U.S. patent application number 13/348825 was filed with the patent office on 2012-05-10 for solid forms comprising 4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9h-purin-2-y- lamino]-cyclohexan-1-ol, compositions thereof, and uses therewith.
Invention is credited to Marie G. Beauchamps, Louise Michelle Cameron, Robert Hilgraf, Mohit Atul Kothare, Manohar T. Saindane, Jean Xu.
Application Number | 20120115890 13/348825 |
Document ID | / |
Family ID | 39149400 |
Filed Date | 2012-05-10 |
United States Patent
Application |
20120115890 |
Kind Code |
A1 |
Beauchamps; Marie G. ; et
al. |
May 10, 2012 |
SOLID FORMS COMPRISING
4-[9-(TETRAHYDRO-FURAN-3-YL)-8-(2,4,6-TRIFLUORO-PHENYLAMINO)-9H-PURIN-2-Y-
LAMINO]-CYCLOHEXAN-1-OL, COMPOSITIONS THEREOF, AND USES
THEREWITH
Abstract
Solid forms comprising
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol, compositions comprising the solid forms,
methods of making the solid forms and methods of their use for the
treatment of various diseases and/or disorders are disclosed.
Inventors: |
Beauchamps; Marie G.;
(Flander, NJ) ; Cameron; Louise Michelle;
(Nazareth, PA) ; Hilgraf; Robert; (San Diego,
CA) ; Kothare; Mohit Atul; (Bridgewater, NJ) ;
Saindane; Manohar T.; (Monmouth Junction, NJ) ; Xu;
Jean; (Warren, NJ) |
Family ID: |
39149400 |
Appl. No.: |
13/348825 |
Filed: |
January 12, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12200146 |
Aug 28, 2008 |
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13348825 |
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11977759 |
Oct 26, 2007 |
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12200146 |
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60854757 |
Oct 27, 2006 |
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Current U.S.
Class: |
514/263.23 ;
544/277 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 29/00 20180101; A61P 37/08 20180101; C07D 487/04 20130101;
A61P 27/02 20180101; A61P 35/02 20180101; A61P 3/10 20180101; A61P
13/12 20180101; A61P 11/06 20180101; A61P 17/02 20180101; A61P
11/00 20180101; A61P 9/10 20180101; A61P 11/02 20180101; A61P 35/00
20180101; A61P 1/04 20180101; A61P 5/14 20180101; A61P 11/04
20180101; A61P 3/04 20180101; A61P 37/02 20180101; A61P 9/00
20180101; A61P 1/06 20180101; A61P 19/08 20180101; A61P 21/04
20180101; A61P 3/00 20180101; A61P 9/12 20180101; A61P 25/04
20180101; A61P 37/00 20180101; A61P 25/00 20180101; A61P 7/08
20180101 |
Class at
Publication: |
514/263.23 ;
544/277 |
International
Class: |
A61K 31/52 20060101
A61K031/52; A61P 35/00 20060101 A61P035/00; A61P 9/00 20060101
A61P009/00; A61P 13/12 20060101 A61P013/12; A61P 9/12 20060101
A61P009/12; A61P 29/00 20060101 A61P029/00; A61P 27/02 20060101
A61P027/02; A61P 9/10 20060101 A61P009/10; A61P 25/00 20060101
A61P025/00; A61P 3/00 20060101 A61P003/00; C07D 473/16 20060101
C07D473/16; A61P 37/00 20060101 A61P037/00 |
Claims
1. A crystal form comprising the compound of the formula:
##STR00003## which has an X-ray powder diffraction pattern
comprising peaks at 12.4, 16.0, 18.5 and 24.1
.degree.2.theta..+-.0.1 when measured using Cu K.alpha.
radiation.
2. The crystal of claim 1 which has a differential scanning
calorimetry thermogram having an endotherm with an onset
temperature of approximately 225.degree. C.
3. The crystal form of claim 2 which has a thermogravimetric
analysis thermogram having a total mass loss of less than 1% of the
total mass of the sample when heated from about 25.degree. C. to
about 200.degree. C.
4. The crystal form of claim 1 which comprises less than 2% by
weight of other crystal forms.
5. The crystal form of claim 1 further comprising peaks at 17.7 and
23.2 .degree.2.theta..+-.0.1 when measured using Cu K.alpha.
radiation.
6. The crystal form of claim 5 further comprising one or more
additional peaks at 10.0, 12.8, 15.2, 16.3, 18.9, 19.4, 20.0, 20.6,
20.9, 21.6, 22.7, 26.1, 26.6, 26.8, 25.7, 26.0, 26.4, 26.6, 27.2,
27.9, 30.2, 30.8, 31.0, 31.5 .degree.2.theta..+-.0.1 when measured
using Cu K.alpha. radiation.
7. A pharmaceutical composition comprising a crystal form of claim
1 and a pharmaceutically acceptable diluent, excipient or
carrier.
8. The pharmaceutical composition of claim 7 suitable for oral,
parenteral, mucosal, transdermal or topical administration.
9. A single unit dosage form comprising a crystal form of claim 1,
and a pharmaceutically acceptable carrier, excipient or
diluent.
10. The single unit dosage form of claim 9 suitable for oral,
parenteral, mucosal, transdermal or topical administration.
11. The crystal form of claim 1 which has a thermogravimetric
analysis thermogram having a total mass loss of approximately 1% of
the total mass of the sample when heated from about 25.degree. C.
to about 200.degree. C.
12. The crystal form of claim 1 which comprises about 2% by weight
of other crystal forms.
13. A solid form which has an X-ray powder diffraction pattern
comprising peaks at approximately 12.4, 16.0 and 18.5
.degree.2.theta., prepared by a process comprising evaporating a
solution comprising the compound of formula (I): ##STR00004## or a
salt thereof, in a solvent selected from the group consisting of
acetone, n-butanol, ethanol, methanol, 2-propanol, tetrahydrofuran,
ethanol/water (1/1) and mixtures thereof.
14. The solid form of claim 13 which is crystalline.
15. A solid form which has an X-ray powder diffraction pattern
comprising peaks at approximately 12.4, 16.0 and 18.5
.degree.2.theta., prepared by a process comprising slurrying a
solution comprising the compound of formula (I): ##STR00005## or a
salt thereof, in a solvent selected from the group consisting of
acetone, acetonitrile, n-butanol, ethanol, ethyl acetate, heptane,
methylene chloride, methyl ethyl ketone, methyl t-butyl ether,
2-propanol, toluene, water, ethanol/water (1/1) and mixtures
thereof.
16. The solid form of claim 15 which is crystalline.
17. A solid form which has an X-ray powder diffraction pattern
comprising peaks at approximately 12.4, 16.0 and 18.5
.degree.2.theta., prepared by a process comprising
solvent/antisolvent precipitation of a solution comprising the
compound of formula (I): ##STR00006## or a salt thereof, wherein
the solvent/antisolvent system is selected from the group
consisting of ethanol/water, ethanol/methyl t-butyl ether,
ethanol/heptane, tetrahydrofuran/methyl t-butyl ether,
tetrahydrofuran/heptane and tetrahydrofuran/toluene.
18. The solid form of claim 17 which is crystalline.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 12/200,146, filed Aug. 28, 2008, currently allowed, which is a
continuation of U.S. application Ser. No. 11/977,759, filed Oct.
26, 2007, which claims the benefit of U.S. Provisional Application
No. 60/854,757, filed Oct. 27, 2006, the entire contents of each
are incorporated herein by reference.
1. FIELD OF THE INVENTION
[0002] Provided herein are solid forms comprising
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol, compositions comprising the solid forms,
methods of making the solid forms and methods of their use for the
treatment of various diseases and/or disorders.
2. BACKGROUND OF THE INVENTION
[0003] The identification and selection of a solid form of a
pharmaceutical compound is complex, given that a change in solid
form may affect a variety of physical and chemical properties,
which may provide benefits or drawbacks in processing, formulation,
stability and bioavailability, among other important pharmaceutical
characteristics. Potential pharmaceutical solids include
crystalline solids and amorphous solids. Amorphous solids are
characterized by a lack of long-range structural order, whereas
crystalline solids are characterized by structural periodicity. The
desired class of pharmaceutical solid depends upon the specific
application; amorphous solids are sometimes selected on the basis
of, e.g., an enhanced dissolution profile, while crystalline solids
may be desirable for properties such as, e.g., physical or chemical
stability (see, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv.
Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001)
48:27-42).
[0004] Whether crystalline or amorphous, potential solid forms of a
pharmaceutical compound include single-component and
multiple-component solids. Single-component solids consist
essentially of the pharmaceutical compound in the absence of other
compounds. Variety among single-component crystalline materials may
potentially arise from the phenomenon of polymorphism, wherein
multiple three-dimensional arrangements exist for a particular
pharmaceutical compound (see, e.g., S. R. Byrn et al., Solid State
Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of
discovering polymorphs was underscored by the case of Ritonavir, an
HIV protease inhibitor that was formulated as soft gelatin
capsules. About two years after the product was launched, the
unanticipated precipitation of a new, less soluble polymorph in the
formulation necessitated the withdrawal of the product from the
market until a more consistent formulation could be developed (see
S. R. Chemburkar et al., Org. Process Res. Dev., (2000)
4:413-417).
[0005] Additional diversity among the potential solid forms of a
pharmaceutical compound may arise from the possibility of
multiple-component solids. Crystalline solids comprising two or
more ionic species are termed salts (see, e.g., Handbook of
Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl
and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types
of multiple-component solids that may potentially offer other
property improvements for a pharmaceutical compound or salt thereof
include, e.g., hydrates, solvates, co-crystals and clathrates,
among others (see, e.g., S. R. Byrn et al., Solid State Chemistry
of Drugs, (1999) SSCI, West Lafayette). Moreover,
multiple-component crystal forms may potentially be susceptible to
polymorphism, wherein a given multiple-component composition may
exist in more than one three-dimensional crystalline arrangement.
The discovery of solid forms is of great importance in the
development of a safe, effective, stable and marketable
pharmaceutical compound.
[0006] The compound chemically named
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol was disclosed in U.S. patent application
Ser. No. 11/332,617, filed Jan. 12, 2006, and International Pub.
No. WO 2006/076595, the entireties of each of which is incorporated
by reference herein. We have discovered multiple solid forms of
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I"), and have found that not all
of the solid forms of Compound I are equally useful, as assessed by
their physical and chemical properties. Thus, certain embodiments
herein address the need for improved solid forms of Compound I for,
e.g., purity, stability, manufacture, efficacy and
bioavailability.
3. SUMMARY OF THE INVENTION
[0007] Provided herein are solid forms comprising
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I"), having particular utility
for the treatment, prevention or management of conditions and
disorders including, but not limited to, cancer, a cardiovascular
disease, a renal disease, an autoimmune condition, an inflammatory
condition, macular degeneration, ischemia-reperfusion injury, pain
and related syndromes, disease-related wasting, an asbestos-related
condition, pulmonary hypertension, central nervous system (CNS)
injury/damage or a condition treatable or preventable by inhibition
of a kinase pathway.
[0008] In certain embodiments, the solid forms are single-component
crystal forms of the free base of Compound I. In other embodiments,
the solid forms are multiple-component crystal forms, including,
but not limited to, salts, co-crystals, solvates, hydrates and/or
clathrates of Compound I. In other embodiments, the solid forms are
single-component amorphous forms of the free base of Compound I. In
other embodiments, the solid forms are multiple-component amorphous
forms, including, but not limited to, salts of Compound I. Without
intending to be limited by any particular theory, the storage
stability, compressibility, bulk density or dissolution properties
of the solid forms are believed to be beneficial for manufacturing,
formulation and bioavailability of Compound I. Also provided herein
are pharmaceutical compositions comprising the solid forms and
methods of their use for the treatment, prevention or management of
conditions and disorders including, but not limited to, cancer, a
cardiovascular disease, a renal disease, an autoimmune condition,
an inflammatory condition, macular degeneration,
ischemia-reperfusion injury, pain and related syndromes,
disease-related wasting, an asbestos-related condition, pulmonary
hypertension, central nervous system (CNS) injury/damage or a
condition treatable or preventable by inhibition of a kinase
pathway.
[0009] The solid forms are formed from Compound I, which is
described in U.S. patent application Ser. No. 11/332,617, filed
Jan. 12, 2006, and International Pub. No. WO 2006/076595, the
entireties of each of which is incorporated by reference
herein.
[0010] Compound I has the following structure (I):
##STR00001##
[0011] Also provided herein are pharmaceutical compositions
comprising a single-component crystal form, a multiple-component
crystal form, a single-component amorphous form and/or a
multiple-component amorphous form of Compound I and a
pharmaceutically acceptable diluent, excipient or carrier.
[0012] Also provided herein are methods for the treatment,
prevention or management of conditions or disorders including, but
not limited to, cancer, a cardiovascular disease, a renal disease,
an autoimmune condition, an inflammatory condition, macular
degeneration, ischemia-reperfusion injury, pain and related
syndromes, disease-related wasting, an asbestos-related condition,
pulmonary hypertension, central nervous system (CNS) injury/damage
or a condition treatable or preventable by inhibition of a kinase
pathway, wherein such methods comprise administering to a subject,
e.g., a human, in need of such treatment, prevention or management
a therapeutically and prophylactically effective amount of a solid
form provided herein.
[0013] Further embodiments herein provide methods of making,
isolating and/or characterizing the solid forms of the
invention.
[0014] Certain solid forms provided herein are useful as active
pharmaceutical ingredients for the preparation of formulations for
use in animals or humans. Thus, certain embodiments provided herein
encompass the use of these solid forms as a final drug product.
Certain solid forms and final drug products provided herein are
useful, for example, for the treatment, prevention or management of
the conditions and disorders listed above.
4. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 provides a representative X-ray powder diffraction
(XRPD) pattern of Form A of the free base of Compound I.
[0016] FIG. 2 provides a representative differential scanning
calorimetry (DSC) thermogram of Form A of the free base of Compound
I.
[0017] FIG. 3 provides a representative thermal gravimetric
analysis (TGA) thermogram of Form A of the free base of Compound
I.
[0018] FIG. 4 provides a representative XRPD pattern of a hydrate
crystal form of the free base of Compound I.
[0019] FIG. 5 provides a representative DSC thermogram of a hydrate
crystal form of the free base of Compound I.
[0020] FIG. 6 provides a representative TGA thermogram of a hydrate
crystal form of the free base of Compound I.
[0021] FIG. 7 and FIG. 8 provide representative XRPD patterns of
Form A of the hydrochloride salt of Compound I.
[0022] FIG. 9 provides a representative DSC thermogram of Form A of
the hydrochloride salt of Compound I.
[0023] FIG. 10 provides a representative TGA thermogram of Form A
of the hydrochloride salt of Compound I.
[0024] FIG. 11 provides a representative XRPD pattern of Form A of
the hydrobromide salt of Compound I.
[0025] FIG. 12 provides a representative XRPD pattern of Form A of
the sulfate salt of Compound I.
[0026] FIG. 13 provides an exemplary reaction scheme for the
synthesis of Compound I.
[0027] FIG. 14 provides the chemical structures of compounds which,
in certain embodiments, may be present in compositions comprising
Compound I.
[0028] FIG. 15 provides an exemplary reaction scheme for the
synthesis of Compound I.
[0029] FIG. 16 provides an exemplary reaction scheme for the
synthesis of Compound I.
5. DETAILED DESCRIPTION OF THE INVENTION
5.1 Definitions
[0030] As used herein, the term "Compound I" means the compound
that is chemically named
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol, and includes its free base form and its
ionized forms, which have undergone salt formation such that the
molecule is protonated at one or more basic centers. The term
"Compound I" also includes the solid forms of
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol described herein.
[0031] Particular salts described below include "hydrochloride
salts" or "HCl salts" of Compound I. A hydrochloride salt or HCl
salt of Compound I is an acid addition salt which may be formed by
reacting Compound I with hydrochloric acid.
[0032] A "bis-hydrochloride salt" or "bis-HCl salt" of Compound I
is a salt which contains about two molar equivalents of
hydrochloric acid per mole of Compound I.
[0033] Particular salts described below include "hydrobromide
salts" or "HBr salts" of Compound I. A hydrobromide salt or HBr
salt of Compound I is an acid addition salt which may be formed by
reacting Compound I with hydrobromic acid.
[0034] Particular salts described below include "sulfate salts" of
Compound I. A sulfate salt of Compound I is an acid addition salt
which may be formed by reacting Compound I with sulfuric acid.
[0035] As used herein, the term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically acceptable acids,
including inorganic acids and organic acids. Suitable acids
include, but are not limited to, acetic, benzenesulfonic, benzoic,
camphorsulfonic, carbonic, citric, dihydrogenphosphoric,
ethanesulfonic, fumaric, galactunoric, gluconic, glucuronic,
glutamic, hydrobromic, hydrochloric, hydriodic, isobutyric,
isethionic, lactic, maleic, malic, malonic, mandelic,
methanesulfonic, monohydrogencarbonic, monohydrogenphosphoric,
monohydrogensulfuric, mucic, nitric, pamoic, pantothenic,
phosphoric, phthalic, propionic, suberic, succinic, sulfuric,
tartaric, toluenesulfonic, including p-toluenesulfonic
m-toluenesulfonic and o-toluenesulfonic acids, and the like (see,
e.g., S. M. Berge et al., J. Pharm. Sci., 66:1-19 (1977); and
Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.
H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Also
included are salts of other compounds that possess acidic
character, including amino acids, such as aspartic acid and the
like, and other compounds, such as aspirin, ibuprofen, saccharin,
and the like. Acid addition salts can be obtained by contacting the
neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable solvent. As solids,
salts can exist in crystalline or amorphous modifications.
[0036] The terms "solid form," "solid forms" and related terms,
when used herein to refer to Compound I, refer to a physical form
comprising Compound I which is not predominantly in a liquid or a
gaseous state. Crystal forms and amorphous forms are examples of
solid forms.
[0037] The term "crystalline" and related terms used herein, when
used to describe a substance, component, product, or form, means
that the substance, component or product is substantially
crystalline as determined by X-ray diffraction. See, e.g.,
Remington's Pharmaceutical Sciences, 18.sup.th ed., Mack
Publishing, Easton Pa., 173 (1990); The United States Pharmacopeia,
23.sup.rd ed., 1843-1844 (1995).
[0038] The term "crystal form," "crystalline form" and related
terms herein refer to a crystalline solid form comprising a
chemical compound, and may refer to a particular single-component
or multiple-component crystal form, including, but not limited to,
a polymorph, a solvate, a hydrate, a cocrystal or other molecular
complex, a salt, a solvate of a salt, a hydrate of a salt, a
cocrystal or other molecular complex of a salt, or a polymorph
thereof.
[0039] The terms "polymorphs," "polymorphic forms" and related
terms herein refer to two or more crystal forms that comprise the
same molecule, molecules or ions. Different polymorphs may have
different physical properties such as, for example, melting
temperatures, heats of fusion, solubilities, dissolution rates
and/or vibrational spectra as a result of the arrangement or
conformation of the molecules or ions in the crystal lattice. The
differences in physical properties exhibited by polymorphs affect
pharmaceutical parameters such as storage stability,
compressibility and density (important in formulation and product
manufacturing), and dissolution rate (an important factor in
bioavailability). Differences in stability can result from changes
in chemical reactivity (e.g., differential oxidation, such that a
dosage form discolors more rapidly when comprised of one polymorph
than when comprised of another polymorph) or mechanical changes
(e.g., tablets crumble on storage as a kinetically favored
polymorph converts to thermodynamically more stable polymorph) or
both (e.g., tablets of one polymorph are more susceptible to
breakdown at high humidity). As a result of solubility/dissolution
differences, in the extreme case, some polymorphic transitions may
result in lack of potency or, at the other extreme, toxicity. In
addition, the physical properties of the crystal may be important
in processing; for example, one polymorph might be more likely to
form solvates or might be difficult to filter and wash free of
impurities (e.g., particle shape and size distribution might be
different between polymorphs).
[0040] The term "solvate" and "solvated," as used herein, refer to
a crystal form of a substance which contains solvent. The term
"hydrate" and "hydrated" refer to a solvate wherein the solvent is
water. "Polymorphs of solvates" refers to the existence of more
than one crystal form for a particular solvate composition.
Similarly, "polymorphs of hydrates" refers to the existence of more
than one crystal form for a particular hydrate composition. The
term "desolvated solvate," as used herein, refers to a crystal form
of a substance which can only be made by removing the solvent from
a solvate.
[0041] The term "amorphous," "amorphous form," and related terms
used herein mean that the substance, component or product in
question is not substantially crystalline as determined by X-ray
diffraction. In certain embodiments, a sample comprising an
amorphous form of a substance may be substantially free of other
amorphous forms and/or crystal forms.
[0042] As used herein, and unless otherwise specified, the terms
"about" and "approximately," when used in connection with doses,
amounts, or weight percent of ingredients of a composition or a
dosage form, mean a dose, amount, or weight percent that is
recognized by those of ordinary skill in the art to provide a
pharmacological effect equivalent to that obtained from the
specified dose, amount, or weight percent. Specifically, the terms
"about" and "approximately," when used in this context, contemplate
a dose, amount, or weight percent within 15%, more specifically
within 10%, more specifically within 5%, of the specified dose,
amount, or weight percent.
[0043] Techniques for characterizing crystal forms and amorphous
forms include, but are not limited to, thermal gravimetric analysis
(TGA), differential scanning calorimetry (DSC), X-ray powder
diffractometry (XRPD), single-crystal X-ray diffractometry,
vibrational spectroscopy, e.g., infrared (IR) and Raman
spectroscopy, solid-state and solution nuclear magnetic resonance
(NMR) spectroscopy, optical microscopy, hot stage optical
microscopy, scanning electron microscopy (SEM), electron
crystallography and quantitative analysis, particle size analysis
(PSA), surface area analysis, solubility studies and dissolution
studies.
[0044] As used herein, and unless otherwise specified, the terms
"about" and "approximately," when used in connection with a numeric
value or range of values which is provided to characterize a
particular solid form, e.g., a specific temperature or temperature
range, such as, for example, that describing a melting,
dehydration, desolvation or glass transition temperature; a mass
change, such as, for example, a mass change as a function of
temperature or humidity; a solvent or water content, in terms of,
for example, mass or a percentage; or a peak position, such as, for
example, in analysis by IR or Raman spectroscopy or XRPD; indicate
that the value or range of values may deviate to an extent deemed
reasonable to one of ordinary skill in the art while still
describing the particular solid form. Specifically, the terms
"about" and "approximately," when used in this context, indicate
that the numeric value or range of values may vary, in particular
embodiments, within 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%,
1%, 0.5%, or 0.25% of the recited value or range of values.
[0045] As used herein, a solid form (e.g., a crystal form or
amorphous form) that is "substantially pure" may comprise, in
particular embodiments, less than about 20%, 15%, 10%, 5%, 3%, 2%,
1%, 0.75%, 0.5%, 0.25% or 0.1% by weight of one or more other
crystal forms, amorphous forms and/or chemical compounds. In
certain embodiments, a solid form that is substantially pure is
substantially free of one or more other particular crystal forms,
amorphous forms and/or chemical compounds.
[0046] As used herein and unless otherwise indicated, a composition
that is "substantially free" of a solid form and/or chemical
substance contains less than about 20%, 15%, 10%, 5%, 3%, 2%, 1%,
0.75%, 0.5%, 0.25% or 0.1% by weight of the solid form and/or
chemical compound.
[0047] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" refer to the eradication or
amelioration of a disease or disorder, or of one or more symptoms
associated with the disease or disorder. In certain embodiments,
the terms refer to minimizing the spread or worsening of the
disease or disorder resulting from the administration of one or
more prophylactic or therapeutic agents to a subject with such a
disease or disorder.
[0048] As used herein, and unless otherwise specified, the terms
"prevent," "preventing" and "prevention" refer to the prevention of
the onset, recurrence or spread of a disease or disorder, or of one
or more symptoms thereof.
[0049] As used herein, and unless otherwise specified, the terms
"manage," "managing" and "management" refer to preventing or
slowing the progression, spread or worsening of a disease or
disorder, or of one or more symptoms thereof. Often, the beneficial
effects that a subject derives from a prophylactic or therapeutic
agent do not result in a cure of the disease or disorder.
[0050] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment or
management of a disease or disorder, or to delay or minimize one or
more symptoms associated with the disease or disorder. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment or management
of the disease or disorder. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or
enhances the therapeutic efficacy of another therapeutic agent.
[0051] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease or disorder, or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of therapeutic agent, alone or in combination with other
agents, which provides a prophylactic benefit in the prevention of
the disease. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0052] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients (and in
the specified amounts, if indicated), as well as any product which
results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. By "pharmaceutically
acceptable" it is meant the diluent, excipient or carrier must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0053] The term "therapeutically and prophylactically effective
amount" refers to the amount of the subject solid form that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher,
veterinarian, medical doctor or other clinician or that is
sufficient to prevent development of or alleviate to some extent
one or more of the symptoms of the disease being treated.
[0054] The terms "subject" and "patient," unless otherwise
specified, are defined herein to include animals such as mammals,
including, but not limited to, primates (e.g., humans), cows,
sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
In specific embodiments, the subject or patient is a human.
[0055] In addition to solid forms comprising Compound I,
embodiments herein provide solid forms of prodrugs of Compound I.
Prodrugs of the compounds described herein are structurally
modified forms of the compound that readily undergo chemical
changes under physiological conditions to provide the compound.
Additionally, prodrugs can be converted to the compound by chemical
or biochemical methods in an ex vivo environment. For example,
prodrugs can be slowly converted to a compound when placed in a
transdermal patch reservoir with a suitable enzyme or chemical
reagent. Prodrugs are often useful because, in some situations,
they may be easier to administer than the compound, or parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent drug is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug. A
wide variety of prodrug derivatives are known in the art, such as
those that rely on hydrolytic cleavage or oxidative activation of
the prodrug. An example, without limitation, of a prodrug would be
a compound which is administered as an ester (the "prodrug"), but
then is metabolically hydrolyzed to the carboxylic acid, the active
entity. Additional examples include peptidyl derivatives of a
compound.
[0056] In certain embodiments, Compound I may contain unnatural
proportions of atomic isotopes at one or more of the atoms. For
example, the compound may be radiolabeled with radioactive
isotopes, such as for example tritium (.sup.3H), iodine-125
(.sup.125I) sulfur-35 (.sup.35S), or carbon-14 (.sup.14C).
Radiolabeled compounds are useful as therapeutic agents, e.g.,
cancer therapeutic agents, research reagents, e.g., binding assay
reagents, and diagnostic agents, e.g., in vivo imaging agents. All
isotopic variations of the Compound I, whether radioactive or not,
are intended to be encompassed within the scope of the embodiments
provided herein.
5.2 Solid Forms Comprising Compound I
[0057] Certain embodiments herein provide single-component and
multiple-component solid forms comprising
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I"), which has the chemical
structure shown below:
##STR00002##
[0058] Compound I can be synthesized or obtained according to any
method apparent to those of skill in the art based upon the
teachings herein, including the methods described in detail in the
examples below. Compound I can also be prepared according to the
methods described in U.S. patent application Ser. No. 11/332,617,
filed Jan. 12, 2006, and International Pub. No. WO 2006/076595, the
entireties of each of which is incorporated by reference
herein.
[0059] In certain embodiments, Compound I is prepared by a process
comprising the steps of: (1) substitution of a nitropyrimidine with
an amine-containing compound (e.g., an amine-containing
heterocycle, such as an amine-substituted tetrahydrofuran) or salt
thereof; (2) further substitution with an additional
amine-containing compound (e.g., amine-containing carbocycle, such
as an amine-substituted cyclohexanol) or salt thereof; (3)
reduction of the nitro group to the corresponding amine (e.g., to
substituted aniline); (4) coupling with an isothiocyanate
substituted aryl or heteroaryl compound (e.g.,
2,4,6-trifluorophenyl isothiocyanate); and (5) ring closure
resulting in substituted purine formation. In certain embodiments,
two or more of the steps of the process may be combined and/or
conducted in sequence without isolation of intermediate
compound(s). In certain embodiments, the steps of the process are
performed in the order in which they are listed. In certain
embodiments, the steps of the process are performed in an order
other than that in which they are listed.
[0060] In a particular embodiment, step (1) is carried out in the
presence of N,N-diisopropylethylamine (DIPEA). In another
particular embodiment, step (2) is carried out in the presence of
DIPEA. In another particular embodiment, step (3) is carried out in
the presence of Pd catalyst. In another particular embodiment, step
(4) is carried out in THF. In another particular embodiment, step
(5) is carried out in the presence of
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(EDC).
[0061] Solid forms comprising Compound I provided herein include
single-component and multiple-component forms, including crystal
forms and amorphous forms, and including, but not limited to,
polymorphs, salts, solvates, hydrates, co-crystals and clathrates.
Solid forms provided herein can be prepared by the methods
described herein, including the methods described in detail in the
examples below, or by techniques known in the art, including
heating, melt cooling, rapid melt cooling, freeze drying,
lyophilization, quench cooling the melt, rapid solvent evaporation,
slow solvent evaporation, solvent recrystallization, slurry
recrystallization, crystallization from the melt, desolvation,
sublimation, recrystallization in confined spaces such as, e.g., in
nanopores or capillaries, recrystallization on surfaces or
templates such as, e.g., on polymers, recrystallization in the
presence of additives, such as, e.g., co-crystal counter-molecules,
desolvation, dehydration, rapid cooling, slow cooling, vapor
diffusion, sublimation, grinding, cryo-grinding, solvent-drop
grinding, microwave-induced precipitation, ultrasonication-induced
precipitation, laser-induced precipitation and precipitation from a
supercritical fluid.
[0062] Particular embodiments herein provide compositions
comprising one or more of the solid forms. Certain embodiments
herein provide to compositions of one or more solid forms in
combination with other active ingredients. Certain embodiments
herein provide methods of using these compositions in the
treatment, prevention or management of conditions and disorders
including, but not limited to, cancer, a cardiovascular disease, a
renal disease, an autoimmune condition, an inflammatory condition,
macular degeneration, ischemia-reperfusion injury, pain and related
syndromes, disease-related wasting, an asbestos-related condition,
pulmonary hypertension, central nervous system (CNS) injury/damage
or a condition treatable or preventable by inhibition of a kinase
pathway.
[0063] Particular embodiments herein provide a composition
comprising a crystal form and/or an amorphous form of Compound I
further comprising one or more of the compounds provided in FIG.
14. In specific embodiments, a composition comprising a crystal
form and/or an amorphous form of Compound I further comprises a
compound provided in FIG. 14 in an amount of less than about 0.01%,
0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%,
1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5%, 6%, 7%, 8%, 9% or 10%
of the total amount of Compound I in the composition on a weight
basis.
[0064] While not intending to be bound by any particular theory,
certain solid forms provided herein are characterized by physical
properties, e.g., stability, solubility and dissolution rate,
appropriate for clinical and therapeutic dosage forms. Moreover,
while not wishing to be bound by any particular theory, certain
salts and crystal forms provided herein are characterized by
physical properties, e.g., crystal morphology, compressibility and
hardness, suitable for manufacture of a solid dosage form. Such
properties can be determined using techniques such as X-ray
diffraction, microscopy, IR spectroscopy and thermal analysis, as
described herein and known in the art.
[0065] 5.2.1 Single-Component Solid Forms of Compound I
[0066] Certain embodiments herein provide single-component solid
forms of the free base of
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I") having utility for the
treatment, prevention or management of conditions and disorders
including, but not limited to, cancer, a cardiovascular disease, a
renal disease, an autoimmune condition, an inflammatory condition,
macular degeneration, ischemia-reperfusion injury, pain and related
syndromes, disease-related wasting, an asbestos-related condition,
pulmonary hypertension, central nervous system (CNS) injury/damage
or a condition treatable or preventable by inhibition of a kinase
pathway.
[0067] Certain embodiments herein provide single-component
amorphous solid forms of the free base of Compound I. Certain
embodiments herein provide single-component crystal forms, or
polymorphs, of the free base of Compound I.
[0068] The single-component solid forms of Compound I can be
prepared by any method apparent to those skilled in the art based
upon the teachings herein. The single-component solid forms of
Compound I can also be prepared according to the techniques
described herein, including the methods described in detail in the
examples below.
[0069] As described below, certain single-component solid forms of
Compound I display superior properties in comparison to other solid
forms of Compound I.
5.2.1.1 Form A of the Free Base of Compound I
[0070] Certain embodiments herein provide the Form A crystal form
of the free base of Compound I. In certain embodiments, Form A of
the free base of Compound I can be obtained by a procedure
comprising evaporating a solution of the free base in one or more
solvents including, but not limited to, acetone, n-butanol,
ethanol, methanol, 2-propanol, tetrahydrofuran (THF), ethanol/water
(1/1) and mixtures of two more thereof. In certain embodiments, the
evaporation may be performed, e.g., at about 25.degree. C. or about
50.degree. C. In certain embodiments, Form A of the free base of
Compound I can be obtained by a procedure comprising slurrying the
free base in one or more solvents, including, but not limited to,
acetone, acetonitrile, n-butanol, ethanol, ethyl acetate, heptane,
methylene chloride, methyl ethyl ketone, methyl t-butyl ether
(MTBE), 2-propanol, toluene, water, ethanol/water (1/1) and
mixtures of two more thereof. In certain embodiments, the slurry
may be performed, e.g., at about 25.degree. C. or about 50.degree.
C. In certain embodiments, Form A of the free base of Compound I
can be obtained by a procedure comprising solvent/antisolvent
precipitation, including, but not limited to, ethanol/water,
ethanol/MTBE, ethanol/heptane, THF/MTBE, THF/heptane and
THF/toluene solvent systems. In certain embodiments, the
precipitation may be performed, e.g., at solvent/antisolvent ratios
of about 1/10 and at temperatures of about 50.degree. C. In certain
embodiments, Form A of the free base of Compound I can be obtained
by a procedure comprising slurrying another solid form comprising
the free base of Compound I (e.g., a hydrate of Compound I) in a
solvent, such as, e.g., acetonitrile, heptane, ethyl acetate, MTBE,
toluene and mixtures of two or more thereof. In certain
embodiments, Form A of the free base of Compound I can be obtained
from various solvents, including, but not limited to, ethanol,
water, and an ethanol/water mixture.
[0071] A representative XRPD pattern of Form A of the free base of
Compound I is provided in FIG. 1. In certain embodiments, Form A of
the free base of Compound I is characterized by XRPD peaks located
at one or more of the following approximate positions: 10.0, 12.4,
12.8, 15.2, 16.0, 16.3, 17.7, 18.5, 18.9, 19.4, 20.0, 20.6, 20.9,
21.6, 22.7, 23.2, 26.1, 26.6, 26.8, 25.7, 26.0, 26.4, 26.6, 27.2,
27.9, 30.2, 30.8, 31.0, 31.5 degrees 2.theta.. In particular
embodiments, Form A of the free base of Compound I is characterized
by XRPD peaks located at one, two, three, four, five or six of the
following approximate positions: 12.4, 16.0, 17.7, 18.5, 23.2, 24.1
degrees 2.theta.. In certain embodiments, Form A of the free base
of Compound I has an XRPD pattern comprising peaks at approximately
12.4, 16.0 and 18.5 .degree.2.theta.. In certain embodiments, Form
A of the free base of Compound I has an XRPD pattern further
comprising peaks at approximately 17.7, 23.2 and 24.1
.degree.2.theta..
[0072] Representative thermal characteristics of Form A of the free
base of Compound I are shown in FIG. 2 and FIG. 3. A representative
DSC thermogram, presented in FIG. 2, exhibits an endothermic event
with an onset temperature at about 225.degree. C. In particular
embodiments, the thermal event at about 225.degree. C. is a melting
event. In particular embodiments, Form A melts at about
225.0.degree. C. A representative TGA thermogram, presented in FIG.
3, exhibits a small mass loss, on the order of less than about 1%
of the total mass of the sample, upon heating from ambient
temperature to about 200.degree. C. The thermal data indicate that
Form A of the free base of Compound I does not contain substantial
amounts of either water or solvent in the crystal lattice. In
certain embodiments, Form A is unsolvated. In certain embodiments,
Form A is anhydrous.
[0073] Form A of the free base of Compound I exhibits desirable
characteristics for the synthesis, processing and manufacture of
drug product containing Compound I. For example, in certain
embodiments, Form A of the free base of Compound I has an
advantageous stability profile, which is an important
characteristic for processing and manufacturing. In certain
embodiments, Form A of the free base of Compound I is stable during
drying at temperatures up to about 40-45.degree. C. In certain
embodiments, the crystallization and/or recrystallization of Form A
of the free base of Compound I provides an effective means of
purification by removing or reducing the levels of chemical
impurities (such as, e.g., one or more of the chemical compounds
provided in FIG. 14) in the resulting material. In certain
embodiments, Form A of the free base of Compound I is substantially
pure. In certain embodiments, Form A of the free base of Compound I
is non-hygroscopic, e.g., exhibits a mass gain of less than about
2% of when subjected to an increase in humidity from about 0% to
about 80% relative humidity (RH). For example, in certain
embodiments, when subjected to moisture sorption analysis, Form A
exhibits a mass gain of about 0.5% when increased from about 0% to
about 80% RH, and exhibits a mass gain of about 1.4% when increased
from about 0% to about 95% RH. In certain embodiments, following
moisture sorption analysis, the XRPD pattern of the Form A material
is substantially unchanged. In certain embodiments, Form A of the
free base of Compound I is stable upon compression. For example, in
certain embodiments, when subjected to compression testing
involving about 2000-psi pressure for about 1 min, the XRPD pattern
of Form A is substantially unchanged.
[0074] Certain embodiments herein provide the Form A crystal form
of the free base of Compound I which is substantially pure. In
particular embodiments, a sample of substantially pure Form A is
substantially free of other solid forms, including other solid
forms comprising Compound I, such as, e.g., other solid forms
comprising Compound I described herein. In particular embodiments,
a sample of substantially pure Form A is substantially free of
other chemical compounds, including, e.g., solvent, water, and/or
the compounds depicted in FIG. 14.
5.2.1.2 Form B of the Free Base of Compound I
[0075] Certain embodiments herein provide the Form B crystal form
of the free base of Compound I. In certain embodiments, Form B has
an onset melting temperature at approximately 213.degree. C., as
measured, e.g., by DSC. In certain embodiments, the Form B crystal
form of the free base of Compound I may be prepared, e.g., by
heating a hydrate form of the free base of Compound I above about
185.degree. C. Characterization data for Form B of the free base of
Compound I is provided in FIG. 5, in which a hydrate of the free
base of Compound I is converted into Form B of the free base of
Compound I by dehydration upon heating.
[0076] 5.2.2 Multiple-Component Solid Forms of Compound I
[0077] Certain embodiments herein provide multiple-component solid
forms comprising Compound I having utility for the treatment,
prevention or management of conditions and disorders including, but
not limited to, cancer, a cardiovascular disease, a renal disease,
an autoimmune condition, an inflammatory condition, macular
degeneration, ischemia-reperfusion injury, pain and related
syndromes, disease-related wasting, an asbestos-related condition,
pulmonary hypertension, central nervous system (CNS) injury/damage
or a condition treatable or preventable by inhibition of a kinase
pathway.
[0078] Certain embodiments herein provide multiple-component
amorphous forms comprising Compound I. Certain embodiments herein
provide multiple-component crystal forms comprising Compound I. The
multiple-component solid forms comprising Compound I may be neutral
or ionic complexes, or may comprise both neutral and ionic
components together in the solid form. Multiple-component solid
forms provided herein include solid forms which may be described by
the terms salt, co-crystal, hydrate, solvate, clathrate and/or
polymorph, and include solid forms which may be accurately
described by one or more of these terms.
[0079] The multiple-component solid forms comprising Compound I can
be prepared by any method apparent to those skilled in the art
based upon the teachings herein. The multiple-component solid forms
of Compound I can also be prepared according to the techniques
described herein, including the methods described in detail in the
examples below.
[0080] As described below, certain multiple-component solid forms
of Compound I display superior properties in comparison to other
solid forms of Compound I.
5.2.2.1 Hydrate of the Free Base of Compound I
[0081] Certain embodiments herein provide a hydrate crystal form of
the free base of Compound I. In certain embodiments, this hydrate
of the free base of Compound I can be obtained by precipitating
Compound I from various solvents, including, but not limited to,
ethanol, water or a mixture thereof. In certain embodiments, this
hydrate of the free base of Compound I can be obtained by
precipitation following a cooling procedure. In certain
embodiments, the ratio of water in the resulting product can be
confirmed using elemental analysis, Karl Fischer analysis, thermal
gravimetric (TG) analysis, TG coupled with infrared spectroscopy
analysis (TG/IR), TG coupled with mass spectrometry analysis
(TG/MS) and/or crystal structure determination. In certain
embodiments, the hydrate of the free base of Compound I contains
about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0 molar
equivalents of water per mole of Compound I in the crystal lattice.
In certain embodiments, the hydrate contains about 9% water on a
weight basis. In certain embodiments, the hydrate material can be
dehydrated, e.g., by heating above at temperature of about
100.degree. C.
[0082] A representative XRPD pattern of this hydrate of the free
base of Compound I is provided in FIG. 4. In certain embodiments,
the hydrate crystal form of the free base of Compound I is
characterized by XRPD peaks located at one or more of the following
approximate positions: 6.5, 9.2, 10.3, 11.2, 13.0, 13.4, 15.9,
18.4, 19.5, 20.1, 20.5, 21.1, 21.5, 21.8, 23.0, 23.8, 24.7, 25.6,
26.0, 26.8 degrees 2.theta.. In particular embodiments, the hydrate
crystal form of the free base of Compound I is characterized by
XRPD peaks located at one, two, three, four, five, six or seven of
the following approximate positions: 6.5, 13.0, 13.4, 19.5, 20.1,
23.0, 23.8 degrees 2.theta.. In certain embodiments, the hydrate
crystal form of the free base of Compound I has an XRPD pattern
comprising peaks at approximately 6.5, 13.0 and 23.0
.degree.2.theta.. In certain embodiments, the hydrate crystal form
of the free base of Compound I has an XRPD pattern further
comprising peaks at approximately 13.4, 20.1 and 23.8
.degree.2.theta..
[0083] Representative thermal characteristics of this hydrate of
the free base of Compound I are shown in FIG. 5 and FIG. 6. A
representative DSC thermogram, presented in FIG. 5, exhibits
initial endothermic events with peak temperatures at about
79.degree. C. and about 95.degree. C., followed by an exothermic
event with a peak temperature at about 181.degree. C., followed by
two endothermic events with onset temperatures at about 215.degree.
C. and about 227.degree. C. A representative TGA thermogram,
presented in FIG. 6, exhibits a mass loss of about 10% of the total
mass of the sample upon heating from ambient temperature to about
200.degree. C. TG/IR analysis indicated that the mass loss
comprised a loss of water.
[0084] This hydrate crystal form of the free base of Compound I
exhibits desirable characteristics for the synthesis, processing
and manufacture of drug product containing Compound I. For example,
the crystallization or recrystallization of this hydrate of the
free base of Compound I provides an effective means of
purification. In certain embodiments, the hydrate of the free base
of Compound I is substantially pure.
5.2.2.2 Form A of the HCl Salt of Compound I
[0085] Certain embodiments herein provide the Form A crystal form
of the HCl salt of Compound I. In certain embodiments, Form A of
the HCl salt of Compound I can be obtained by reacting Compound I
with HCl in various solvents, including, but not limited to,
ethanol, isopropanol, water or mixtures thereof. The HCl may be
charged to the reaction as a solution, e.g., a concentrated aqueous
solution, or as a gas. In certain embodiments, the stoichiometry of
the resulting product can be confirmed, e.g., using elemental
analysis for chlorine. In certain embodiments, the HCl salt of
Compound I contains approximately two molar equivalents of chloride
ion per mole of Compound I. In certain embodiments, the Form A of
the HCl salt of Compound I is a bis-HCl salt of Compound I. In
certain embodiments, Form A of the HCl salt of Compound I can be
prepared, e.g., by precipitation following evaporation (e.g., at
about 25.degree. C. or about 50.degree. C.) from solutions of the
HCl salt in solvents including, but not limited to, n-butanol,
ethanol, methanol, 2-propanol, water, ethanol/water (1/1), and
mixtures of two or more thereof. In certain embodiments, Form A of
the HCl salt of Compound I can be prepared, e.g., by slurrying the
HCl salt (e.g., at about 25.degree. C. or about 50.degree. C.) in
solvents including, but not limited to, acetone, acetonitrile,
n-butanol, ethyl acetate, heptane, methylene chloride, methyl ethyl
ketone, MTBE, 2-propanol, toluene and THF, and mixtures of two or
more thereof.
[0086] A representative XRPD pattern of Form A of the HCl salt of
Compound I is provided in FIG. 7. In certain embodiments, Form A of
the HCl salt of Compound I is characterized by XRPD peaks located
at one or more of the following approximate positions: 5.2, 6.1,
14.2, 17.3, 18.7, 21.1, 21.9, 22.4, 23.5, 24.8, 27.7, 29.3, 31.2
degrees 2.theta.. In particular embodiments, Form A of the HCl salt
of Compound I is characterized by XRPD peaks located at one, two,
three, four or five of the following approximate positions: 17.3,
18.7, 21.1, 22.4, 23.5, 24.8 degrees 2.theta.. In certain
embodiments, Form A of the HCl salt of Compound I has an XRPD
pattern comprising peaks at approximately 17.3, 18.7 and 22.4
.degree.2.theta.. In certain embodiments, Form A of the HCl salt of
Compound I has an XRPD pattern comprising peaks approximately 21.1,
23.5 and 24.8 .degree.2.theta.. In certain embodiments, Form A of
the HCl salt of Compound I has an XRPD pattern comprising a peak
located at least one of the following two positions: 5.2, 6.1
degrees 2.theta..
[0087] Representative thermal characteristics of Form A of the HCl
salt of Compound I are shown in FIG. 9 and FIG. 10. A
representative DSC thermogram, presented in FIG. 9 exhibits an
initial broad endothermic event followed by another endothermic
event with an onset temperature at about 170.degree. C. A
representative TGA thermogram, presented in FIG. 10, exhibits a
mass loss on the order of between about 1-2% of the total mass of
the sample upon heating from ambient temperature to about
125.degree. C.
[0088] Form A of the HCl salt of Compound I exhibits desirable
characteristics for the synthesis, processing and manufacture of
drug product containing Compound I. For example, in certain
embodiments, the crystallization or recrystallization of Form A of
the HCl salt of Compound I provides an effective means of
purification by removing or reducing the levels of chemical
impurities in the resulting drug substance. In certain embodiments,
Form A of the HCl salt of Compound I is substantially pure. In
certain embodiments, Form A of the HCl salt of Compound I is stable
upon slurry in particular solvents at particular temperatures. For
example, in certain embodiments, Form A of the HCl salt is stable
in, e.g., acetone, acetonitrile, ethyl acetate, heptane, MTBE,
toluene, THF and mixtures of two or more thereof at about
40.degree. C. for about four weeks. In certain embodiments, Form A
of the HCl salt is stable upon storage at particular stress
conditions. For example, in certain embodiments, Form A of the HCl
salt of Compound I is stable upon storage at about 40.degree. C.
and about 75% RH for about four weeks.
5.2.2.3 Form A of the HBr Salt of Compound I
[0089] Certain embodiments herein provide the Form A crystal form
of the HBr salt of Compound I. In certain embodiments, Form A of
the HBr salt of Compound I can be obtained by reacting Compound I
with HBr in various solvents, including, but not limited to,
ethanol, isopropanol, water or mixtures thereof. The HBr may be
charged to the reaction as a solution, e.g., a concentrated aqueous
solution, or as a gas. A representative XRPD pattern of Form A of
the HBr salt of Compound I is provided in FIG. 11. In certain
embodiments, Form A of the HBr salt of Compound I is characterized
by XRPD peaks located at one or more of the following approximate
positions: 5.1, 5.8, 16.9, 18.5, 18.7, 20.9, 21.5, 22.7, 23.1,
24.1, 26.0, 26.8, 27.8, 28.9, 29.3 degrees 2.theta.. In particular
embodiments, Form A of the HBr salt of Compound I is characterized
by XRPD peaks located at one, two, three, four, or five of the
following approximate positions: 5.1, 5.8, 18.5, 21.5, 27.8 degrees
2.theta..
[0090] Form A of the HBr salt of Compound I exhibits desirable
characteristics for the synthesis, processing and manufacture of
drug product containing Compound I. For example, the
crystallization or recrystallization of Form A of the HBr salt of
Compound I provides an effective means of purification by removing
or reducing the levels of chemical impurities in the resulting drug
substance. In certain embodiments, Form A of the HBr salt of
Compound I is substantially pure.
5.2.2.4 Form A of the Sulfate Salt of Compound I
[0091] Certain embodiments herein provide the Form A crystal form
of the sulfate salt of Compound I. In certain embodiments, Form A
of the sulfate salt of Compound I can be obtained by reacting
Compound I with sulfuric acid in various solvents, including, but
not limited to, ethanol, isopropanol, water or mixtures
thereof.
[0092] A representative XRPD pattern of Form A of the sulfate salt
of Compound I is provided in FIG. 12. In certain embodiments, Form
A of the sulfate salt of Compound I is characterized by XRPD peaks
located at one or more of the following approximate positions: 7.0,
14.1, 16.7, 17.6, 17.9, 19.9, 20.3, 20.8, 21.2, 21.7, 23.1, 23.7,
23.9, 24.3, 25.3 degrees 2.theta.. In particular embodiments, Form
A of the sulfate salt of Compound I is characterized by XRPD peaks
located at one, two, three, four or five of the following
approximate positions: 7.0, 14.1, 17.6, 23.7, 24.3 degrees
2.theta.. In certain embodiments, Form A of the sulfate salt of
Compound I is substantially pure.
5.3 Methods of Use
[0093] The solid forms comprising Compound I have utility as
pharmaceuticals to treat, prevent and/or manage disease in animals
or humans. Further, the solid forms comprising Compound I are
active against protein kinases including those involved in cancer,
inflammatory conditions, immunological conditions,
neurodegenerative diseases, cardiovascular diseases, metabolic
conditions, insulin resistance, diabetes, fibrotic diseases, and
disorders caused, induced or exacerbated by ozone, cold or
exercise. Accordingly, provided herein are many uses of the solid
forms comprising Compound I, including the treatment or prevention
of those diseases set forth below, as well as those described in
U.S. patent application Ser. No. 11/332,617, filed Jan. 12, 2006,
and International Pub. No. WO 2006/076595, U.S. patent application
Ser. No. 11/411,413, filed Apr. 26, 2006, published as U.S. Pat.
App. Pub. No. 2007/0060598 on Mar. 15, 2007, and U.S. patent
application Ser. No. 11/708,150, filed Feb. 15, 2007, the
entireties of each of which is incorporated by reference
herein.
[0094] Representative immunological conditions that the solid forms
comprising Compound I are useful for treating or preventing
include, but are not limited to, rheumatoid arthritis, rheumatoid
spondylitis, osteoarthritis, multiple sclerosis, lupus,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
myasthenia gravis, Grave's disease and diabetes (e.g., Type I
diabetes).
[0095] Representative inflammatory conditions that the solid forms
comprising Compound I are useful for treating or preventing
include, but are not limited to, asthma and allergic rhinitis,
bronchitis, chronic obstructive pulmonary disease, cystic fibrosis,
inflammatory bowel disease, irritable bowel syndrome, Crohn's
disease, mucous colitis, ulcerative colitis, (e.g., Type I diabetes
and Type II diabetes) and obesity.
[0096] Representative metabolic conditions that the solid forms
comprising Compound I are useful for treating or preventing
include, but are not limited to, obesity and diabetes (e.g., Type
II diabetes).
[0097] Representative cardiovascular diseases that the solid forms
comprising Compound I are useful for treating or preventing
include, but are not limited to, stroke, myocardial infarction or
iscehmic damage to the heart, lung, gut, kidney, liver, pancreas,
spleen or brain.
[0098] Representative cardiovascular and renal diseases that stent
or stent graft coated with or containing a solid form comprising
Compound I is useful for treating or preventing include
atherosclerosis and the treatment or prevention of restenosis after
vascular intervention such as angioplasty.
[0099] Representative neurodegenerative diseases that the solid
forms comprising Compound I are useful for treating or preventing
include, but are not limited to, Huntington's disease, Alzheimer's
disease and HIV-associated encephalitis.
[0100] Representative disorders caused, induced or exacerbated by
ozone, cold or exercise include, but are not limited to, asthma,
bronchitis, rhinitis, chronic obstructive pulmonary disease, lung
inflammation or airway hyperresponsiveness.
[0101] In another embodiment, provided herein are methods for the
treatment or prevention of syndrome X or metabolic syndrome.
[0102] In a particular embodiment, provided herein are methods for
the treatment or prevention of insulin resistance. In certain
embodiments, provided herein are methods for the treatment or
prevention of insulin resistance that leads to diabetes (e.g., Type
II diabetes).
[0103] In another embodiment, provide herein are methods for the
treatment or prevention of diabetes. Representative diabetes that
the solid forms comprising Compound I are useful for treating or
preventing include, but are not limited to, Type II diabetes, Type
I diabetes, slow-onset Type I diabetes, diabetes insipidus,
diabetes mellitus, gestational diabetes mellitus, maturity-onset
diabetes, juvenile diabetes, insulin-dependant diabetes,
non-insulin dependant diabetes, malnutrition-related diabetes,
ketosis-prone diabetes, pre-diabetes, cystic fibrosis related
diabetes or ketosis-resistant diabetes.
[0104] In another embodiment, provided herein are methods for the
treatment or prevention of fibrotic diseases and disorders.
Representative fibrotic diseases that the solid forms comprising
Compound I are useful for treating or preventing include, but are
not limited to, idiopathic pulmonary fibrosis, myelofibrosis,
hepatic fibrosis, renal fibrosis, chronic allograft nephropathy,
glomerulonephritis, steatofibrosis or steatohepatitis.
[0105] A solid form comprising Compound I containing or coated
stent or stent graft can further comprise an effective amount of
another active agent useful for treating or preventing a
cardiovascular or renal disease, including, but are not limited to,
an anticoagulant agent, an antimetabolite agent, an
anti-inflammatory agent, an antiplatelet agent, an antithrombin
agent, an antimitotic agent, a cytostatic agent or an
antiproliferative agent.
[0106] The solid forms comprising Compound I are also useful for
treating or preventing ischemia/reperfusion injury in general.
Accordingly, the solid forms comprising Compound I are useful for
treating or preventing acute or chronic organ transplant rejection
and for the preservation of tissue and organs.
[0107] Representative cancers that the solid forms comprising
Compound I are useful for treating or preventing include, but are
not limited to, cancers of the head, neck, eye, mouth, throat,
esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon,
rectum, stomach, prostate, urinary bladder, uterine, cervix,
breast, ovaries, testicles or other reproductive organs, skin,
thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or
central nervous system.
[0108] Cancers within the scope of the methods provided herein
include those associated with BCR-ABL, and mutants or isoforms
thereof, as well as kinases from the src kinase family, kinases
from the Rsk kinase family, kinases from the CDK family, kinases
from the MAPK kinase family, and tyrosine kinases such as Fes, Lyn,
and Syk kinases, and mutants or isoforms thereof.
[0109] In a particular embodiment, provided herein are methods for
the treatment or prevention of a disease or disorder associated
with the modulation, for example inhibition, of a kinase,
including, but are not limited to, tyrosine-protein kinase (SYK),
tyrosine-protein kinase (ZAP-70), protein tyrosine kinase 2 beta
(PYK2), focal adhesion kinase 1 (FAK), B lymphocyte kinase (BLK),
hemopoietic cell kinase (HCK), v-yes-1 Yamaguchi sarcoma viral
related oncogene homolog (LYN), T cell-specific protein-tyrosine
kinase (LCK), proto-oncogene tyrosine-protein kinase (YES),
proto-oncogene tyrosine-protein kinase (SRC), proto-oncogene
tyrosine-protein kinase (FYN), proto-oncogene tyrosine-protein
kinase (FGR), proto-oncogene tyrosine-protein kinase (FER),
proto-oncogene tyrosine-protein kinase (FES), C--SRC kinase,
protein-tyrosine kinase (CYL), tyrosine protein kinase (CSK),
megakaryocyte-associated tyrosine-protein kinase (CTK),
tyrosine-protein kinase receptor (EPH), Ephrin type-A receptor 1,
Ephrin type-A receptor 4 (EPHA4), Ephrin type-B receptor 3 (EPHB3),
Ephrin type-A receptor 8 (EPHA8), neurotrophic tyrosine kinase
receptor, type 1 (NTRK1), protein-tyrosine kinase (PTK2),
syk-related tyrosine kinase (SRK), protein tyrosine kinase (CTK),
tyro3 protein tyrosine kinase (TYRO3), bruton agammaglobulinemia
tyrosine kinase (BTK), leukocyte tyrosine kinase (LTK),
protein-tyrosine kinase (SYK), protein-tyrosine kinase (STY), tek
tyrosine kinase (TEK), elk-related tyrosine kinase (ERK), tyrosine
kinase with immunoglobulin and egf factor homology domains (TIE),
protein tyrosine kinase (TKF), neurotrophic tyrosine kinase,
receptor, type 3 (NTRK3), mixed-lineage protein kinase-3 (MLK3),
protein kinase, mitogen-activated 4 (PRKM4), protein kinase,
mitogen-activated 1 (PRKM1), protein tyrosine kinase (PTK7),
protein tyrosine kinase (EEK), minibrain (drosophila) homolog
(MNBH), bone marrow kinase, x-linked (BMX), eph-like tyrosine
kinase 1 (ETK1), macrophage stimulating 1 receptor (MST1R),
btk-associated protein, 135 kd, lymphocyte-specific protein
tyrosine kinase (LCK), fibroblast growth factor receptor-2 (FGFR2),
protein tyrosine kinase-3 (TYK3), protein tyrosine kinase (TXK),
tec protein tyrosine kinase (TEC), protein tyrosine kinase-2
(TYK2), eph-related receptor tyrosine kinase ligand 1 (EPLG1),
t-cell tyrosine kinase (EMT), eph tyrosine kinase 1 (EPHT1), zona
pellucida receptor tyrosine kinase, 95 kd (ZRK), protein kinase,
mitogen-activated, kinase 1 (PRKMK1), eph tyrosine kinase 3
(EPHT3), growth arrest-specific gene-6 (GAS6), kinase insert domain
receptor (KDR), axl receptor tyrosine kinase (AXL), fibroblast
growth factor receptor-1 (FGFR1), v-erb-b2 avian erythroblastic
leukemia viral oncogene homolog 2 (ERBB2), fms-like tyrosine
kinase-3 (FLT3), neuroepithelial tyrosine kinase (NEP),
neurotrophic tyrosine kinase receptor-related 3 (NTRKR3),
eph-related receptor tyrosine kinase ligand 5 (EPLG5), neurotrophic
tyrosine kinase, receptor, type 2 (NTRK2), receptor-like tyrosine
kinase (RYK), tyrosine kinase, b-lymphocyte specific (BLK), eph
tyrosine kinase 2 (EPHT2), eph-related receptor tyrosine kinase
ligand 2 (EPLG2), glycogen storage disease VIII, eph-related
receptor tyrosine kinase ligand 7 (EPLG7), janus kinase 1 (JAK1),
fms-related tyrosine kinase-1 (FLT1), protein kinase,
camp-dependent, regulatory, type I, alpha (PRKAR1A), wee-1 tyrosine
kinase (WEE1), eph-like tyrosine kinase 2 (ETK2), receptor tyrosine
kinase musk, insulin receptor (INSR), janus kinase 3 (JAK3),
fms-related tyrosine kinase-3 ligand protein kinase c, beta 1
(PRKCB1), tyrosine kinase-type cell surface receptor (HER3), janus
kinase 2 (JAK2), lim domain kinase 1 (LIMK1), dual specificity
phosphatase 1 (DUSP1), hemopoietic cell kinase (HCK), tyrosine
3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta
polypeptide (YWHAH), ret proto-oncogene (RET), tyrosine
3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta
polypeptide (YWHAZ), tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein, beta polypeptide (YWHAB),
hepatoma transmembrane kinase (HTK), map kinase 6,
phosphatidylinositol 3-kinase, catalytic, alpha polypeptide
(PIK3CA), cyclin-dependent kinase inhibitor 3 (CDKN3),
diacylglycerol kinase, delta, 130 kd, protein-tyrosine phosphatase,
nonreceptor type, 13 (PTPN13), abelson murine leukemia viral
oncogene homolog 1 (ABL1), diacylglycerol kinase, alpha (DAGK1),
focal adhesion kinase 2, epithelial discoidin domain receptor 1
(EDDR1), anaplastic lymphoma kinase (ALK), phosphatidylinositol
3-kinase, catalytic, gamma polypeptide (PIK3CG),
phosphatidylinositol 3-kinase regulatory subunit, (PIK3R1), eph
homology kinase-1 (EHK1), v-kit hardy-zuckerman 4 feline sarcoma
viral oncogene homolog (KIT), fibroblast growth factor receptor-3
(FGFR3), vascular endothelial growth factor c (VEGFC), epidermal
growth factor receptor (EGFR), oncogene (TRK), growth factor
receptor-bound protein-7 (GRB7), ras p21 protein activator (RASA2),
met proto-oncogene (MET), src-like adapter (SLA), vascular
endothelial growth factor (VEGF), vascular endothelial growth
factor receptor (VEGFR), nerve growth factor receptor (NGFR),
platelet derived growth factor receptor (PDGFR), platelet derived
growth factor receptor beta (PDGFRB), dual-specificity
tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2),
dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 3
(DYRK3), dual-specificity tyrosine-(Y)-phosphorylation regulated
kinase 4 (DYRK4), dual-specificity tyrosine-(Y)-phosphorylation
regulated kinase 1A (DYRK1A), dual-specificity
tyrosine-(Y)-phosphorylation regulated kinase 1B (DYRK1B), CDC-like
kinase 1 (CLK1), protein tyrosine kinase STY, CDC-like kinase 4
(CLK4), CDC-like kinase 2 (CLK2) or CDC-like kinase 3 (CLK3).
[0110] In another embodiment, provided herein are methods for the
treatment or prevention of a disease or disorder associated with
the modulation, for example inhibition, of serine/threonine kinases
or related molecules, including, but not limited to,
cyclin-dependent kinase 7 (CDK7), rac serine/threonine protein
kinase, serine-threonine protein kinase n (PKN), serine/threonine
protein kinase 2 (STK2), zipper protein kinase (ZPK),
protein-tyrosine kinase (STY), bruton agammaglobulinemia tyrosine
kinase (BTK), mkn28 kinase, protein kinase, x-linked (PRKX),
elk-related tyrosine kinase (ERK), ribosomal protein s6 kinase, 90
kd, polypeptide 3 (RPS6KA3), glycogen storage disease VIII,
death-associated protein kinase 1 (DAPK1), pctaire protein kinase 1
(PCTK1), protein kinase, interferon-inducible double-stranded rna
(PRKR), activin a receptor, type II-like kinase 1 (ACVRLK1),
protein kinase, camp-dependent, catalytic, alpha (PRKACA), protein
kinase, y-linked (PRKY), G protein-coupled receptor kinase 2
(GPRK21), protein kinase c, theta form (PRKCQ), lim domain kinase 1
(LIMK1), phosphoglycerate kinase 1 PGK1), lim domain kinase 2
(LIMK2), c-jun kinase, activin a receptor, type II-like kinase 2
(ACVRLK2), janus kinase 1 (JAK1), elkl motif kinase (EMK1), male
germ cell-associated kinase (MAK), casein kinase 2, alpha-prime
subunit (CSNK2A2), casein kinase 2, beta polypeptide (CSNK2B),
casein kinase 2, alpha 1 polypeptide (CSNK2A1), ret proto-oncogene
(RET), hematopoietic progenitor kinase 1, conserved
helix-loop-helix ubiquitous kinase (CHUK), casein kinase 1, delta
(CSNK1D), casein kinase 1, epsilon (CSNK1E), v-akt murine thymoma
viral oncogene homolog 1 (AKT1), tumor protein p53 (TP53), protein
phosphatase 1, regulatory (inhibitor) subunit 2 (PPP1R2), oncogene
pim-1 (PIM1), transforming growth factor-beta receptor, type II
(TGFBR2), transforming growth factor-beta receptor, type I
(TGFBR1), v-raf murine sarcoma viral oncogene homolog b1 (BRAF),
bone morphogenetic receptor type II (BMPR2), v-raf murine sarcoma
3611 viral oncogene homolog 1 (ARAF1), v-raf murine sarcoma 3611
viral oncogene homolog 2 (ARAF2), protein kinase C (PKC), v-kit
hardy-zuckerman 4 feline sarcoma viral oncogene homolog (KIT) or
c-KIT receptor (KITR).
[0111] In another embodiment, provided herein are methods for the
treatment or prevention of a disease or disorder associated with
the modulation, for example inhibition, of a MAP kinase, including,
but not limited to, mitogen-activated protein kinase 3 (MAPK3),
p44erk1, p44mapk, mitogen-activated protein kinase 3 (MAP kinase 3;
p44), ERK1, PRKM3, P44ERK1, P44MAPK, mitogen-activated protein
kinase 1 (MAPK1), mitogen-activated protein kinase 1 (MEK1),
MAP2K1protein tyrosine kinase ERK2, mitogen-activated protein
kinase 2, extracellular signal-regulated kinase 2, protein tyrosine
kinase ERK2, mitogen-activated protein kinase 2, extracellular
signal-regulated kinase 2, ERK, p38, p40, p41, ERK2, ERT1, MAPK2,
PRKM1, PRKM2, P42MAPK, p41mapk, mitogen-activated protein kinase 7
(MAPK7), BMK1 kinase, extracellular-signal-regulated kinase 5,
BMK1, ERK4, ERK5, PRKM7, nemo-like kinase (NLK), likely ortholog of
mouse nemo like kinase, mitogen-activated protein kinase 8 (MAPK8),
protein kinase JNK1, JNK1 beta protein kinase, JNK1 alpha protein
kinase, c-Jun N-terminal kinase 1, stress-activated protein kinase
JNK1, JNK, JNK1, PRKM8, SAPK1, JNK1A2, JNK21B1/2, mitogen-activated
protein kinase 10 (MAPK10), c-Jun kinase 3, JNK3 alpha protein
kinase, c-Jun N-terminal kinase 3, stress activated protein kinase
JNK3, stress activated protein kinase beta, mitogen-activated
protein kinase 9 (MAPK9), MAP kinase 9, c-Jun kinase 2, c-Jun
N-terminal kinase 2, stress-activated protein kinase JNK2, JNK2,
JNK2A, JNK2B, PRKM9, JNK-55, JNK2BETA, p54aSAPK, JNK2ALPHA,
mitogen-activated protein kinase 14 (MAPK14), p38 MAP kinase, MAP
kinase Mxi2, Csaids binding protein, MAX-interacting protein 2,
stress-activated protein kinase 2A, p38 mitogen activated protein
kinase, cytokine suppressive anti-inflammatory drug binding
protein, RK, p38, EXIP, Mxi2, CSBP1, CSBP2, CSPB1, PRKM14, PRKM15,
SAPK2A, p38ALPHA, mitogen-activated protein kinase 11 (MAPK11),
stress-activated protein kinase-2, stress-activated protein
kinase-2b, mitogen-activated protein kinase p38-2,
mitogen-activated protein kinase p38beta, P38B, SAPK2, p38-2,
PRKM11, SAPK2B, p38Beta, P38BETA2, mitogen-activated protein kinase
13 (MAPK13), stress-activated protein kinase 4, mitogen-activated
protein kinase p38 delta, SAPK4, PRKM13, p38delta,
mitogen-activated protein kinase 12 (MAPK12), p38gamma,
stress-activated protein kinase 3, mitogen-activated protein kinase
3, ERK3, ERK6, SAPK3, PRKM12, SAPK-3, P38GAMMA, mitogen-activated
protein kinase 6 (MAPK6), MAP kinase isoform p97, mitogen-activated
5 protein kinase, mitogen-activated 6 protein kinase, extracellular
signal-regulated kinase 3, extracellular signal-regulated kinase,
p97, ERK3, PRKM6, p97MAPK, mitogen-activated protein kinase 4
(MAPK4), Erk3-related protein kinase, mitogen-activated 4 protein
kinase (MAP kinase 4; p63), PRKM4, p63MAPK, ERK3-RELATED or
Extracellular signal-regulated kinase 8 (ERK7).
[0112] More particularly, cancers and related disorders that can be
treated or prevented by methods and compositions provided herein
include but are not limited to the following: Leukemias such as but
not limited to, acute leukemia, acute lymphocytic leukemia, acute
myelocytic leukemias such as myeloblastic, promyelocytic,
myelomonocytic, monocytic, erythroleukemia leukemias and
myelodysplastic syndrome (or a symptom thereof such as anemia,
thrombocytopenia, neutropenia, bicytopenia or pancytopenia),
refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with
excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia
and chronic myelomonocytic leukemia (CMML), chronic leukemias such
as but not limited to, chronic myelocytic (granulocytic) leukemia,
chronic lymphocytic leukemia, hairy cell leukemia; polycythemia
vera; lymphomas such as but not limited to Hodgkin's disease,
non-Hodgkin's disease; multiple myelomas such as but not limited to
smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic
myeloma, plasma cell leukemia, solitary plasmacytoma and
extramedullary plasmacytoma; Waldenstrom's macroglobulinemia;
monoclonal gammopathy of undetermined significance; benign
monoclonal gammopathy; heavy chain disease; bone and connective
tissue sarcomas such as but not limited to bone sarcoma,
osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell
tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma,
soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma,
Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma,
metastatic cancers, neurilemmoma, rhabdomyosarcoma, synovial
sarcoma; brain tumors such as but not limited to, glioma,
astrocytoma, brain stem glioma, ependymoma, oligodendroglioma,
nonglial tumor, acoustic neurinoma, craniopharyngioma,
medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary
brain lymphoma; breast cancer, including, but not limited to,
adenocarcinoma, lobular (small cell) carcinoma, intraductal
carcinoma, medullary breast cancer, mucinous breast cancer, tubular
breast cancer, papillary breast cancer, primary cancers, Paget's
disease, and inflammatory breast cancer; adrenal cancer such as but
not limited to pheochromocytom and adrenocortical carcinoma;
thyroid cancer such as but not limited to papillary or follicular
thyroid cancer, medullary thyroid cancer and anaplastic thyroid
cancer; pancreatic cancer such as but not limited to, insulinoma,
gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and
carcinoid or islet cell tumor; pituitary cancers such as but
limited to Cushing's disease, prolactin-secreting tumor,
acromegaly, and diabetes insipius; eye cancers such as but not
limited to ocular melanoma such as iris melanoma, choroidal
melanoma, and cilliary body melanoma, and retinoblastoma; vaginal
cancers such as squamous cell carcinoma, adenocarcinoma, and
melanoma; vulvar cancer such as squamous cell carcinoma, melanoma,
adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease;
cervical cancers such as but not limited to, squamous cell
carcinoma, and adenocarcinoma; uterine cancers such as but not
limited to endometrial carcinoma and uterine sarcoma; ovarian
cancers such as but not limited to, ovarian epithelial carcinoma,
borderline tumor, germ cell tumor, and stromal tumor; esophageal
cancers such as but not limited to, squamous cancer,
adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma,
adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous
carcinoma, and oat cell (small cell) carcinoma; stomach cancers
such as but not limited to, adenocarcinoma, fungaling (polypoid),
ulcerating, superficial spreading, diffusely spreading, malignant
lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon
cancers; rectal cancers; liver cancers such as but not limited to
hepatocellular carcinoma and hepatoblastoma, gallbladder cancers
such as adenocarcinoma; cholangiocarcinomas such as but not limited
to pappillary, nodular, and diffuse; lung cancers such as non-small
cell lung cancer, squamous cell carcinoma (epidermoid carcinoma),
adenocarcinoma, large-cell carcinoma and small-cell lung cancer;
testicular cancers such as but not limited to germinal tumor,
seminoma, anaplastic, classic (typical), spermatocytic,
nonseminoma, embryonal carcinoma, teratoma carcinoma,
choriocarcinoma (yolk-sac tumor), prostate cancers such as but not
limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma;
penal cancers; oral cancers such as but not limited to squamous
cell carcinoma; basal cancers; salivary gland cancers such as but
not limited to adenocarcinoma, mucoepidermoid carcinoma, and
adenoidcystic carcinoma; pharynx cancers such as but not limited to
squamous cell cancer, and verrucous; skin cancers such as but not
limited to, basal cell carcinoma, squamous cell carcinoma and
melanoma, superficial spreading melanoma, nodular melanoma, lentigo
malignant melanoma, acral lentiginous melanoma; kidney cancers such
as but not limited to renal cell cancer, adenocarcinoma,
hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis
and/or uterer); Wilms' tumor; bladder cancers such as but not
limited to transitional cell carcinoma, squamous cell cancer,
adenocarcinoma, carcinosarcoma. In addition, cancers include
myxosarcoma, osteogenic sarcoma, endotheliosarcoma,
lymphangioendotheliosarcoma, mesothelioma, synovioma,
hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,
bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland
carcinoma, papillary carcinoma and papillary adenocarcinomas (for a
review of such disorders, see Fishman et al., Medicine, (1985), 2d
ed., J.B. Lippincott Co., Philadelphia; and Murphy et al., Informed
Decisions: The Complete Book of Cancer Diagnosis, Treatment, and
Recovery, (1997), Viking Penguin, Penguin Books U.S.A., Inc.,
United States of America).
[0113] Accordingly, the methods and compositions provided herein
are also useful in the treatment or prevention of a variety of
cancers or other abnormal proliferative diseases, including (but
not limited to) the following: carcinoma, including that of the
bladder, breast, colon, kidney, liver, lung, ovary, pancreas,
stomach, cervix, thyroid and skin; including squamous cell
carcinoma; hematopoietic tumors of lymphoid lineage, including
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell lymphoma, Berketts lymphoma; hematopoietic
tumors of myeloid lineage, including acute and chronic myelogenous
leukemias and promyelocytic leukemia; tumors of mesenchymal
orignin, including fibrosarcoma and rhabdomyoscarcoma; other
tumors, including melanoma, seminoma, tetratocarcinoma,
neuroblastoma and glioma; tumors of the central and peripheral
nervous system, including astrocytoma, glioblastoma multiforme,
neuroblastoma, glioma, and schwannomas; solid and blood born
tumors; tumors of mesenchymal origin, including fibrosafcoma,
rhabdomyoscarama, and osteosarcoma; and other tumors, including
melanoma, xenoderma pegmentosum, keratoactanthoma, seminoma,
thyroid follicular cancer and teratocarcinoma. It is also
contemplated that cancers caused by aberrations in apoptosis would
also be treated by the methods and compositions disclosed herein.
Such cancers may include but not be limited to follicular
lymphomas, carcinomas with p53 mutations, hormone dependent tumors
of the breast, prostate and ovary, and precancerous lesions such as
familial adenomatous polyposis, and myelodysplastic syndromes. In
specific embodiments, malignancy or dysproliferative changes (such
as metaplasias and dysplasias), or hyperproliferative disorders,
are treated or prevented in the ovary, bladder, breast, colon,
lung, skin, pancreas, or uterus. In other specific embodiments,
sarcoma, melanoma, or leukemia is treated or prevented.
[0114] In another embodiment, the methods and compositions provided
herein are also useful for administration to patients in need of a
bone marrow transplant to treat a malignant disease (e.g., patients
suffering from acute lymphocytic leukemia, acute myelogenous
leukemia, chronic myelogenous leukemia, chronic lymphocytic
leukemia, myelodysplastic syndrome ("preleukemia"), monosomy 7
syndrome, non-Hodgkin's lymphoma, neuroblastoma, brain tumors,
multiple myeloma, testicular germ cell tumors, breast cancer, lung
cancer, ovarian cancer, melanoma, glioma, sarcoma or other solid
tumors), those in need of a bone marrow transplant to treat a
non-malignant disease (e.g., patients suffering from hematologic
disorders, congenital immunodeficiences, mucopolysaccharidoses,
lipidoses, osteoporosis, Langerhan's cell histiocytosis,
Lesch-Nyhan syndrome or glycogen storage diseases), those
undergoing chemotherapy or radiation therapy, those preparing to
undergo chemotherapy or radiation therapy and those who have
previously undergone chemotherapy or radiation therapy.
[0115] In another embodiment, provided herein are methods for the
treatment of myeloproliferative disorders or myelodysplastic
syndromes, comprising administering to a patient in need thereof an
effective amount of a solid form comprising Compound I or a
composition thereof. In certain embodiments, the myeloproliferative
disorder is polycythemia rubra vera; primary thrombocythemia;
chronic myelogenous leukemia; acute or chronic granulocytic
leukemia; acute or chronic myelomonocytic leukemia;
myelofibro-erythroleukemia; or agnogenic myeloid metaplasia.
[0116] In another embodiment, provided herein are methods for the
treatment of cancer or tumors resistant to other kinase inhibitors
such as imatinib mesylate (STI-571 or Gleevec.TM.) treatment,
comprising administering to a patient in need thereof an effective
amount of a solid form comprising Compound I or a composition
thereof. In a particular embodiment, provided herein are methods
for the treatment of leukemias, including, but not limited to,
gastrointestinal stromal tumor (GIST), acute lymphocytic leukemia
or chronic myelocytic leukemia resistant to imatinib mesylate
(STI-571 or Gleevec.TM.) treatment, comprising administering to a
patient in need thereof an effective amount of a solid form
comprising Compound I or a composition thereof.
[0117] In one embodiment, provided herein are methods for treating
or preventing a disease or disorder treatable or preventable by
modulating a kinase pathway, in one embodiment, the JNK pathway,
comprising administering an effective amount of a solid form
comprising Compound I to a patient in need of the treating or
preventing. Particular diseases which are treatable or preventable
by modulating, for example, inhibiting, a kinase pathway, in one
embodiment, the JNK pathway, include, but are not limited to,
rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout;
asthma, bronchitis; allergic rhinitis; chronic obstructive
pulmonary disease; cystic fibrosis; inflammatory bowel disease;
irritable bowel syndrome; mucous colitis; ulcerative colitis;
Crohn's disease; Huntington's disease; gastritis; esophagitis;
hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus
erythematosus; Type II diabetes; obesity; atherosclerosis;
restenosis following angioplasty; left ventricular hypertrophy;
myocardial infarction; stroke; ischemic damages of heart, lung,
gut, kidney, liver, pancreas, spleen and brain; acute or chronic
organ transplant rejection; preservation of the organ for
transplantation; organ failure or loss of limb (e.g., including,
but not limited to, that resulting from ischemia-reperfusion
injury, trauma, gross bodily injury, car accident, crush injury or
transplant failure); graft versus host disease; endotoxin shock;
multiple organ failure; psoriasis; burn from exposure to fire,
chemicals or radiation; eczema; dermatitis; skin graft; ischemia;
ischemic conditions associated with surgery or traumatic injury
(e.g., vehicle accident, gunshot wound or limb crush); epilepsy;
Alzheimer's disease; Parkinson's disease; immunological response to
bacterial or viral infection; cachexia; angiogenic and
proliferative diseases; solid tumor; and cancers of a variety of
tissues such as colon, rectum, prostate, liver, lung, bronchus,
pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood,
larynx, esophagus, mouth, pharynx, urinary bladder, ovary or
uterine.
[0118] Compound I can be combined with other pharmacologically
active compounds ("second active agents") in methods and
compositions described herein. It is believed that certain
combinations may work synergistically in the treatment of
particular types diseases or disorders, and conditions and symptoms
associated with such diseases or disorders. Compound I can also
work to alleviate adverse effects associated with certain second
active agents, and vice versa.
[0119] One or more second active ingredients or agents can be used
in the methods and compositions described herein. Second active
agents can be large molecules (e.g., proteins) or small molecules
(e.g., synthetic inorganic, organometallic, or organic
molecules).
[0120] Examples of large molecule second active agents include, but
are not limited to, hematopoietic growth factors, cytokines, and
monoclonal and polyclonal antibodies. Specific examples of the
active agents are anti-CD40 monoclonal antibodies (such as, for
example, SGN-40); histone deacetylyase inhibitors (such as, for
example, SAHA and LAQ 824); heat-shock protein-90 inhibitors (such
as, for example, 17-AAG); insulin-like growth factor-1 receptor
kinase inhibitors; vascular endothelial growth factor receptor
kinase inhibitors (such as, for example, PTK787); insulin growth
factor receptor inhibitors; lysophosphatidic acid acyltransrerase
inhibitors; IkB kinase inhibitors; p38MAPK inhibitors; EGFR
inhibitors (such as, for example, gefitinib and erlotinib HCL);
HER-2 antibodies (such as, for example, trastuzumab
(Herceptin.RTM.) and pertuzumab (Omnitarg.TM.)); VEGFR antibodies
(such as, for example, bevacizumab (Avastin.TM.)); VEGFR inhibitors
(such as, for example, flk-1 specific kinase inhibitors, SU5416 and
ptk787/zk222584); P13K inhibitors (such as, for example,
wortmannin); C-Met inhibitors (such as, for example, PHA-665752);
monoclonal antibodies (such as, for example, rituximab
(Rituxan.RTM.), tositumomab (Bexxar.RTM.) edrecolomab
(Panorex.RTM.) and G250); and anti-TNF-.alpha. antibodies. Examples
of small molecule active agents include, but are not limited to,
small molecule anti-cancer agents and antibiotics (e.g.,
clarithromycin).
[0121] Specific second active compounds that can be combined with
Compound I vary depending on the specific indication to be treated,
prevented or managed.
[0122] For instance, for the treatment, prevention or management of
cancer, second active agents include, but are not limited to:
semaxanib; cyclosporin; etanercept; doxycycline; bortezomib;
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
cedefingol; celecoxib; chlorambucil; cirolemycin; cisplatin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;
dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone;
docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene;
droloxifene citrate; dromostanolone propionate; duazomycin;
edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;
enpromate; epipropidine; epirubicin hydrochloride; erbulozole;
esorubicin hydrochloride; estramustine; estramustine phosphate
sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;
fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone;
fostriecin sodium; gemcitabine; gemcitabine hydrochloride;
hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;
iproplatin; irinotecan; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; safingol; safingol hydrochloride; semustine; simtrazene;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur;
talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone
hydrochloride; temoporfin; teniposide; teroxirone; testolactone;
thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine;
toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole
hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin;
vinblastine sulfate; vincristine sulfate; vindesine; vindesine
sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine
sulfate; vorozole; zeniplatin; zinostatin; and zorubicin
hydrochloride.
[0123] Other second agents include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorins;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clathromycin; clomifene analogues; clotrimazole;
collismycin A; collismycin B; combretastatin A4; combretastatin
analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (Gleevec.RTM.),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (Genasense.RTM.); O6-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0124] Specific second active agents include, but are not limited
to, 2-methoxyestradiol, telomestatin, inducers of apoptosis in
multiple myeloma cells (such as, for example, TRAIL), bortezomib,
statins, semaxanib, cyclosporin, etanercept, doxycycline,
bortezomib, oblimersen (Genasense.RTM.), remicade, docetaxel,
celecoxib, melphalan, dexamethasone (Decadron.RTM.), steroids,
gemcitabine, cisplatinum, temozolomide, etoposide,
cyclophosphamide, temodar, carboplatin, procarbazine, gliadel,
tamoxifen, topotecan, methotrexate, Arisa.RTM., taxol, taxotere,
fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon
alpha, pegylated interferon alpha (e.g., PEG INTRON-A),
capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,
liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,
vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic
acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate,
arsenic trioxide, vincristine, doxorubicin (Doxil.RTM.),
paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate
(Emcyt.RTM.), sulindac, and etoposide.
[0125] Similarly, examples of specific second active agents
according to the indications to be treated, prevented, or managed
can be found in the following references, all of which are
incorporated herein in their entireties: U.S. Pat. Nos. 6,281,230
and 5,635,517; U.S. application Ser. Nos. 10/411,649, 10/483,213,
10/411,656, 10/693,794, 10/699,154, and 10/981,189; and U.S.
provisional application Nos. 60/554,923, 60/565,172, 60/626,975,
60/630,599, 60/631,870, and 60/533,862.
[0126] Examples of additional second active agents include, but are
not limited to, conventional therapeutics used to treat or prevent
pain such as antidepressants, anticonvulsants, antihypertensives,
anxiolytics, calcium channel blockers, muscle relaxants,
non-narcotic analgesics, opioid analgesics, anti-inflammatories,
cox-2 inhibitors, immunomodulatory agents, alpha-adrenergic
receptor agonists or antagonists, immunosuppressive agents,
corticosteroids, hyperbaric oxygen, ketamine, other anesthetic
agents, NMDA antagonists, and other therapeutics found, for
example, in the Physician's Desk Reference 2003. Specific examples
include, but are not limited to, salicylic acid acetate
(Aspirin.RTM.), celecoxib (Celebrex.RTM.), Enbrel.RTM., ketamine,
gabapentin (Neurontin.RTM.), phenyloin (Dilantin.RTM.),
carbamazepine (Tegretol.RTM.), oxcarbazepine (Trileptal.RTM.),
valproic acid (Depakene.RTM.), morphine sulfate, hydromorphone,
prednisone, griseofulvin, penthonium, alendronate, dyphenhydramide,
guanethidine, ketorolac (Acular.RTM.) thyrocalcitonin,
dimethylsulfoxide (DMSO), clonidine (Catapress.RTM.), bretylium,
ketanserin, reserpine, droperidol, atropine, phentolamine,
bupivacaine, lidocaine, acetaminophen, nortriptyline
(Pamelor.RTM.), amitriptyline (Elavil.RTM.), imipramine
(Tofranil.RTM.), doxepin (Sinequan.RTM.), clomipramine
(Anafranil.RTM.), fluoxetine (Prozac.RTM.), sertraline
(Zoloft.RTM.), nefazodone (Serzone.RTM.), venlafaxine
(Effexor.RTM.), trazodone (Desyrel.RTM.), bupropion
(Wellbutrin.RTM.), mexiletine, nifedipine, propranolol, tramadol,
lamotrigine, ziconotide, ketamine, dextromethorphan,
benzodiazepines, baclofen, tizanidine and phenoxybenzamine.
[0127] Examples of additional second active agents include, but are
not limited to, a steroid, a light sensitizer, an integrin, an
antioxidant, an interferon, a xanthine derivative, a growth
hormone, a neutrotrophic factor, a regulator of neovascularization,
an anti-VEGF antibody, a prostaglandin, an antibiotic, a
phytoestrogen, an anti-inflammatory compound or an antiangiogenesis
compound, or a combination thereof. Specific examples include, but
are not limited to, verteporfin, purlytin, an angiostatic steroid,
rhuFab, interferon-2 , pentoxifylline, tin etiopurpurin, motexafin
lutetium,
9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-
-3,20-dione, latanoprost (see U.S. Pat. No. 6,225,348),
tetracycline and its derivatives, rifamycin and its derivatives,
macrolides, metronidazole (U.S. Pat. Nos. 6,218,369 and 6,015,803),
genistein, genistin, 6'-O-Mal genistin, 6'-O--Ac genistin,
daidzein, daidzin, 6'-O-Mal daidzin, 6'-O--Ac daidzin, glycitein,
glycitin, 6'-O-Mal glycitin, biochanin A, formononetin (U.S. Pat.
No. 6,001,368), triamcinolone acetomide, dexamethasone (U.S. Pat.
No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. 5,632,984),
basic fibroblast growth factor (bFGF), transforming growth factor b
(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen
activator factor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals),
LY333531 (Eli Lilly), Miravant, and RETISERT implant (Bausch &
Lomb). All of the references cited above are incorporated herein in
their entireties by reference.
[0128] Examples of additional second active agents include, but are
not limited to, keratolytics, retinoids, .alpha.-hydroxy acids,
antibiotics, collagen, botulinum toxin, interferon, and
immunomodulatory agents. Specific examples include, but are not
limited to, 5-fluorouracil, masoprocol, trichloroacetic acid,
salicylic acid, lactic acid, ammonium lactate, urea, tretinoin,
isotretinoin, antibiotics, collagen, botulinum toxin, interferon,
corticosteroid, transretinoic acid and collagens such as human
placental collagen, animal placental collagen, Dermalogen,
AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast,
and Isolagen.
[0129] Examples of additional second active agents include, but are
not limited to, anticoagulants, diuretics, cardiac glycosides,
calcium channel blockers, vasodilators, prostacyclin analogues,
endothelin antagonists, phosphodiesterase inhibitors (e.g., PDE V
inhibitors), endopeptidase inhibitors, lipid lowering agents,
thromboxane inhibitors, and other therapeutics known to reduce
pulmonary artery pressure. Specific examples include, but are not
limited to, warfarin (Coumadin.RTM.), a diuretic, a cardiac
glycoside, digoxin-oxygen, diltiazem, nifedipine, a vasodilator
such as prostacyclin (e.g., prostaglandin 12 (PGI2), epoprostenol
(EPO, Floran.RTM.), treprostinil (Remodulin.RTM.), nitric oxide
(NO), bosentan (Tracleer.RTM.), amlodipine, epoprostenol
(Floran.RTM.), treprostinil (Remodulin.RTM.), prostacyclin,
tadalafil (Cialis.RTM.), simvastatin (Zocor.RTM.), omapatrilat
(Vanlev.RTM.), irbesartan (Avapro.RTM.), pravastatin
(Pravachol.RTM.), digoxin, L-arginine, iloprost, betaprost, and
sildenafil (Viagra.RTM.).
[0130] Examples of additional second active agents include, but are
not limited to, anthracycline, platinum, alkylating agent,
oblimersen (Genasense.RTM.), cisplatinum, cyclophosphamide,
temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan,
methotrexate, taxotere, irinotecan, capecitabine, cisplatin,
thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,
dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,
busulphan, prednisone, bisphosphonate, arsenic trioxide,
vincristine, doxorubicin (Doxil.RTM.), paclitaxel, ganciclovir,
adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine,
thiotepa, tetracycline and gemcitabine.
[0131] Examples of additional second active agents include, but are
not limited to, chloroquine, quinine, quinidine, pyrimethamine,
sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,
primaquine, hydroxychloroquine, proguanil, atovaquone,
azithromycin, suramin, pentamidine, melarsoprol, nifurtimox,
benznidazole, amphotericin B, pentavalent antimony compounds (e.g.,
sodium stiboglucuronate), interfereon gamma, itraconazole, a
combination of dead promastigotes and BCG, leucovorin,
corticosteroids, sulfonamide, spiramycin, IgG (serology),
trimethoprim, and sulfamethoxazole.
[0132] Examples of additional second active agents include, but are
not limited to: antibiotics (therapeutic or prophylactic) such as,
but not limited to, ampicillin, clarithromycin, tetracycline,
penicillin, cephalosporins, streptomycin, kanamycin, and
erythromycin; antivirals such as, but not limited to, amantadine,
rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma;
immunologic enhancing drugs such as, but not limited to, levami
sole and isoprinosine; biologics such as, but not limited to,
gammaglobulin, transfer factor, interleukins, and interferons;
hormones such as, but not limited to, thymic; and other immunologic
agents such as, but not limited to, B cell stimulators (e.g.,
BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growth factors
(e.g., TGF- ), antibodies (e.g., anti-CD40 and IgM),
oligonucleotides containing unmethylated CpG motifs, and vaccines
(e.g., viral and tumor peptide vaccines).
[0133] Examples of additional second active agents include, but are
not limited to: a dopamine agonist or antagonist, such as, but not
limited to, Levodopa, L-DOPA, cocaine, .alpha.-methyl-tyrosine,
reserpine, tetrabenazine, benzotropine, pargyline, fenodolpam
mesylate, cabergoline, pramipexole dihydrochloride, ropinorole,
amantadine hydrochloride, selegiline hydrochloride, carbidopa,
pergolide mesylate, Sinemet CR, and Symmetrel; a MAO inhibitor,
such as, but not limited to, iproniazid, clorgyline, phenelzine and
isocarboxazid; a COMT inhibitor, such as, but not limited to,
tolcapone and entacapone; a cholinesterase inhibitor, such as, but
not limited to, physostigmine saliclate, physostigmine sulfate,
physostigmine bromide, meostigmine bromide, neostigmine
methylsulfate, ambenonim chloride, edrophonium chloride, tacrine,
pralidoxime chloride, obidoxime chloride, trimedoxime bromide,
diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; an
anti-inflammatory agent, such as, but not limited to, naproxen
sodium, diclofenac sodium, diclofenac potassium, celecoxib,
sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen,
ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,
sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenylate
mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab,
daclizumab, salicylic acid, acetylsalicylic acid, methyl
salicylate, diflunisal, salsalate, olsalazine, sulfasalazine,
acetaminophen, indomethacin, sulindac, mefenamic acid,
meclofenamate sodium, tolmetin, ketorolac, dichlofenac,
flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam,
droxicam, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone,
antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold
sodium thiomalate, auranofin, methotrexate, colchicine,
allopurinol, probenecid, sulfinpyrazone and benzbromarone or
betamethasone and other glucocorticoids; and an antiemetic agent,
such as, but not limited to, metoclopromide, domperidone,
prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron, hydroxyzine, acetylleucine
monoethanolamine, alizapride, azasetron, benzquinamide,
bietanautine, bromopride, buclizine, clebopride, cyclizine,
dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,
metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine,
sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine,
tropisetron, and a mixture thereof.
[0134] Examples of additional second active agents include, but are
not limited to, immunomodulatory agents, immunosuppressive agents,
antihypertensives, anticonvulsants, fibrinolytic agents,
antiplatelet agents, antipsychotics, antidepressants,
benzodiazepines, buspirone, amantadine, and other known or
conventional agents used in patients with CNS injury/damage and
related syndromes. Specific examples include, but are not limited
to: steroids (e.g., glucocorticoids, such as, but not limited to,
methylprednisolone, dexamethasone and betamethasone); an
anti-inflammatory agent, including, but not limited to, naproxen
sodium, diclofenac sodium, diclofenac potassium, celecoxib,
sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen,
ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,
sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate
mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab,
daclizumab, salicylic acid, acetylsalicylic acid, methyl
salicylate, diflunisal, salsalate, olsalazine, sulfasalazine,
acetaminophen, indomethacin, sulindac, mefenamic acid,
meclofenamate sodium, tolmetin, ketorolac, dichlofenac,
flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam,
droxicam, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone,
antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold
sodium thiomalate, auranofin, methotrexate, colchicine,
allopurinol, probenecid, sulfinpyrazone and benzbromarone; a cAMP
analog including, but not limited to, db-cAMP; an agent comprising
a methylphenidate drug, which comprises 1-threo-methylphenidate,
d-threo-methylphenidate, dl-threo-methylphenidate,
1-erythro-methylphenidate, d-erythro-methylphenidate,
dl-erythro-methylphenidate, and a mixture thereof; and a diuretic
agent such as, but not limited to, mannitol, furosemide, glycerol,
and urea.
[0135] Examples of additional second active agents include, but are
not limited to, a tricyclic antidepressant agent, a selective
serotonin reuptake inhibitor, an antiepileptic agent (gabapentin,
pregabalin, carbamazepine, oxcarbazepine, levitiracetam,
topiramate), an antiaryhthmic agent, a sodium channel blocking
agent, a selective inflammatory mediator inhibitor, an opioid
agent, a second immunomodulatory compound, a combination agent, and
other known or conventional agents used in sleep therapy. Specific
examples include, but are not limited to, Neurontin, oxycontin,
morphine, topiramate, amitryptiline, nortryptiline, carbamazepine,
Levodopa, L-DOPA, cocaine, .alpha.-methyl-tyrosine, reserpine,
tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,
cabergoline, pramipexole dihydrochloride, ropinorole, amantadine
hydrochloride, selegiline hydrochloride, carbidopa, pergolide
mesylate, Sinemet CR, Symmetrel, iproniazid, clorgyline,
phenelzine, isocarboxazid, tolcapone, entacapone, physostigmine
saliclate, physostigmine sulfate, physostigmine bromide,
meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,
edrophonium chloride, tacrine, pralidoxime chloride, obidoxime
chloride, trimedoxime bromide, diacetyl monoxim, endrophonium,
pyridostigmine, demecarium, naproxen sodium, diclofenac sodium,
diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal,
etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone, refecoxib,
methotrexate, leflunomide, sulfasalazine, gold salts, RHo-D Immune
Globulin, mycophenylate mofetil, cyclosporine, azathioprine,
tacrolimus, basiliximab, daclizumab, salicylic acid,
acetylsalicylic acid, methyl salicylate, diflunisal, salsalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,
dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,
aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,
colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,
betamethasone and other glucocorticoids, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture thereof.
[0136] Examples of additional second active agents include, but are
not limited to: interleukins, such as IL-2 (including recombinant
IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18;
interferons, such as interferon alfa-2a, interferon alfa-2b,
interferon alfa-n1, interferon alfa-n3, interferon beta-I a, and
interferon gamma-I b; and G-CSF; hydroxyurea; butyrates or butyrate
derivatives; nitrous oxide; HEMOXIN.TM. (NIPRISAN.TM.; see U.S.
Pat. No. 5,800,819); Gardos channel antagonists such as
clotrimazole and triaryl methane derivatives; Deferoxamine; protein
C; and transfusions of blood, or of a blood substitute such as
Hemospan.TM. or Hemospan.TM. PS (Sangart).
[0137] Administration of Compound I and a second active agent to a
patient can occur simultaneously or sequentially by the same or
different routes of administration. The suitability of a particular
route of administration employed for a particular active agent will
depend on the active agent itself (e.g., whether it can be
administered orally without decomposing prior to entering the blood
stream) and the disease being treated. In certain embodiments,
Compound I is administered orally. Preferred routes of
administration for the second active agents or ingredients provided
herein are known to those of ordinary skill in the art. See, e.g.,
Physicians' Desk Reference, 1755-1760 (56th ed., 2002).
[0138] In one embodiment, the second active agent is administered
intravenously or subcutaneously. In another embodiment, the second
active agent is administered intravenously or subcutaneously once
or twice daily in an amount of from about 1 to about 1000 mg, from
about 5 to about 500 mg, from about 10 to about 350 mg, or from
about 50 to about 200 mg. The specific amount of the second active
agent will depend on the specific agent used, the type of disease
being treated or managed, the severity and stage of disease, and
the amount(s) of Compound I and any optional additional active
agents concurrently administered to the patient.
5.4 Pharmaceutical Compositions and Routes of Administration
[0139] The solid forms comprising Compound I can be administered to
a patient orally or parenterally in the conventional form of
preparations, such as capsules, microcapsules, tablets, granules,
powder, troches, pills, suppositories, injections, suspensions and
syrups. Suitable formulations can be prepared by methods commonly
employed using conventional, organic or inorganic additives, such
as an excipient (e.g., sucrose, starch, mannitol, sorbitol,
lactose, glucose, cellulose, talc, calcium phosphate or calcium
carbonate), a binder (e.g., cellulose, methylcellulose,
hydroxymethylcellulose, polypropylpyrrolidone,
polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol,
sucrose or starch), a disintegrator (e.g., starch,
carboxymethylcellulose, hydroxypropylstarch, low substituted
hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or
calcium citrate), a lubricant (e.g., magnesium stearate, light
anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring
agent (e.g., citric acid, menthol, glycine or orange powder), a
preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben
or propylparaben), a stabilizer (e.g., citric acid, sodium citrate
or acetic acid), a suspending agent (e.g., methylcellulose,
polyvinyl pyrroliclone or aluminum stearate), a dispersing agent
(e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and
base wax (e.g., cocoa butter, white petrolatum or polyethylene
glycol). The effective amount of the solid forms comprising
Compound I in the pharmaceutical composition may be at a level that
will exercise the desired effect; for example, about 0.005 mg/kg of
a patient's body weight to about 10 mg/kg of a patient's body
weight in unit dosage for both oral and parenteral
administration.
[0140] The physical characteristics of different solid forms can,
in some cases, affect their bioavailability, but the amounts of the
solid forms that are therapeutically or prophylactically effective
in the treatment of various diseases and conditions can be readily
determined by those of ordinary skill in the pharmacy or medical
arts. In general, the solid forms comprising Compound I can be
administered one to four times a day in a dose of about 0.005 mg/kg
of a patient's body weight to about 10 mg/kg of a patient's body
weight in a patient, but the above dosage may be properly varied
depending on the age, body weight and medical condition of the
patient and the type of administration. In one embodiment, the dose
is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of
a patient's body weight, about 0.05 mg/kg of a patient's body
weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg
of a patient's body weight to about 0.75 mg/kg of a patient's body
weight or about 0.25 mg/kg of a patient's body weight to about 0.5
mg/kg of a patient's body weight. In one embodiment, one dose is
given per day. In any given case, the amount of the solid form
comprising Compound I administered will depend on such factors as
the solubility of the active component, the formulation used and
the route of administration.
[0141] In another embodiment, provided herein are methods for the
treatment or prevention of a disease or disorder comprising the
administration of about 0.375 mg/day to about 750 mg/day, about
0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75
mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to
about 37 mg/day of a solid form comprising Compound I to a patient
in need thereof.
[0142] In another embodiment, provided herein are methods for the
treatment or prevention of a disease or disorder comprising the
administration of about 1 mg/day to about 1200 mg/day, about 10
mg/day to about 1200 mg/day, about 100 mg/day to about 1200 mg/day,
about 400 mg/day to about 1200 mg/day, about 600 mg/day to about
1200 mg/day, about 400 mg/day to about 800 mg/day or about 600
mg/day to about 800 mg/day of a solid form comprising Compound Ito
a patient in need thereof. In a particular embodiment, the methods
disclosed herein comprise the administration of 400 mg/day, 600
mg/day or 800 mg/day of a solid form comprising Compound Ito a
patient in need thereof.
[0143] In another embodiment, provided herein are unit dosage
formulations that comprise between about 1 mg and 200 mg, about 35
mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg
and about 1000 mg, or about 500 mg and about 1000 mg of a solid
form comprising Compound I.
[0144] In a particular embodiment, provided herein are unit dosage
formulation comprising about 100 mg or 400 mg of a solid form
comprising Compound I.
[0145] In another embodiment, provided herein are unit dosage
formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg,
35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250
mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400
mg of a solid form comprising Compound I.
[0146] A solid form comprising Compound I can be administered once,
twice, three, four or more times daily. In a particular embodiment,
doses of 600 mg or less are administered as a once daily dose and
doses of more than 600 mg are administered twice daily in an amount
equal to one half of the total daily dose.
[0147] A solid form comprising Compound I can be administered
orally for reasons of convenience. In one embodiment, when
administered orally, Compound I is administered with a meal and
water. In another embodiment, the Compound I is dispersed in water
or juice (e.g., apple juice or orange juice) and administered
orally as a suspension.
[0148] The solid form comprising Compound I can also be
administered intradermally, intramuscularly, intraperitoneally,
percutaneously, intravenously, subcutaneously, intranasally,
epidurally, sublingually, intracerebrally, intravaginally,
transdermally, rectally, by inhalation, or topically to the ears,
nose, eyes, or skin. The mode of administration is left to the
discretion of the health-care practitioner, and can depend in-part
upon the site of the medical condition.
[0149] In one embodiment, provided herein are capsules containing a
solid form comprising Compound I without an additional carrier,
excipient or vehicle.
[0150] In another embodiment, provided herein are compositions
comprising an effective amount of a solid form comprising Compound
I and a pharmaceutically acceptable carrier or vehicle, wherein a
pharmaceutically acceptable carrier or vehicle can comprise an
excipient, diluent, or a mixture thereof. In one embodiment, the
composition is a pharmaceutical composition.
[0151] The compositions can be in the form of tablets, chewable
tablets, capsules, solutions, parenteral solutions, troches,
suppositories and suspensions and the like. Compositions can be
formulated to contain a daily dose, or a convenient fraction of a
daily dose, in a dosage unit, which may be a single tablet or
capsule or convenient volume of a liquid. In one embodiment, the
solutions are prepared from water-soluble salts, such as the
hydrochloride salt. In general, all of the compositions are
prepared according to known methods in pharmaceutical chemistry.
Capsules can be prepared by mixing a solid form comprising Compound
I with a suitable carrier or diluent and filling the proper amount
of the mixture in capsules. The usual carriers and diluents
include, but are not limited to, inert powdered substances such as
starch of many different kinds, powdered cellulose, especially
crystalline and microcrystalline cellulose, sugars such as
fructose, mannitol and sucrose, grain flours and similar edible
powders.
[0152] Tablets can be prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives are also useful.
Typical tablet binders are substances such as starch, gelatin and
sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates,
methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol, ethylcellulose and waxes can also serve as binders.
[0153] A lubricant might be necessary in a tablet formulation to
prevent the tablet and punches from sticking in the die. The
lubricant can be chosen from such slippery solids as talc,
magnesium and calcium stearate, stearic acid and hydrogenated
vegetable oils. Tablet disintegrators are substances that swell
when wetted to break up the tablet and release the compound. They
include starches, clays, celluloses, algins and gums. More
particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood cellulose, powdered natural sponge, cation-exchange
resins, alginic acid, guar gum, citrus pulp and carboxymethyl
cellulose, for example, can be used as well as sodium lauryl
sulfate. Tablets can be coated with sugar as a flavor and sealant,
or with film-forming protecting agents to modify the dissolution
properties of the tablet. The compositions can also be formulated
as chewable tablets, for example, by using substances such as
mannitol in the formulation.
[0154] When it is desired to administer a solid form comprising
Compound I as a suppository, typical bases can be used. Cocoa
butter is a traditional suppository base, which can be modified by
addition of waxes to raise its melting point slightly.
Water-miscible suppository bases comprising, particularly,
polyethylene glycols of various molecular weights are in wide
use.
[0155] The effect of the solid form comprising Compound I can be
delayed or prolonged by proper formulation. For example, a slowly
soluble pellet of the solid form comprising Compound I can be
prepared and incorporated in a tablet or capsule, or as a
slow-release implantable device. The technique also includes making
pellets of several different dissolution rates and filling capsules
with a mixture of the pellets. Tablets or capsules can be coated
with a film that resists dissolution for a predictable period of
time. Even the parenteral preparations can be made long-acting, by
dissolving or suspending the solid form comprising Compound I in
oily or emulsified vehicles that allow it to disperse slowly in the
serum.
6. EXAMPLES
[0156] The following Examples are presented by way of illustration,
not limitation.
6.1 Example 1
Synthesis of
4-[9-(Tetrahydro-Furan-3-yl)-8-(2,4,6-Trifluoro-Phenylamino)-9H-Purin-2-Y-
lamino]-Cyclohexan-1-ol
[0157] The compound named
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I"), can be prepared using the
synthesis outlined in FIG. 13. Starting from Compound A
(2,4-dichloro-5-nitropyrimidine), Compound I is obtained in 40%
overall yield and the purity is >99% (HPLC area percent). A
total of 550 g of Compound I was prepared by this process.
[0158] Stages 1A & 1B involve a "one-pot" formation of Compound
B (2,4-diamino-substituted-5-nitropyrimidine) via a sequential
chemoselective displacement of the chloro groups with the
appropriate amine. Compound A (2,4-dichloro-5-nitropyrimidine) (363
g, 1.87 mol, 1.0 eq.) was charged to a reaction vessel with
(S)-3-amino tetrahydrofuran (1) (230 g, 1.87 mol, 1.0 eq.) and
CH.sub.2Cl.sub.2 (DCM) (3.45 L, 15 vol.). The displacement of the
4-chloro group with (S)-3-amino tetrahydrofuran (1) in the presence
of DIPEA (684 mL, 3.93 mol, 2.1 eq.) was performed at -30 to
-20.degree. C. followed by warming the reaction to 20-25.degree. C.
over 10-18 h. Upon consumption of Compound A (IPC indicated <1
AP, HPLC) the reaction mixture was charged with trans-4-amino
cyclohexanol (3) (215 g, 1.87 mol, 1.0 eq.) and additional DIPEA
(391 mL, 2.24 mol, 1.2 eq.). The mixture was heated at
35-40.degree. C. for 10-18 h or until HPLC analysis indicated <1
AP, (HPLC) of 2. A solvent swap of DCM to MeCN was carried out by
distilling off about 12 volumes of DCM and adding about 3 volumes
of MeCN. Water (4.6 L, 20 vol) was then added and the reaction
mixture was cooled to between about 0-5.degree. C. and stirred for
about 1-2 h to give Compound B as a filterable solid. The solids
were collected by filtration, washed with water (2.3 L, 10 vol),
washed with MTBE (2.3 L, 10 vol) and dried at 35-40.degree. C.
until KF<3% (yield 82-89 M %, HPLC purity 90-95 AP).
[0159] Stage 2A involves the reduction of the nitro group of
Compound B to the corresponding aniline (4). A mixture of Compound
B (120 g, 0.37 mol, 1.0 eq.) and 10% Pd/C (50% wet, 10 wt %) (12 g,
10 wt %) were charged with MeOH (1.5 L, 12.5 vol). The mixture was
hydrogenated at 35-40.degree. C., 40-50 psi H.sub.2 for 2-4 h with
shaking (or until HPLC analysis indicated <1 AP (HPLC) of
Compound B remaining) The catalyst was removed by filtration
through a celite bed. The celite was washed with warm
(35-40.degree. C.) MeOH (1.2 L, 10 vol). The filtrate was
concentrated and a solvent swap of MeOH to THF was carried out by
distilling off MeOH and charging with THF (1.8 L, 15 vol) to give a
THF solution/slurry of Stage 2A product (4), which was carried to
the next step (yield assumed >99 M %, HPLC purity >94 AP).
The solvent swap with THF was performed until the .sup.1H NMR of
the distillate revealed <2% of MeOH. The THF solution can be
stored for up to 24 h at ambient temperature (20-25.degree. C.)
under N.sub.2 without degradation.
[0160] Stage 2B involves the coupling of Stage 2A product (4) with
commercially available 2,4,6-trifluorophenyl isothiocyanate (5).
Stage 2A product (4) (217.7 g, 0.742 mol, 1 eq.) as a THF solution
was reacted with 2,4,6-trifluorophenyl isothiocyanate (5) with
stirring at 20-25.degree. C. for 15-18 h (or until IPC indicated
<1 AP (HPLC) of (4)) to afford the intermediate thiourea (6).
The reaction was charged with EDC (156.5 g, 0.816 mol, 1.1 eq.) and
heated at 60-65.degree. C. for 3.5-6 h (or until IPC indicated
<1 AP (HPLC) of (6)) to give the desired crude purine (Compound
I). The mixture was then treated with AcOH/H.sub.2O (212 mL, 3.71
mol, 5 eq.) and water (650 mL, 3 vol) and heated for 1.5-2 h at
60-65.degree. C. The mixture was then cooled to 20-25.degree. C.
and diluted with EtOAc (3.3 L, 15 vol). The phases were separated
and the organic phase was washed with water (2.times.5 vol),
Na.sub.2CO.sub.3 (2.times.5 vol, 5 eq.) (or until pH=9-11) and
again with water (5 vol). The organic phase (EtOAc) was collected
and water was removed by azeotropic distillation using EtOAc) until
KF<5%. A solvent swap with EtOH was performed by distilling off
EtOAc and charging with EtOH (1.1 L, 5 vol) until the .sup.1H NMR
of the distillate revealed <2% of EtOAc. The ethanol slurry of
crude Compound I can be stored for up to 64 h at 20-25.degree. C.
under an inert atmosphere. The resultant slurry was then heated to
78-83.degree. C. and water (15 volumes) was added at such a rate as
to maintain the reaction temperature at >75.degree. C. The
solution was seeded (1-2 wt % Compound I), followed by the addition
of water (5 volumes) and cooling of the reaction mixture to
20-25.degree. C. Crude Compound I was collected by filtration and
dried in vacuo at 35-40.degree. C. for 18-24 h (or until KF<1%)
(yield 55-62 M %, HPLC purity 88-99 AP).
[0161] Stage 3 involves recrystallization of crude Compound I.
Crude Compound I (717 g, 1.0 eq.) was heated in EtOH (6.1 L, 8.5
vol) at 78-83.degree. C. and stirred until solids dissolved. The
solution of crude Compound I was cooled to 50-55.degree. C. and
polish filtered. The solution was then heated to 78-83.degree. C.
and water (10.8 L, 15 volumes) was added while maintaining the
temperature at >75.degree. C. The solution was seeded (7 g, 1-2
wt % Compound I), followed by cooling of the reaction mixture to
20-25.degree. C. Recrystallized Compound I was collected by
filtration and dried at up to 40.degree. C. (or until KF<1%)
(recovery 78-80 M %, HPLC purity 99.42 AP).
[0162] Compound I was also prepared according to the alternative
methods depicted in FIG. 15 and FIG. 16.
6.2 Example 2
Preparation of Solid Forms: General Procedures
[0163] Equilibration/slurry and evaporation experiments were
carried out by adding an excess of Compound I free base or HCl salt
to 2 mL of solvent. The resulting mixture was agitated for at least
24 hours at 25.degree. C. and 50.degree. C. in two separate sets of
experiments. Upon reaching equilibrium, the saturated supernatant
solution was removed and allowed to evaporate slowly in an open
vial under nitrogen at 25.degree. C. or 50.degree. C.,
respectively. The slurry resulting from the equilibration was
filtered and air-dried.
[0164] Crystallization using cooling methods were performed for
Compound I free base. Compound I was dissolved in a solvent at an
elevated temperature, approximately 65.degree. C., and allowed to
cool to ambient temperature. Samples that did not crystallize at
ambient temperature were placed in a refrigerator (about
2-8.degree. C.). Solids were isolated by decantation and allowed to
dry in the air.
[0165] Precipitations for Compound I free base were also carried
out using solvent/antisolvent combinations. The solid was dissolved
in a solvent in Compound I had high solubility, and then a selected
solvent in which Compound I was relatively insoluble (i.e., an
antisolvent) was added to the solution. A precipitate was formed
immediately in some solvent/antisolvent systems. If precipitation
did not immediately occur, the resulting mixture was allowed to
cool in a refrigerator until a precipitate formed. The precipitate
was then isolated by decantation and allowed to dry in the air.
TABLE-US-00001 Results of Compound I Free Base Crystallization
Experiments Solvent Condition Resulting Form by XRPD Acetone
Evaporation at about 25.degree. C. Compound I Free Base Form A
n-Butanol Evaporation at about 25.degree. C. Compound I Free Base
Form A Absolute ethanol Evaporation at about 25.degree. C. Compound
I Free Base Form A Methanol Evaporation at about 25.degree. C.
Compound I Free Base Form A 2-Propanol Evaporation at about
25.degree. C. Compound I Free Base Form A Tetrahydrofuran
Evaporation at about 25.degree. C. Compound I Free Base Form A
Ethanol/Water (1/1) Evaporation at about 25.degree. C. Compound I
Free Base Form A Acetone Evaporation at about 50.degree. C.
Compound I Free Base Form A n-Butanol Evaporation at about
50.degree. C. Compound I Free Base Form A Absolute ethanol
Evaporation at about 50.degree. C. Compound I Free Base Form A
Methanol Evaporation at about 50.degree. C. Compound I Free Base
Form A 2-Propanol Evaporation at about 50.degree. C. Compound I
Free Base Form A Tetrahydrofuran Evaporation at about 50.degree. C.
Compound I Free Base Form A Ethanol/Water (1/1) Evaporation at
about 50.degree. C. Compound I Free Base Form A Acetone Slurry at
about 25.degree. C. Compound I Free Base Form A Acetonitrile Slurry
at about 25.degree. C. Compound I Free Base Form A n-Butanol Slurry
at about 25.degree. C. Compound I Free Base Form A Ethanol Slurry
at about 25.degree. C. Compound I Free Base Form A Ethyl acetate
Slurry at about 25.degree. C. Compound I Free Base Form A Heptane
Slurry at about 25.degree. C. Compound I Free Base Form A Methylene
chloride Slurry at about 25.degree. C. Compound I Free Base Form A
Methyl ethyl ketone Slurry at about 25.degree. C. Compound I Free
Base Form A Methyl t-butyl ether Slurry at about 25.degree. C.
Compound I Free Base Form A 2-Propanol Slurry at about 25.degree.
C. Compound I Free Base Form A Toluene Slurry at about 25.degree.
C. Compound I Free Base Form A Water Slurry at about 25.degree. C.
Compound I Free Base Form A Ethanol/Water (1/1) Slurry at about
25.degree. C. Compound I Free Base Form A Acetone Slurry at about
50.degree. C. Compound I Free Base Form A Acetonitrile Slurry at
about 50.degree. C. Compound I Free Base Form A n-Butanol Slurry at
about 50.degree. C. Compound I Free Base Form A Ethanol Slurry at
about 50.degree. C. Compound I Free Base Form A Ethyl acetate
Slurry at about 50.degree. C. Compound I Free Base Form A Heptane
Slurry at about 50.degree. C. Compound I Free Base Form A Methyl
ethyl ketone Slurry at about 50.degree. C. Compound I Free Base
Form A 2-Propanol Slurry at about 50.degree. C. Compound I Free
Base Form A Toluene Slurry at about 50.degree. C. Compound I Free
Base Form A Water Slurry at about 50.degree. C. Compound I Free
Base Form A Ethanol/Water (1/1) Slurry at about 50.degree. C.
Compound I Free Base Form A Ethanol Antisolvent precipitation with
Compound I Free Base Form A MTBE (1:10 solvent:antisolvent ratio at
50.degree. C.) Ethanol Antisolvent precipitation with Compound I
Free Base Form A heptane (1:10 solvent:antisolvent ratio at
50.degree. C.) THF Antisolvent precipitation with Compound I Free
Base Form A MTBE (1:10 solvent:antisolvent ratio at 50.degree. C.)
THF Antisolvent precipitation with Compound I Free Base Form A
heptane (1:10 solvent:antisolvent ratio at 50.degree. C.) THF
Antisolvent precipitation with Compound I Free Base Form A toluene
(1:10 solvent:antisolvent ratio at 50.degree. C.) Acetone
Equilibrate Form A in solvent for 4 Compound I Free Base Form A
weeks at 40.degree. C. Acetonitrile Equilibrate Form A in solvent
for 4 Compound I Free Base Form A weeks at 40.degree. C. Ethyl
acetate Equilibrate Form A in solvent for 4 Compound I Free Base
Form A weeks at 40.degree. C. Heptane Equilibrate Form A in solvent
for 4 Compound I Free Base Form A weeks at 40.degree. C. 2-Propanol
Equilibrate Form A in solvent for 4 Compound I Free Base Form A
weeks at 40.degree. C. MTBE Equilibrate Form A in solvent for 4
Compound I Free Base Form A weeks at 40.degree. C. Toluene
Equilibrate Form A in solvent for 4 Compound I Free Base Form A
weeks at 40.degree. C. Water Equilibrate Form A in solvent for 4
Compound I Free Base Form A weeks at 40.degree. C. Ethanol/water
(1/1) Slow cooling crystallization Compound I Free Base Hydrate
TABLE-US-00002 Results of Compound I HCl Salt Crystallization
Experiments Solvent Condition Resulting Form by XRPD n-Butanol
Evaporation at about 25.degree. C. Compound I HCl Salt Form A
Absolute ethanol Evaporation at about 25.degree. C. Compound I HCl
Salt Form A Methanol Evaporation at about 25.degree. C. Compound I
HCl Salt Form A 2-Propanol Evaporation at about 25.degree. C.
Compound I HCl Salt Form A Water Evaporation at about 25.degree. C.
Compound I HCl Salt Form A Ethanol/Water (1/1) Evaporation at about
25.degree. C. Compound I HCl Salt Form A n-Butanol Evaporation at
about 25.degree. C. Compound I HCl Salt Form A Absolute ethanol
Evaporation at about 25.degree. C. Compound I HCl Salt Form A
Methanol Evaporation at about 25.degree. C. Compound I HCl Salt
Form A + amorphous 2-Propanol Evaporation at about 25.degree. C.
Compound I HCl Salt Form A Water Evaporation at about 25.degree. C.
Compound I HCl Salt amorphous Ethanol/Water (1/1) Evaporation at
about 25.degree. C. Compound I HCl Salt amorphous Acetone Slurry at
about 25.degree. C. Compound I HCl Salt Form A Acetonitrile Slurry
at about 25.degree. C. Compound I HCl Salt Form A n-Butanol Slurry
at about 25.degree. C. Compound I HCl Salt Form A Ethyl acetate
Slurry at about 25.degree. C. Compound I HCl Salt Form A Heptane
Slurry at about 25.degree. C. Compound I HCl Salt Form A Methylene
chloride Slurry at about 25.degree. C. Compound I HCl Salt Form A
Methyl ethyl ketone Slurry at about 25.degree. C. Compound I HCl
Salt Form A Methyl t-butyl ether Slurry at about 25.degree. C.
Compound I HCl Salt Form A 2-Propanol Slurry at about 25.degree. C.
Compound I HCl Salt Form A Toluene Slurry at about 25.degree. C.
Compound I HCl Salt Form A Tetrahydrofuran Slurry at about
25.degree. C. Compound I HCl Salt Form A Acetone Slurry at about
50.degree. C. Compound I HCl Salt Form A Acetonitrile Slurry at
about 50.degree. C. Compound I HCl Salt Form A n-Butanol Slurry at
about 50.degree. C. Compound I HCl Salt Form A Ethyl acetate Slurry
at about 50.degree. C. Compound I HCl Salt Form A Heptane Slurry at
about 50.degree. C. Compound I HCl Salt Form A Methyl ethyl ketone
Slurry at about 50.degree. C. Compound I HCl Salt Form A 2-Propanol
Slurry at about 50.degree. C. Compound I HCl Salt Form A Toluene
Slurry at about 50.degree. C. Compound I HCl Salt Form A
Tetrahydrofuran Slurry at about 50.degree. C. Compound I HCl Salt
Form A Acetone Equilibrate HCl salt in solvent for 4 Compound I HCl
Salt Form A weeks at 40.degree. C. Acetonitrile Equilibrate Form A
in solvent for 4 Compound I HCl Salt Form A weeks at 40.degree. C.
Ethyl acetate Equilibrate Form A in solvent for 4 Compound I HCl
Salt Form A weeks at 40.degree. C. Heptane Equilibrate Form A in
solvent for 4 Compound I HCl Salt Form A weeks at 40.degree. C.
2-Propanol Equilibrate Form A in solvent for 4 Compound I HCl Salt
Form A weeks at 40.degree. C. MTBE Equilibrate Form A in solvent
for 4 Compound I HCl Salt Form A weeks at 40.degree. C. Toluene
Equilibrate Form A in solvent for 4 Compound I HCl Salt Form A
weeks at 40.degree. C. THF Equilibrate Form A in solvent for 4
Compound I HCl Salt Form A weeks at 40.degree. C.
6.3 Example 3
Approximate Solubilities of Solid Forms
[0166] A weighed sample comprising either the free base or the HCl
salt of Compound I was treated with 2 mL of a solvent (either HPLC
or reagent grade). The resulting mixture was agitated for at least
24 hours at about 25.degree. C. When all of the solids were
dissolved by visual inspection, the estimated solubility was
calculated. The solubility was estimated from these experiments
based on the total volume of solvent used to give a complete
solution. Measured values are provided in the tables below. The
actual solubility may be greater than those calculated due to the
use of a large amount of solvent or a slow rate of dissolution. A
known volume of filtrate was evaporated to dryness and the weight
of the residue was measured.
TABLE-US-00003 Approximate Solubilties of Solid Form Comprising
Compound I Approximate Solubility Approximate Solubility (mg/mL) of
Form A of the (mg/mL) of Form A of the Solvent Free Base of
Compound I Free Base of Compound I Acetone 11.58 1.14 Acetonitrile
2.58 1.56 n-Butanol 19.31 7.50 Absolute 47.09 >50 ethanol Ethyl
acetate 3.91 0.02 Heptane 0.55 0.51 Methylene 11.57 5.00 chloride
Methyl ethyl 8.74 0.68 ketone Methanol >50 >50 Methyl t- 1.10
0.46 butyl ether 2-Propanol 15.65 6.39 Tetrahydro- >50 2.03
furan Toluene 0.36 0.04 Water 0.41 >50 Ethanol/Water 11.63
>50 (1/1)
6.4 Example 4
Preparation of Form a of the Free Base of Compound I
[0167] Crude
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I") (5 g) was dissolved in
ethanol (35 ml, 7 vol) at reflux (78-82.degree. C.). Water (75 ml,
15 vol) was added, maintaining the temperature above 75.degree. C.
The solution was seeded (0.5-1%) and allowed to cool to ambient
temperature (20-25.degree. C.) over 4-6 h. The product was
collected by filtration and washed with water (25 ml, 5 vol) then
dried (18 h, 40-45.degree. C.) to yield Form A of the free base of
Compound I as an off-white crystalline solid.
6.5 Example 5
Preparation of a Hydrate of the Free Base of Compound I
[0168] Crude
4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-y-
lamino]-cyclohexan-1-ol ("Compound I") (100 mg) was dissolved in a
1:1 mixture of ethanol and water (2 mL) at approximately 65.degree.
C. The solution was cooled slowly to about 4.degree. C. Resulting
solids were isolated by decanting the liquid, and the solids were
allowed to air dry. The resulting white solid was characterized by
XRPD, DSC and TG/IR as a crystalline hydrate of the free base of
Compound I. By microscopy, the solid comprised needle-shaped
crystals.
6.6 Example 6
Preparation of Form a of the HCl Salt of Compound I
[0169] Form A of the bis-HCl salt of Compound I can be prepared by
the two procedures described below.
[0170] Procedure 1: To a sample (100-200 mg) of the free base of
Compound I was added solvent (15-30 volumes) and the mixture was
heated (60-85.degree. C.) until dissolution occurred. The solution
was allowed to cool to room temperature (20-25.degree. C.) and
gaseous hydrochloric acid (1-3 eq) was added. The sample was stored
between 5-25.degree. C. and monitored for crystallization for up to
3 weeks. The Form A crystal form of the bis-HCl salt of Compound I
that crystallized from this procedure was isolated by filtration,
dried (20-40.degree. C.) and analyzed.
[0171] Procedure 2: A 7.2 g batch of Form A the bis-HCl salt of
Compound I was prepared from 8 g of the free base of Compound I.
The free base of Compound I was dissolved in ethanol (9 volumes) at
75-80.degree. C. The solution was allowed to cool to room
temperature (20-25.degree. C.), then concentrated (12 M aqueous)
HCl (3 eq) was added. The solution was cooled to 0-5.degree. C. for
2-4 h until crystallization was observed. The crystals of the Form
A crystal form of the bis-HCl salt of Compound I were isolated by
filtration, dried and analyzed.
6.7 Example 7
Preparation of Form a of the HBr Salt of Compound I
[0172] Form A of the HBr salt of Compound I was prepared by the
procedure described below.
[0173] To a sample (100-200 mg) of the free base of Compound I was
added solvent (15-30 volumes) and the mixture was heated
(60-85.degree. C.) until dissolution occurred. The solution was
allowed to cool to room temperature (20-25.degree. C.) and gaseous
hydrobromic acid (1-3 eq) was added. The sample was stored between
5-25.degree. C. and monitored for crystallization for up to 3
weeks. The Form A crystal form of the HBr salt of Compound I that
crystallized from this procedure was isolated by filtration, dried
(20-40.degree. C.) and analyzed.
6.8 Example 8
Preparation of Form a of the Sulfate Salt of Compound I
[0174] Form A of the sulfate salt of Compound I was prepared by the
procedures described below.
[0175] The free base of Compound I was dissolved in 15 volumes of
ethanol at a temperature of 70-75.degree. C. Following dissolution,
excess sulfuric acid was added to the solution. Crystallization of
Form A of the sulfate salt of Compound I was observed after 18
h.
[0176] The free base of Compound I was dissolved in 30 volumes of
isopropanol at a temperature of 80-85.degree. C. Following
dissolution, excess sulfuric acid was added to the solution.
Crystallization of Form A of the sulfate salt of Compound I was
observed after 18 h.
6.9 Example 9
Analytical Methods
[0177] 6.9.1 X-Ray Powder Diffraction
[0178] X-ray powder diffraction (XRPD) measurements were performed
in accordance with United States Pharmacopeia (USP) monograph
<941> entitled "X-ray Diffraction" (See, e.g., The United
States Pharmacopeia, The National Formulary, 2003, The Unites
States Pharmacopeial Convention, Inc., Rockville, Md., 2002, which
is herein incorporated by reference in its entirety). A Thermo ARL
X'TRA X-ray powder diffractometer (Thermo Electron Corp., Waltham,
Mass.), equipped with Nickel-filtered Cu K.alpha. radiation at 1.54
A, was used for XRPD measurements from about 1.5 .degree.2.theta.
to about 40 .degree.2.theta., with a step size of about
0.020.degree., a count time of about 0.50 seconds per step, and a
step scan rate of about 2.40.degree./min. The instrument was
equipped with a fine focus X-ray tube. The voltage and amperage
were set at 45 kV and 40 mA, respectively. The divergence slits
were set at 0.5 mm and 0.2 mm. Diffracted radiation was measured
using a Peltier-cooled Si (Li) solid-state detector. Representative
XRPD patterns were presented displaying intensity (counts per
second) versus position (.degree. 2.theta.). A sintered alumina
standard was used to check peak positions. Peak positions may vary
from sample to sample by approximately .+-.0.1 .degree.2.theta..
Variation in peak position may depend upon multiple factors,
including particle size, sample preparation, data collection
temperature and parameters. Variation in peak intensity may occur,
e.g., as a result of preferred orientation and/or variation in
crystal habit.
[0179] 6.9.2 Thermal Analysis
[0180] Differential scanning calorimetry (DSC) measurements were
performed in accordance with United States Pharmacopeia (USP)
monograph <891> entitled "Thermal Analysis" (See, e.g., The
United States Pharmacopeia, The National Formulary, 2003, The
Unites States Pharmacopeial Convention, Inc., Rockville, Md., 2002,
which is incorporated herein by reference in its entirety). A DSC
model Q1000 (TA Instruments, New Castle, Del.) was used to obtain
DSC measurements. Indium was used as the calibration standard.
Analysis was performed on accurately weighed samples with masses
ranging between about 2 mg and about 5 mg. Samples were heated
under nitrogen from about 25.degree. C. to about 300.degree. C. at
a constant heating rate of about 10.degree. C./min. Representative
DSC thermograms were presented displaying heat flow (W/g) versus
temperature (.degree. C.). Melting points were reported as
extrapolated onset temperatures.
[0181] Thermal gravimetric analysis (TGA) measurements were
performed in accordance with United States Pharmacopeia (USP)
monograph <891> entitled "Thermal Analysis" (See, e.g., The
United States Pharmacopeia, The National Formulary, 2003, The
Unites States Pharmacopeial Convention, Inc., Rockville, Md., 2002,
which is incorporated herein by reference in its entirety). A TGA
model Q500 (TA Instruments, New Castle, Del.) was used to obtain
TGA measurements. Analysis was performed on samples with masses
ranging between about 10.0 mg and about 50.0 mg. Samples were
heated under nitrogen from about 25.degree. C. to about 300.degree.
C. at a constant heating rate of about 10.degree. C./min.
Representative TGA thermograms were presented with one trace
displaying weight (%) versus temperature (.degree. C.), and a
second trace displaying derivative weight (%/.degree. C.) versus
temperature (.degree. C.).
[0182] 6.9.3 Morphology Analysis
[0183] Morphology analysis of the samples was carried out using an
Olympus optical microscope. The instrument was calibrated according
to USP standards.
[0184] 6.9.4 Moisture Sorption Analysis
[0185] Hygroscopicity (moisture sorption/desorption) was determined
by Dynamic Vapor Sorption (DVS). A solid sample comprising Compound
I ranging from 10 to 50 mg was placed into the DVS instrument at 0%
relative humidity (RH). The RH was increased from 0% to 80% or 95%.
The RH was then decreased in a similar manner to accomplish a full
sorption/desorption cycle.
[0186] 6.9.5 HPLC Analysis
[0187] HPLC methods for analysis of the purity of Compound I and/or
its synthetic intermediates are provided as guidelines, and
appropriate changes may be added to obtain comparable results. HPLC
methods provided below correspond to the synthetic steps depicted
in FIG. 13.
[0188] Stage 1A, In-Process: A sample of the reaction mixture (0.1
ml) was diluted with 10 ml of 1:1 CH.sub.3CN:0.1% aq.
H.sub.3PO.sub.4 and then analyzed using the following HPLC
conditions. Column: Phenomenex Hypersil BDS C8 (4.6.times.250 mm),
5.mu., 120 A; Detection: 210, 240 nm, UV detector; Injection
volume: 10.0 .mu.l; Temperature: 35.degree. C.; Run time: 20 min;
Mobile phase: A=CH.sub.3CN, B=aq. 10 mmol KH.sub.2PO.sub.4, pH=3
(H.sub.3PO.sub.4); Flow: 1.00 ml/min; Gradient: 0 min=10.0% A+90.0%
B, 20.00 min=70.0% A+30.0% B, 20.01 min=10.0% A+90.0% B. The
reaction was considered complete when <0.1% (HPLC AP) of the
starting material, Compound A, remained (approximate retention time
of Compound A was 14.83 min).
[0189] Stage 1B, In-Process: A sample of the reaction mixture (0.1
ml) was diluted with 10 ml of 1:1 CH.sub.3CN:0.1% aq.
H.sub.3PO.sub.4 and then analyzed using the following HPLC
conditions. Column: Phenomenex Hypersil BDS C8 (4.6.times.250 mm),
5.mu., 120 A; Detection: 210, 240 nm, UV detector; Injection
volume: 10.0 .mu.l; Temperature: 35.degree. C.; Run time: 20 min;
Mobile phase: A=CH.sub.3CN, B=aq. 10 mmol KH.sub.2PO.sub.4, pH=3
(H.sub.3PO.sub.4); Flow: 1.00 ml/min; Gradient: 0 min=10.0% A+90.0%
B, 20.00 min=70.0% A+30.0% B, 20.01 min=10.0% A+90.0% B. The
reaction was considered complete when <0.1% (HPLC AP) of
intermediate 2 remained (approximate retention time of 2 was 13.23
min).
[0190] Compound B, Purity: 50 mg of Compound B was dissolved and
diluted with 100 ml of 1:1 CH.sub.3CN:0.1% aq. H.sub.3PO.sub.4 and
then analyzed using the following HPLC conditions. Column:
Phenomenex Hypersil BDS C8 (4.6.times.250 mm), 5.mu., 120 A;
Detection: 210, 240 nm, UV detector; Injection volume: 10.0 .mu.l;
Temperature: 35.degree. C.; Run time: 30 min; Mobile phase:
A=CH.sub.3CN, B=aq. 10 mmol KH.sub.2PO.sub.4, pH=3
(H.sub.3PO.sub.4); Flow: 1.00 ml/min; Gradient: 0 min=10.0% A+90.0%
B, 30.00 min=40.0% A+60.0% B, 30.01 min=10.0% A+90.0% B. The
approximate retention time of Compound B was 18.92 min.
[0191] Stage 2A, In-Process: A sample of the reaction mixture (0.1
ml) was diluted with 10 ml of 1:1 CH.sub.3CN:0.1% aq.
H.sub.3PO.sub.4, filtered to remove the Pd catalyst, then analyzed
using the following HPLC conditions. Column: Phenomenex Hypersil
BDS C8 (4.6.times.250 mm), 5.mu., 120 A; Detection: 210, 240 nm, UV
detector; Injection volume: 10.0 .mu.l; Temperature: 35.degree. C.;
Run time: 20 min; Mobile phase: A=CH.sub.3CN, B=aq. 10 mmol
KH.sub.2PO.sub.4, pH=3 (H.sub.3PO.sub.4); Flow: 1.00 ml/min;
Gradient: 0 min=1.0% A+99.0% B, 10.00 min=60.0% A+40.0% B, 15.00
min=85.0% A+15.0% B, 16.00 min=85.0% A+15.0% B, 16.01 min=1.0%
A+99.0% B. The reaction was considered complete when <1% (HPLC
AP) of Compound B remained (approximate retention time of Compound
B was 10.15 min).
[0192] Stage 2B, Synthesis of Intermediate 6, In-Process: A sample
of the reaction mixture (0.1 ml) was diluted with 10 ml of 1:1
CH.sub.3CN:0.1% aq. H.sub.3PO.sub.4 and then analyzed using the
following HPLC conditions. Column: Phenomenex Hypersil BDS C8
(4.6.times.250 mm), 5.mu., 120 A; Detection: 210, 240 nm, UV
detector; Injection volume: 10.0 .mu.l; Temperature: 35.degree. C.;
Run time: 20 min; Mobile phase: A=CH.sub.3CN, B=aq. 10 mmol
KH.sub.2PO.sub.4, pH=3 (H.sub.3PO.sub.4); Flow: 1.00 ml/min;
Gradient: 0 min=1.0% A+99.0% B, 10.00 min=60.0% A+40.0% B, 15.00
min=85.0% A+15.0% B, 16.00 min=85.0% A+15.0% B, 16.01 min=1.0%
A+99.0% B. The reaction was considered complete when <1% (HPLC
AP) of intermediate 4 remained (approximate retention time of 4 was
6.93 min).
[0193] Stage 2B, Synthesis of Crude Compound I, In-Process: A
sample of the reaction mixture (0.1 ml) was diluted with 10 ml of
1:1 CH.sub.3CN:0.1% aq. H.sub.3PO.sub.4 and then analyzed using the
following HPLC conditions. Column: Phenomenex Hypersil BDS C8
(4.6.times.250 mm), 5.mu., 120 A; Detection: 210, 240 nm, UV
detector; Injection volume: 10.0 .mu.l; Temperature: 35.degree. C.;
Run time: 20 min; Mobile phase: 20:80 CH.sub.3CN: aq. 10 mmol
KH.sub.2PO.sub.4, pH=3 (H.sub.3PO.sub.4); Flow: 1.00 ml/min. The
reaction was considered complete when <1% (HPLC AP) of
intermediate 6 remained (approximate retention time of 6 was 15.4
min).
[0194] Crude or Recrystallized Compound I, Purity: 50 mg of Crude
Compound I was dissolved and diluted with 100 ml of 1:1
CH.sub.3CN:0.1% aq. H.sub.3PO.sub.4 and then analyzed using the
following HPLC conditions. Column: Phenomenex Hypersil BDS C8
(4.6.times.250 mm), 5.mu., 120 A; Detection: 210, 240 nm, UV
detector; Injection volume: 10.0 .mu.l; Temperature: 35.degree. C.;
Run time: 20 min; Mobile phase: A=CH.sub.3CN, B=aq. 10 mmol
KH.sub.2PO.sub.4, pH=3 (H.sub.3PO.sub.4); Flow: 1.00 ml/min;
Gradient: 0 min=1.0% A+99.0% B, 10.00 min=60.0% A+40.0% B, 15.00
min=85.0% A+15.0% B, 16.00 min=85.0% A+15.0% B, 16.01 min=1.0%
A+99.0% B. The approximate retention time of Compound I was 10.0
min.
[0195] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing embodiments have been described in some detail by way
of illustration and example for purposes of clarity of
understanding, it will be readily apparent to those of ordinary
skill in the art in light of the teachings provided herein that
certain changes and modifications may be made thereto without
departing from the spirit or scope of the appended claims.
* * * * *