Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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4-(4'-HYDROXYPHENYL)AMINO-6,7-DIMETHOXYQUINAZOLINE TO
PREVENT DEVELOPMENT OF COLORECTAL CANCER
This application is being filed as a PCT International Patent
application in the name of Parker Hughes Institute, a U.S. national
corporation,
(applicant for all countries except US), and Fatih M. Uckun, a U.S. citizen
(applicant
for US only), on 14 November 2000, designating all countries.
FIELD OF THE INVENTION
The present invention relates to quinazoline compounds,
compositions and therapeutic methods for the treatment of cancers by
administering
quinazoline compounds.
BACKGROUND OF THE INVENTION
Currently, there is a need for methods useful for preventing the
development or recurrence of cancer in mammals. Quinazoline compounds have
been suggested as useful compounds in the treatment of cell growth and
differentiation characterized by activity of the human epidermal growth factor
receptor type2 (HER2). See, for example, Myers et.al., U.S. Patent No.
5,721,237.
Some quinazoline derivatives have been suggested as useful as anti-cancer
agents for
the treatment of specific receptor tyrosine kinase-expressing cancers;
especially
those expressing epithelial growth factor (EGF) receptor tyrosine kinase. See,
for
example, Barker et. al., U.S. Patent No. 5,457,105. It is generally taught
that
quinazolines exert their anti-tumor effects via tyrosine kinase inhibition.
However,
while some quinazoline compounds inhibit the growth of tumor cells, such as
brain
tumor cells, others with equally potent tyrosine kinase inhibitory activity
fail to do
so (Naria et.al., 1998, Clin.Cancer Res. 4:1405-1414; Naria et.al., 1998,
Clin. Cancer Res. 4:2463-2471 ).
Some quinazoline derivatives have also been suggested as useful
agents for treating precancerous legions and inhibiting the growth of
neoplastic cells.
See for example, Pamukeu et al., U.S. Patents Nos. 5,990,117; 6,037,345; and
6,046,206. Although many of the disclosed quinazoline derivatives are useful
for
treating precancerous legions and inhibiting the growth of neoplastic cells,
there still
exists the need to discover better compounds for the treatment of cancer, in
particular colorectal cancer.
Cancer of the colon and/or rectum is now the third most common
cause of death from cancer in the United States. Over 150,000 new cases of
colon
and/or rectal cancer are diagnosed each year. In addition, the incidence of
colon
cancer reportedly increases with age, particularly after the age of 40. Since
the mean
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ages of populations in America and Western Europe are increasing, the
prevalence
of colorectal cancer should increase in the future.
To date, the only effective cure for colorectal cancer is surgery at an
extremely early stage. Unfortunately, most cases of colorectal cancer are
discovered
too late for surgical cure. In many cases, the patient does not experience
symptoms
until the cancer has progressed to a malignant stage. The search for drugs
useful for
treating and preventing colorectal cancer continues.
What is needed in the art is a useful therapeutic agent for the
treatment of colorectal cancer.
SUMMARY OF THE INVENTION
It has been discovered that 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline is effective as a therapeutic agent for the treatment of
colorectal cancer. The present invention demonstrates the improved
chemopreventive activity of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
compared to known therapeutic agents.
The present invention provides a method of preventing the
development or recurrence of colorectal cancer in a mammal comprising
administering to the mammal, an effective cancer preventative amount of 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable
salt thereof.
The present invention also provides the use of 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable
salt thereof, to prepare a medicament useful for preventing the development or
recurrence of colorectal cancer in a mammal.
These and other features and advantages of the present invention will
become apparent after a review of the following detailed description of the
disclosed
embodiments and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
It has been discovered unexpectedly that 4-(4'-hydroxyphenyl)amino-
6,7-dimethoxyquinazoline possesses increased activity against colorectal
cancer. As
such, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is particularly
useful as
an active agent for anticancer compositions and for methods of treating
cancers, such
as colorectal cancer.
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Definitions
A number of terms are used throughout the present disclosure. Some
of these terms are defined as shown below.
All scientific and technical terms used in this application have
meanings commonly used in the art unless otherwise specified. As used in this
application, the following words or phrases have the meanings specified.
As used herein, "pharmaceutically acceptable carrier" means any
material which, when combined with 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline, allows 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline to retain biological activity, such as the ability to
potentiate
antibacterial activity of mast cells and macrophages. Examples include, but
are not
limited to, any of the standard pharmaceutical carriers such as a phosphate
buffered
saline solution, water, emulsions such as oil/water emulsions, and various
types of
wetting agents. Compositions comprising such carriers are formulated by well-
known conventional methods (see, for example, Remington's Pharmaceutical
Sciences, Chapter 43, 14th Ed., Mack Publishing Co., Easton, PA).
The term "conjugate" means a compound formed as a composite
between two or more molecules. More specifically, in the present invention, 4-
(4'
hydroxyphenyl)amino-6,7-dimethoxyquinazoline is bonded, for example,
covalently
bonded, to cell-specific targeting moieties forming a conjugate compound for
efficient and specific delivery of 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline to a cell of interest.
The phrase "targeting moiety" means a molecule, which serves to
deliver 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to a specific site
for
the desired activity. Targeting moieties include, for example, molecules that
specifically bind molecules on a specific cell surface. Such targeting
moieties useful
in the present invention include anti-cell surface antigen antibodies.
Cytokines,
including interleukins and factors such as granulocyte/macrophage stimulating
factor
(GMCSF) are also specific targeting moieties, known to bind to specific cells
expressing high levels of their receptors.
The term "prodrug moiety" is a substitution group, which facilitates
use of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, for example by
facilitating entry of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline into
cells
or administration of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. The
prodrug moiety may be cleaved from 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline, for example by cleavage enzymes in vivo. Examples of
prodrug moieties include phosphate groups, peptide linkers, and sugars, which
moieties can be hydrolyzed in vivo.
3
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As used herein, "inhibit" means to reduce by a measurable amount, or
to prevent entirely.
As used herein, "to treat" means to inhibit or block at least one
symptom that characterizes a pathologic condition, in a mammal threatened by,
or
afflicted with, the condition.
Compounds For Use In The Present Invention
Compounds for use in the present invention include 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable
salts thereof. Pharmaceutically acceptable salts of 4-(4'-hydroxyphenyl)amino-
6,7-
dimethoxyquinazoline may include organic acid addition salts formed with
acids,
which form a physiological acceptable anion, including, but not limited to,
tosylate,
methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate,
ascorbate,
a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be
1 S formed, including, but not limited to, hydrochloride, sulfate, nitrate,
bicarbonate, and
carbonate salts.
Acceptable salts may be obtained using standard procedures well
known in the art, for example by reacting a sufficiently basic compound such
as an
amine with a suitable acid affording a physiologically acceptable anion.
Synthesis of 4-(4'-hydroxyphenyl)amino-6, 7-dinZetlZOxyguinazoline
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline useful in the
present invention may be synthesized from a key starting material, 4-chloro-
6,7-
dimethoxyquinazoline, prepared using published procedures (Nomoto, et al.,
1990,
Chem. Pharm. Bull., 38:1591-1595; Thomas, C. L., 1970, Academic Press, Neu
York, NY, "I. Synthesis of quinazoline derivatives") as outlined below in
Scheme 1
and as described more fully in the Examples below:
4
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0 0
CH3 ~ ( OOH SOQ, CH3 ~ ~NHz CuS04
\ N~ NI-OOH CH3 \ ( N NaBH4
az
O O
CH3 ~ ~NHz HRH CH3 ~ ~ ~ H POC73
~3~ \ ~ ~3 \ N/
2
CI
CH3 ~ ~ N
\ i NJ
Scheme 1
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is then
prepared by the condensation of 4-chloro-6,7-dimethoxyquinazoline with 4
aminophenol as outlined below in Scheme 2:
OH
CI NHS HN
CH,O / ~ N / CH,O / ~ N
CH,O ~ ~ J , ~ CH,O
OH
Scheme 2
Compositions Useful In The Present Invention
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be useful
as a pharmaceutical composition prepared with a therapeutically effective
amount of
5
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4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline and a pharmaceutically
acceptable carrier or diluent.
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be
formulated as a pharmaceutical composition and administered to a mammalian
host,
such as a human patient, in a variety of forms adapted to the chosen route of
administration, i.e., orally or parenterally, by intravenous, intramuscular,
topical or
subcutaneous routes.
Thus, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be
systemically administered, e.g., orally, in combination with a
pharmaceutically
acceptable vehicle such as an inert diluent or an assimilable edible carrier,
or by
inhalation or insufflation. The components may be enclosed in hard or soft
shell
gelatin capsules, may be compressed into tablets, or may be incorporated
directly
with the food of the patient's diet. For oral therapeutic administration, 4-
(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be combined with one or
more excipients and used in the form of ingestible tablets, buccal tablets,
troches,
capsules, elixirs, suspensions, syrups, wafers, and the like. 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be combined with a fine inert
powdered carrier and inhaled by the subject or insufflated. Such compositions
and
preparations preferably contain at least 0.1 wt% of 4-(4'-hydroxyphenyl)amino-
6,7-
dimethoxyquinazoline. The percentage of 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline within a composition or preparation may, of course, be
varied
and may conveniently be between about 2 to about 60 wt% of a given unit dosage
form. The amount of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline in such
therapeutically useful compositions is such that an effective dosage level
will be
obtained.
The tablets, troches, pills, capsules, and the like may also contain one
or more of the following: binders such as gum tragacanth, acacia, corn starch
or
gelatin; excipients such as dicalcium phosphate; a disintegrating agent such
as com
starch, potato starch, alginic acid and the like; a lubricant such as
magnesium
stearate; and a sweetening agent such as sucrose, fructose, lactose or
aspartame or a
flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
When
the unit dosage form is a capsule, it may contain, in addition to materials of
the
above type, a liquid Garner, such as a vegetable oil or a polyethylene glycol.
Various other materials may be present as coatings or to otherwise modify the
physical form of the solid unit dosage form. For instance, tablets, pills, or
capsules
maybe coated with gelatin, wax, shellac or sugar and the like. A syrup or
elixir may
contain 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, sucrose or
fructose
as a sweetening agent, methyl and propylparabens as preservatives, a dye and
6
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flavoring such as cherry or orange flavor. Of course, any material used in
preparing
any unit dosage form should be pharmaceutically acceptable and substantially
non-
toxic in the amounts employed.
In addition, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
may be incorporated into sustained-release preparations and devices. Further,
4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be administered intravenously
or intraperitoneally by infusion or injection. Solutions of 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be prepared in water,
optionally mixed with a nontoxic surfactant. Dispersions may also be prepared
in
glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in
oils.
Under ordinary conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion
may include sterile aqueous solutions or dispersions or sterile powders
comprising
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, which are adapted for the
extemporaneous preparation of sterile injectable or infusible solutions or
dispersions,
optionally encapsulated in liposomes. In all cases, the ultimate dosage form
must be
sterile, fluid and stable under the conditions of manufacture and storage. The
liquid
carrier or vehicle may be a solvent or liquid dispersion medium comprising,
for
example, water, ethanol, a polyol (for example, glycerol, propylene glycol,
liquid
polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters,
and
suitable mixtures thereof. The proper fluidity may be maintained, for example,
by
the formation of liposomes, by the maintenance of the required particle size
in the
case of dispersions or by the use of surfactants. The prevention of the action
of
microorganisms may be brought about by various antibacterial and antifungal
agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
and
the like. In many cases, it will be preferable to include isotonic agents, for
example,
sugars, buffers or sodium chloride. Prolonged absorption of the injectable
compositions may be brought about by the use in the compositions of agents
delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions may be prepared by incorporating 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline in the required amount in the
appropriate solvent with various of the other ingredients enumerated above, as
required, followed by filter sterilization. In the case of sterile powders for
the
preparation of sterile injectable solutions, the preferred methods of
preparation are
vacuum drying and freeze drying techniques, which yield a powder of 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline plus any additional desired
ingredient present in the previously sterile-filtered solutions.
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Useful solid carriers include finely divided solids such as talc, clay,
microcrystalline cellulose, silica, alumina and the like. Other solid carriers
include
nontoxic polymeric nanoparticles or microparticles. Useful liquid carriers
include
water, alcohols or glycols or water-alcohol/glycol blends, in which 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline can be dissolved or dispersed at
effective levels, optionally with the aid of non-toxic surfactants.
Generally, the concentration of 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline in a liquid composition will be from about 0.1 to about
25
wt%, preferably from about 0.5 to about 10 wt%. The concentration of 4-(4'-
hydroxyphenyl)amino-6,7--dimethoxyquinazoline in a semi-solid or solid
composition such as a gel or a powder will be about 0.1 to about 5 wt%,
preferably
about 0.5 to about 2.5 wt%.
Dosage Of 4-(4'-hyclroxyphenyl)amino-6, 7-dimethoxyguinazoline
The amount of 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline required for use in a given treatment will vary depending
on a
number of factors including, but not limited to, the route of administration,
the
nature of the condition being treated, and the age and condition of the
patient. The
amount of a given dosage will be ultimately at the discretion of the attendant
physician or clinician. In general, however, a suitable dose will be in the
range of
from about 0.1 mg/kg to about 100 mg/kg of body weight per day. Preferably,
the
dose will range from about 10 to about 75 mg/kg of body weight per day, more
preferably from about 3 to about 50 mg/kg of body weight per day, even more
preferably from about 6 to about 90 mg/kg of body weight per day, and even
more
preferably from about 15 to 60 mg/kg of body weight per day.
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is
conveniently administered in unit dosage form; for example, containing from
about
5 to about 1000 mg, preferably from about 10 to about 750 mg, and more
preferably
from about 50 to about 500 mg of active ingredient per unit dosage form.
Ideally, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is
administered to achieve peak plasma concentrations of from about 0.5 to about
75 ~
M, preferably from about 1 to about 50 ~,M, and more preferably from about 2
to
about 30 ELM. This may be achieved, for example, by the intravenous injection
of a
0.05 to 5 wt% solution of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,
optionally in saline, or orally administered as a bolus containing about 1 to
100 mg
of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. Desirable blood levels
may be maintained by continuous infusion to provide about 0.01 to about 5.0
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mg/kg/hr or by intermittent infusions containing from about 0.4 to about 15
mg/kg
of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline.
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may
conveniently be presented in a single dose or as divided doses administered at
appropriate intervals, for example, as two, three, four or more sub-doses per
day.
The sub-dose itself may be further divided, e.g., into a number of discrete
loosely
spaced administrations, such as multiple inhalations from an insufflator.
Targeting 4-(4'-hydroxyphenyl)amino-6, 7-dimethoxyquinazoline To Cells
In one aspect of the present invention, 4-(4'-hydroxyphenyl)amino-
6,7-dimethoxyquinazoline may be targeted to cells where treatment is desired,
in
particular, to colorectal cells. 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline
may be targeted to the desired cell by conjugation to a targeting moiety that
specifically binds to the desired cell, thereby directing administration of a
conjugated molecule. Useful targeting moieties are ligands, which specifically
bind
cell antigens or cell surface ligands, for example, antibodies against the B
cell
antigen, CD19 (such as B43) and the like.
To form conjugates for use in the present invention, targeting
moieties are covalently bonded to sites on 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline. The targeting moiety, which is often a polypeptide
molecule, is bound to 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline at
reactive sites, including, but not limited to, OH, and the like. Specific
linking agents
are used to join the compounds. Preferred linking agents are chosen according
to the
reactive site to which the targeting moiety is to be attached.
Methods for selecting an appropriate linking agent and reactive site
for attachment of the targeting moiety to 4-(4'-hydroxyphenyl)amino-6,7-
dimethoxyquinazoline are known, and are described, for example, in Hermanson,
et
al., Bioconjugate Techniques, Academic Press, 1996; Hermanson, et al.,
Immobilized
Affinity Ligand Techniques, Academic Press, 1992; and Pierce Catalog and
Handbook, 1996, pp. T155-T201.
Measuring The Effectiveness of 4-(4'-hydroxyphenyl)amino-6, 7-
dinaethoxyquinazoline
The ability of 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
to prevent the development or recurrence of a cancer may be determined using
pharmacological models, which are well known to the art, or using the methods
as
described herein. As used herein, preventing the development or recurrence
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includes both slowing the development or recurrence, as well as completely
eliminating the development or recurrence.
The present invention is described above and further illustrated below
by way of examples, which are not to be construed in any way as imposing
limitations upon the scope of the invention. On the contrary, it is to be
clearly
understood that resort may be had to various other embodiments, modifications,
and
equivalents thereof which, after reading the description herein, may suggest
themselves to those skilled in the art without departing from the spirit of
the present
invention and/or the scope of the appended claims.
EXAMPLES
All chemicals used in the following Examples were purchased from
the Aldrich Chemical Company, Milwaukee, Wisconsin, and were used directly for
synthesis. Anhydrous solvents such as acetonitrile, methanol, ethanol, ethyl
acetate,
tetrahydrofuran, chloroform, and methylene chloride were obtained from Aldrich
as
sure seal bottles under nitrogen and were transferred to reaction vessels by
cannulation. All reactions were carried out under a nitrogen atmosphere.
EXAMPLE 1
Synthesis of 4-(4'-hydroxyphenyl)amino-6, 7-dimethoxyquinazoline
The key starting material, 4-chloro-6,7-dimethoxyquinazoline, was
prepared using published procedures (Nomoto, et al., 1990, Chem. Pharm. Bull.,
38:1591-1595; Thomas, C. L., 1970, Academic Press, New York, NY, "I. Synthesis
of quinazoline derivatives") as outlined below in Scheme 1 above.
Specifically, 4,5-dimethoxy-2-nitrobenzoic acid (compound 1 ) was
treated with thionyl chloride to form acid chloride, followed by reacting with
ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (compound 2). Compound 2
was reduced with sodium borohydride in the presence of catalytic amounts of
copper
sulphate to give 4,5-dimethoxy-2-aminobenzamide (compound 3), which was
directly refluxed with formic acid to yield 6,7-dimethoxyquinazoline-4(3H)-one
(compound 4). Compound 4 was refluxed with phosphorus oxytrichloride to give 4-
chloro-6,7-dimethoxyquinazoline (compound 5) in good yield.
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline was prepared
by the condensation of 4-chloro-6,7-dimethoxyquinazoline with 4-aminophenol as
outlined below in Scheme 2 above.
Specifically, a mixture of 4-chloro-6,7-dimethoxyquinazoline (448
mg, 2 mmols) and 4-aminophenol (2.5 mmols) in EtOH (20 ml) was heated to
reflux. After refluxing for 4 to 24 hours, an excess amount of Et3N was added,
and
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the solvent was concentrated to give the crude product which was recrystalized
from
DMF.
EXAMPLE 2
Characterization of 4-(4'-hydroxyphenyl)amino-6, 7-dimethoxyquinazoline
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline was
synthesized as described in Example 1 and characterized. The structure is
shown
below, along with its identifying analytical test results. Proton and carbon
Nuclear
Magnetic Resonance ('H and'3C NMR) spectra were recorded on a Mercury 2000
Varian spectrometer operating at 300 MHz and 75 MHz, respectively, using an
automatic broad band probe. Unless otherwise noted, all NMR spectra were
recorded
in CDCl3 at room temperature. 'H chemical shifts are quoted in parts per
million (d
in ppm) downfield from tetramethyl silane (TMS), which was used as an internal
standard at 0 ppm and s, d, t, q, m designate singlet, doublet, triplet,
quartet and
multiplet, respectively. Melting points were determined using a Fisher-Johns
melting
apparatus and are uncorrected. UV spectra were recorded using a Beckmann Model
# DU 7400 UV/V is spectrometer with a cell path length of 1 cm. Methanol was
used as the solvent for the UV spectra. Fourier Transform Infrared spectra
were
recorded using an FT-Nicolet model Protege #460 instrument. The infrared
spectra
of the liquid samples were run as neat liquids using KBr discs. The KBr pellet
method was used for all solid samples. The GC/mass spectrum analysis was
conducted using a Hewlett-Packard GC/mass spectrometer model # 6890 equipped
with a mass ion detector and Chem Station software. The temperature of the
oven
was steadily increased from 70°C to 250°C and the carrier gas
was helium.
4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline
yield 84.29%; m.p. 245.0-248Ø °C; UV(MeOH)
~oH 7v," a~: 203.0, 222.0, 251.0, 320.0 nm; IR(KBr)
Hn , un,aa: 3428, 2836, 1635, 1516, 1443, 1234 cm';
cH,o ~ ~ N 'H NMR(DMSO-d6): 11.21(s, 1H, -NH), 9.70(s,
cH3o~ j 1H, -OH), 8.74(s, 1H, 2-H), 8.22(s, 1H, 5-H),
7.40(d, 2H, J = 8.9 Hz, 2',6'-H), 7.29(s, 1H, 8-
H), 6.85(d, 2H, J= 8.9 Hz, 3',5'-H), 3.98(s, 3H,
-OCH3), 3.97(s, 3H, -OCH3); GC/MS m/z 298
(M+ +1, 100.00), 297(M+, 26.56), 296( M+-l,
12.46); Anal. (C,6H,~N303HC1) C, H, N.
1l
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EXAMPLE 3
Administering 4-(4'-hydroxyphenyl)-amino-6, 7-dimethoxyquinazoline to Mice
An APC""" mouse model was used to test the ability of 4-(4'-
hydroxyphenyl)-amino-6,7-dimethoxyquinazoline to prevent the development of
colorectal cancer. A total of 23 APC""" mice were fed rodent chow, which was
supplemented with 0.3 wt% 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline
once a week starting at six weeks of age. A control group of 30 mice were fed
rodent chow without 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline. The
health status of the mice was monitored for thirty weeks. Table 1 below
describes
the Probability of Survival for each group of mice over a period of 210 days.
Table 1. Probability Of Survival For Control Mice and APC""" Mice
Age Control Mice APC""" Mice
(Days) (n=30) (n=23)
90 93 t 5 100 ~ 0
120 93 ~ 5 94 ~ S
150 729 8110
180 34 ~ 10 68 ~ 12
210 178 6812
At thirteen weeks of age, 26% of the control mice developed rectal
bleeding. Gross examination of the mice sacrificed at thirteen weeks of age
revealed
that 60% of the control mice showed polyps in the intestines. In contrast, at
thirteen
weeks of age, none of the APC""" mice developed rectal bleeding or detectable
polyps in the intestines.
By thirty weeks of age, only 17% of the control mice remained alive.
However, 68% of the mice fed 4-(4'-hydroxyphenyl)-amino-6,7-
dimethoxyquinazoline were still alive.
While a detailed description of the present invention has been
provided above, the present invention is not limited thereto. The present
invention
described herein may be modified to include alternative embodiments, as will
be
apparent to those skilled in the art. All such alternatives should be
considered within
the spirit and scope of the present invention, as claimed below.
12
