WO 2006/096591 PCT/US2006/007807
CRYSTAL FORMS OF
2-(3-FLUORO-4-HYDROXYPHENYL)-7-VINYL-l,3-BENZOXAZOL-5-OL
FIELD OF THE INVENTION
The present invention is directed to crystal forms of 2-(3-fluoro-4-hydroxyphenyl)-7-
vinyl-l,3-benzoxazol-5-ol, an estrogenic receptor modulator useful in the treatment of, for
example, diseases related to abnormal levels of estrogen.
BACKGROUND OF THE INVENTION
The pleiotropic effects of estrogens in mammalian tissues have been well
documented, and it is now appreciated that estrogens affect many organ systems. Estrogens
can exert effects on tissues in several ways, and the most well characterized mechanism of
action is their interaction with estrogen receptors leading to alterations in gene transcription.
Estrogen receptors are ligand-activated transcription factors and belong to the nuclear
hormone receptor superfamily. Other members of this family include the progesterone,
androgen, glucocorticoid and mineralocorticoid receptors. Upon binding ligand, these
receptors dimerize and can activate gene transcription either by directly binding to specific
sequences on DNA (known as response elements) or by interacting with other transcription
factors (such as AP1), which in turn bind directly to specific DNA sequences. A class of
"coregulatory" proteins can also interact with the ligand-bound receptor and further modulate
its transcriptional activity. It has also been shown that estrogen receptors can suppress
NF.kappa.B-mediated transcription in both a ligand-dependent and independent manner.
Accordingly, compounds which are estrogen receptor modulators are useful in the
treatment or inhibition of conditions, disorders, or disease states that are at least partially
mediated by an estrogen deficiency or excess, or which may be treated or inhibited through
the use of an estrogenic agent. Such compounds can be particularly useful in treating a peri-
menopausal, menopausal, or postmenopausal patient in which the levels of endogenous
estrogens produced are greatly diminished. For example, estrogenic compounds are also
useful in inhibiting or treating hot flushes, vaginal or vulvar atrophy, atrophic vaginitis,
vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary incontinence, and
urinary tract infections. Other reproductive tract uses include the treatment or inhibition of
dysfunctional uterine bleeding and endometriosis.
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Certain substituted benzoxazole compounds have been found to be effective
estrogenic receptor modulators. An example benzoxazole is 2-(3-fluoro-4-hydroxyphenyl)-7-
vinyl-l,3-benzoxazol-5-ol, shown below in Formula I. The effectiveness of this compound
as an estrogenic modulator, as well as its preparation, are reported in U.S. Pat. No. 6,794,403,
which is incorporated herein by reference in its entirety.

The crystalline form of a particular drug (e.g., hydrate, solvate, polymorph, etc) is
often an important determinant of the drug's ease of preparation, stability, solubility, storage
stability, ease of formulation and in vivo pharmacology. Different crystalline forms occur
when a compound crystallizes in different lattice arrangements or where solvent molecules
(including water molecules) are incorporated into the crystalline lattice, resulting in solids
with different thermodynamic properties and stabilities specific to the particular form. It is
entirely possible that one crystal form is preferable over another where certain aspects such as
ease of preparation, stability, etc. are deemed to be critical. Similarly, greater solubility
and/or superior pharmacokinetics may be the desired characteristics.
Because improved drug formulations showing, for example, better bioavailability or
better stability are consistently sought, there is an ongoing need for new or purer crystal
forms of existing drug molecules. The crystal forms of 2-(3-fluoro-4-hydroxyphenyl)-7-
vinyl-1,3-benzoxazol-5-ol described herein are directed toward this end.
SUMMARY OF THE INVENTION
The present invention provides anhydrate and monohydrate crystal forms of 2-(3-
fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol, characterized according to the powder
X-ray diffraction data, differential scanning calorimetry, thermogravimetric analysis, and
dynamic vapor sorption data provided herein.
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The present invention further provides compositions containing the crystal forms of
the invention.
The present invention further provides a method of preparing the monohydrate crystal
form of the invention comprising precipitating the monohydrate from a solution comprising
water.
The present invention further provides a method of preparing the anhydrate crystal
form of the invention comprising precipitating the anhydrate from an anhydrous solution.
The present invention further provides compounds prepared by the above methods.
The present invention further provides methods of modulating an estrogen receptor
comprising contacting the receptor with a crystal form of the invention.
The present invention further provides methods of treating prostatitis, interstitial
cystitis, inflammatory bowel disease, Crohn's disease, ulcerative proctitis, colitis, prostatic
hypertrophy, uterine leiomyomas, breast cancer, endometrial cancer, polycystic ovary
syndrome, endometrial polyps, endometriosis, benign breast disease, adenomyosis, ovarian
cancer, melanoma, prostrate cancer, colon cancer, glioma, astioblastomia, free radical
induced disease states, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus,
dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections,
vasomotor symptoms, arthritis, joint swelling or erosion, joint damage secondary to
arthroscopic or surgical procedures, psoriasis, dermatitis, ischemia, reperfusion injury,
asthma, pleurisy, multiple sclerosis, systemic lupus erythematosis, uveitis, sepsis,
hemmorhagic shock, or type II diabetes, in a mammal in need thereof, which comprises
providing to the mammal a therapeutically effective amount of a crystal form of the
invention.
The present invention further provides methods of lowering cholesterol, triglycerides,
Lp(a), or LDL levels; inhibiting or treating hypercholesteremia, hyperlipidemia,
cardiovascular disease, atherosclerosis, hypertension, peripheral vascular disease, restenosis,
or vasospasm; or inhibiting vascular wall damage from cellular events leading toward
immune mediated vascular damage in a mammal in need thereof, which comprises providing
to the mammal a therapeutically effective amount of a crystal form of the invention.
The present invention further provides methods of providing cognition enhancement
or neuroprotection; or treating or inhibiting senile dementias, Alzheimer's disease, cognitive
decline, stroke, anxiety, or neurodegenerative disorders in a mammal in need thereof, which
comprises providing to the mammal an effective amount of the crystal form of the invention.
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The present invention further provides methods of inhibiting conception in a mammal
in need thereof, which comprises providing to the mammal an effective amount of a crystal
form of the invention.
The present invention further provides a crystal form of the invention for use in
therapy.
The present invention further provides a crystal form of the invention for use in the
preparation of a medicament for use in therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts X-Ray powder diffraction (XRPD) patterns for both the monohydrate
(upper) and anhydrate (lower) crystal forms of the invention.
Figure 2 depicts a differential scanning calorimetry (DSC) thermogram of the
monohydrate crystal form of the invention.
Figure 3 depicts a thermogravimetric analysis (TGA) of the monohydrate crystal form
of the invention.
Figure 4 depicts a differential scanning calorimetry (DSC) thermogram of the
anhydrate crystal form of the invention.
Figure 5 depicts a thermogravimetric analysis (TGA) of the anhydrate crystal form of
the invention.
Figure 6 depicts a dynamic vapor sorption (DVS) isotherm plot for the monohydrate
crystal form of the invention.
Figure 7 depicts a dynamic vapor sorption (DVS) isotherm plot for the anhydrate
crystal form of the invention.
DETAILED DESCRIPTION
Crystalline forms
The present invention provides, inter alia, two crystalline forms of 2-(3-fluoro-4-
hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol (I), an anhydrate form and a monohydrate form.
The crystalline forms of I can be identified by their unique solid state signatures with respect
to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD),
and other solid state methods. Further characterization with respect to water or solvent
content of the crystalline forms can be gauged by any of various routine methods such as
thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), DSC and other
techniques. For DSC, it is known that the temperatures observed will depend upon the rate
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of temperature change as well as sample preparation technique and the particular instrument
employed. Thus, the values reported herein relating to DSC thermograms can vary by plus or
minus about 4 °C. For XRPD, the relative intensities of the peaks can vary, depending upon
the sample preparation technique, the sample mounting procedure and the particular
instrument employed. Moreover, instrument variation and other factors can often affect the
2-theta values. Therefore, the peak assignments of diffraction patterns can vary by plus or
minus about 0.2°. The physical properties and X-ray data distinguishing each of the
crystalline forms of the invention are summarized in Tables 1 and 2 below.

Table 1
Monohydratc Anhydratc
Peak position,2q° Peak Description Peak position,2q° Peak Description
6.9 W 7.3 W
9.2 S 8.2 S
12.2 Strongest 10.3 S
13.9 W, with a right shoulder 13.2 W
15.2 VS 14.6 strongest
17.2 W 15.1 S
17.6 VW 16.3 S
18.6 M 18.3 M
19.5 M 19.7 W
19.7 M 20.7 VW
20.2 W 22.3 S, with a left shoulder
20.9 M 23.4 S
21.8 M 24.8 S
22.4 W 25.9 M
23.1 W 26.7 S
24.3 S 28.0 M
24.6 VW 28.8 W
25.4 M 29.5 W,B
26.2 M 30.6 W,B
26.6 M 31.5 M,B
27.3 W 32.6 W
27.6 W 33.0 VW
28.0 M 34.0 M-
29.6 W 34.9 W
30.7 M 35.8 W
31.0 W 36.4 W,sh
31.6 VW,B 37.3 M,B
32.4 VW,B 37.9 M, with a right shoulder
33.1 W 39.5 M
33.8 M VS: very high peak intensity
34.6 M S: relatively high peak intensity
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35.9 M M: middle range peak intensity
35.3 W W: relatively weak peak intensity
35.8 W VW: very weak peak intensity
36.3 VW B: relatively broad peak
37.7 M,B sh: shown as a shoulder peak
38.0 M,B
39.7 M,B

Table 2
Monohydrate Anhydrate
TGA 6.1 % water (6.23% theory) less than 0.02%
DSC Dehydration event: onset around Melt onset~250 °C
~114 °C (varies)
Melt onset ~250 °C
XRPD 9.2, 12.2 °2q 8.2, 10.3 °2q
DVS 0.1% gain (0-90% RH) 0.2% gain (0-90% RH)
Water 2.34 (pH 7.11) 10.0 (pH 7.29)
Solubility 2.21 (pH 7.51) 12.75 (pH 7.70)
(mg/mL)
Data of Table 2 pertaining to water content of the crystalline forms, shows that the
monohydrate crystal form was determined to contain close to the theoretical amount of water
of 6.23 wt% according to TGA (see, e.g., Figure 3). DSC confirms the presence of water in
the monohydrate, showing a dehydration event around 100 °C (varies from sample to sample,
see, e.g., Figure 2)). In contrast, the anhydrate has essentially no water content, showing less
than 0.02% by TGA (Figure 5) and a lack of a dehydration endotherm in the DSC (Figure 5).
In accordance with the distinguishing features provided by DSC and TGA analysis,
the present invention provides a monohydrate of the compound of Formula I having a
differential scanning calorimetry trace comprising a dehydration endotherm. In some
embodiments, the monohydrate has a differential scanning calorimetry trace comprising a
dehydration endotherm having an onset at about 95 to about 120, about 98 to about 118, or
about 95 to about 115 °C. In some embodiments, the monohydrate is characterized with a
DSC further comprising both a dehydration endotherm and a melting endotherm with an
onset of about 250 °C. In further embodiments, the monohydrate has a differential scanning
calorimetry trace substantially as shown in Figure 2. In some embodiments, the monohydrate
has a thermogravimetric analysis profile showing about 5.0 to about 7.0%, about 5.5 to about
6.5, or about 5.9 to about 6.4 % weight loss from about 60 to about 150 °C. In further
embodiments, the monohydrate has a thermogravimetric analysis profile substantially as
shown in Figure 3.
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The present invention further provides an anhydrous crystal form of the compound of
Formula I having a differential scanning calorimetry trace comprising a melting endotherm
having an onset at about 250 °C and substantially lacking an endotherm corresponding to a
dehydration event. In some embodiments, the crystal form has a differential scanning
calorimetry trace substantially as shown in Figure 4. In further embodiments, the crystal
form can have a thermogravimetric analysis profile showing less than about 1%, less than
about 0.5%, less than about 0.2%, less than about 0.1%, or less than about 0.05% weight loss
from about 60 to about 150 °C. In yet further embodiments, the crystal form can have a have
a thermogravimetric analysis profile substantially as shown in Figure 5.
DVS data (see Figures 6 and 7) of Table 2 reveal little weight gain for both crystalline
forms, indicating that both the monohydrate and anhydrate forms are largely non-
hygroscopic. In contrast, water solubility of the two forms shown in Table 2 markedly differ,
with the monohydrate having significantly lower solubility than the anhydrate.
The two crystalline forms (see, e.g., Figure 1) have distinct XRPD patterns, allowing
characterization of each the forms based on unique spectral signature.
Accordingly, the present invention provides a monohydrate of the compound of
Formula I. In some embodiments, the monohydrate has an X-ray powder diffraction pattern
comprising peaks, in terms of 2q, at about 9.2° and about 12.2°. In some embodiments, the
monohydrate has an X-ray powder diffraction pattern comprising peaks, in terms of 2q, at
about 9.2°, about 12.2°, and about 15.2°. In further embodiments, the monohydrate has an X-
ray powder diffraction pattern comprising peaks, in terms of 20, at about 9.2°, about 12.2°,
about 15.2°, and about 24.3°. In yet further embodiments, the monohydrate has an X-ray
powder diffraction pattern comprising peaks, in terms of 29, at about 9.2°, about 12.2°, about
15.2°, about 24.3°, about 25.4° and about 28.0°. In yet further embodiments, the monohydrate
has an X-ray powder diffraction pattern substantially as shown in Figure 1 (upper).
The present invention further provides an anhydrous crystal form of the compounds of
Formula I having an X-ray powder diffraction pattern comprising peaks, in terms of 2q, at
about 8.2°, about 10.3°, and about 14.6°. In some embodiments, the crystal form has an X-ray
powder diffraction pattern comprising peaks, in terms of 2q, at about 8.2°, about 10.3°, about
14.6°, about 15.1°, and about 16.3°. In some embodiments, the crystal form has an X-ray
powder diffraction pattern comprising peaks, in terms of 28, at about 8.2°, about 10.3°, about
14.6°, about 15.1°, about 16.3°, about 22.3°, about 24.8°, and about 26.7°. In further
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embodiments, the crystal form has an X-ray powder diffraction pattern substantially as shown
in Figure 1 (lower).
Compositions
The present invention further provides compositions containing one or more of the
two crystal forms of the invention. In some embodiments, the compositions of the invention
include at least about 50 %, at least about 60 %, at least about 70 %, at least about. 80 %, at
least about 90 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about
98 %, at least about 99 %, at least about 99.1 %, at least about 99.2 %, at least about 99.3 %,
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 %, at least about 99.9 %, by weight of either the monohydrate or anhydrate
crystal form of the compound of Formula I. In some embodiments, the compositions of the
invention contain a mixture of the monohydrate and anhydrate crystal forms. In some
embodiments, compositions of the invention include the monohydrate or the anhydrate and a
pharmaceutically acceptable carrier. In some embodiments, the compositions further include
and additional active ingredient such as a progestin.
Preparations
The monohydrate of the invention can be prepared by any of various suitable means.
In some embodiments, the process for preparing the monohydrate of the invention involves
precipitating the monohydrate from a solution containing water. The solution can further
contain one or more additional solvents, such as solvents that are miscible with water. In
some embodiments, the solution contains an alcohol such as methanol, ethanol, n-propanol or
isopropanol. In some embodiments, the alcohol is ethanol. The solution can contain alcohol
or water in any suitable content. In some embodiments, the weight ratio of alcohol to water
is about 1:1 to about 3:1, about 1.5:1 to about 2.5:1, or about 2:1. The solution can be
prepared by mixing a compound of formula I in water and optionally a solvent. The solution
can be optionally heated and/or stirred to help dissolve the compound. Precipitation can be
achieved by any suitable means including cooling, adding antisolvent to, or changing pH of
the solution, or combination thereof. In some embodiments, the solution is cooled from a
temperature of about 65 to about 95, about 70 to about 90, or about 75 to about 80 °C down
to a temperature of about -20 to about 50, about 0 to about 20, about 0 to about 10, or about 0
to about 5 °C. In some embodiments, the solution is cooled from a temperature of about 75
to about 80 down to a temperature of about 0 to about 5 °C. In some embodiments, the
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solution is held at an intermediate temperature for a period of time before reaching the final
cooled temperature. In some embodiments, the intermediate temperature is about 40 to about
60, about 45 to about 55, or about 50 °C.
In alternative embodiments, the monohydrate can be precipitated from a solution
containing water by adjusting pH of the solution. For example, the pH of a solution can be
raised, thereby inducing precipitation of the monohydrate. In some embodiments, the pH is
raised from about 7 (or lower) to about 9 or higher. pH can be adjusted according to routine
methods such as the addition of a base such as hydroxide (e.g., NaOH). The monohydrate can
also be precipitated by addition of antisolvent to a solution in which the compound of
Formula I is dissolved. Suitable antisolvents include water or other liquids of the sort.
Suitable solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, or
mixtures thereof or other water miscible solvents. The monohydrate can also be prepared by
slurrying anhydrous compound of Formula I in water or a solvent containing water (e.g.,
ethanol/water mixture).
The anhydrate can be prepared by precipitation from an anhydrous solution. An
anhydrous solution can contain less than about 1%, less than about 0.5%, less than about
0.2%, less than about 0.1%, less than about 0.05%, or less than 0.01% water. Suitable
solvents for precipitating the anhydrate crystal form include hydrocarbons such as pentane,
hexanes, heptanes, and the like, ethers such as diethyl ether or tetrahydrofuran, aromatics
such as benzene or toluene and the like, chlorinated hydrocarbons such as dichloromethane
and the like, as well as other organics such as ethyl acetate and the like, and mixture thereof.
In some embodiments, the anhydrate is precipitated from a solvent containing ethyl acetate.
In some embodiments, the solvent further contains a hydrocarbon such a heptane. In further
embodiments, the weight ratio of ethyl acetate to hydrocarbon is about 3:1 to about 1:1, about
1:1 to about 1:1, or about 1.5:1.
Precipitation of the anhydrate can be induced by any of the various well known
methods of precipitation. For example, precipitation can be induced by cooling the solution
or addition of antisolvent. In some embodiments, the solution is cooled from a temperature
of about 60 to about 90, about 70 to about 85, or about 75 to about 80 °C down to a .
temperature of about -20 to about 30, about 0 to about 10, or about 0 to about 5 °C. During
the cooling process, the temperature can be optionally held at an intermediate temperature
such as about 40 to about 60 ° C (e.g., about 45 to about 50 °C) for a period of time.
Antisolvent methods can include addition of suitable antisolvents such as hydrocarbons (e.g.,
pentane, hexanes, heptanes in which the compound of Formula I is poorly soluble) to a
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solvent in which the compound of Formula I is dissolved. Suitable solvents include those
that at least partially dissolve the compound of Formula I such as ethyl acetate,
dichloromethane, tetrahydrofuran, and the like.
Methods of Use and Pharmaceutical Formulations
The crystal forms of this invention are estrogen receptor modulators useful in the
treatment or inhibition of conditions, disorders, or disease states that are at least partially
mediated by an estrogen deficiency or excess, or which can be treated or inhibited through
the use of an estrogenic agent. Accordingly, the present invention provides a method of
modulating an estrogen receptor comprising contacting the receptor with a crystal form of the
invention. The crystal forms of this invention are particularly useful in treating a peri-
menopausal, menopausal, or postmenopausal patient in which the levels of endogenous
estrogens produced are greatly diminished. Menopause is generally defined as the last natural
menstrual period and is characterized by the cessation of ovarian function, leading to the
substantial diminution of circulating estrogen in the bloodstream. As used herein, menopause
also includes conditions of decreased estrogen production that may be surgically, chemically,
or be caused by a disease state which leads to premature diminution or cessation of ovarian
function.
The crystal forms of this invention are also useful in inhibiting or treating other
effects of estrogen deprivation including, hot flushes, vaginal or vulvar atrophy, atrophic
vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary
incontinence, and urinary tract infections. Other reproductive tract uses include the treatment
or inhibition of dysfunctional uterine bleeding. The crystal forms are also useful in treating or
inhibiting endometriosis.
The crystal forms of this invention are also active in the brain and are therefore useful
for inhibiting or treating Alzheimer's disease, cognitive decline, decreased libido, senile
dementia, neurodegenerative disorders, depression, anxiety, insomnia, schizophrenia, and
infertility. The crystal forms of this invention are also useful in treating or inhibiting benign
or malignant abnormal tissue growth including, glomerulosclerosis, prostatic hypertrophy,
uterine leiomyomas, breast cancer, scleroderma, fibromatosis, endometrial cancer, polycystic
ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer,
melanoma, prostate cancer, cancers of the colon, and CNS cancers, such as glioma or
astioblastomia.
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The crystal forms of this invention are cardioprotective and are antioxidants, and are
useful in lowering cholesterol, triglycerides, Lp(a), and LDL levels; inhibiting or treating
hypercholesteremia, hyperlipidemia, cardiovascular disease, atherosclerosis, peripheral
vascular disease, restenosis, and vasospasm; and inhibiting vascular wall damage.from
cellular events leading toward immune mediated vascular damage. The compounds of this
invention are also useful in treating disorders associated with inflammation or autoimmune
diseases, including inflammatory bowel disease (Crohn's disease, ulcerative colitis,
indeterminate colitis), arthritis (rheumatoid arthritis, spondyloarthropathies, osteoarthritis),
pleurisy, ischemia/reperfusion injury (e.g. stroke, transplant rejection, myocardial infarction,
etc.), asthma, giant cell arteritis, prostatitis, uveitis, psoriasis, multiple sclerosis, systemic
lupus erythematosus and sepsis.
The crystal forms of this invention are also useful in treating or inhibiting ocular
disorders, including cataracts, uveitis, and macular degeneration, and in treating skin
conditions such as aging, alopecia, and acne.
The crystal forms of this invention are also useful in treating or inhibiting metabolic
disorders such as type-II diabetes, of lipid metabolism, and of appetite (e.g. anorexia nervosa
and bulimia).
Crystal forms in this invention are also useful in treating or inhibiting bleeding
disorders such as hereditary hemorrhagic telangiectasia, dysfunctional uterine bleeding, and
combating hemorrhagic shock.
The crystal forms of this invention are useful in disease states where amenorrhea is
advantageous, such as leukemia, endometrial ablations, chronic renal or hepatic disease or
coagulation diseases or disorders.
The crystal forms of this invention can be used as a contraceptive agent, particularly
when combined with a progestin.
The crystal forms of the invention can be used as medicaments. In some
embodiments, the present invention provides crystal forms as described herein for use as
medicaments in treating the diseases and conditions described herein. In some embodiments,
the present invention provides crystal forms as described herein for use in the preparation of a
medicament for use in treating the diseases and conditions described herein.
Methods of treating the diseases and syndromes listed herein are understood to
involve administering to an individual in need of such treatment a therapeutically effective
amount of a crystal form of the invention, or composition containing the same. As used
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herein, the term "treating" in reference to a disease is meant to refer to preventing, inhibiting
and/or ameliorating the disease.
As used herein, the term "individual" or "patient," used interchangeably, refers to any
animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount' refers to the amount of
active compound or pharmaceutical agent that elicits the biological or medicinal response in a
tissue, system, animal, individual or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes one or more of the following:
(1) preventing the disease; for example, preventing a disease, condition or disorder in
an individual that may be predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the disease;
(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an
individual that is experiencing or displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., arresting or slowing further development of the pathology and/or
symptomatology); and
(3) ameliorating the disease; for example, ameliorating a disease, condition or
disorder in an individual that is experiencing or displaying the pathology or symptomatology
of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
As used herein, the term "contacting" refers to the bringing together of indicated
moieties in an in vitro system or an in vivo system. For example, "contacting" an estrogen
receptor with a crystal form of the invention includes the administration of a crystal form of
the present invention to an individual or patient, such as a human, having an estrogen
receptor, as well as, for example, introducing a crystal form of the invention into a sample
containing a cellular or purified preparation containing the estrogen receptor.
When administered for the treatment or inhibition of a particular disease state or
disorder, it is understood that the effective dosage may vary depending upon the particular
compound utilized, the mode of administration, the condition, and severity thereof, of the
condition being treated, as well as the various physical factors related to the individual being
treated. Effective administration of the crystal forms of this invention may be given at an oral
dose of from about 0.1 mg/day to about 1,000 mg/day. Preferably, administration will be
from about 10 mg/day to about 600 mg/day, more preferably from about 50 mg/day to about
600 mg/day, in a single dose or in two or more divided doses. The projected daily dosages are
expected to vary with route of administration.
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Such doses may be administered in any manner useful in directing the active
compounds herein to the recipient's bloodstream, including orally, via implants, parentally
(including intravenous, intraperitoneal, intraarticularly and subcutaneous injections), rectally,
intranasally, topically, ocularly (via eye drops), vaginally, and transdermally.
Oral formulations containing the active crystal forms of this invention may comprise
any conventionally used oral forms, including tablets, capsules, buccal forms, troches,
lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the
active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable
starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered
celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
Useful tablet formulations may be made by conventional compression, wet granulation or dry
granulation methods and utilize pharmaceutically acceptable diluents, binding agents,
lubricants, disintegrants, surface modifying agents (including surfactants), suspending or
stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium
lauryl sxilfate, microcrystalline cellulose, carboxymethylcellulose calcium,
polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate,
complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate,
calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered
sugar. Preferred surface modifying agents include nonionic and anionic surface modifying
agents. Representative examples of surface modifying agents include, but are not limited to,
poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium
dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein
may utilize standard delay or time release formulations to alter the absorption of the active
compound(s). The oral formulation may also consist of administering the active ingredient in
water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed.
In some cases it may be desirable to administer the crystal forms directly to the
airways in the form of an aerosol.
The crystal forms of this invention may also be administered parenterally or
intraperitoneally. Solutions or suspensions of these active compounds as a free base or
pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant
such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and
use, these preparations contain a preservative to inhibit the growth of microorganisms.
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The pharmaceutical forms suitable for injectable use include sterile aqueous solutions
or dispersions and sterile powders for the extemporaneous preparation of sterile injectable
solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent
that easy syringability exists. It must be stable under the conditions of manufacture and
storage and must be preserved against the contaminating action of microorganisms such as
bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene
glycol), suitable mixtures thereof, and vegetable oils.
For the purposes of this disclosure, transdermal administrations are understood to
include all administrations across the surface of the body and the inner linings of bodily
passages including epithelial and mucosal tissues. Such administrations may be carried out
using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams,
foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Transdermal administration may be accomplished through the use of a transdermal
patch containing the active compound and a carrier that is inert to the active compound, is
non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood
stream via the skin. The carrier may take any number of forms such as creams and ointments,
pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or
semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of
absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active
ingredient may also be suitable. A variety of occlusive devices may be used to release the
active ingredient into the blood stream such as a semi-permeable membrane covering a
reservoir containing the active ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the literature.
Suppository formulations may be made from traditional materials, including cocoa
butter, with or without the addition of waxes to alter the suppository's melting point, and
glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular
weights, may also be used.
In order that the invention disclosed herein may be more efficiently understood,
examples are provided below. It should be understood that these examples are for illustrative
purposes only and are not to be construed as limiting the invention in any manner.
EXAMPLES
Example 1
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Preparation of the Anhydrate Crystal Form
Solid 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol (170 g, 0.627 mol)
was dissolved in ethyl acetate (3946 g, 23 volumes) at 75-80 °C. The resulting solution was
treated with charcoal (17 g) at 75-80 °C. The filtrate was then concentrated at atmospheric
pressure to 7 volumes and to the slurry was added heptane (793 g, 6 volumes) while
maintaining at 75-80 °C, then cooled to 45-50 °C, held for 0.5 h, then cooled to 0-5 °C, and
held for 1 h. The solid was filtered off, dried at 55-65 °C, 5-10 mm Hg, to afford an 87 %
recovery and 99.4 % purity.
Example 2
Preparation of the Monohydrate Crystal Form
A 3 L multi-neck flask with agitator, condenser, and temperature probe was charged
with 274 g of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol and 1375 mL of
pre-filtered ethanol. The mixture was heated to 75-80 °C to form a solution after 10 min.
Water (688 mL) was added to the solution over the course of 0.5 h at 75-80 °C. The solution
was then cooled to 50 °C over the course of 0.5 h and subsequently held at 50 °C for another
0.5 h (crystals began to appear at around 74 °C). The resulting suspension was then cooled to
0-5 °C over 0.5 h and held at 0-5 °C for 1 h. The solid was collected by filtration and the
cake washed with 2 x 300 mL ethanohwater (2:1 v/v) precooled to 0-5 °C. The washed cake
was dried at 32-38 °C, 20-25 mmHg for 20 h to give 281.8 g (96.11% yield) of final
monohydrate product. Water Content (KF) - 6.5%; TGA - 6.35 % water; DSC and XRPD
consistent with monohydrate.
Example 3
Conversion of Anhydrate to Monohydrate
pH Method
Anhydrous 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazoI-5-ol (71 mg) was
added to 2 mL of water and the mixture was pH adjusted to pH 10 with 1 N NaOH at which
point the solution became clear. After 2 hours, the solution became light yellow and cloudy.
The solution was centrifuged, the supernatant decanted and the precipitate air dried and then
vacuum dried. XRPD and TGA of the product was consistent with the monohydrate.
Solvent/Antisolvent Method
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Anhydrous 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol (about 100
mg) was dissolved in 3 mL of ethanol afterwhich 4 mL water was added slowly until the
solution became cloudy. The solution was centrifliged, the supernatant decanted, and the
precipitate air dried and then vacuum dried. XRPD and TGA of the product was consistent
with the monohydrate.
Aqueous Suspension Method
Anhydrous 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol (84 mg) was
suspended in 4.2 mL of water and stirred at room temperature for 40 hours. The solution was
centrifuged, the supernatant decanted, and the precipitate air dried and then vacuum dried.
XRPD and TGA was consistent with a mixture of anhydrate and monohydrate (2.4% water
content by TGA).
Example 4
Stability Studies
Short Term
XRPD studies revealed that the monohydrate was stable at 70 °C for one hour but
partially dehydrated at 90 °C after one half hour, and completely dehydrated at 90 °C after
one hour.
Medium Term
Samples of monohydrate were stored at room temperature, 56 °C, and 70 °C for one
week. At room temperature, humidity was maintained at 0% RH. Humidity was not
controlled for the higher temperatures.
The samples were analyzed by XRPD and TGA. Those samples stored at room
temperature and 56 °C showed no obvious dehydration after one week. The sample at 70 °C
showed no obvious hydration after 1 day, but after 4 days, the sample became partially
dehydrated. After 7 days, the sample at 70 °C was mostly dehydrated.
Long Term
Non-micronized samples of monohydrate and anhydrate were stored at 40 °C/75%RH
for three months. The monohydrate was also stored at 40 °C without humidity control.
During the three months, the samples were checked after two weeks, one month, two months,
and three months. XRPD and TGA revealed that both the monohydrate and anhydrate did
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not transform after three months, and HPLC revealed that the samples are chemically stable
under the test conditions.
In a separate study, XRPD revealed that micronized samples of anhydrate did not
transform to the monohydrate after storage at 25 °C/60% RH for three months; however,
micronized samples did partially transform to the monohydrate after one month at 40 °C/75%
RH. In contrast, non-micronized samples of anhydrate stored under the same conditions (40
°C/75% RH) did not show any obvious transformation.
Example 5
Acquisition of X-Ray Powder Diffraction Data
X-Ray data (e.g., see Figure 1 and Table 1) was acquired using an X-ray powder
diffractometer (Scintag Inc., Cupertino, CA) having the following parameters: voltage 45 kV,
current 40.0 mA, power 1.80 kW, scan range (28) 3 to 40°, scan step size 0.02°, total scan
time 22.6 minutes.
Example 6
Acquisition of Differential Scanning Calorimetry Data
Differential scanning calorimetry data (see Figures 2 and 3) were collected using a
DSC (Perkin Elmer, Norwalk, CT) under the following parameters: 20 mL/min purge gas
(N2), scan range 25 to 300 °C, scan rate 10 °C/min.
Example 7
Acquisition of Thermogravimetric Analysis Data
Thermogravimetric analysis data (see Figures 4 and 5) was collected using a TGA
instrument (Perkin Elmer, Norwalk, CT) under the following parameters: 20 mL/min purge
gas(N2); scan range 25 to 300°C, scan rate 10°C/min.
Example 8
Acquisition of Dynamic Vapor Sorption Data
Dynamic Vapor Sorption (Allentown, PA) was used to measure the hygroscopicity of
the anhydrate and monohydrate of the invention (see Figures 6 and 7). The step conditions
were three hours each at 0%, 30%, 52.5%, 75% and 90% RH, two full cycles.
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Example 9
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydrate Crystal Form of the Invention (unit dose of 75 mg/tablet)
The pharmaceutical formulation was prepared by steps 1-7 of the following procedure
utilizing the weight/weight percentages (% wt/wt) of the ingredients shown in the table
below. The tablets were prepared by steps 8-10 of the following procedure. Each tablet
contained the unit dose amounts shown in the table below.
1. An aqueous solution of polyvinylpyrrolidone (povidone K25) and sodium lauryl
sulfate in purified water was prepared.
2. The anhydrate crystal form of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-
5-ol was mixed with a portion of mannitol (Pearlitol 200SD), and then the mixture was
passed through an appropriate screen and placed in a high shear mixer bowl.
3. The remainder of the mannitol, microcrystalline cellulose (Avicel pH 113), and
croscarmellose sodium was passed through an appropriate screen into the mixer bowl and
mixed.
4. The blend from Step 3 was granulated using the Step 1 solution, and was followed
with additional purified water if needed.
5. The Step 4 granulation was dried and passed through an appropriate screen.
6. The magnesium stearate was passed through an appropriate screen.
7. The magnesium stearate was premixed with an equal portion of the blend in Step 5,
and then the premix was added to the remainder of the Step 5 material and mixed in a
blender.
8. The final blend from Step 7 was compressed into tablets using a suitable tablet press.
9. A 7.5% solid solution of Opaglos 2 was prepared.
10. A sufficient amount of coating solution was applied on the tablets to provide a 3.0 %
wt/wt increase in dried tablet weight.
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Composition of the Pharmaceutical Formulation and Tablet
Ingredient % wt/wt in thepharmaceuticalformulation batch Unit Dose(mg/tablet)
Anhydrate Crystal Form of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol 25.0 75.0
Mannitol (Pearlitol 200SD)a 51.5 154.5
Microystalline Cellulose (Avicel PH113) 15.0 45.0
Croscarmellose Sodium 4.0 12.0
Polyvinylpyrrolidone (Povidone K25) 2.0 6.0
Sodium Lauryl Sulfate 2.0 6.0
Magnesium Stearate 0.5 1.5
Purified Water b --- ---
Total 100.0 % 300.0
Film CoatOpaglos 2, green97W11753 3.0 9.0
a. If assay is other than 100.0 %, adjust the amount of input against mannitol accordingly.b. Used in the process, but does not appear in the final tablet product.
Example 10
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydrate Crystal Form of the Invention (tablet unit dose of 25 mg/tablet)
The pharmaceutical formulation was prepared by steps 1-7 of the procedure of
Example 9, utilizing the weight/weight percentages (% wt/wt) of the ingredients shown in the
table below. The tablets were prepared by steps 8-10 of the procedure of Example 9. Each
tablet contained the unit dose amounts shown in the table below.
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Composition of the Tablet:
Ingredient %wt/wt in thepharmaceuticalformulation batch Unit Dose(mg/tablet)
Anhydrate Crystal Form of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l,3-benzoxazol-5-ol 25.0 25.0
Mannitol (Pearlitol 200SD)a 51.5 51.5
Microystalline Cellulose (Avicel PH113) 15.0 15.0
Croscarmellose Sodium 4.0 4.0
Polyvinylpyrrolidone (Povidone K25) 2.0 2.0
Sodium Lauryl Sulfate 2.0 2.0
Magnesium Stearate 0.5 0.5
Purified Water b --- ---
Total 100.0 % 100.0
Film CoatOpaglos 2, green97W11753 3.0 3.0
a. If assay is other than 100.0 %, adjust the amount of input against mannitol accordingly.b. Used in the process, but does not appear in the final tablet product.
Example 11
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydrate Crystal Form of the Invention (tablet unit dose of 5 mg/tablet)
The pharmaceutical formulation was prepared by steps 1-7 of the procedure of
Example 9, utilizing the weight/weight percentages (% wt/wt) of the ingredients shown in the
table below. The tablets were prepared by steps 8-10 of the procedure of Example 9. Each
tablet contained the unit dose amounts shown in the table below.
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Composition of the Tablet:
Ingredient % wt/wt in thepharmaceuticalformulation batch Unit Dose(mg/tablet)
Anhydrate Crystal Form of 2-(3-fluoro-4-hydroxyphenyl)-7-vmyl-l,3-benzoxazol-5-ol 5.0 5.0
Mannitol (Pearlitol 200SD) a 71.5 71.5
Microystalline Cellulose (Avicel PH113) 15.0 15.0
Croscarmellose Sodium 4.0 4.0
Polyvinylpyrrolidone (Povidone K25) 2.0 2.0
Sodium Lauryl Sulfate 2.0 2.0
Magnesium Stearate 0.5 0.5
Purified Water b --- ---
Total 100.0 % 300.0
Film CoatOpaglos 2, green97W11753 3.0 3.0
a. If assay is other than 100.0 %, adjust the amount of input against mannitol accordingly,b. Used in the process, but does not appear in the final tablet product.
Example 12
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydrate Crystal Form of the Invention (tablet unit dose of 150 mg/tablet)
The pharmaceutical formulation was prepared by steps 1-7 of the procedure of
Example 9, utilizing the weight/weight percentages (% wt/wt) of the ingredients shown in the
table below. The tablets were prepared by steps 8-10 of the procedure of Example 9. Each
tablet contained the unit dose amounts shown in the table below.
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Composition of the Tablet:
Ingredient % wt/wt in thepharmaceuticalformulation batch Unit Dose(mg/tablet)
Anhydrate Crystal Form of 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-l ,3 -benzoxazol-5-ol 25.0 150.0
Mannitol (Pearlitol 200SD) a 51.5 309.0
Microystalline Cellulose (Avicel PH113) 15.0 90.0
Croscarmellose Sodium 4.0 24.0
Polyvinylpyrrolidone (Povidone K25) 2.0 12.0
Sodium Lauryl Sulfate 2.0 12.0
Magnesium Stearate 0.5 3.0
Purified Water b --- ---
Total 100.0 % 600.0
Film CoatOpaglos 2, green97W11753 3.0 18.0
a. If assay is other than 100.0 %, adjust the amount of input against mannitol accordingly.b. Used in the process, but does not appear in the final tablet product.
Example 13
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydratc Crystal Form of the Invention (unit dose of 75 mg/tablet)
The pharmaceutical formulation and tablet were prepared as described for Example 9
except that Opadry AMB, yellow, was substituted for Opaglos 2, green.
Example 14
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydrate Crystal Form of the Invention (unit dose of 25 mg/tablet)
The pharmaceutical formulation and tablet were prepared as described for Example
10 except that Opadry AMB, yellow, was substituted for Opaglos 2, green.
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Example 15
Preparation of a Pharmaceutical Formulation and Composition Containing the
Anhydrate Crystal Form of the Invention (unit dose of 150 mg/tablet)
The pharmaceutical formulation and tablet were prepared as described for Example
12 except that Opadry AMB, yellow, was substituted for Opaglos 2, green.
This application claims benefit of priority of U.S. Provisional Application Ser. No.
60/659,459 filed March 8, 2005, the entire disclosure of which is incorporated herein by
reference in its entirety.
Various modifications of the invention, in addition to those described herein, will be
apparent to those skilled in the art from the foregoing description. Such modifications are
also intended to fall within the scope of the appended claims. Each reference cited in the
present application, including patents, published applications, and journal articles, is
incorporated herein by reference in its entirety.
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What is claimed is:
1. A compound which is 2-(3-fluoro-4-hydroxyphenyl)-7-vmyl-l,3-benzoxazol-5-ol
monohydrate.
2. The monohydrate of claim 1 having an X-ray powder diffraction pattern comprising
peaks, in terms of 2q, at about 9.2° and about 12.2°.
3. The monohydrate of claim 1 having an X-ray powder diffraction pattern comprising
peaks, in terms of 2q, at about 9.2°, about 12.2°, and about 15.2°.
4. The monohydrate of claim 1 having an X-ray powder diffraction pattern comprising
peaks, in terms of 2q, at about 9.2°, about 12.2°, about 15.2°, and about 24.3°.
5. The monohydrate of claim 1 having an X-ray powder diffraction pattern comprising
peaks, in terms of 2q, at about 9.2°, about 12.2°, about 15.2°, about 24.3°, about 25.4° and
about 28.0°.
6. The monohydrate of any one of claims 1 to 5 having an X-ray powder diffraction
pattern substantially as shown in Figure 1 (upper).
7. The monohydrate of any one of claims 1 to 6 having a differential scanning
calorimetry trace comprising a dehydration endotherm.
8. The monohydrate of claim 7 having a differential scanning calorimetry trace
comprising dehydration endotherm having an onset at about 95 to about 120 °C.
9. The monohydrate of claim 8 having a differential scanning calorimetry trace
comprising a dehydration endotherm having an onset of about 95 to about 120 °C and a
melting endotherm having an onset at about 250 °C.
10. The monohydrate of any one of claims 1 to 9 having a differential scanning
calorimetry trace substantially as shown in Figure 2.
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11. The monohydrate of any one of claims 1 to 10 having a thermogravimetric analysis
profile showing about 5 to about 7 % weight loss from about 60 to about 150 °C.
12. The monohydrate of claim 11 having a thermogravimetric analysis profile showing
about 5.9 to about 6.4 % weight loss from about 60 about 150 °C.
13. The monohydrate of any one of claims 1 to 12 having a thermogravimetric analysis
profile substantially as shown in Figure 3.
14. An anhydrous crystal form of 2-(3 -fiuoro-4-hydroxyphenyl)-7-vinyl-1,3 -benzoxazol-
5-ol having an. X-ray powder diffraction pattern comprising peaks, in terms of 2q, at about
8.2°. about 10.3°, and about 14.6°.
15. The crystal form of claim 14 having an X-ray powder diffraction pattern comprising
peaks, in terms of 2q, at about 8.2°, about 10.3°, about 14.6°, about 15.1°, and about 16.3°.
16. The crystal form of claim 14 having an X-ray powder diffraction pattern comprising
peaks, in terms of 2q, at about 8.2°, about 10.3°, about 14.6°, about 15.1°, about 16.3°, about
22.3°, about 24.8°, and about 26.7°.
17. The crystal form of claim 14 having an X-ray powder diffraction pattern substantially
as shown in Figure 1 (lower).
18. The crystal form of any one of claims 14 to 17 having a differential scanning
calorimetry trace comprising a melting endotherm having an onset at about 250 °C.
19. The crystal form of any one of claims 14 to 18 having a differential scanning
calorimetry trace substantially as shown in Figure 4.
20. The crystal form of any one of claims 14 to 19 having a thermogravimetric analysis
profile showing less than about 1% weight loss from about 60 to about 150 °C.
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21. The crystal form of any one of claims 14 to 20 having a thermogravimetric analysis
profile substantially as shown in Figure 5.
22. A composition comprising the monohydrate of any one of claims 1 to 13 or the crystal
form claimed in any one of claims 14 to 21.
23. The composition of claim 22 wherein said monohydrate or crystal form constitutes at
least about 50% by weight of said composition.
24. The composition of claim 23 wherein said monohydrate or crystal form constitutes at
least about 80% by weight of said composition.
25. The composition of claim 24 wherein said monohydrate or crystal form constitutes at
least about 90% by weight of said composition.
26. The composition of claim 25 wherein said monohydrate or crystal form constitutes at
least about 95% by weight of said composition.
27. The composition of claim 26 wherein said monohydrate or crystal form constitutes at
least about 98% by weight of said composition.
28. The composition of claim 27 wherein said monohydrate or crystal form constitutes at
least about 99% by weight of said composition.
29. The composition of claim 28 wherein the crystal form constitutes:
at least about 99.5%, or
at least about 99.6%, or
at least about 99.7%, or
at least about 99.8%, or
at least about 99.9%,
by weight of said composition.
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30. A composition comprising the monohydrate of any one of claims 1 to 13, or the
crystal form claimed in any one of claims 14 to 21, and a pharmaceutically acceptable carrier.
31. A process for preparing the monohydrate of any one of claims 1 to 13 comprising
precipitating said monohydrate from a solution comprising water.
32. The process of claim 31 wherein said solution further comprises an alcohol.
33. The process of claim 32 wherein said alcohol comprises ethanol.
34. The process of claim 32 or claim 33 wherein the weight ratio of alcohol to water is
about 1:1 to about 3:1.
35. The process of claim 32 or claim 33 wherein the weight ratio of alcohol to water is
about 2:1.
36. The process of any one of claims 31 to 35 wherein said precipitating is induced by
cooling said solution, adding antisolvent to said solution, or changing pH of said solution.
37. A process for preparing the crystal form of any one of claims 14 to 21 comprising
precipitating said crystal form from an anhydrous solution.
38. The process of claim 37 wherein said anhydrous solution comprises ethyl acetate.
39. The process of claim 38 wherein said solution further comprises a hydrocarbon.
40. The process of claim 39 wherein said hydrocarbon is heptane.
41. The process of any one of claims 37 to 40 wherein said precipitating is induced by
cooling said solution or adding antisolvent to said solution.
42. A compound prepared by or obtainable by the process of any one of claims 31 to 41.
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43. A method of modulating an estrogen receptor comprising contacting said receptor
with the monohydrate of any one of claims 1 to 13 or the crystal form of any one of claims 14
to 21.
44. A method of treating prostatitis, interstitial cystitis, inflammatory bowel disease,
Crohn's disease, ulcerative proctitis, colitis, prostatic hypertrophy, uterine leiomyomas, breast
cancer, endometrial cancer, polycystic ovary syndrome, endometrial polyps, endometriosis,
benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, colon
cancer, glioma, astioblastomia, free radical induced disease states, vaginal or vulvar atrophy,
atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary
incontinence, urinary tract infections, vasomotor symptoms, arthritis, joint swelling or
erosion, joint damage secondary to arthroscopic or surgical procedures, psoriasis, dermatitis,
ischemia, reperfusion injury, asthma, pleurisy, multiple sclerosis, systemic lupus
erythematosis, uveitis, sepsis, hemmorhagic shock, or type II diabetes, in a mammal in need
thereof, which comprises providing to said mammal a therapeutically effective amount of the
monohydrate of any one of claims 1 to 13 or the crystal form of any one of claims 14 to 21.
45. A method of lowering cholesterol, triglycerides, Lp(a), or LDL levels; inhibiting or
treating hypercholesteremia, hyperlipidemia, cardiovascular disease, atherosclerosis,
hypertension, peripheral vascular disease, restenosis, or vasospasm; or inhibiting vascular
wall damage from cellular events leading toward immune mediated vascular damage in a
mammal in need thereof, which comprises providing to said mammal a therapeutically
effective amount of the monohydrate as claimed in any one of claims 1 to 13 or the crystal
form of any one of claims 14 to 21.
46. A method of providing cognition enhancement or neuroprotection; or treating or
inhibiting senile dementias, Alzheimer's disease, cognitive decline, stroke, anxiety, or
neurodegenerative disorders in a mammal in need thereof, which comprises providing to said
mammal an effective amount of the monohydrate as claimed in any one of claims 1 to 13 or
the crystal form of any one of claims 14 to 21.
47. A method of inhibiting conception in a mammal in need thereof, which comprises
providing to said mammal an effective amount of the monohydrate as claimed in any one of
claims 1 to 13 or the crystal form of any one of claims 14 to 21.
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48. A monohydrate as claimed in any one of claims 1 to 13 or a crystal form as claimed in
any one of claims 14 to 21 for use as a medicament.
49. Use of a monohydrate as claimed in any one of claims 1 to 13 or a crystal form as
claimed in any one of claims 14 to 21 in the preparation of a medicament for the treatment of
prostatitis, interstitial cystitis, inflammatory bowel disease, Crohn's disease, ulcerative
proctitis, colitis, prostatic hypertrophy, uterine leiomyomas, breast cancer, endometrial
cancer, polycystic ovary syndrome, endometrial polyps, endometriosis, benign breast disease,
adenomyosis, ovarian cancer, melanoma, prostrate cancer, colon cancer, glioma,
astioblastomia, free radical induced disease states, vaginal or vulvar atrophy, atrophic
vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary
incontinence, urinary tract infections, vasomotor symptoms, arthritis, joint swelling or
erosion, joint damage secondary to arthroscopic or surgical procedures, psoriasis, dermatitis,
ischemia, reperfusion injury, asthma, pleurisy, multiple sclerosis, systemic lupus
erythematosis, uveitis, sepsis, hemmorhagic shock, or type II diabetes in a mammal in need
thereof.
50. Use of a monohydrate as claimed in any one of claims 1 to 13 or a crystal form as
claimed in any one of claims 14 to 21 in the preparation of a medicament for the lowering of
cholesterol, triglycerides, Lp(a), or LDL levels; the inhibition or treatment of
hypercholesteremia, hyperlipidemia, cardiovascular disease, atherosclerosis, hypertension,
peripheral vascular disease, restenosis, or vasospasm; or the inhibition of vascular wall
damage from cellular events leading toward immune mediated vascular damage in a mammal
in need thereof.
51. Use of a monohydrate as claimed in any one of claims 1 to 13 or a crystal form as
claimed in any one of claims 14 to 21 in the preparation of a medicament for the provision of
cognition enhancement or neuroprotection; or the treatment or inhibition of senile dementias.
Alzheimer's disease, cognitive decline, stroke, anxiety, or neurodegenerative disorders in a
mammal in need thereof.
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52. Use of a monohydrate as claimed in any one of claims 1 to 13 or a crystal form as
claimed in any one of claims 14 to 21 in the preparation of a medicament for the inhibition of
conception in a mammal in need thereof.
30

The present invention is directed to monohydrate and anhydrate crystal forms of 2-(3- fluoro-4-hydroxyphenyl)-7-
vinyl-l,3-benzoxazol-5-ol, an estrogenic receptor modulator useful in the treatment of, for example, diseases related to abnormal
levels of estrogen.