms of a compound having an active form
bearing a carboxylic acid moiety. Examples of pharmaceutically
acceptable esters of the compounds of this invention include, but
are not limited to, alkyl esters (for example, those between about
one and about six carbons) the alkyl group is a straight or
branched chain. Acceptable esters also include cycloalkyl esters
and arylalkyl esters such as, but not limited to, benzyl. Examples
of pharmaceutically acceptable amides of the compounds of this
invention include, but are not limited to, primary amides and
secondary and tertiary alkyl amides (for example, those between
about one and about six carbons). Amides and esters of the
compounds of the present invention may be prepared according to
conventional methods. A thorough discussion of prodrugs is provided
in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,"
Vol 14 of the A.C.S. Symposium Series and Bioreversible Carriers in
Drug Design, ed. Edward B. Roche, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated herein by reference for all purposes.
[0036] "Therapeutically effective amount" is an amount of a
compound of the invention that, when administered to a patient,
ameliorates a symptom of the disease. A therapeutically effective
amount is intended to include an amount of a compound alone or in
combination with other active ingredients. It will also be
effective to modulate c-Met and/or VEGFR2 or to treat or prevent
cancer. The amount of a compound of the invention which constitutes
a "therapeutically effective amount" will vary depending on the
compound, the disease state and its severity, the age of the
patient to be treated, and other factors. The therapeutically
effective amount can be determined by one of ordinary skill in the
art.
[0037] "Treating" or "treatment" of a disease, disorder, or
syndrome, as used herein, includes: (i) preventing the disease,
disorder, or syndrome from occurring in a human, for instance, by
causing the clinical symptoms of the disease, disorder, or syndrome
not to develop in an animal that may be exposed to or predisposed
to the disease, disorder, or syndrome but does not yet experience
or display symptoms of the disease, disorder, or syndrome; (ii)
inhibiting the disease, disorder, or syndrome, for instance, by
arresting its development; and (iii) relieving the disease,
disorder, or syndrome, for instance, by causing regression of the
disease, disorder, or syndrome. As is known in the art, adjustments
for systemic versus localized delivery, age, body weight, general
health, sex, diet, time of administration, drug interaction, and
the severity of the condition may be necessary, and will be
ascertainable with routine experience.
[0038] All patents and patent publications cited herein that are
assigned to the same assignee as the present invention are
incorporated by reference in their entirety unless stated to the
contrary.
EMBODIMENTS
[0039] In one embodiment the method employs a compound of Formula
I:
##STR00010##
or a pharmaceutically acceptable salt thereof, wherein:
[0040] R.sup.1 is halo;
[0041] R.sup.2 is halo;
[0042] R.sup.3 is (C.sub.1-C.sub.6)alkyl;
[0043] R.sup.4 is (C.sub.1-C.sub.6)alkyl; and
[0044] Q is CH or N.
[0045] In another embodiment, the compound of Formula I is a
compound of Formula I(a)
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein:
[0046] R.sup.1 is halo;
[0047] R.sup.2 is halo; and
[0048] Q is CH or N.
[0049] In another embodiment of the method, the compound of Formula
I is Compound 1:
##STR00012##
or a pharmaceutically acceptable salt thereof. As indicated
previously, Compound 1 is also known as
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide. WO 2005/030140 describes the synthesis
of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide (Example 12, 37, 38, and 48) and also
discloses the therapeutic activity of this molecule to inhibit,
regulate and/or modulate the signal transduction of kinases,
(Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in
WO 2005/030140.
[0050] In other embodiments, the compound of Formula I, Ia, or
Compound 1, or a pharmaceutically acceptable salt thereof, is
administered as a pharmaceutical composition, wherein the
pharmaceutical composition additionally comprises a
pharmaceutically acceptable carrier, excipient, or diluent.
[0051] The compound of Formula I, Ia, and Compound 1, as described
herein, includes both the recited compounds as well as individual
isomers and mixtures of isomers. In each instance, the compound of
Formula I, Ia, and Compound 1, includes the pharmaceutically
acceptable salts, hydrates, and/or solvates of the recited
compounds and any individual isomers or mixtures of isomers
thereof.
[0052] In other embodiments, the compound of Formula I can be the
(L)-malate salt. The malate salt of the Compound of Formula I, Ia,
and of Compound 1 is disclosed in PCT/US2010/021194 and U.S. Ser.
No. 61/325,095.
[0053] In other embodiments, the compound of Formula (I) can be the
malate salt.
[0054] In other embodiments, the compound of Formula (I) can be the
(D)-malate salt.
[0055] In other embodiments, the compound of Formula (I) can be the
(L)-malate salt.
[0056] In other embodiments, the compound of Formula I(a) can be
the malate salt.
[0057] In other embodiments, the compound of Formula I(a) can be
the (D)-malate salt.
[0058] In other embodiments, the compound of Formula I(a) can be
the (L)-malate salt.
[0059] In other embodiments, Compound 1 can be the malate salt.
[0060] In other embodiments, Compound 1 can be the (D)-malate
salt.
[0061] In other embodiments, the compound of Formula (I) can be the
(L)-malate salt of Compound 1.
[0062] In another embodiment, the malate salt is in the crystalline
N-1 form of the (L) malate salt and/or the (D) malate salt of
Compound 1 as disclosed in PCT/US10/021,194, which is incorporated
herein by reference in its entirety.
[0063] In another embodiment, the invention is directed to a method
for ameliorating the symptoms of ocular melanoma, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound of Formula I in any
of the embodiments disclosed herein.
Administration
[0064] Administration of the compound of Formula I, Ia, or Compound
1, or a pharmaceutically acceptable salt thereof, in pure form or
in an appropriate pharmaceutical composition, can be carried out
via any of the accepted modes of administration or agents for
serving similar utilities. Thus, administration can be, for
example, orally, nasally, parenterally (intravenous, intramuscular,
or subcutaneous), topically, transdermally, intravaginally,
intravesically, intracistemally, or rectally; in the form of solid,
semi-solid, lyophilized powder, or liquid dosage forms, such as,
for example, tablets, suppositories, pills, soft elastic and hard
gelatin dosages (which can be in capsules or tablets), powders,
solutions, suspensions, or aerosols, or the like, specifically in
unit dosage forms suitable for simple administration of precise
dosages.
[0065] The compositions will include a conventional pharmaceutical
carrier or excipient and a compound of Formula I as the/an active
agent and, in addition, may include carriers, adjuvants, and the
like.
[0066] Adjuvants include preserving, wetting, suspending,
sweetening, flavoring, perfuming, emulsifying, and dispensing
agents. Prevention of the action of microorganisms can be ensured
by various antibacterial and antifungal agents, for example,
parabens, chlorobutanol, phenol, sorbic acid, and the like. It may
also be desirable to include isotonic agents, for example sugars,
sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the use of
agents delaying absorption, for example, aluminum monostearate and
gelatin.
[0067] If desired, a pharmaceutical composition of the compound of
Formula I may also contain minor amounts of auxiliary substances
such as wetting or emulsifying agents, pH buffering agents, and
antioxidants, such as citric acid, sorbitan monolaurate,
triethanolamine oleate, butylalted hydroxytoluene, etc.
[0068] The choice of formulation depends on various factors such as
the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills, or capsules) and the
bioavailability of the drug substance. Recently, pharmaceutical
formulations have been developed, especially for drugs that show
poor bioavailability based upon the principle that bioavailability
can be increased by increasing the surface area, for instance, by
decreasing particle size. For example, U.S. Pat. No. 4,107,288
describes a pharmaceutical formulation having particles in the size
range from 10 to 1,000 nm in which the active material is supported
on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684
describes the production of a pharmaceutical formulation in which
the drug substance is pulverized to nanoparticles (average particle
size of 400 nm) in the presence of a surface modifier and then
dispersed in a liquid medium to give a pharmaceutical formulation
that exhibits remarkably high bioavailability.
[0069] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions, or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include: water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil), and
injectable organic esters (such as ethyl oleate). Proper fluidity
can be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0070] One specific route of administration is oral, using a
convenient daily dosage regimen that can be adjusted according to
the degree of severity of the disease-state to be treated.
[0071] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders,
for example, cellulose derivatives, starch, alignates, gelatin,
polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, for
example, glycerol, (d) disintegrating agents, for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, croscarmellose sodium, complex silicates, and sodium
carbonate, (e) solution retarders, for example paraffin, (f)
absorption accelerators, as for example, quaternary ammonium
compounds, (g) wetting agents, for example, cetyl alcohol, and
glycerol monostearate, magnesium stearate, and the like (h)
adsorbents, for example, kaolin and bentonite, and (i) lubricants,
as for example, talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
In the case of capsules, tablets, and pills, the dosage forms may
also comprise buffering agents.
[0072] Solid dosage forms, as described above, can be prepared with
coatings and shells, such as enteric coatings and others well known
in the art. They may contain pacifying agents and can also be of
such composition that they release the active compound or compounds
in a certain part of the intestinal tract in a delayed manner.
Examples of embedded compositions that can be used are polymeric
substances and waxes. The active compounds can also be in
microencapsulated form, if appropriate, with one or more of the
above-mentioned excipients.
[0073] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. Such dosage forms are prepared, for example,
by dissolving, dispersing, etc., the compound of Formula I, or a
pharmaceutically acceptable salt thereof, and optional
pharmaceutical adjuvants in a carrier, such as water, saline,
aqueous dextrose, glycerol, ethanol, and the like; solubilizing
agents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propyleneglycol, 1,3-butyleneglycol, or dimethylformamide; oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame oil; glycerol, tetrahydrofurfuryl
alcohol, polyethyleneglycols, and fatty acid esters of sorbitan; or
mixtures of these substances and the like, to thereby form a
solution or suspension.
[0074] Suspensions, in addition to the active compounds, may
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol, and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, and tragacanth, mixtures of these substances, and the
like.
[0075] Compositions for rectal administration are, for example,
suppositories that can be prepared by mixing the compound of
Formula I with, for example, suitable non-irritating excipients or
carriers such as cocoa butter, polyethyleneglycol, or a suppository
wax, which are solid at ordinary temperatures but liquid at body
temperature and therefore melt while in a suitable body cavity,
releasing the active component therein.
[0076] Dosage forms for topical administration of the compound of
Formula I include ointments, powders, sprays, and inhalants. The
active component is admixed under sterile conditions with a
physiologically acceptable carrier and any preservatives, buffers,
or propellants as may be required. Ophthalmic formulations, eye
ointments, powders, and solutions are also contemplated as being
within the scope of this disclosure.
[0077] Compressed gases may be used to disperse the compound of
Formula I in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0078] Generally, depending on the intended mode of administration,
the pharmaceutically acceptable compositions will contain about 1%
to about 99% by weight of a compound(s) of Formula I, or a
pharmaceutically acceptable salt thereof, and 99% to 1% by weight
of a suitable pharmaceutical excipient. In one example, the
composition will be between about 5% and about 75% by weight of a
compound(s) of Formula I, Ia, or Compound 1, or a pharmaceutically
acceptable salt thereof, with the rest being suitable
pharmaceutical excipients.
[0079] Actual methods of preparing such dosage forms are known, or
will be apparent, to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing
Company, Easton, Pa., 1990). The composition to be administered
will, in all cases, contain a therapeutically effective amount of a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, for treatment of a disease-state in accordance with the
teachings of this disclosure.
[0080] The compounds of this disclosure, or their pharmaceutically
acceptable salts or solvates, are administered in a therapeutically
effective amount which will vary depending upon a variety of
factors including: the activity of the specific compound employed,
the metabolic stability and length of action of the compound, the
age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular disease-states, and the host undergoing therapy.
The compound of Formula I, Ia, or Compound 1, can be administered
to a patient at dosage levels in the range of about 0.1 to about
1,000 mg per day. For a normal human adult having a body weight of
about 70 kilograms, a dosage in the range of about 0.01 to about
100 mg per kilogram of body weight per day is an example. The
specific dosage used, however, can vary. For example, the dosage
can depend on a number of factors, including the requirements of
the patient, the severity of the condition being treated, and the
pharmacological activity of the compound being used. The
determination of optimum dosages for a particular patient is well
known to one of ordinary skill in the art.
[0081] In other embodiments, the compound of Formula I, Ia, or
Compound 1 can be administered to the patient concurrently with
other cancer treatments. Such treatments include other cancer
chemotherapeutics, hormone replacement therapy, radiation therapy,
or immunotherapy, among others. The choice of other therapy will
depend on a number of factors including the metabolic stability and
length of action of the compound, the age, body weight, general
health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular
disease-states, and the host undergoing therapy.
Preparation of the Compound 1
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof
[0082] The synthetic route used for the preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-M-(4-fluorophenyl)cycl-
opropane-1,1-dicarboxamide and the (L)-malate salt thereof is
depicted in Scheme 1.
##STR00013##
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0083] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L).
The resulting mixture was heated to approximately 65.degree. C. and
phosphorus oxychloride (POCl.sub.3, 50.0 kg) was added. After the
addition of POCl.sub.3, the temperature of the reaction mixture was
raised to approximately 80.degree. C. The reaction was deemed
complete (approximately 9.0 hours) when less than 2 percent of the
starting material remained (in process high-performance liquid
chromotography [HPLC] analysis). The reaction mixture was cooled to
approximately 10.degree. C. and then quenched into a chilled
solution of dichloromethane (DCM, 238.0 kg), 30 percent NH.sub.4OH
(135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to
approximately 14.degree. C., and phases were separated. The organic
phase was washed with water (40.0 kg) and concentrated by vacuum
distillation with the removal of solvent (approximately 190.0 kg).
Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and
the mixture was cooled to approximately 10.degree. C., during which
time the product crystallized out. The solids were recovered by
centrifugation, washed with n heptane (20.0 kg), and dried at
approximately 40.degree. C. to afford the title compound (8.0
kg).
Preparation of 6,7-Dimethyl-4-(4-nitro-phenoxy)-quinoline
[0084] A reactor was sequentially charged with
4-chloro-6,7-dimethoxy-quinoline (8.0 kg), 4 nitrophenol (7.0 kg),
4 dimethylaminopyridine (0.9 kg), and 2,6-lutidine (40.0 kg). The
reactor contents were heated to approximately 147.degree. C. When
the reaction was complete (less than 5% starting material remaining
as determined by in process HPLC analysis, approximately 20 hours),
the reactor contents were allowed to cool to approximately
25.degree. C. Methanol (26.0 kg) was added, followed by potassium
carbonate (3.0 kg) dissolved in water (50.0 kg). The reactor
contents were stirred for approximately 2 hours. The resulting
solid precipitate was filtered, washed with water (67.0 kg), and
dried at 25.degree. C. for approximately 12 hours to afford the
title compound (4.0 kg).
Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0085] A solution containing potassium formate (5.0 kg), formic
acid (3.0 kg), and water (16.0 kg) was added to a mixture of
6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium
on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (40.0
kg) that had been heated to approximately 60.degree. C. The
addition was carried out such that the temperature of the reaction
mixture remained approximately 60.degree. C. When the reaction was
deemed complete as determined using in-process HPLC analysis (less
than 2 percent starting material remaining, typically 1.5-15
hours), the reactor contents were filtered. The filtrate was
concentrated by vacuum distillation at approximately 35.degree. C.
to half of its original volume, which resulted in the precipitation
of the product. The product was recovered by filtration, washed
with water (12.0 kg), and dried under vacuum at approximately
50.degree. C. to afford the title compound (3.0 kg; 97 percent
AUC).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic
acid
[0086] Triethylamine (8.0 kg) was added to a cooled (approximately
4.degree. C.) solution of commercially available
cyclopropane-1,1-dicarboxylic acid (10.0 kg) in THF (63.0 kg) at a
rate such that the batch temperature did not exceed 10.degree. C.
The solution was stirred for approximately 30 minutes, and then
thionyl chloride (9.0 kg) was added, keeping the batch temperature
below 10.degree. C. When the addition was complete, a solution of
4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such
that the batch temperature did not exceed 10.degree. C. The mixture
was stirred for approximately 4 hours and then diluted with
isopropyl acetate (87.0 kg). This solution was washed sequentially
with aqueous sodium hydroxide (2.0 kg dissolved in 50.0 L of
water), water (40.0 L), and aqueous sodium chloride (10.0 kg
dissolved in 40.0 L of water). The organic solution was
concentrated by vacuum distillation followed by the addition of
heptane, which resulted in the precipitation of solid. The solid
was recovered by centrifugation and then dried at approximately
35.degree. C. under vacuum to afford the title compound (10.0
kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
[0087] Oxalyl chloride (1.0 kg) was added to a solution of
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg)
in a mixture of THF (11 kg) and N,N-dimethylformamide (DMF; 0.02
kg) at a rate such that the batch temperature did not exceed
30.degree. C. This solution was used in the next step without
further processing.
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide
[0088] The solution from the previous step containing
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was
added to a mixture of
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg), and
potassium carbonate (4.0 kg) in THF (27.0 kg), and water (13.0 kg)
at a rate such that the batch temperature did not exceed 30.degree.
C. When the reaction was complete (approximately 10 minutes), water
(74.0 kg) was added. The mixture was stirred at 15 to 30.degree. C.
for approximately 10 hours, which resulted in the precipitation of
the product. The product was recovered by filtration, washed with a
pre made solution of THF (11.0 kg) and water (24.0 kg), and dried
at approximately 65.degree. C. under vacuum for approximately 12
hours to afford the title compound (free base, 5.0 kg). .sup.1H NMR
(400 MHz, d.sub.6-DMSO): .delta. 10.2 (s, 1H), 10.05 (s, 1H), 8.4
(s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25
(m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H).
LC/MS: M+H=502.
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-M-(4-fluorophenyl)cycl-
opropane-1,1-dicarboxamide, (L) malate salt
[0089] A solution of L-malic acid (2.0 kg) in water (2.0 kg) was
added to a solution of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide
(4-fluoro-phenyl)-amide free base (1 5, 5.0 kg) in ethanol,
maintaining a batch temperature of approximately 25.degree. C.
Carbon (0.5 kg) and thiol silica (0.1 kg) were then added, and the
resulting mixture was heated to approximately 78.degree. C., at
which point water (6.0 kg) was added. The reaction mixture was then
filtered, followed by the addition of isopropanol (38.0 kg). The
reaction mixture was allowed to cool to approximately 25.degree. C.
The product was recovered by filtration and washed with isopropanol
(20.0 kg) and dried at approximately 65.degree. C. to afford the
title compound (5.0 kg).
[0090] An alternative route that for the preparation of Compound 1
is depicted in Scheme 2.
##STR00014##
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0091] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg).
The resulting mixture was heated to approximately 60.degree. C. and
phosphorus oxychloride (POCl.sub.3, 130.6 kg) was added. After the
addition of POCl.sub.3, the temperature of the reaction mixture was
raised to approximately 77.degree. C. The reaction was deemed
complete (approximately 13 hours) when less than 3 percent of the
starting material remained (in-process high-performance liquid
chromatography [HPLC] analysis). The reaction mixture was cooled to
approximately 2 to 7.degree. C. and then quenched into a chilled
solution of dichloromethane (DCM, 482.8 kg), 26 percent NH.sub.4OH
(251.3 kg), and water (900 L). The resulting mixture was warmed to
approximately 20 to 25.degree. C., and phases were separated. The
organic phase was filtered through a bed of AW hyflo super-cel NF
(Celite; 5.4 kg), and the filter bed was washed with DCM (118.9
kg). The combined organic phase was washed with brine (282.9 kg)
and mixed with water (120 L). The phases were separated and the
organic phase was concentrated by vacuum distillation with the
removal of solvent (approximately 95 L residual volume). DCM (686.5
kg) was charged to the reactor containing organic phase and
concentrated by vacuum distillation with the removal of solvent
(approximately 90 L residual volume). Methyl t-butyl ether (MTBE,
226.0 kg) was then charged and the temperature of the mixture was
adjusted to -20 to 25.degree. C. and held for 2.5 hours. This
resulted in solid precipitate, which was then filtered, washed with
n-heptane (92.0 kg), and dried on a filter at approximately
25.degree. C. under nitrogen to afford the title compound. (35.6
kg).
Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0092] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide
(DMA, 184.3 kg) was charged to a reactor containing
4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide, (21.4
kg) and DMA (167.2 kg) at 20 to 25.degree. C. This mixture was then
heated to 100 to 105.degree. C. for approximately 13 hours. After
the reaction was deemed complete as determined using in-process
HPLC analysis (less than 2 percent starting material remaining),
the reactor contents were cooled at 15 to 20.degree. C. and water
(pre-cooled, 2 to 7.degree. C., 587 L) charged at a rate to
maintain 15 to 30.degree. C. temperature. The resulting solid
precipitate was filtered, washed with a mixture of water (47 L) and
DMA (89.1 kg) and finally with water (214 L). The filter cake was
then dried at approximately 25.degree. C. on filter to yield crude
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6
kg dry calculated based on LOD). Crude
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed
(approximately 75.degree. C.) in a mixture of tetrahydrofuran (THF,
211.4 kg) and DMA (108.8 kg) for approximately 1 hour and then
cooled to 0 to 5.degree. C. and aged for approximately 1 hour after
which time the solid was filtered, washed with THF (147.6 kg), and
dried on a filter under vacuum at approximately 25.degree. C. to
yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0
kg).
Alternative Preparation of
4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0093] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-Aminophenol
(30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35
wt percent in THF) were charged to a reactor, followed by
N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated
to 105 to 115.degree. C. for approximately 9 hours. After the
reaction was deemed complete as determined using in-process HPLC
analysis (less than 2 percent starting material remaining), the
reactor contents were cooled at 15 to 25.degree. C., and water (315
kg) was added over a two hour period while maintaining the
temperature between 20 and 30.degree. C. The reaction mixture was
then agitated for an additional hour at 20 to 25.degree. C. The
crude product was collected by filtration and washed with a mixture
of water (88 kg) and DMA (82.1 kg), followed by water (175 kg). The
product was dried on a filter drier for 53 hours. The LOD showed
less than 1 percent weight/weight (w/w).
[0094] In an alternative procedure, 1.6 equivalents of sodium
tert-pentoxide were used, and the reaction temperature was
increased from 110 to 120.degree. C. In addition, the cool down
temperature was increased to 35 to 40.degree. C., and the starting
temperature of the water addition was adjusted to 35 to 40.degree.
C., with an allowed exotherm to 45.degree. C.
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic
acid
[0095] Triethylamine (19.5 kg) was added to a cooled (approximately
5.degree. C.) solution of cyclopropane-1,1-dicarboxylic acid (24.7
kg) in THF (89.6 kg) at a rate such that the batch temperature did
not exceed 5.degree. C. The solution was stirred for approximately
1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping
the batch temperature below 10.degree. C. When the addition was
complete, the solution was stirred for approximately 4 hours
keeping the temperature below 10.degree. C. A solution of
4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate
such that the batch temperature did not exceed 10.degree. C. The
mixture was stirred for approximately 10 hours, after which the
reaction was deemed complete. The reaction mixture was then diluted
with isopropyl acetate (218.1 kg). This solution was washed
sequentially with aqueous sodium hydroxide (10.4 kg, 50% dissolved
in 119 L of water), further diluted with water (415 L), then with
water (100 L), and finally with aqueous sodium chloride (20.0 kg
dissolved in 100 L of water). The organic solution was concentrated
by vacuum distillation (100 L residual volume) below 40.degree. C.,
followed by the addition of n-heptane (171.4 kg), which resulted in
the precipitation of solid. The solid was recovered by filtration
and washed with n-Heptane (102.4 kg), resulting in wet crude,
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg).
The crude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
was dissolved in methanol (139.7 kg) at approximately 25.degree.
C., followed by the addition of water (320 L), resulting in slurry
which was recovered by filtration, washed sequentially with water
(20 L) and n-heptane (103.1 kg), and then dried on the filter at
approximately 25.degree. C. under nitrogen to afford the title
compound (25.4 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
[0096] Oxalyl chloride (12.6 kg) was added to a solution of
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg)
in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23
kg) at a rate such that the batch temperature did not exceed
25.degree. C. This solution was used in the next step without
further processing.
Alternative Preparation of
1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
[0097] A reactor was charged with
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg),
DMF (344 g), and THF (175 kg). The reaction mixture was adjusted to
12 to 17.degree. C., and then to the reaction mixture was charged
19.9 kg of oxalyl chloride over a period of 1 hour. The reaction
mixture was left stirring at 12 to 17.degree. C. for 3 to 8 hours.
This solution was used in the next step without further
processing.
Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide
[0098] The solution from the previous step containing
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was
added to a mixture of compound
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and
potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L)
at a rate such that the batch temperature did not exceed 30.degree.
C. When the reaction was complete (in approximately 20 minutes),
water (653 L) was added. The mixture was stirred at 20 to
25.degree. C. for approximately 10 hours, which resulted in the
precipitation of the product. The product was recovered by
filtration, washed with a pre-made solution of THF (68.6 kg) and
water (256 L), and dried first on a filter under nitrogen at
approximately 25.degree. C. and then dried at approximately
45.degree. C. under vacuum to afford the title compound (41.0 kg,
38.1 kg, calculated based on LOD).
Alternative Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinolone-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide
[0099] A reactor was charged with
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1
equivalent), followed by THF (412.9 kg). To the reaction mixture
was charged a solution of K.sub.2CO.sub.3 (48.3 g) in water (169
kg). The acid chloride solution described in the Alternative
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride above was transferred to the reactor containing
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine while maintaining
the temperature between 20 to 30.degree. C. over a minimum of two
hours. The reaction mixture was stirred at 20 to 25.degree. C. for
a minimum of three hours. The reaction temperature was then
adjusted to 30 to 25.degree. C., and the mixture was agitated. The
agitation was stopped and the phases of the mixture were allowed to
separate. The lower aqueous phase was removed and discarded. Water
(804 kg) was added to the remaining upper organic phase. The
reaction was left stirring at 15 to 25.degree. C. for a minimum of
16 hours.
[0100] The product precipitated. The product was filtered and
washed with a mixture of water (179 kg) and THF (157.9 kg) in two
portions. The crude product was dried under a vacuum for at least
two hours. The dried product was then taken up in THF (285.1 kg).
The resulting suspension was transferred to reaction vessel and
agitated until the suspension became a clear (dissolved) solution,
which required heating to 30 to 35.degree. C. for approximately 30
minutes. Water (456 kg) was then added to the solution, as well as
SDAG-1 (20 kg) ethanol (ethanol denatured with methanol over two
hours). The mixture was agitated at 15-25.degree. C. for at least
16 hours. The product was filtered and washed with a mixture of
water (143 kg) and THF (126.7 kg) in two portions. The product was
dried at a maximum temperature set point of 40.degree. C.
[0101] In an alternative procedure, the reaction temperature during
acid chloride formation was adjusted to 10 to 15.degree. C. The
recrystallization temperature was changed from 15 to 25.degree. C.
to 45 to 50.degree. C. for 1 hour and then cooled to 15 to
25.degree. C. over 2 hours.
Preparation of Cyclopropane-1,1-dicarboxylic acid
14-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl'-amide
(4-fluoro-phenyl)-amide, (L) malate salt
[0102] Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl
ethyl ketone (MEK; 188.6 kg), and water (37.3 kg) were charged to a
reactor, and the mixture was heated to reflux (approximately
74.degree. C.) for approximately 2 hours. The reactor temperature
was reduced to 50 to 55.degree. C., and the reactor contents were
filtered. These sequential steps described above were repeated two
more times starting with similar amounts of
cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide (13.3 kg), L-Malic acid (4.96 kg), MEK
(198.6 kg), and water (37.2 kg). The combined filtrate was
azeotropically dried at atmospheric pressure using MEK (1133.2 kg)
(approximate residual volume 711 L; KF.ltoreq.0.5% w/w) at
approximately 74.degree. C. The temperature of the reactor contents
was reduced to 20 to 25.degree. C. and held for approximately 4
hours, resulting in solid precipitate which was filtered, washed
with MEK (448 kg), and dried under vacuum at 50.degree. C. to
afford the title compound (45.5 kg).
Alternative Preparation of Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide, (I) malate salt
[0103] Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg
methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a
reactor, and the mixture was heated 50 to 55.degree. C. for
approximately 1 to 3 hours, and then at 55 to 60.degree. C. for an
additional 4 to 5 hours. The mixture was clarified by filtration
through a 1 .mu.m cartridge. The reactor temperature was adjusted
to 20 to 25.degree. C. and vacuum distilled with a vacuum at
150-200 mm Hg with a maximum jacket temperature of 55.degree. C. to
the volume range of 558-731 L.
[0104] The vacuum distillation was performed two more times with
the charge of 380 kg and 380.2 kg methyl ethyl ketone,
respectively. After the third distillation, the volume of the batch
was adjusted to 18 volume/weight (v/w) of
cyclopropane-,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide by charging methyl ethyl ketone (159.9 kg)
to give a total volume of 880 L. An additional vacuum distillation
was carried out by adjusting methyl ethyl ketone (245.7 kg). The
reaction mixture was left with moderate agitation at 20 to
25.degree. C. for at least 24 hours. The product was filtered and
washed with methyl ethyl ketone (415.1 kg) in three portions. The
product was dried under a vacuum with the jacket temperature set
point at 45.degree. C.
[0105] In an alternative procedure, the order of addition was
changes so that a solution of L-malic acid (17.7 kg) dissolved in
water (129.9 kg) was added to cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide
(4-fluoro-phenyl)-amide (48.7 kg) in methyl ethyl ketone (673.3
kg).
Clinical Results
[0106] Compound 1 was used in a Phase 2 randomized discontinuation
trial study of adults with melanoma, including ocular melanoma (See
NCT00940225, Abstract 371). Compound 1 was administered at a daily
dose of 100 mg (125 mg salt equivalent). The study endpoints
included objective response rate (ORR) per mRECIST in the lead-in
stage, and progression-free survival in the randomized stage.
[0107] The eligibility criteria included: (a) pathologically and
radiologically confirmed diagnosis of advanced melanoma; (b)
cutaneous, mucosal, or ocular subtypes; (c) up to two lines of
prior systemic treatment (not including immunotherapy); (d)
documented progressive disease and measurable target lesion(s) per
mRECIST; and (e) no known brain metastases. Tumors were assessed by
CT/MRI at baseline and every 6 weeks thereafter. Archival tumor
tissue was retained for genotyping and biomarker analysis.
[0108] Objective tumor shrinkage was observed in sixty percent of
the patients with melanoma who were enrolled in the study.
[0109] In all, 18 patients (28 percent) with ocular melanoma were
enrolled. The results are summarized in FIG. 1-4. FIGS. 1 through 4
show a positive response to treatment with Compound 1 in patients
of ocular melanoma. FIG. 1 presents mutation data based on archival
tumor tissue and investigator reporting. Analyses for ocular
melanoma were typically limited to commonly mutated GNAQ and GNA1,
as well as BRAF. One partial response was observed at week 6.
[0110] FIG. 2 summarizes the baseline mutation status for patients
in the study. Analyses for ocular melanoma were typically limited
to commonly mutated GNAQ and GNA1, as well as BRAF. Analyses for
non-ocular subtypes were generally limited to BRAF, NRAS, and
KIT.
[0111] FIG. 3 summarizes the results. Eight of the fourteen
patients with ocular melanoma who were tested showed a positive
disease control rate.
[0112] FIG. 4 provides an overview of patients with the best
response rate. Patients with ocular melanoma (Patients 5, 6, 14,
15, 18, 20, 22, 26, 28, and 29) all showed stable disease.
[0113] At week 12, Compound 1 showed a positive disease control
rate of 14 percent in patients with ocular cancer. At six months,
Compound 1 showed evidence of objective tumor regression in 48
percent of the patients with ocular cancer.
OTHER EMBODIMENTS
[0114] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. The invention has been described with reference to
various specific and preferred embodiments and techniques. It
should be understood, however, that many variations and
modifications can be made while remaining within the spirit and
scope of the invention. It will be obvious to one of skill in the
art that changes and modifications can be practiced within the
scope of the appended claims. It is to be understood that the above
description is intended to be illustrative and not restrictive.
[0115] The scope of the invention should, therefore, be determined
not with reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *