U.S. patent application number 17/535304 was filed with the patent office on 2022-05-19 for solid forms of a compound modulating kinases.
The applicant listed for this patent is Plexxikon Inc.. Invention is credited to Prabha N. Ibrahim, Gary Conard Visor.
Application Number | 20220153737 17/535304 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-19 |
United States Patent
Application |
20220153737 |
Kind Code |
A1 |
Ibrahim; Prabha N. ; et
al. |
May 19, 2022 |
SOLID FORMS OF A COMPOUND MODULATING KINASES
Abstract
Solid forms of the compound,
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I) and its
free base, active on the receptor protein kinases c-Kit and/or
c-Fms and/or Flt3, were prepared and characterized: ##STR00001##
Also provided are methods of using the solid forms.
Inventors: |
Ibrahim; Prabha N.;
(Mountain View, CA) ; Visor; Gary Conard; (Castro
Valley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Plexxikon Inc. |
South San Francisco |
CA |
US |
|
|
Appl. No.: |
17/535304 |
Filed: |
November 24, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17238076 |
Apr 22, 2021 |
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17535304 |
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17018986 |
Sep 11, 2020 |
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17238076 |
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16749893 |
Jan 22, 2020 |
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17018986 |
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16219730 |
Dec 13, 2018 |
10584122 |
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16749893 |
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15725197 |
Oct 4, 2017 |
10189833 |
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16219730 |
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15147692 |
May 5, 2016 |
9802932 |
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15725197 |
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62157902 |
May 6, 2015 |
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International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/437 20060101 A61K031/437; A61K 31/337 20060101
A61K031/337; A61K 31/352 20060101 A61K031/352; A61K 31/4188
20060101 A61K031/4188; A61K 31/436 20060101 A61K031/436; A61K
31/444 20060101 A61K031/444; A61K 45/06 20060101 A61K045/06 |
Claims
1. (canceled)
2. A method for treating a subject suffering from Erdheim-Chester
disease comprising administering to the subject a therapeutically
effective amount of a crystalline form of Compound I: ##STR00005##
characterized by an X-ray powder diffractogram comprising peaks
(.+-.0.2.degree.) at 7.3, 23.3 and 28.2.degree. 2.theta. as
determined on a diffractometer using Cu-K.alpha. radiation.
3. A method for treating a subject suffering from Erdheim-Chester
disease comprising administering to the subject a composition
comprising a therapeutically effective amount of a crystalline form
of Compound I: ##STR00006## characterized by an X-ray powder
diffractogram comprising peaks (.+-.0.2.degree.) at 7.3, 23.3 and
28.2.degree. 2.theta. as determined on a diffractometer using
Cu-K.alpha. radiation, and a pharmaceutically acceptable
excipient.
4. The method of claim 2, further comprising administering to the
subject a therapeutically effective amount of another therapeutic
agent, wherein the another therapeutic agent is: i) an alkylating
agent; ii) an antibiotic; iii) an antimetabolite; iv) an antibody
therapy agent; v) a hormone or hormone antagonist; vi) a taxane;
vii) a retinoid; viii) an alkaloid; ix) an antiangiogenic agent; x)
a topoisomerase inhibitor; xi) a protein kinase inhibitor selected
from a PI3K inhibitor, Cdk4 inhibitors; an Akt inhibitor; a Mek
inhibitor, a c-Kit mutant inhibitor, or an EGFR inhibitor; xii) a
targeted signal transduction inhibitor; xiii) a biological response
modifier; xiv) a chemotherapeutic agent; xv) an Hsp90 inhibitor;
xvi) a farnesyltransferase inhibitor; xvii) an aromatase inhibitor;
xvii) an IDO inhibitor; xix) a histone acetyltransferase (HAT)
inhibitor; xx) histone deacetylase (HDAC) inhibitor; xxi) a sirtuin
(SIRT) inhibitor; xxii) a BET inhibitor; or xxiii) an
antiangiogenic agent.
5. The method of claim 3, further comprising administering to the
subject a therapeutically effective amount of another therapeutic
agent, wherein the another therapeutic agent is: i) an alkylating
agent; ii) an antibiotic; iii) an antimetabolite; iv) an antibody
therapy agent; v) a hormone or hormone antagonist; vi) a taxane;
vii) a retinoid; viii) an alkaloid; ix) an antiangiogenic agent; x)
a topoisomerase inhibitor; xi) a protein kinase inhibitor selected
from a PI3K inhibitor, Cdk4 inhibitors; an Akt inhibitor; a Mek
inhibitor, a c-Kit mutant inhibitor, or an EGFR inhibitor; xii) a
targeted signal transduction inhibitor; xiii) a biological response
modifier; xiv) a chemotherapeutic agent; xv) an Hsp90 inhibitor;
xvi) a farnesyltransferase inhibitor; xvii) an aromatase inhibitor;
xvii) an IDO inhibitor; xix) a histone acetyltransferase (HAT)
inhibitor; xx) histone deacetylase (HDAC) inhibitor; xxi) a sirtuin
(SIRT) inhibitor; xxii) a BET inhibitor; or xxiii) an
antiangiogenic agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 17/238,076, filed Apr. 22, 2021, which is a continuation of
U.S. application Ser. No. 17/018,986, filed Sep. 11, 2020, now
abandoned, which is a continuation of U.S. application Ser. No.
16/749,893, filed Jan. 22, 2020, now abandoned, which is a
continuation of U.S. application Ser. No. 16/219,730, filed Dec.
13, 2018, now U.S. Pat. No. 10,584,122, which is a continuation of
U.S. application Ser. No. 15/725,197, filed Oct. 4, 2017, now U.S.
Pat. No. 10,189,833, which is a divisional of U.S. application Ser.
No. 15/147,692, filed May 5, 2016, now U.S. Pat. No. 9,802,932,
which application claims the benefit under 35 U.S.C. .sctn. 119(e)
to U.S. Provisional Application No. 62/157,902, filed May 6, 2015,
all of which are hereby incorporated by reference in their
entireties.
FIELD
[0002] The present disclosure relates generally to solid forms of
Compound I, named
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]--
(6-trifluoromethyl-pyridin-3-ylmethyl)-amine HCl salt, solid form
of its free base, Compound II, processes for making the solid
forms, and their therapeutic methods of use.
BACKGROUND
[0003] There remains a need to develop effective treatments for
subjects suffering from or at risk of a c-Kit and/or c-Fms and/or
Flt3 mediated disease or condition. Suitable compounds, including
Compound I and Compound II, for the treatment of such diseases and
conditions are disclosed in U.S. Pat. No. 7,893,075, U.S.
Publication No. 2014-0037617 and U.S. Publication No. 2013-0274259,
the disclosures of all of which is incorporated herein by reference
in their entirety.
[0004] However, Compound I was not heretofore known in any of the
specific crystalline forms A-D as described herein. Also, Compound
II was not heretofore known in the specific crystalline form as
described herein.
SUMMARY
[0005] The present disclosure fulfills these needs and others by
providing solid forms of Compound I or Compound II. The present
disclosure also provides crystalline forms of Compound I or
Compound II.
##STR00002##
[0006] The present disclosure also provides pharmaceutical
compositions comprising the solid forms of Compound I or Compound
II. The disclosure also provides processes for making the solid
forms and methods for using them in the treatment of c-Kit and/or
c-Fms and/or Flt3 mediated diseases or conditions.
[0007] Thus, one embodiment is directed to a solid form of Compound
I. Another embodiment is directed to a polymorphic form of Compound
I. Another embodiment is directed to a crystalline form of Compound
I. In one embodiment, the crystalline form of Compound I is
Compound I Form A. In another embodiment, the crystalline form of
Compound I is Compound I Form B. In another embodiment, the
crystalline form of Compound I is Compound I Form C. In another
embodiment, the crystalline form of Compound I is Compound I Form
D. This disclosure also provides a solid form of Compound II.
Another embodiment is directed to a crystalline form of Compound
II.
[0008] Thus, one embodiment is directed to crystalline
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I Form A).
Compound I Form A is characterized by an X-ray powder diffractogram
comprising the following peaks (.+-.0.2.degree.): at 7.1, 22.9 and
27.6.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation.
[0009] Another embodiment is directed to crystalline
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I Form B).
Compound I Form B is characterized by an X-ray powder diffractogram
comprising the following peaks (.+-.0.2.degree.): at 6.6, 23.2 and
28.1.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation.
[0010] Another embodiment is directed to crystalline
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I Form C).
Compound I Form C is characterized by an X-ray powder diffractogram
comprising the following peaks (.+-.0.2.degree.): at 7.3, 23.3 and
28.2.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation.
[0011] Another embodiment is directed to crystalline
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt methanol solvate
(Compound I Form D). Compound I Form D is characterized by an X-ray
powder diffractogram comprising the following peaks
(.+-.0.2.degree.): at 6.9, 20.9 and 26.7.degree. 2.theta., as
determined on a diffractometer using Cu-K.alpha. radiation.
[0012] Another embodiment is directed to crystalline
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine (Compound II). Compound II is
characterized by an X-ray powder diffractogram comprising the
following peaks (.+-.0.2.degree.): at 10.9, 19.7 and 26.4.degree.
2.theta., as determined on a diffractometer using Cu-K.alpha.
radiation.
[0013] One embodiment is a pharmaceutical composition comprising a
compound selected from the group consisting of Compound I Form A,
Compound I Form B, Compound I Form C and Compound I Form D,
crystalline Compound II and a pharmaceutically acceptable
excipient.
[0014] Another embodiment is directed to a method for treating a
subject suffering from or at risk of a disease or condition
mediated by a protein kinase selected from c-Fms, c-Kit, Flt3 or
combinations thereof and/or macrophages or microglia, comprising
administering to the subject a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D or crystalline Compound II.
[0015] Another embodiment is directed to a method for treating a
subject suffering from or at risk of a disease or condition
mediated by a protein kinase selected from c-Fms, c-Kit, Flt3 or
combinations thereof and/or macrophages or microglia, comprising
administering to the subject a composition comprising a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D or crystalline
Compound II and a pharmaceutically acceptable excipient.
[0016] Another embodiment is directed to a method for treating a
subject suffering from or at risk of tenosynovial giant cell tumor
(TGCT) comprising administering to the subject a therapeutically
effective amount of Compound I Form A, Compound I Form B, Compound
I Form C, Compound I Form D or crystalline Compound II.
[0017] Another embodiment is directed to a method for treating a
subject suffering from or at risk of pigmented villonodular
synovitis (PVNS) comprising administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, crystalline Compound
II or a composition thereof.
[0018] Another embodiment is directed to a method for treating a
subject suffering from or at risk of malignant peripheral nerve
sheath tumors (MPNST) comprising administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D, crystalline Compound
II or a composition thereof.
[0019] Another embodiment is directed to a method for treating a
subject suffering from or at risk of breast cancer comprising
administering to the subject a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, crystalline Compound II or a composition thereof.
[0020] Another embodiment is directed to a method for treating a
subject suffering from or at risk of plexiform neurofibromas
comprising administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D, crystalline Compound II or a composition
thereof.
[0021] Another embodiment is directed to a method for treating a
subject suffering from or at risk of melanoma, or unresectable or
metastatic melanoma with a KIT mutation, comprising administering
to the subject a therapeutically effective amount of Compound I
Form A, Compound I Form B, Compound I Form C, Compound I Form D,
crystalline Compound II or a composition thereof.
[0022] Another embodiment is directed to a method for treating a
subject suffering from or at risk of glioblastoma comprising
administering to the subject a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, crystalline Compound II or a composition thereof.
[0023] Another embodiment is directed to a method for treating a
subject suffering from or at risk of acute myeloid leukemia
comprising administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D, crystalline Compound II or a composition
thereof.
[0024] Another embodiment is directed to a method for treating a
subject suffering from or at risk of ovarian cancer comprising
administering to the subject a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D, crystalline Compound II or a composition thereof.
[0025] Another embodiment is directed to preparing a capsule
comprising Compound I Form C comprising combining Compound I Form C
with a pharmaceutically acceptable carrier or excipient.
[0026] Another embodiment is directed to preparing a tablet
comprising Compound I Form C comprising combining Compound I Form C
with a pharmaceutically acceptable carrier or excipient.
[0027] Still an additional embodiment includes, optionally in
combination with any other embodiment described herein, is the use
of any one of Compound I Forms A-D or crystalline Compound II in
the manufacture of a medicament for treating subjects suffering
from or at risk of a disease or condition mediated by a protein
kinase selected from c-Fms, c-Kit, Flt3 or combinations thereof
and/or macrophages or microglia.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 is an X-ray powder diffraction pattern of Compound I
Form A.
[0029] FIG. 2 is differential scanning calorimetry (DSC) curve of
Compound I Form A.
[0030] FIG. 3 is thermogravimetric analysis (TGA) of Compound I
Form A.
[0031] FIG. 4 is dynamic vapor sorption (DVS) curve of Compound I
Form A.
[0032] FIG. 5 is Raman spectrum of Compound I Form A.
[0033] FIG. 6 is an X-ray powder diffraction pattern of Compound I
Form B.
[0034] FIG. 7 is differential scanning calorimetry (DSC) curve of
Compound I Form B.
[0035] FIG. 8 is thermogravimetric analysis (TGA) of Compound I
Form B.
[0036] FIG. 9 is Raman spectrum of Compound I Form B.
[0037] FIG. 10 is an X-ray powder diffraction pattern of Compound I
Form C.
[0038] FIG. 11 is differential scanning calorimetry (DSC) curve of
Compound I Form C.
[0039] FIG. 12 is thermogravimetric analysis (TGA) of Compound I
Form C.
[0040] FIG. 13 is dynamic vapor sorption (DVS) curve of Compound I
Form C.
[0041] FIG. 14 is a nuclear magnetic resonance spectra CH NMR) of
Compound I Forms A-C (from top to bottom).
[0042] FIG. 15 is IR spectra of Compound I Form A.
[0043] FIG. 16 is IR spectra of Compound I Form B.
[0044] FIG. 17 is X-ray powder diffraction pattern of Compound I
Form D.
[0045] FIG. 18 is X-ray powder diffraction pattern comparison of
Compound I Form B and Compound I Form C (from top to bottom).
[0046] FIG. 19 is X-ray powder diffraction pattern of compound I
amorphous.
[0047] FIG. 20 is X-ray powder diffraction pattern of crystalline
Compound II.
[0048] FIG. 21 is differential scanning calorimetry (DSC) curve of
crystalline Compound II.
[0049] FIG. 22 is dynamic vapor sorption (DVS) curve of crystalline
Compound II.
[0050] FIG. 23 is thermogravimetric analysis (TGA) of Compound I
Form D.
DETAILED DESCRIPTION
[0051] The compound named
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I), or its
free base (Compound II), is useful in treatments for subjects
suffering from or at risk of a c-Kit and/or c-Fms mediated disease
or condition and has the following structure:
##STR00003##
[0052] The present disclosure relates to solid forms of Compounds I
and II. The present disclosure also relates to polymorphic forms of
Compounds I and II. The present disclosure also relates to various
crystalline forms of Compound I or a crystalline form of Compound
II and processes for making the crystalline forms. The crystalline
forms of Compound I are described herein as "Compound I Form A,"
"Compound I Form B," "Compound I Form C," and "Compound I Form D."
In some embodiments, such forms of Compound I may be a solvate.
Definitions
[0053] As used herein the following definitions apply unless
clearly indicated otherwise.
[0054] All atoms designated within a Formula described herein,
either within a structure provided, or within the definitions of
variables related to the structure, is intended to include any
isotope thereof, unless clearly indicated to the contrary. It is
understood that for any given atom, the isotopes may be present
essentially in ratios according to their natural occurrence, or one
or more particular atoms may be enhanced with respect to one or
more isotopes using synthetic methods known to one skilled in the
art. Thus, hydrogen includes for example .sup.1H, .sup.2H, .sup.3H;
carbon includes for example .sup.11C, .sup.12C, .sup.13C, .sup.14C;
oxygen includes for example .sup.16O, .sup.17O, .sup.18O; nitrogen
includes for example .sup.13N, .sup.14N, .sup.15N; sulfur includes
for example .sup.32S, .sup.33S, .sup.34S, .sup.35S, .sup.36S,
.sup.37S, .sup.38S; fluoro includes for example .sup.17F, .sup.18F,
.sup.19F; chloro includes for example .sup.35Cl, .sup.36Cl,
.sup.37Cl, .sup.38Cl, .sup.39Cl; and the like.
[0055] Certain compounds contemplated for use in accordance with
the present disclosure can exist in unsolvated forms as well as
solvated forms, including hydrated forms. "Hydrate" refers to a
complex formed by combination of water molecules with molecules or
ions of the solute. "Solvate" refers to a complex formed by
combination of solvent molecules with molecules or ions of the
solute. The solvent can be an organic compound, an inorganic
compound, or a mixture of both. Solvate is meant to include
hydrate, hemi-hydrate, channel hydrate etc. Some examples of
solvents include, but are not limited to, methanol,
N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and
water. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
disclosure. Certain compounds contemplated for use in accordance
with the present disclosure may exist in multiple crystalline or
amorphous forms. In general, all physical forms are equivalent for
the uses contemplated by the present disclosure and are intended to
be within the scope of the present disclosure.
[0056] The term "desolvated" refers to a Compound I form that is a
solvate as described herein, and from which solvent molecules have
been partially or completely removed. Desolvation techniques to
produce desolvated forms include, without limitation, exposure of a
Compound I form (solvate) to a vacuum, subjecting the solvate to
elevated temperature, exposing the solvate to a stream of gas, such
as air or nitrogen, or any combination thereof. Thus, a desolvated
Compound I form can be anhydrous, i.e., completely without solvent
molecules, or partially solvated wherein solvent molecules are
present in stoichiometric or non-stoichiometric amounts.
[0057] As used herein, the term "solid form" refers to a type of
solid-state material that includes amorphous as well as crystalline
forms. The term "crystalline form" refers to polymorphs as well as
solvates, hydrates, etc. The term "polymorph" refers to a
particular crystal structure having particular physical properties
such as X-ray diffraction, melting point, and the like.
[0058] The term "condis crystal" refers to mesophase or liquid
crystal, and it is a state of matter that falls between a crystal
and a liquid. It is a crystal in which the positional and
conformational order in the packing of macromolecules arranged in
parallel is lost to some degree. Condis crystal particles may look
like solid crystals, but may flow like a liquid when these crystals
are pressed upon.
[0059] As used herein, the terms "treat", "treating", "therapy",
"therapies", and like terms refer to the administration of
material, e.g., any one or more compound(s) as described herein in
an amount effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or condition, i.e., indication, and/or
to prolong the survival of the subject being treated.
[0060] Compound I and Compound II are inhibitors of Fms, Kit and
Flt3 protein kinases. The Kinase assays that can measure the
IC.sub.50 values for these targets are described in US Publication
Nos. US 2007/0032519, US 2009/0076046 and US 2011/0112127. Compound
I and II have IC.sub.50 values of less than 0.05 .mu.M for each of
these three kinase targets.
[0061] As used herein, the term "Fms and/or Kit and/or Flt3 protein
kinase mediated disease or condition" refers to a disease or
condition in which the biological function of a Fms protein kinase,
including any mutation thereof, a Kit protein kinase, including any
mutation thereof, a Flt3 protein kinase, including any mutation
thereof or both a Fms and Kit protein kinase, including any
mutations thereof, affects the development, course, and/or symptoms
of the disease or condition, and/or in which modulation of the Fms
and/or Kit and/r Flt3 protein kinase alters the development,
course, and/or symptoms of the disease or condition. A Fms and/or
Kit and/or Flt3 protein kinase mediated disease or condition
includes a disease or condition for which modulation provides a
therapeutic benefit, e.g. wherein treatment with Fms and/or Kit
and/or Flt3 protein kinase inhibitor(s), including one or more
solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II as described herein, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein provides a therapeutic benefit to the subject suffering from
or at risk of the disease or condition.
[0062] As used herein, the terms "Fms protein kinase mediated
disease or condition," "c-Fms mediated disease or condition," and
the like refer to a disease or condition in which the biological
function of a Fms protein kinase, including any mutations thereof,
affects the development, course, and/or symptoms of the disease or
condition, and/or in which modulation of the Fms protein kinase
alters the development, course, and/or symptoms of the disease or
condition. The Fms protein kinase mediated disease or condition
includes a disease or condition for which Fms inhibition provides a
therapeutic benefit, e.g. wherein treatment with Fms inhibitor(s),
including one or more solid, crystalline or polymorphs of Compound
I or solid or crystalline forms of Compound II as described herein,
or a composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein provides a therapeutic benefit to the subject suffering from
or at risk of the disease or condition.
[0063] As used herein, the terms "Kit protein kinase mediated
disease or condition," "c-Kit mediated disease or condition," and
the like refer to a disease or condition in which the biological
function of a Kit protein kinase, including any mutations thereof,
affects the development, course, and/or symptoms of the disease or
condition, and/or in which modulation of the Kit protein kinase
alters the development, course, and/or symptoms of the disease or
condition. The Kit protein kinase mediated disease or condition
includes a disease or condition for which Kit inhibition provides a
therapeutic benefit, e.g. wherein treatment with Kit inhibitor(s),
including one or more solid, crystalline or polymorphs of Compound
I or solid or crystalline forms of Compound II as described herein,
or a composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein provides a therapeutic benefit to the subject suffering from
or at risk of the disease or condition.
[0064] As used herein, the term "composition" refers to a
pharmaceutical preparation suitable for administration to an
intended subject for therapeutic purposes that contains at least
one pharmaceutically active compound, including any solid form
thereof. The composition may include at least one pharmaceutically
acceptable component to provide an improved formulation of the
compound, such as a suitable carrier or excipient.
[0065] As used herein, the term "subject" refers to a living
organism that is treated with compounds as described herein,
including, but not limited to, any mammal, such as a human, other
primates, sports animals, animals of commercial interest such as
cattle, farm animals such as horses, or pets such as dogs and
cats.
[0066] The term "pharmaceutically acceptable" indicates that the
indicated material does not have properties that would cause a
reasonably prudent medical practitioner to avoid administration of
the material to a patient, taking into consideration the disease or
conditions to be treated and the respective route of
administration. For example, it is commonly required that such a
material be essentially sterile, e.g., for injectibles.
[0067] In the present context, the term "therapeutically effective"
or "effective amount" indicates that the materials or amount of
material is effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or medical condition, and/or to prolong
the survival of the subject being treated. The therapeutically
effective amount will vary depending on the compound, the disorder
or condition and its severity and the age, weight, etc., of the
mammal to be treated. For example, an effective amount is an amount
sufficient to effectuate a beneficial or desired clinical result.
The effective amounts can be provided all at once in a single
administration or in fractional amounts that provide the effective
amount in several administrations. The precise determination of
what would be considered an effective amount may be based on
factors individual to each subject, including their size, age,
injury, and/or disease or injury being treated, and amount of time
since the injury occurred or the disease began. One skilled in the
art will be able to determine the effective amount for a given
subject based on these considerations which are routine in the
art.
[0068] As used herein, the term "modulating" or "modulate" refers
to an effect of altering a biological activity, especially a
biological activity associated with a particular biomolecule such
as a protein kinase. For example, an inhibitor of a particular
biomolecule modulates the activity of that biomolecule, e.g., an
enzyme, by decreasing the activity of the biomolecule, such as an
enzyme. Such activity is typically indicated in terms of an
inhibitory concentration (IC.sub.50) of the compound for an
inhibitor with respect to, for example, an enzyme.
[0069] As used herein, the phrase "substantially as shown in
Figure" as applied to DSC thermograms is meant to include a
variation of .+-.3.degree. Celsius and as applied to
thermogravimetric analysis (TGA) is meant to include a variation of
.+-.2% in weight loss.
[0070] As used herein, the phrase "major peaks" in the XRPD pattern
refers to a subset of the entire observed peak list. Major peaks
are selected from observed peaks by identifying preferably
non-overlapping, low-angle peaks, with strong intensity.
[0071] In the context of the use, testing, or screening of
compounds that are or may be modulators, the term "contacting"
means that the compound(s) are caused to be in sufficient proximity
to a particular molecule, complex, cell, tissue, organism, or other
specified material that potential binding interactions and/or
chemical reaction between the compound and other specified material
can occur.
[0072] In addition, abbreviations as used herein have respective
meanings as follows:
TABLE-US-00001 D Days DMSO Dimethylsulfoxide DSC differential
scanning calorimetry DVS dynamic vapor sorption EtOAc ethyl acetate
EtOH Ethanol HPLC High pressure liquid chromatography IPA
Isopropanol IR Infrared spectrum kV Kilovolt mA Milliampere MeOH
Methanol Pks Peaks RH relative humidity RT room temperature TGA
thermogravimetric analysis .mu.L Microliter .mu.m Micrometer .mu.M
Micromolar v/v volume to volume XRPD X-ray powder diffraction
Compounds I and II
[0073] Compounds I and II were synthesized according to the
following synthetic procedure of Scheme I:
##STR00004##
Step 1: Conversion of (a) to (c)
[0074] The reactor was charged with isopropyl alcohol, and the
chamber was flushed with nitrogen.
Tert-butyl[(tert-butoxy)-N-(5-formyl-(2-pyridyl))carbonylamino]formate
(a) was dissolved in isopropyl alcohol with stirring, and the
reaction mixture was cooled to about 0-5.degree. C.
5-Chloro-7-azaindole (b), potassium carbonate, and
tetrabutylammonium bisulfate were added one by one to the reactor,
and the reaction mixture was stirred at room temperature for about
24 hours. The reaction progress was monitored by analyzing the
reaction mixture by HPLC. When the content of (a) was 2% or less,
the reaction was cooled to about 5-10.degree. C., and purified
water was added to precipitate crude
tert-butyl[(tert-butoxy)-N-{5-[(5-chloropyrrolo[2,3-b]pyridine-3-yl)hydro-
xymethyl]-(2-pyridyl)}carbonylamino)formate (c). The precipitate
was filtered, washed with purified water, dried, and tested for
purity. If the purity was >90% no further work-up was conducted.
If the purity was <90%, the crude product was stirred with hot
ethyl acetate for about 1 hour, cooled to about 0-5.degree. C., and
filtered. The filtered solids were washed with ethyl acetate and
dried.
Step 2: Conversion of (c) to (d)
[0075] The reactor was charged with acetonitrile, and the chamber
was flushed with nitrogen. Compound (c) was dissolved in
acetonitrile with stirring, and the reaction mixture was cooled to
about 0-5.degree. C. Triethylsilane and trifluoroacetic acid were
added to the reactor, and the reaction mixture was stirred at room
temperature for about 24 hours and then refluxed for about 8 hours.
The reaction progress was monitored by analyzing the reaction
mixture by HPLC. When the (c) content was .ltoreq.1.0%, crude
5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-ylamine
trifluoroacetic acid salt (d) was precipitated by concentrating the
volume, adding water, and concentrating again. The suspension was
stirred for 1 to 1.5 hours at about 60-65.degree. C., cooled to
about 0-5.degree. C., and filtered, and the resulting solids were
washed with purified water. The solids were then stirred with ethyl
acetate for about 3 hours, filtered, washed with ethyl acetate and
dried.
Step 3: Conversion of (d) to Compound II (Free Base)
[0076] The reactor was charged with acetonitrile, and the chamber
was flushed with nitrogen. Compound (d) and
6-trifluoromethyl-pyridine-3-carboxaldehyde (e) were dissolved in
acetonitrile with stirring, and the reaction mixture was cooled to
about 0-5.degree. C. Trifluoroacetic acid was added to the reactor,
and the reaction mixture was stirred for about 6 hours at about
10.degree. C. Triethylsilane was then added to the reactor, and the
reaction mixture was refluxed for about 24 hours. The reaction
progress was monitored by analyzing the reaction mixture by HPLC.
When Compound II content was <1.0% the reaction was worked up by
concentrating the volume, adding water, and concentrating again.
Ammonium hydroxide was then added to raise the pH of the liquid to
be between 8 and 9 and precipitate crude Compound II. The solids
were filtered, washed with purified water and dried.
Step 4: Conversion of Compound II to Compound I.
[0077] The reactor was charged with ethyl acetate, and the chamber
was flushed with nitrogen. Compound II was heated with ethyl
acetate at about 55.degree. C. for 7 to 8 hours, cooled to room
temperature, stirred for about 16 hours, filtered, and dried.
Compound II was reacted with 1.25 equivalents of hydrochloric acid
in methanol at <30.degree. C. then heated at reflux for about 1
hour, filtered then cooled to room temperature. The slurry was
filtered and the solids were refluxed in methyl tert-butyl ether,
cooled to room temperature, filtered, and dried to isolate Compound
I.
Crystalline Forms of Compound I
[0078] As described generally above, the present disclosure
provides crystalline forms of Compound I, and a crystalline form of
its free base, Compound II, which are disclosed herein.
[0079] In one embodiment, this disclosure provides a process of
preparing Compound I Form A comprising recrystallizing Compound I
from a mixture of methanol and water.
[0080] Compound I Form A is characterized by an X-ray powder
diffractogram comprising peaks (.+-.0.2.degree.) at 7.1, 22.9 and
27.6.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. The diffractogram comprises additional peaks
(.+-.0.2.degree.) at 21.7 and 23.7.degree. 2.theta.. Form A is also
characterized by its full X-ray powder diffractogram as
substantially shown in FIG. 1. Major peaks in the XRPD pattern are
shown in Table 1 below. In one embodiment, this disclosure provides
Compound I Form A comprising two or more peaks (.+-.0.2.degree.)
listed in the Table 1 below as determined on a diffractometer using
Cu-K.alpha. radiation.
TABLE-US-00002 TABLE 1 Major Peaks in the XRPD Pattern for Compound
I Form A .degree.2.theta. (.+-. 0.2.degree.) d-space [.ANG.] 7.14
12.368 .+-. 0.346 13.65 6.482 .+-. 0.095 14.32 6.179 .+-. 0.086
15.08 5.870 .+-. 0.077 16.52 5.363 .+-. 0.064 16.78 5.278 .+-.
0.062 20.16 4.402 .+-. 0.043 20.81 4.265 .+-. 0.041 21.72 4.089
.+-. 0.037 22.04 4.030 .+-. 0.036 22.34 3.977 .+-. 0.035 22.59
3.933 .+-. 0.034 22.89 3.882 .+-. 0.033 23.74 3.745 .+-. 0.031
24.80 3.587 .+-. 0.028 25.81 3.450 .+-. 0.026 26.16 3.404 .+-.
0.026 27.55 3.235 .+-. 0.023 29.17 3.059 .+-. 0.021
[0081] In some embodiments, Form A is also characterized by its
differential scanning calorimetry (DSC) curve comprising an
endotherm comprising signal maximum at about 231.degree. C. with an
onset temperature at about 222.degree. C. In another embodiment,
the DSC curve is substantially as shown in FIG. 2.
[0082] In some embodiments, Form A is also characterized by
thermogravimetric analysis (TGA) comprising a thermogram
substantially as shown in FIG. 3.
[0083] In some embodiments, Form A is also characterized by a
dynamic vapor sorption (DVS) curve substantially as shown in FIG.
4.
[0084] In some embodiments, Form A is also characterized by a Raman
spectrum substantially as shown in FIG. 5.
[0085] In some embodiments, Compound I Form A is also characterized
by its IR spectrum as shown in FIG. 15.
[0086] In another embodiment, this disclosure provides a process of
preparing Compound I Form B comprising contacting Compound II (free
base) with hydrochloric acid. Compound I Form B is characterized by
an X-ray powder diffractogram comprising peaks (.+-.0.2.degree.) at
6.6, 23.2 and 28.1.degree. 2.theta., as determined on a
diffractometer using Cu-K.alpha. radiation. The diffractogram
comprises additional peaks (.+-.0.2.degree.) at 22.3 and
26.7.degree. 2.theta.. Form B is also characterized by its full
X-ray powder diffractogram as substantially shown in FIG. 6. Major
peaks in the XRPD pattern are shown in Table 2 below. In one
embodiment, this disclosure provides Compound I Form B comprising
two or more peaks (.+-.0.2.degree.) listed in the Table 2 below as
determined on a diffractometer using Cu-K.alpha. radiation.
TABLE-US-00003 TABLE 2 Major Peaks in the XRPD Pattern for Compound
I Form B .degree.2.theta. (.+-. 0.2.degree.) d-space [.ANG.] 6.63
13.320 .+-. 0.401 7.15 12.360 .+-. 0.345 8.37 10.560 .+-. 0.252
13.66 6.477 .+-. 0.094 14.34 6.170 .+-. 0.086 15.10 5.862 .+-.
0.077 16.54 5.356 .+-. 0.064 17.45 5.078 .+-. 0.058 20.19 4.395
.+-. 0.043 20.83 4.261 .+-. 0.040 21.27 4.175 .+-. 0.039 21.59
4.113 .+-. 0.038 21.86 4.063 .+-. 0.037 22.34 3.975 .+-. 0.035
22.59 3.934 .+-. 0.034 23.17 3.836 .+-. 0.033 23.76 3.741 .+-.
0.031 23.96 3.712 .+-. 0.031 25.98 3.427 .+-. 0.026 26.22 3.397
.+-. 0.025 26.46 3.365 .+-. 0.025 26.67 3.340 .+-. 0.025 28.14
3.168 .+-. 0.022 28.72 3.106 .+-. 0.021 29.92 2.984 .+-. 0.019
[0087] In some embodiments, Form B is also characterized by its
differential scanning calorimetry (DSC) curve comprising endotherms
comprising signal maximums at about 127.degree. C. and 233.degree.
C. (with an onset temperature at about 226.degree. C.). In another
embodiment, the DSC curve is substantially as shown in FIG. 7.
[0088] In some embodiments, Form B is also characterized by
thermogravimetric analysis (TGA) comprising a thermogram
substantially as shown in FIG. 8.
[0089] In some embodiments, Form B is also characterized by a Raman
spectrum substantially as shown in FIG. 9.
[0090] In some embodiments, Compound I Form B is also characterized
by its IR spectrum as shown in FIG. 16.
[0091] In another embodiment, this disclosure provides a process of
preparing Compound I Form C comprising recrystallizing Compound I
Form A from a solvent selected from acetone, 1,4-dioxane, ethanol,
methanol, and a mixture of isopropanol and water. In another
embodiment, this disclosure provides a process of preparing
Compound I Form C comprising recrystallizing Compound I Form A from
ethanol.
[0092] Compound I Form C is characterized by an X-ray powder
diffractogram comprising peaks (.+-.0.2.degree.) at 7.3, 23.3 and
28.2.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. The diffractogram comprises additional peaks
(.+-.0.2.degree.) at 16.6 and 20.9.degree. 2.theta.. Form C is also
characterized by its full X-ray powder diffractogram as
substantially shown in FIG. 10. Major peaks in the XRPD pattern are
shown in Table 3 below. In one embodiment, this disclosure provides
Compound I Form C comprising two or more peaks (.+-.0.2.degree.)
listed in the Table 3 below as determined on a diffractometer using
Cu-K.alpha. radiation.
TABLE-US-00004 TABLE 3 Major Peaks in the XRPD Pattern for Compound
I Form C .degree.2.theta. (.+-. 0.2.degree.) d-space [.ANG.] 7.3
12.176 .+-. 0.335 8.5 10.422 .+-. 0.245 13.8 6.427 .+-. 0.093 14.4
6.127 .+-. 0.084 15.2 5.820 .+-. 0.076 16.6 5.321 .+-. 0.063 16.9
5.240 .+-. 0.062 20.3 4.372 .+-. 0.043 20.9 4.239 .+-. 0.040 21.3
4.159 .+-. 0.039 22.4 3.968 .+-. 0.035 23.3 3.816 .+-. 0.032 26.7
3.331 .+-. 0.024 28.2 3.160 .+-. 0.022
[0093] In some embodiments, Form C is also characterized by its
differential scanning calorimetry (DSC) curve comprising an
endotherm comprising signal maximum at about 234.degree. C. with an
onset temperature of about 227.degree. C. In another embodiment,
the DSC curve is substantially as shown in FIG. 11.
[0094] In some embodiments, Form C is also characterized by
thermogravimetric analysis (TGA) comprising a thermogram
substantially as shown in FIG. 12.
[0095] In some embodiments, Form C is also characterized by a
dynamic vapor sorption (DVS) curve substantially as shown in FIG.
13.
[0096] In some embodiments, Compound I Forms A-C (from top to
bottom) are also characterized by their nuclear magnetic resonance
spectra (.sup.1H NMR) as shown in FIG. 14.
[0097] In another embodiment, this disclosure provides a process of
preparing Compound I Form D comprising recrystallizing Compound I
Form A from a mixture of acetone and methanol.
[0098] Compound I Form D is characterized by an X-ray powder
diffractogram comprising peaks (.+-.0.2.degree.) at 6.9, 20.9 and
26.7.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. The diffractogram comprises additional peaks
(.+-.0.2.degree.) at 12.9 and 24.0.degree. 2.theta.. Form D is also
characterized by its full X-ray powder diffractogram as
substantially shown in FIG. 17. Major peaks in the XRPD pattern are
shown in Table 4 below. In one embodiment, this disclosure provides
Compound I Form D comprising two or more peaks (.+-.0.2.degree.)
listed in the Table 4 below as determined on a diffractometer using
Cu-K.alpha. radiation.
[0099] In some embodiments, Form D is also characterized by
thermogravimetric analysis (TGA) comprising a thermogram
substantially as shown in FIG. 23.
TABLE-US-00005 TABLE 4 Major Peaks in the XRPD Pattern for Compound
I Form D .degree.2.theta. (.+-. 0.2.degree.) d-space [.ANG.] 6.90
12.809 .+-. 0.371 12.91 6.854 .+-. 0.106 16.21 5.463 .+-. 0.046
19.52 4.545 .+-. 0.036 20.91 4.245 .+-. 0.040 22.07 4.024 .+-.
0.036 23.96 3.710 .+-. 0.031 25.22 3.529 .+-. 0.028 26.73 3.332
.+-. 0.024 28.62 3.117 .+-. 0.021
Crystalline Form of Compound II
[0100] Compound II is characterized by an X-ray powder
diffractogram comprising peaks (.+-.0.2.degree.) at 10.9, 19.7 and
26.4.degree. 2.theta., as determined on a diffractometer using
Cu-K.alpha. radiation. The diffractogram comprises additional peaks
(.+-.0.2.degree.) at 20.8 and 25.3.degree. 2.theta.. The free base
is also characterized by its full X-ray powder diffractogram as
substantially shown in FIG. 20. Major peaks in the XRPD pattern are
shown in Table 5 below. In one embodiment, this disclosure provides
a crystalline Compound II comprising two or more peaks
(.+-.0.2.degree.) listed in the Table 5 below as determined on a
diffractometer using Cu-K.alpha. radiation.
TABLE-US-00006 TABLE 5 Major Peaks in the XRPD Pattern for Compound
II .degree.2.theta. (.+-. 0.2.degree.) d-space [.ANG.] 10.9 8.128
.+-. 0.149 13.6 6.500 .+-. 0.095 15.1 5.854 .+-. 0.077 17.6 5.043
.+-. 0.057 19.7 4.499 .+-. 0.045 20.2 4.391 .+-. 0.043 20.4 4.354
.+-. 0.042 20.8 4.259 .+-. 0.040 21.8 4.066 .+-. 0.037 22.7 3.912
.+-. 0.034 23.3 3.816 .+-. 0.032 23.9 3.719 .+-. 0.031 24.3 3.667
.+-. 0.030 25.3 3.515 .+-. 0.027 26.4 3.374 .+-. 0.025 27.5 3.243
.+-. 0.023 27.7 3.214 .+-. 0.023 28.1 3.178 .+-. 0.022 28.5 3.133
.+-. 0.022
Characterization of Crystalline Forms A-D of Compound I and
Crystalline Compound II
[0101] Compound I Form A
[0102] Form A is unsolvated. Form A was obtained as described in
Example 1 and was utilized as the source material for the polymorph
screen. Form A was also obtained from the desolvation of Form D,
which is a methanol solvate, under mild heating conditions.
[0103] The approximate solubility of Form A was calculated in a
variety of solvents using the Solvent Addition Method discussed in
the Examples and the results are as shown below.
[0104] Approximate Solubility of Compound I Form A.
TABLE-US-00007 Solubility Solvent (mg/mL).sup.1 Acetone <2
Acetonitrile (ACN) <2 Dichloromethane (DCM) <2 1,4-Dioxane
<2 Dimethyl Formamide (DMF) >145 Dimethyl Sulfoxide (DMSO)
>153 Ethanol (EtOH) 5 Ethyl Acetate (EtOAc) <2 Heptane <2
Isopropyl alcohol (IPA) 2 Methanol (MeOH) 31 Methyl tert-Butyl
Ether (MTBE) <2 Tetrahydrofuran (THF) <2 Toluene <2 Water
<2 .sup.1Solubilities are calculated based on the total solvent
used to give a solution; actual solubilities may be greater because
of the volume of the solvent portions utilized or a slow rate of
dissolution. Solubilities are rounded to the nearest mg/mL.
[0105] The thermograms of the Form A are displayed in FIG. 2 and
FIG. 3. The DSC curve exhibits a melt and concurrent decomposition
endotherm with an onset temperature at 222.degree. C. (signal
maximum at 231.degree. C.). A minor endotherm is also observed at
about 76.degree. C. This event is likely related to a phase
transition based on physical stability and hotstage microscopy
data. The TG curve exhibits a negligible weight loss up to
150.degree. C., suggesting that it is not solvated. Weight loss
above this temperature is due to decomposition.
[0106] These thermal events were investigated by hotstage
microscopy. The material exhibits birefringence and extinction,
typical for crystalline material. A change in birefringence was
observed near 65.degree. C. (consistent with the minor endotherm in
the DSC above) followed by two distinct melt onsets (184 and
196.degree. C.). These events suggest that a partial phase
transformation occurred upon heating, resulting in a mixture of two
forms, each with a distinct melt.
[0107] The physical stability of Form A was investigated in order
to support the hotstage microscopy observations and the results are
shown in the table below.
TABLE-US-00008 Conditions Description XRPD Result 80.degree. C./7d
(<<100 mg) White solid C 80.degree. C./4d (<100 mg)
Off-white solid A 80.degree. C./4d (8d consecutive, <100 mg)
Off-white solid A RT/85% RH/14d White solid A + minor C 40.degree.
C./75% RH/14d White solid A + C
[0108] A small sample of Form A (<<100 mg) converted to Form
C (unsolvated form) upon exposure to 80.degree. C. for 7 days. A
partial conversion to Form C was obtained when Form A was exposed
to elevated humidity. In addition, complete conversion to Form C
was obtained when Form A was slurried in ethanol for 21 days. This
indicates that Form A is physically metastable (at the conditions
investigated) and will undergo a phase transition to Form C.
[0109] The DVS isotherm suggests that Form A is hygroscopic (FIG.
4). During the sorption step, the material exhibits a weight gain
of 0.6% from 5% to 75% RH and an additional 1.7% weight above 75%
RH. Minor hysteresis was observed upon desorption. The resulting
sample was Form A, by XRPD.
[0110] The .sup.1H NMR spectrum is consistent with the structure of
Compound I (FIG. 14, top one). Peaks at approximately 2.5 and 3.6
ppm are assigned to deuterated DMSO (due to residual protons in the
NMR solvent) and water, respectively.
[0111] Raman and IR spectra (FIG. 5 and FIG. 15, respectively) of
Form A were obtained for comparison with that of Form B. The
spectra for each exhibit a flat baseline with generally well
resolved and sharp bands. Differences within the Raman spectra
between the forms were negligible. However, there are differences
in intensities and band positions between the IR spectra,
indicating that there are chemical and/or physical differences
between the forms. Several obvious IR differences in intensities
and band positions were noted at approximately 3500-2600 cm.sup.-1,
1645 cm.sup.-1, and 1110 cm.sup.-1.
[0112] Thus, Form A is unsolvated. It is hygroscopic above 75% RH.
Form A is physically metastable (at the conditions investigated)
and can convert to Form C.
[0113] Compound I Form B
[0114] Form B was obtained as described in Example 2 and was
utilized for an analytical comparison with other forms.
[0115] The XRPD of Form B contains all the X-ray reflections
observed in the pattern of Form C, as well as additional
reflections. A comparison of both patterns is shown in FIG. 18.
This suggests that Form B is a two phase mixture comprised of Form
C (unsolvated form) and a hydrated form based on the
characterization described below.
[0116] The thermograms of Form B are displayed in FIG. 7 and FIG.
8. The DSC curve exhibits a broad desolvation endotherm (with
shoulder) with a signal maximum at 127.degree. C. This event is
associated with a TG weight loss of approximately 6.0% (up to
150.degree. C.). Assuming this is due to the volatilization of
water (no other solvents were identified by NMR), the weight loss
corresponds to 1.5 moles of water for every mole of Compound I.
Karl Fischer analysis indicates the material contains 3.45% water
by weight. (The water content discrepancy between techniques may be
due to losses upon ambient storage. While this explanation has not
been confirmed, the KF analysis was performed 14 days after the TG
analysis.) In the DSC curve, a minor exotherm and endotherm are
also observed at 187 and 203.degree. C., respectively. These events
are likely related to a phase transition, based on physical
stability and hotstage microscopy data (see below). A sharp
endotherm with an onset temperature of 226.degree. C. (signal
maximum at 233.degree. C.) is due to the melt and concurrent
decomposition. Significant decomposition weight losses are observed
at this temperature by TG.
[0117] These thermal events were investigated by hotstage
microscopy. The material exhibits birefringence and extinction. A
loss of birefringence and a solid to liquid transition was observed
between about 70 and about 130.degree. C., consistent with the
desolvation event described by the TG and DSC thermograms above.
Recrystallization was observed near 142.degree. C. and was followed
by a melt between about 192.degree. C. and about 200.degree. C.
[0118] The physical stability of Form B was investigated in order
to support the hotstage microscopy observations.
Desolvation/conversion to Form C (unsolvated form) was obtained by
exposing Form B to about 150.degree. C. for about 5 minutes.
[0119] The .sup.1H NMR spectrum is consistent with the structure of
Compound I (FIG. 14, middle one). Minor peaks at approximately 7.1,
7.25, and 7.38 ppm were not identified. Peaks at approximately 2.5
and 4.1 ppm are assigned to deuterated DMSO (due to residual
protons in the NMR solvent) and water, respectively.
[0120] Raman and IR spectra (FIG. 9 and FIG. 16, respectively) of
Form B were obtained for comparison with that of Form A
(unsolvated). The spectra for each exhibit a flat baseline with
generally well resolved and sharp bands. Differences within the
Raman spectra between the forms were negligible. However, there are
differences in intensities and band positions between the IR
spectra, indicating that there are chemical and/or physical
differences between the forms. Several obvious IR differences in
intensities and band positions were noted at approximately
3500-2600 cm.sup.-1, 1645 cm.sup.-1, and 1110 cm.sup.-1.
[0121] Thus, based on XRPD, Form B is a two phase mixture comprised
of Form C and an unidentified hydrated form. Desolvation/conversion
of Form B to Form C was obtained by exposing the material to about
150.degree. C. for about 5 minutes.
[0122] Compound I Form C
[0123] Form C is unsolvated. Form C was obtained from a wide
variety of experiments as discussed in Example 3 and, consequently,
was the most frequently observed form. It was crystallized directly
out of ethanol by a crash cool experiment, obtained from thermal
conversion of Form A, and through the desolvation of Form B or Form
D.
[0124] The thermograms of Form C are displayed in FIG. 11 and FIG.
12. The DSC curve exhibits a sharp endotherm, indicative of a melt,
with an onset temperature at about 227.degree. C. (signal maximum
at 234.degree. C.). The TG curve exhibits a negligible weight loss
up to the melt endotherm, suggesting that the material is not
solvated. Significant weight loss at and above this temperature
indicate that decomposition occurs concurrently with the melt.
[0125] The DVS isotherm suggests that Form C is less hygroscopic
than Form A (FIG. 13). During the sorption step, the material
exhibits a weight gain of only 0.96% from 5% to 95% RH. Minor
hysteresis was observed upon desorption. The resulting sample
remained unchanged by XRPD.
[0126] Form C is more physically stable than Form A. As discussed
above, Form C was obtained through the conversion of Form A by
exposure to elevated temperature or humidity. In addition, a
complete conversion to Form C was obtained when Form A was slurried
in ethanol for 21 days (Example 3). This indicates that Form A is
physically metastable and will undergo a solid state phase
transition to Form C.
[0127] The .sup.1H NMR spectrum is consistent with the structure of
Compound I (FIG. 14, bottom one). Peaks at approximately 2.5 and
3.6 ppm are assigned to deuterated DMSO (due to residual protons in
the NMR solvent) and water, respectively.
[0128] Thus, Form C is an unsolvated form that melts concurrently
with decomposition at about 227.degree. C. It is less hygroscopic
than Form A. Form C is the physically stable unsolvated form.
[0129] Compound I Form D
[0130] Form D appears to be a methanol solvate. It was crystallized
directly out of (88:12) acetone/MeOH by a slow cool experiment
(Example 3). It was also obtained by exposing Form A to methanol
vapor.
[0131] The DSC scan of Form D displays a broad endotherm with a
peak maximum at approximately 70.degree. C. that suggests loss of
volatile components. Form D also exhibited approximately 5.3%
weight loss upon equilibration at 5% RH, confirming that the
material contained at least that amount of volatile easily removed
at low RH conditions. During the sorption/desorption phases of the
experiment, the sample exhibited negligible weight gain (0.9%)/loss
(0.9%), similar to the isotherm observed for Form C. The TG curve
exhibits about 6% weight loss up to 73.degree. C.
[0132] The physical stability of Form D was investigated. The form
desolvated to Form A upon exposure to 80.degree. C. for 15 minutes.
The material then converted to Form C upon continued exposure to
80.degree. C. for 2 days.
[0133] Thus, based on the method of preparation and previous
characterization data, Form D appears to be a methanol solvate. The
form desolvates to Forms A or C upon exposure to elevated
temperatures.
[0134] Compound I Amorphous
[0135] Compound I amorphous was isolated through rotary evaporation
from trifluoroethanol. It was obtained by dissolving 20 mg of
Compound I Form A in 100 .mu.L of trifluoroethanol and rotary
evaporation at 60.degree. C. for 7 minutes provided the amorphous
form as a white solid. The XRPD indicates amorphous material (FIG.
19).
[0136] Compound II
[0137] Compound II was prepared by the synthetic method above and
the resulting crystals were characterized.
[0138] The DSC thermogram of free base is displayed in FIG. 21. The
DSC curve displays a small endotherm at approximately 124.degree.
C. with a larger endotherm at approximately 192.degree. C. that is
consistent with sample melting.
[0139] DVS results indicate 0.3-0.4% weight loss upon equilibration
at 5% RH (FIG. 22). Results for the freebase show that the majority
of the weight gained (.about.21.6%) is from 45% to 95% RH. The
sample subsequently loses all weight gained during the desorption
phase. The free base appears to be hygroscopic.
[0140] Light microscopy observations were made. The free base
exhibits birefringence with extinction when the microscope stage is
rotated. Additionally, it exhibits flow when pressure is applied to
the cover glass, suggesting that the material is a mesophase or a
condis crystal. Images of the free base show bladed-micaceous
particles.
[0141] Salts of Compound II
[0142] In addition to the hydrochloride salt (Compound I), several
other salts can be prepared for the free base (Compound II). In
some embodiments, the salt is selected from acetate, besylate,
bromide, calcium, citrate, decanoate/caprate, dimeglumine,
dipropionate, fumarate, lactate, maleate, meglumine, mesylate,
nitrate, pamoate, phosphate, potassium, sodium, succinate, sulfate,
tartrate and trometamol. In other embodiment, the salt is selected
from acetonide, aspartate, axetil, benzoate, butoxide, butyrate,
camsylate, carbonate, cypionate, dimethyl sulfoxide, disoproxil,
edisylate, enanthate, epolamine, erbumine, estolate, etabonate,
etexilate, ethanolate, ethylsuccinate, fenofibrate, fosamil,
furoate, gluconate, hexacetonide, hippurate, bromide/hydrobromide,
iodide, isethionate, lysine, magnesium, malate, medoxomil,
methylbromide, napsylate, olamine, oleate, oxalate, oxyquinoline,
palmitate, pentanoate, peroxide, pivalate, pivoxil, polacrilex,
polistirex, polylysine, polystyrate, probutate, proxetil,
saccharate, stearate, subcitrate, subsalicylate, sulfadiazine,
sulfonate, tosylate, triflate, valerate, xinafoate, and zinc. Each
of the above-mentioned salts is prepared by methods known to one of
skill in the art.
[0143] Compositions
[0144] In one embodiment, this disclosure provides a composition
comprising a compound of this disclosure and a pharmaceutically
acceptable carrier or excipient. In another embodiment, the
compound is selected from Compound I Form A, Compound I Form B,
Compound I Form C Compound I Form D and crystalline Compound
II.
[0145] In one embodiment, this disclosure provides a composition
comprising two or more compounds selected from the group consisting
of Compound I Form A, Compound I Form B, Compound I Form C and
Compound I Form D as described herein.
[0146] In another embodiment, the composition comprises Compound I
Form A and Compound I Form C. In another embodiment, the
composition comprises Compound I Form A and at least 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, or 95% w/w of Compound I Form C. In yet another embodiment,
the composition comprises Compound I Form A and at least 50% of w/w
of Compound I Form C.
[0147] In another embodiment, the composition comprises Compound I
Form B and Compound I Form C. In another embodiment, the
composition comprises Compound I Form B and at least 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, or 95% w/w of Compound I Form C. In yet another embodiment,
the composition comprises Compound I Form B and at least 50% w/w of
Compound I Form C.
Formulations and Administration
[0148] The methods and compounds will typically be used in therapy
for human subjects. However, they may also be used to treat similar
or identical indications in other animal subjects. Compounds
described herein can be administered by different routes, including
injection (i.e. parenteral, including intravenous, intraperitoneal,
subcutaneous, and intramuscular), oral, transdermal, transmucosal,
rectal, or inhalant. Such dosage forms should allow the compound to
reach target cells. Other factors are well known in the art, and
include considerations such as toxicity and dosage forms that
retard the compound or composition from exerting its effects.
Techniques and formulations generally may be found in Remington:
The Science and Practice of Pharmacy, 21st edition, Lippincott,
Williams and Wilkins, Philadelphia, Pa., 2005 (hereby incorporated
by reference herein).
[0149] In some embodiments, compositions used in the methods of the
present disclosure will comprise pharmaceutically acceptable
carriers or excipients, such as fillers, binders, disintegrants,
glidants, lubricants, complexing agents, solubilizers, and
surfactants, which may be chosen to facilitate administration of
the compound by a particular route. Examples of carriers include
calcium carbonate, calcium phosphate, various sugars such as
lactose, glucose, or sucrose, types of starch, cellulose
derivatives, gelatin, lipids, liposomes, nanoparticles, and the
like. Carriers also include physiologically compatible liquids as
solvents or for suspensions, including, for example, sterile
solutions of water for injection (WFI), saline solution, dextrose
solution, Hank's solution, Ringer's solution, vegetable oils,
mineral oils, animal oils, polyethylene glycols, liquid paraffin,
and the like. Excipients may also include, for example, colloidal
silicon dioxide, silica gel, talc, magnesium silicate, calcium
silicate, sodium aluminosilicate, magnesium trisilicate, powdered
cellulose, macrocrystalline cellulose, carboxymethyl cellulose,
cross-linked sodium carboxymethylcellulose, sodium benzoate,
calcium carbonate, magnesium carbonate, stearic acid, aluminum
stearate, calcium stearate, magnesium stearate, zinc stearate,
sodium stearyl fumarate, syloid, stearowet C, magnesium oxide,
starch, sodium starch glycolate, glyceryl monostearate, glyceryl
dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil,
hydrogenated cotton seed oil, castor seed oil mineral oil,
polyethylene glycol (e.g. PEG 4000-8000), polyoxyethylene glycol,
poloxamers, povidone, crospovidone, croscarmellose sodium, alginic
acid, casein, methacrylic acid divinylbenzene copolymer, sodium
docusate, cyclodextrins (e.g. 2-hydroxypropyl-delta-cyclodextrin),
polysorbates (e.g. polysorbate 80), cetrimide, TPGS
(d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium
lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers,
di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene
sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester
Tweee), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty
acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such
as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol,
maltose, lactose, lactose monohydrate or lactose spray dried,
sucrose, fructose, calcium phosphate, dibasic calcium phosphate,
tribasic calcium phosphate, calcium sulfate, dextrates, dextran,
dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,
polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl
celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose,
and the like.
[0150] In some embodiments, oral administration may be used.
Pharmaceutical preparations for oral use can be formulated into
conventional oral dosage forms such as capsules, tablets, and
liquid preparations such as syrups, elixirs, and concentrated
drops. Compounds described herein may be combined with solid
excipients, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain, for example, tablets, coated tablets, hard
capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or
oily solutions) and the like. Suitable excipients are, in
particular, fillers such as sugars, including lactose, glucose,
sucrose, mannitol, or sorbitol; cellulose preparations, for
example, corn starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),
and/or polyvinylpyrrolidone (PVP: povidone); oily excipients,
including vegetable and animal oils, such as sunflower oil, olive
oil, or codliver oil. The oral dosage formulations may also contain
disintegrating agents, such as the cross-linked
polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such
as sodium alginate; a lubricant, such as talc or magnesium
stearate; a plasticizer, such as glycerol or sorbitol; a sweetening
such as sucrose, fructose, lactose, or aspartame; a natural or
artificial flavoring agent, such as peppermint, oil of wintergreen,
or cherry flavoring; or dye-stuffs or pigments, which may be used
for identification or characterization of different doses or
combinations. Also provided are dragee cores with suitable
coatings. For this purpose, concentrated sugar solutions may be
used, which may optionally contain, for example, gum arabic, talc,
poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures.
[0151] In some embodiments, the formulation comprises a tablet or a
capsule. In one embodiment, this disclosure provides a tablet
comprising a compound of this disclosure and a pharmaceutically
acceptable carrier or excipient. In another embodiment, the
compound is selected from Compound I Form A, Compound I Form B,
Compound I Form C, Compound I Form D and crystalline Compound II.
In another embodiment, this disclosure provides a capsule
comprising a compound of this disclosure and a pharmaceutically
acceptable carrier or excipient. In a further embodiment, the
compound is selected from Compound I Form A, Compound I Form B,
Compound I Form C, Compound I Form D and crystalline Compound
II.
[0152] In one embodiment, this disclosure provides a tablet
comprising Compound I Form C and a pharmaceutically acceptable
carrier or excipient. In some embodiments, the tablet comprises at
least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, or 95% w/w of Compound I Form C.
[0153] In one embodiment, this disclosure provides a capsule
comprising Compound I Form C and a pharmaceutically acceptable
carrier or excipient. In some embodiments, the capsule comprises at
least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, or 95% w/w of Compound I Form C.
[0154] In another embodiment, this disclosure provides a process of
making a tablet or a capsule comprising combining a compound of
this disclosure and a pharmaceutically acceptable carrier or
excipient. In another embodiment, this disclosure provides a
process of making a tablet comprising Compound I Form C by
combining Compound I Form C with a pharmaceutically acceptable
carrier or excipient. In another embodiment, this disclosure
provides a process of making a capsule comprising Compound I Form C
by combining Compound I Form C with a pharmaceutically acceptable
carrier or excipient.
[0155] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin ("gelcaps"), as well as soft,
sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols.
[0156] In some embodiments, injection (parenteral administration)
may be used, e.g., intramuscular, intravenous, intraperitoneal,
and/or subcutaneous. Compounds described herein for injection may
be formulated in sterile liquid solutions, preferably in
physiologically compatible buffers or solutions, such as saline
solution, Hank's solution, or Ringer's solution. Dispersions may
also be prepared in non-aqueous solutions, such as glycerol,
propylene glycol, ethanol, liquid polyethylene glycols, triacetin,
and vegetable oils. Solutions may also contain a preservative, such
as methylparaben, propylparaben, chlorobutanol, phenol, sorbic
acid, thimerosal, and the like. In addition, the compounds may be
formulated in solid form, including, for example, lyophilized
forms, and redissolved or suspended prior to use.
[0157] In some embodiments, transmucosal, topical or transdermal
administration may be used. In such formulations of compounds
described herein, penetrants appropriate to the barrier to be
permeated are used. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration, bile
salts and fusidic acid derivatives. In addition, detergents may be
used to facilitate permeation. Transmucosal administration, for
example, may be through nasal sprays or suppositories (rectal or
vaginal). Compositions of compounds described herein for topical
administration may be formulated as oils, creams, lotions,
ointments, and the like by choice of appropriate carriers known in
the art. Suitable carriers include vegetable or mineral oils, white
petrolatum (white soft paraffin), branched chain fats or oils,
animal fats and high molecular weight alcohol (greater than C12).
In some embodiments, carriers are selected such that the active
ingredient is soluble. Emulsifiers, stabilizers, humectants and
antioxidants may also be included as well as agents imparting color
or fragrance, if desired. Creams for topical application are
preferably formulated from a mixture of mineral oil,
self-emulsifying beeswax and water in which mixture the active
ingredient, dissolved in a small amount of solvent (e.g., an oil),
is admixed. Additionally, administration by transdermal means may
comprise a transdermal patch or dressing such as a bandage
impregnated with an active ingredient and optionally one or more
carriers or diluents known in the art. To be administered in the
form of a transdermal delivery system, the dosage administration
will be continuous rather than intermittent throughout the dosage
regimen.
[0158] In some embodiments, compounds are administered as
inhalants. Compounds described herein may be formulated as dry
powder or a suitable solution, suspension, or aerosol. Powders and
solutions may be formulated with suitable additives known in the
art. For example, powders may include a suitable powder base such
as lactose or starch, and solutions may comprise propylene glycol,
sterile water, ethanol, sodium chloride and other additives, such
as acid, alkali and buffer salts. Such solutions or suspensions may
be administered by inhaling via spray, pump, atomizer, or
nebulizer, and the like. The compounds described herein may also be
used in combination with other inhaled therapies, for example
corticosteroids such as fluticasone proprionate, beclomethasone
dipropionate, triamcinolone acetonide, budesonide, and mometasone
furoate; beta agonists such as albuterol, salmeterol, and
formoterol; anticholinergic agents such as ipratroprium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes
such as DNAase; therapeutic proteins; immunoglobulin antibodies; an
oligonucleotide, such as single or double stranded DNA or RNA,
siRNA; antibiotics such as tobramycin; muscarinic receptor
antagonists; leukotriene antagonists; cytokine antagonists;
protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
cromoglycate.
[0159] The amounts of various compounds to be administered can be
determined by standard procedures taking into account factors such
as the compound activity (in vitro, e.g. the Compound IC.sub.50 vs.
target, or in vivo activity in animal efficacy models),
pharmacokinetic results in animal models (e.g. biological half-life
or bioavailability), the age, size, and weight of the subject, and
the disorder associated with the subject. The importance of these
and other factors are well known to those of ordinary skill in the
art. Generally, a dose is in the range of about 0.01 to 50 mg/kg,
also about 0.1 to 20 mg/kg of the subject being treated. Typically,
a dose of about 600 to 1200 mg/day is used. Multiple doses may be
used.
[0160] The compounds described herein may also be used in
combination with other therapies for treating the same disease.
Such combination use includes administration of the compounds and
one or more other therapeutics at different times, or
co-administration of the compound and one or more other therapies.
In some embodiments, dosage may be modified for one or more of the
compounds of the disclosure or other therapeutics used in
combination, e.g., reduction in the amount dosed relative to a
compound or therapy used alone, by methods well known to those of
ordinary skill in the art.
[0161] The compounds described herein may be used in combination
with another chemotherapeutic agent or drug or a kinase inhibitor
for treating the same disease. Such combination can be a fixed dose
composition or be administered at different times, or
co-administration of the compound and anther agent, drug or kinase
inhibitor simultaneously or separately. In some embodiments, dosage
may be modified for one or more of the compounds of the disclosure
or another agent, drug or kinase inhibitor used in combination,
e.g., reduction or increase in the amount dosed relative to a
compound used alone to improve safety and/or efficacy, by methods
well known to those of ordinary skill in the art.
[0162] It is understood that use in combination includes use with
other therapies, drugs, medical procedures etc., where the other
therapy or procedure may be administered at different times (e.g.
within a short time, such as within hours (e.g. 1, 2, 3, 4-24
hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days,
1-4 weeks)) than a compound described herein, or at the same time
as a compound described herein. Use in combination also includes
use with a therapy or medical procedure that is administered once
or infrequently, such as surgery, along with a compound described
herein administered within a short time or longer time before or
after the other therapy or procedure. In some embodiments, the
present disclosure provides for delivery of a compound described
herein and one or more other drug therapeutics delivered by a
different route of administration or by the same route of
administration. The use in combination for any route of
administration includes delivery of a compound described herein and
one or more other drug therapeutics delivered by the same route of
administration together in any formulation, including formulations
where the two compounds are chemically linked in such a way that
they maintain their therapeutic activity when administered. In one
aspect, the other drug therapy may be co-administered with a
compound described herein. Use in combination by co-administration
includes administration of co-formulations or formulations of
chemically joined compounds, or administration of two or more
compounds in separate formulations within a short time of each
other (e.g. within an hour, 2 hours, 3 hours, up to 24 hours),
administered by the same or different routes. Co-administration of
separate formulations includes co-administration by delivery via
one device, for example the same inhalant device, the same syringe,
etc., or administration from separate devices within a short time
of each other. Co-formulations of a compound described herein and
one or more additional drug therapies delivered by the same route
includes preparation of the materials together such that they can
be administered by one device, including the separate compounds
combined in one formulation, or compounds that are modified such
that they are chemically joined, yet still maintain their
biological activity. Such chemically joined compounds may have a
linkage that is substantially maintained in vivo, or the linkage
may break down in vivo, separating the two active components.
Methods of Treatment
[0163] In some embodiments, the disclosure provides a method for
treating a disease or condition in a subject in need thereof, by
administering to the subject a therapeutically effective amount one
or more solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II, as described herein, or a
composition thereof. Examples of Crystalline forms that can be used
in the methods described herein include Compound I Form A, Compound
I Form B, Compound I Form C, Compound I Form D, and crystalline
Compound II.
[0164] In some embodiments, the disclosure provides a method of
treating a disease or condition in a subject in need thereof, by
administering to the subject a therapeutically effective amount of
one or more solid, crystalline or polymorphs of Compound I or solid
or crystalline Compound II as described herein, a prodrug of such
compound, a pharmaceutically acceptable salt of such compound or
prodrug, or a pharmaceutically acceptable formulation of such
compound or prodrug in combination with one or more other suitable
therapies for the disease or condition.
[0165] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk of a disease or
condition mediated by c-Fms, c-Kit, Flt3, infiltration or
activation of macrophages and/or microglias or combinations
thereof. The method includes administering to the subject an
effective amount of one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline Compound II as described herein,
or a composition as described herein. In some embodiments, the
method includes administering to the subject a therapeutically
effective amount of Compound I Form A, Compound I Form B, Compound
I Form C, Compound I Form D or crystalline Compound II. In some
embodiments, the method includes administering to the subject a
composition comprising a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D or crystalline Compound II and a pharmaceutically acceptable
excipient.
[0166] In certain embodiments, the method involves administering to
the subject an effective amount of one or more solid, crystalline
or polymorphs of Compound I or solid or crystalline Compound II as
described herein in combination with one or more other suitable
therapies for the disease or condition. In some embodiments, the
disclosure provides a method for treating a subject suffering from
a disease or condition mediated by tumor-associated macrophages
(TAM). In certain embodiments, the disclosure provides a method for
treating a subject suffering from a disease or condition, such as a
tumor, where tumor-associated macrophages play a role in tumor
proliferation, survival, and metastasis. In some embodiments, the
disclosure provides a method for treating a subject suffering from
a disease or condition, where reduction/depletion of macrophages or
microglia provides a benefit. In certain instances, the disease or
condition is as described herein. The method includes administering
to the subject an effective amount of one or more solid,
crystalline or polymorphs of Compound I or solid or crystalline
Compound II as described herein and an agent or a drug as described
herein. In some embodiments, the disclosure provides methods for
treating a subject suffering from tumors that express aberrantly or
otherwise Fms, CSF1R, CSF1 or IL-34, or activating mutations or
translocations of any of the foregoing.
[0167] In some embodiments, the diseases treatable with one or more
solid, crystalline or polymorphs of Compound I or solid or
crystalline Compound II as described herein or compositions as
described herein are c-Fms mediated disease selected from the group
consisting of immune disorders, including, but not limiting to,
rheumatoid arthritis, systemic lupus erythematosis (SLE), and
transplant rejection; stem cell ablation and myelopreparation for
stem cell transplant; inflammatory diseases including, but not
limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative
colitis, Crohn's disease, chronic obstructive pulmonary disease
(COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome
(macrophage activation syndrome), multicentric
reticulohistiocytosis, and atherosclerosis; metabolic disorders,
including, but not limited to, Type I diabetes, Type II diabetes,
insulin resistance, hyperglycemia, obesity, and lipolysis;
disorders of bone structure, mineralization and bone formation and
resorption, including, but not limited to, osteoporosis, increased
risk of fracture, Paget's disease, hypercalcemia,
infection-mediated osteolysis (e.g. osteomyelitis), peri-prosthetic
or wear-debris-mediated osteolysis, and metastasis of cancer to
bone; kidney and genitourinary diseases, including, but not limited
to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial
nephritis, Lupus nephritis), tubular necrosis, diabetes-associated
renal complications (e.g. diabetic nephropathy), and renal
hypertrophy; disorders of the central nervous system, including,
but not limited to, multiple sclerosis, stroke, Alzheimer's disease
and Parkinson's disease; inflammatory and chronic pain, including,
but not limited to, bone pain; and cancers, including, but not
limited to, multiple myeloma, acute myeloid leukemia (AML), chronic
myeloid leukemia (CML), monocytic leukemia, prostate cancer, breast
cancer, ovarian cancer, melanoma, glioblastoma multiforme,
tauopathies, metastasis of tumors to other tissues, and other
chronic myeloproliferative diseases such as myelofibrosis. In some
embodiments, the AML is associated with Fms-like tyrosine kinase 3
(Flt3) mutations that are internal tandem duplication (ITD)
mutations. In some embodiments, the c-Fms mediated diseases include
tumors that express aberrantly or otherwise Fms, CSF1R, CSF1 or
IL-34, or activating mutations or translocations of any of the
foregoing.
[0168] In other embodiments, the disease or condition is mediated
by c-Fms and c-Kit and is selected from the group consisting of
mast cell tumors, small cell lung cancer, testicular cancer,
gastrointestinal stromal tumors, glioblastoma, astrocytoma,
neuroblastoma, carcinomas of the female genital tract, sarcomas of
neuroectodermal origin, colorectal carcinoma, carcinoma in situ,
Schwann cell neoplasia, malignant peripheral nerve cell tumors,
malignant peripheral nerve sheath tumors, pheochromocytomas
cutaneous and plexiform neurofibromas, neurofibromatosis,
neurofibromatosis-1 (NF1), leiomyo-adenomatoid tumor, leiomyo
sarcoma, acute myeloid leukemia, acute lymphocytic leukemia,
chronic myelogenous leukemia, multiple myeloma, mastocytosis,
melanoma, breast cancer, ovarian cancer, prostate cancer, canine
mast cell tumors, metastasis of cancer to bone or other tissues,
chronic myeloproliferative diseases such as myelofibrosis, renal
hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis,
multiple sclerosis, osteoarthritis, inflammatory bowel syndrome,
transplant rejection, systemic lupus erythematosis, ulcerative
colitis, Crohn's disease, chronic obstructive pulmonary disease,
emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage
activation syndrome), multicentric reticulohistiocytosis,
atherosclerosis, Type I diabetes, Type II diabetes, insulin
resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia,
osteoporosis, increased risk of fracture, Paget's disease,
hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis),
peri-prosthetic or wear-debris-mediated osteolysis, endometriosis,
glomerulonephritis, interstitial nephritis, Lupus nephritis,
tubular necrosis, diabetic nephropathy, stroke, Alzheimer's
disease, Parkinson's disease, inflammatory pain, chronic pain, and
bone pain.
[0169] In some embodiments, the disease or condition treatable with
one or more solid, crystalline or polymorphs of Compound I or solid
or crystalline Compound II or compositions as described herein is
selected from alopecia, baldness, wound healing, androgenetic
alopecia (AGA), epilepsy, traumatic brain injury, tauopathies,
Erdheim Chester Disease, Langerhans cell histocytosis, hairy cell
leukemia, non-small cell lung cancer, cleroderma, anterior eye
disease, posterior eye disease, lysosomal storage disease, stem
cell ablation and myelopreparation for stem cell transplant,
primary progressive multiple sclerosis, complex regional pain
syndrome, reflex sympathetic dystrophy, muscular dystrophy,
duchenne muscular dystrophy, causalgia, neuro-inflammation,
neuroinflammatory disorders, benign forgetfulness, HIV, binswager
type dementia, dementia with lewy bodie, prosencephaly,
microencepahy, cerebral palsy, congenital hydrocephalus, abdominal
dropsy, progressive supranuclear palsy, glaucoma, addiction
disorders, dependencies, alcoholism, tremors, Wilson's disease,
vascular dementias, multi infarct dementia, frontotemporal
dementia, pseudo-dementia, bladder cancer, ureter cancer, urethra
cancer, urachus cancer, basal cell carcinoma, cholangiocarcinoma,
colon cancer, endometrial cancer, esophageal cancer, Ewing's
sarcoma, gastric cancer, glioma, hepatocellular carcinoma, Hodgkin
lymphoma, laryngeal carcinoma, leukemia, liver cancer, lung cancer,
melanoma, mesothelioma, pancreatic cancer, rectal cancer, renal
cancer, squamous cell carcinoma, t cell lymphoma, thyroid cancer,
monocytic leukemia, pheochromocytoma, malignant peripheral nerve
cell tumors, malignant peripheral nerve sheath tumors (MPNST),
cutaneous and plexiform neurofibromas, leiomyoadenomatoid tumor,
fibroids, uterine fibroids, leiomyosarcoma, papillary thyroid
cancer, anaplastic thyroid cancer, medullary thyroid cancer,
follicular thyroid cancer, hurthle cell carcinoma, thyroid cancer,
angiosarcomas, liposarcomas, ascites, malignant ascites,
mesothelioma, salivary gland tumors, mucoepidermoid carcinoma of
the salivary gland, acinic cell carcinoma of the salivary gland,
gastrointestinal stromal tumors (GIST--which includes, without
limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant GIST),
tumors that cause effusions in potential spaces of the body,
pleural effusions, pericardial effusions, peritoneal effusions aka
ascites, giant cell tumors (GCT), GCT of bone, pigmented
villonodular synovitis (PVNS), tenosynovial giant cell tumor
(TGCT), TCGT of tendon sheath (TGCT-TS), other sarcomas; tumor
angiogenesis and paracrine tumor growth; and tumors that express
aberrantly or otherwise Fms, CSF1R, CSF1 or IL-34, or activating
mutations or translocations of any of the foregoing.
[0170] In the embodiments and aspects described in this disclosure,
crystalline or polymorphs of Compound I are intended to include,
without limitation, Compound I Form A, Compound I Form B, Compound
I Form C according, and Compound I Form D.
[0171] In some embodiments, the disease or condition treatable with
one or more solid, crystalline or polymorphs of Compound I or solid
or crystalline Compound II or compositions as described herein is
selected from primary progressive multiple sclerosis, malignant
peripheral nerve sheath tumors (MPNST), plexiform neurofibromas,
mesothelioma, multi infarct dementia, fronto temporal dementia,
mucoepidermoid carcinoma of the salivary gland, gastrointestinal
stromal tumors (GIST--which includes, without limitation, 1.sup.st
line, 2.sup.nd line and neoadjuvant GIST), pigmented villonodular
synovitis (PVNS) or tenosynovial giant cell tumor (TGCT).
[0172] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk of tenosynovial giant
cell tumor (TGCT) comprising administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D or crystalline
Compound II or a composition comprising Compound I Form A, Compound
I Form B, Compound I Form C, Compound I Form D, or crystalline
Compound II and a pharmaceutically acceptable carrier. In some
embodiments, the disclosure provides a method for treating a
subject suffering from or at risk of pigmented villonodular
synovitis (PVNS) comprising administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D or crystalline
Compound II or a composition comprising Compound I Form A, Compound
I Form B, Compound I Form C, Compound I Form D or crystalline
Compound II and a pharmaceutically acceptable carrier. In some
embodiments, the disclosure provides a method for treating a
subject suffering from or at risk of malignant peripheral nerve
sheath tumors (MPNST) comprising administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D or crystalline
Compound II or a composition comprising Compound I Form A, Compound
I Form B, Compound I Form C, Compound I Form D or crystalline
Compound II and a pharmaceutically acceptable carrier. In some
embodiments, the disclosure provides a method for treating a
subject suffering from or at risk of plexiform neurofibromas
comprising administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D or crystalline Compound II or a composition
comprising Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D or crystalline Compound II and a pharmaceutically
acceptable carrier. In some embodiments, the disclosure provides a
method for treating a subject suffering from or at risk of
malignant peripheral nerve sheath tumors (MPNST) comprising
administering to the subject a therapeutically effective amount of
Compound I Form C, or a composition comprising Compound I Form C,
and a pharmaceutically acceptable carrier. In some embodiments, the
disclosure provides a method for treating a subject suffering from
or at risk of plexiform neurofibromas comprising administering to
the subject a therapeutically effective amount of Compound I Form
C, or a composition comprising Compound I Form C, and a
pharmaceutically acceptable carrier.
[0173] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk of solid tumors
comprising administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D or crystalline Compound II or a composition
comprising Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D, or crystalline Compound II and a
pharmaceutically acceptable carrier, and optionally further
administering a therapeutically effective amount of paclitaxel. In
some embodiments, the solid tumor is advanced, metastatic or
non-resectable epithelial ovarian cancer, primary peritoneal
cancer, or fallopian tube cancer. In some embodiments, the
disclosure provides a method for treating a subject suffering from
or at risk of advanced, metastatic or non-resectable epithelial
ovarian cancer, primary peritoneal cancer, or fallopian tube
cancer, comprising administering to the subject a therapeutically
effective amount of Compound I Form C, or a composition comprising
Compound I Form C, and a pharmaceutically acceptable carrier.
[0174] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline Compound II described herein,
the disclosure provides methods for treating a Kit-mediated disease
or condition in a subject in need thereof (e.g. a mammal such as a
human, other primates, sports animals, animals of commercial
interest such as cattle, farm animals such as horses, or pets such
as dogs and cats), e.g., a disease or condition characterized by
abnormal Kit activity (e.g. kinase activity). In some embodiments,
the methods may involve administering to the subject suffering from
or at risk of a c-Kit-mediated disease or condition an effective
amount of one or more compound(s) as described herein. In one
embodiment, the Kit mediated disease is selected from the group
consisting of malignancies, including, but not limited to, mast
cell tumors, small cell lung cancer, non-small cell lung cancer
(NSCLC), testicular cancer, pancreatic cancer, breast cancer,
merkel cell carcinoma, carcinomas of the female genital tract,
sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma
in situ, gastrointestinal stromal tumors (GISTs--which includes,
without limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant
GIST), tumor angiogenesis, glioblastoma, astrocytoma,
neuroblastoma, neurofibromatosis (including Schwann cell neoplasia
associated with neurofibromatosis), acute myeloid leukemia, acute
lymphocytic leukemia, chronic myeloid leukemia, mastocytosis,
melanoma, and canine mast cell tumors; cardiovascular disease,
including but not limited to atherosclerosis, cardiomyopathy, heart
failure, pulmonary arterial hypertension and pulmonary fibrosis;
inflammatory and autoimmune indications, including, but not limited
to, allergy, anaphylaxis, asthma, rheumatoid arthritis, allergic
rhinitis, multiple sclerosis, inflammatory bowel disease,
transplant rejection, hypereosinophilia, urticaria and dermatitis;
gastrointestinal indications, including but not limited to
gastroesophageal reflux disease (GERD), esophagitis, and
gastrointestinal tract ulcers; ophthalmic indications, including
but not limited to uveitis and retinitis; and neurologic
indications, including, but not limiting to migraine and tumors
that express aberrantly or otherwise Kit, SCFR, SCF, or activating
mutations or translocations of any of the foregoing.
[0175] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline Compound II as described herein,
the disclosure provides methods for treating a Fms-mediated disease
or condition in a subject in need thereof (e.g. a mammal such as a
human, other primates, sports animals, animals of commercial
interest such as cattle, farm animals such as horses, or pets such
as dogs and cats), e.g., a disease or condition characterized by
abnormal Fms activity (e.g. kinase activity). In some embodiments,
the methods may involve administering to the subject suffering from
or at risk of a Fms-mediated disease or condition an effective
amount of one or more compound(s) as described herein. In one
embodiment, the Fms mediated disease is selected from the group
consisting of inflammatory and autoimmune indications, including,
but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic
arthritis, psoriasis, dermatitis, ankylosing spondylitis,
polymyositis, dermatomyositis, systemic sclerosis, juvenile
idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease,
Langerhan's cell histiocytosis (LCH), Still's disease, inflammatory
bowel disease, ulcerative colitis, Crohn's disease, systemic lupus
erythematosis (SLE), immune thrombocytopenic purpura (ITP),
myelopreparation for autologous transplantation, transplant
rejection, chronic obstructive pulmonary disease (COPD), emphysema,
Kawasaki's Disease, hemophagocytic syndrome (macrophage activation
syndrome), multicentric reticulohistiocytosis, and atherosclerosis;
metabolic disorders, including, but not limited to, Type I
diabetes, Type II diabetes, insulin resistance, hyperglycemia,
obesity, and lipolysis; disorders of bone structure, mineralization
and bone formation and resorption, including, but not limited to,
osteoporosis, osteodystrophy, increased risk of fracture, Paget's
disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), and peri-prosthetic or wear-debris-mediated
osteolysis; kidney and genitourinary diseases, including, but not
limited to, endometriosis, nephritis (e.g. glomerulonephritis,
interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic
nephropathy), and renal hypertrophy; disorders of the nervous
system, including, but not limited to, demyelinating disorders
(e.g. multiple sclerosis, Charcot Marie Tooth syndrome),
amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic
demyelinating polyneuropathy, other demyelinating disorders,
stroke, Alzheimer's disease and Parkinson's disease; pain,
including, but not limited to, chronic pain, acute pain,
inflammatory pain, neuropathic pain, bone pain; malignancies,
including, but not limited to, multiple myeloma, acute myeloid
leukemia (AML), chronic myeloid leukemia (CML), lung cancer,
pancreatic cancer, prostate cancer, breast cancer, ovarian cancer,
neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g.
giant cell tumor of bone, giant cell tumor of tendon sheath
(TGCT)), pigmented villonodular synovitis (PVNS), tumor
angiogenesis, melanoma, glioblastoma multiforme, a subset of
glioblastoma, proneural subset of glioblastoma, glioma, other
tumors of the central nervous system, metastasis of tumors to other
tissues, osteolytic bone metastases, and other chronic
myeloproliferative diseases such as myelofibrosis; vasculitis,
including but not limited to collagen vascular disease,
polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar
Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis,
giant cell arteritis, Takayasu's arteritis; ophthalmic indications,
including but not limited to uveitis, scleritis, retinitis, age
related macular degeneration, choroidal neovascularization,
diabetic retinopathy; inherited disorders, including but not
limited to cherubism, neurofibromatosis; infectious disease
indications, including but not limited to infections associated
with human immunodeficiency virus, hepatitis B virus, hepatitis C
virus, human granulocytic anaplasmosis; lysosomal storage
disorders, including but not limited to Gaucher's disease, Fabry's
disease, Niemann-Pick disease; gastrointestinal indications,
including but not limited to liver cirrhosis; pulmonary
indications, including but not limited to pulmonary fibrosis, acute
lung injury (e.g. ventilator-induced, smoke- or toxin-induced);
surgical indications, including but not limited to
(cardiopulmonary) bypass surgery, vascular surgery, and vascular
grafts; and tumors that express aberrantly or otherwise Fms, CSF1R,
CSF1 or IL-34, or activating mutations or translocations of any of
the foregoing.
[0176] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure is epilepsy.
[0177] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure is traumatic brain injury.
[0178] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure, in combination with dovitinib or vatalanib, is
glioblastoma (GBM).
[0179] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure include tauopathies.
[0180] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure include reducing viral reservoirs in patients.
[0181] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure include Erdheim Chester Disease/Langerhans cell
histocytosis, hairy cell leukemia, and non-small cell lung cancer
(NSCLC).
[0182] In another embodiment of this disclosure, disease that can
be treated by any of compounds in this disclosure is scleroderma.
In this embodiment, the compound of this disclosure is administered
topically, and can be administered in a topical formulation such as
a gel, cream or spray as non-limiting examples.
[0183] In another embodiment of this disclosure, the CSF1R (Fms)
mediated disease that can be treated by any of compounds in this
disclosure is anterior eye disease or posterior eye disease.
Examples of these eye diseases include diseases of the cornea,
conjunctiva, sclera, and lacrimal glands.
[0184] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline Compound II as described herein,
the disclosure provides methods for treating a disease or condition
mediated by Fms and Kit in a subject in need thereof (e.g. a mammal
such as a human, other primates, sports animals, animals of
commercial interest such as cattle, farm animals such as horses, or
pets such as dogs and cats), e.g., a disease or condition
characterized by abnormal Fms activity and Kit activity (e.g.
kinase activity). In some embodiments, the methods may involve
administering to the subject suffering from or at risk of a disease
or condition mediated by Fms and Kit an effective amount of one or
more compound(s) as described herein. In one embodiment, the
condition mediated by Fms and Kit is selected from the group
consisting of rheumatoid arthritis, osteoarthritis, psoriatic
arthritis, psoriasis, dermatitis, allergy, anaphylaxis, asthma,
allergic rhinitis, ankylosing spondylitis, polymyositis,
dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis,
polymyalgia rheumatica, Sjogren's disease, Langerhan's cell
histiocytosis, Still's disease, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, systemic lupus erythematosis,
immune thrombocytopenic purpura, myelopreparation for autologous
transplantation, transplant rejection, chronic obstructive
pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic
syndrome, multicentric reticulohistiocytosis, hypereosinophilia,
and urticaria type I diabetes, type II diabetes, insulin
resistance, hyperglycemia, obesity, and lipolysis, osteoporosis,
osteodystrophy, increased risk of fracture, Paget's disease,
hypercalcemia, infection-mediated osteolysis, and peri-prosthetic
or wear-debris-mediated osteolysis, endometriosis, nephritis,
tubular necrosis, diabetes-associated renal complications, and
renal hypertrophy, multiple sclerosis, Charcot Marie Tooth
syndrome, amyotrophic lateral sclerosis, myasthenia gravis, chronic
demyelinating polyneuropathy, other demyelinating disorders,
stroke, Alzheimer's disease and Parkinson's disease, acute pain,
neuropathic pain, inflammatory pain, chronic pain, migraine,
multiple myeloma, acute lymphocytic leukemia, acute myeloid
leukemia, chronic myeloid leukemia, mast cell tumors, canine mast
cell tumors, lung cancer, testicular cancer, pancreatic cancer,
prostate cancer, breast cancer, ovarian cancer, merkel cell
carcinoma, carcinomas of the female genital tract, colorectal
carcinoma, carcinoma in situ, gastrointestinal stromal tumors,
tumor angiogenesis, astrocytoma, neuroblastoma, sarcoma,
osteosarcoma, sarcomas of neuroectodermal origin, giant cell tumor
of bone, giant cell tumor of tendon sheath, pigmented villonodular
synovitis, melanoma, glioblastoma, glioblastoma multiforme, glioma,
other tumors of the central nervous system, neurofibromatosis
(including Schwann cell neoplasia associated with
neurofibromatosis), mastocytosis, metastasis of tumors to other
tissues, osteolytic bone metastases, and other chronic
myeloproliferative diseases such as myelofibrosis, collagen
vascular disease, polyarteritis nodosa, Behcet's disease,
sarcoidosis, familiar Mediterranean fever, Churg-Strauss
vasculitis, temporal arteritis, giant cell arteritis, Takayasu's
arteritis, uveitis, scleritis, retinitis, age related macular
degeneration, choroidal neovascularization, diabetic retinopathy,
cherubism, neurofibromatosis, infections associated with human
immunodeficiency virus, hepatitis B virus, hepatitis C virus, human
granulocytic anaplasmosis, Gaucher's disease, Fabry's disease,
Niemann-Pick disease, liver cirrhosis, gastroesophageal reflux
disease, esophagitis, and gastrointestinal tract ulcers, pulmonary
fibrosis, acute lung injury, bypass surgery, vascular surgery, and
vascular grafts, atherosclerosis, cardiomyopathy, heart failure,
and pulmonary arterial hypertension.
[0185] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline Compound II as described herein,
the disclosure provides methods for treating a disease or condition
mediated by Fms and Flt-3 in a subject in need thereof (e.g. a
mammal such as a human, other primates, sports animals, animals of
commercial interest such as cattle, farm animals such as horses, or
pets such as dogs and cats), e.g., a disease or condition
characterized by abnormal Fms activity and Flt-3 activity (e.g.
kinase activity). In some embodiments, the methods may involve
administering to the subject suffering from or at risk of a disease
or condition mediated by Fms and Flt-3 an effective amount of one
or more compound(s) as described herein. In one embodiment, the
condition mediated by Fms and Flt-3 is acute myeloid leukemia.
[0186] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, the methods may involve administering an
effective amount of one or more compound(s) or one or more
composition(s) as described herein, and optionally in combination
with another therapeutic agent or therapy as described herein, to a
subject in need thereof suffering from or at risk of a disease or
condition selected from the group consisting of rheumatoid
arthritis, osteoarthritis, osteoporosis, peri-prosthetic
osteolysis, systemic sclerosis, demyelinating disorders, multiple
sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral
sclerosis, Alzheimer's disease, Parkinson's disease, ulcerative
colitis, Crohn's disease, immune thrombocytopenic purpura,
atherosclerosis, systemic lupus erythematosis, myelopreparation for
autologous transplantation, transplant rejection,
glomerulonephritis, interstitial nephritis, Lupus nephritis,
tubular necrosis, diabetic nephropathy, renal hypertrophy, type I
diabetes, acute pain, inflammatory pain, neuropathic pain, acute
myeloid leukemia, melanoma, multiple myeloma, metastatic breast
cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian
cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone
metastases, brain metastases, gastrointestinal stromal tumors, and
giant cell tumors.
[0187] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of lysosomal storage disorders. Non-limiting examples of lysosomal
storage disorders include mucolipodosis, alpha-mannosidosis,
aspartylglucosaminuria, Batten disease, beta-mannosidosis,
cystinosis, Danon disease, Fabry disease, Farber disease,
fucosidosis, galactosialidosis, Gaucher disease, gangliosidosis
(e.g., GM1 gangliosidosis and GM2-gangliosidosis AB variant),
Krabbe disease, metachromatic leukodystrophy, mucopolysaccharidoses
disorders (e.g., MPS 1--Hurler syndrome, MPSII--Hunter syndrome,
MPS III--Sanfilippo (A,B,C,D), MPS IVA--Morquio, MPS
IX--hyaluronidase, deficiency, MPS VI--Maroteaux-Lamy, or MPS
VII--Sly syndrome), mucolipidosis type I (Sialidosis),
mucolipidosis type II (I-Cell disease); mucolipidosis type III
(Pseudo-Hurler polydystrophy), mucolipidosis type IV, multiple
sulfatase deficiency, Niemann-Pick types A, B, C, Pompe disease
(glycogen storage disease), pycnodysostosis, Sandhoff disease,
Schindler disease, Salla disease/sialic acid storage disease,
Tay-Sachs, and Wolman disease.
[0188] Further to any of the aspects and embodiments referred to
herein, a compound as described herein also inhibits the effects of
a mutation of the kinase (e.g. Fms mutant, Kit mutant, Flt-3
mutant, e.g., internal tandem duplications (ITD)), including, but
not limiting to, a mutation that is related to a disease state,
such as a cancer.
[0189] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, the methods involve administering an effective
amount of one or more compound(s) as described herein or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein, to a subject in need thereof suffering from or at risk of a
disease or condition selected from the group consisting of from
stem cell ablation and myelopreparation for stem cell transplant,
monocytic leukemia, primary progressive multiple sclerosis, complex
regional pain syndrome, reflex sympathetic dystrophy, muscular
dystrophy, duchenne muscular dystrophy, causalgia, malignant
peripheral nerve cell tumors, malignant peripheral nerve sheath
tumors, pheochromocytomas cutaneous and plexiform neurofibromas,
neuro-inflammations, benign forgetfulness, HIV, binswager type
dementia, dementia with lewy bodie, prosencephaly, microencepahy,
cerebral palsy, congenital hydrocephalus, tremors, Wilson's
disease, vascular dementias/multi infarct dementia, fronto temporal
type, pseudo-dementia, papillary thyroid cancer, anaplastic thyroid
cancer, medullary thyroid cancer, follicular thyroid cancer,
hurthle cell carcinoma, thyroid cancer, ascites, malignant ascites,
abdominal dropsy, progressive supranuclear palsy, glaucoma,
mesothelioma, salivary gland tumors, mucoepidermoid carcinoma of
the salivary gland, acinic cell carcinoma of the salivary gland,
and others), gastrointestinal stromal tumors (GIST--which includes,
without limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant
GIST), tumors that cause effusions in potential spaces of the body,
pleural effusions, pericardial effusions, peritoneal effusions aka
ascites, giant cell tumors (GCT), GCT of bone, pigmented
villonodular synovitis (PVNS), tenosynovial giant cell tumor
(TGCT), TCGT of tendon sheath (TGCT-TS), other sarcomas, tumor
angiogenesis and paracrine tumor growth; and tumors that express
aberrantly or otherwise Fms, CSF1R, CSF1 or IL-34, or activating
mutations or translocations of any of the foregoing, wherein the
compound is an inhibitor of Kit.
[0190] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, the methods may involve administering an
effective amount of one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein or a composition thereof as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein, to a subject in need thereof suffering from or
at risk of a disease or condition selected from the group
consisting of from alopecia, baldness, wound healing, androgenetic
alopecia (AGA), epilepsy, traumatic brain injury, tauopathies,
Erdheim Chester Disease, Langerhans cell histocytosis, hairy cell
leukemia, non-small cell lung cancer, cleroderma, anterior eye
disease, posterior eye disease, lysosomal storage disease, stem
cell ablation and myelopreparation for stem cell transplant,
primary progressive multiple sclerosis, complex regional pain
syndrome, reflex sympathetic dystrophy, muscular dystrophy,
duchenne muscular dystrophy, causalgia, neuro-inflammation,
neuroinflammatory disorders, benign forgetfulness, HIV, binswager
type dementia, dementia with lewy bodie, prosencephaly,
microencepahy, cerebral palsy, congenital hydrocephalus, abdominal
dropsy, progressive supranuclear palsy, glaucoma, addiction
disorders, dependencies, alcoholism, tremors, Wilson's disease,
vascular dementias, multi infarct dementia, fronto temporal
dementia, pseudo-dementia, bladder cancer, ureter cancer, urethra
cancer, urachus cancer, basal cell carcinoma, cholangiocarcinoma,
colon cancer, endometrial cancer, esophageal cancer, Ewing's
sarcoma, gastric cancer, glioma, hepatocellular carcinoma, Hodgkin
lymphoma, laryngeal carcinoma, leukemia, liver cancer, lung cancer,
melanoma, mesothelioma, pancreatic cancer, rectal cancer, renal
cancer, squamous cell carcinoma, t cell lymphoma, thyroid cancer,
monocytic leukemia, pheochromocytoma, malignant peripheral nerve
cell tumors, malignant peripheral nerve sheath tumors (MPNST),
cutaneous and plexiform neurofibromas, leiomyoadenomatoid tumor,
fibroids, uterine fibroids, leiomyosarcoma, papillary thyroid
cancer, anaplastic thyroid cancer, medullary thyroid cancer,
follicular thyroid cancer, hurthle cell carcinoma, thyroid cancer,
angiosarcomas, liposarcomas, ascites, malignant ascites,
mesothelioma, salivary gland tumors, mucoepidermoid carcinoma of
the salivary gland, acinic cell carcinoma of the salivary gland,
gastrointestinal stromal tumors (GIST--which includes, without
limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant GIST),
tumors that cause effusions in potential spaces of the body,
pleural effusions, pericardial effusions, peritoneal effusions aka
ascites, giant cell tumors (GCT), GCT of bone, pigmented
villonodular synovitis (PVNS), tenosynovial giant cell tumor
(TGCT), TCGT of tendon sheath (TGCT-TS), and other sarcomas; tumor
angiogenesis and paracrine tumor growth and tumors that express
aberrantly or otherwise Fms, CSF1R, CSF1 or IL-34, or activating
mutations or translocations of any of the foregoing.
[0191] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, the methods may involve administering an
effective amount of one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, or a composition thereof as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein, to a subject in need thereof suffering from or
at risk of a disease or condition selected from the group
consisting of alopecia, baldness, wound healing, androgenetic
alopecia (AGA), epilepsy, traumatic brain injury, tauopathies,
Erdheim Chester Disease, Langerhans cell histocytosis, hairy cell
leukemia, non-small cell lung cancer, cleroderma, anterior eye
disease, posterior eye disease, lysosomal storage disease, stem
cell ablation and myelopreparation for stem cell transplant,
primary progressive multiple sclerosis, complex regional pain
syndrome, reflex sympathetic dystrophy, muscular dystrophy,
duchenne muscular dystrophy, causalgia, neuro-inflammation,
neuroinflammatory disorders, benign forgetfulness, HIV, binswager
type dementia, dementia with lewy bodie, prosencephaly,
microencepahy, cerebral palsy, congenital hydrocephalus, abdominal
dropsy, progressive supranuclear palsy, glaucoma, addiction
disorders, dependencies, alcoholism, tremors, Wilson's disease,
vascular dementias, multi infarct dementia, fronto temporal
dementia, pseudo-dementia, bladder cancer, ureter cancer, urethra
cancer, urachus cancer, basal cell carcinoma, cholangiocarcinoma,
colon cancer, endometrial cancer, esophageal cancer, Ewing's
sarcoma, gastric cancer, glioma, hepatocellular carcinoma, Hodgkin
lymphoma, laryngeal carcinoma, leukemia, liver cancer, lung cancer,
melanoma, mesothelioma, pancreatic cancer, rectal cancer, renal
cancer, squamous cell carcinoma, t cell lymphoma, thyroid cancer,
monocytic leukemia, pheochromocytoma, malignant peripheral nerve
cell tumors, malignant peripheral nerve sheath tumors (MPNST),
cutaneous and plexiform neurofibromas, leiomyoadenomatoid tumor,
fibroids, uterine fibroids, leiomyosarcoma, papillary thyroid
cancer, anaplastic thyroid cancer, medullary thyroid cancer,
follicular thyroid cancer, hurthle cell carcinoma, thyroid cancer,
angiosarcomas, liposarcomas, ascites, malignant ascites,
mesothelioma, salivary gland tumors, mucoepidermoid carcinoma of
the salivary gland, acinic cell carcinoma of the salivary gland,
gastrointestinal stromal tumors (GIST--which includes, without
limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant GIST),
tumors that cause effusions in potential spaces of the body,
pleural effusions, pericardial effusions, peritoneal effusions aka
ascites, giant cell tumors (GCT), GCT of bone, pigmented
villonodular synovitis (PVNS), tenosynovial giant cell tumor
(TGCT), TCGT of tendon sheath (TGCT-TS), other sarcomas; tumor
angiogenesis and paracrine tumor growth and tumors that express
aberrantly or otherwise Fms, CSF1R, CSF1 or IL-34, or activating
mutations or translocations of any of the foregoing, wherein the
compound is a dual Fms/Kit inhibitor.
[0192] In aspects and embodiments involving treatment of a disease
or condition with one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, the methods may involve administering an
effective amount one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, or a composition thereof as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein, to a subject in need thereof suffering from or
at risk of acute myeloid leukemia, wherein the compound is a dual
Fms/Flt-3 inhibitor.
[0193] In another aspect, the disclosure provides kits that include
one or more solid, crystalline or polymorphs of Compound I or solid
or crystalline Compound II or composition thereof as described
herein. In some embodiments, the compound or composition is
packaged, e.g., in a vial, bottle, flask, which may be further
packaged, e.g., within a box, envelope, or bag; the compound or
composition is approved by the U.S. Food and Drug Administration or
similar regulatory agency for administration to a mammal, e.g., a
human; the compound or composition is approved for administration
to a mammal, e.g., a human, for a Fms and/or Kit protein kinase
mediated disease or condition; the disclosure kit includes written
instructions for use and/or other indication that the compound or
composition is suitable or approved for administration to a mammal,
e.g., a human, for a Fms and/or Kit protein kinase-mediated disease
or condition; and the compound or composition is packaged in unit
dose or single dose form, e.g., single dose pills, capsules, or the
like.
[0194] In yet another aspect, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used in the
preparation of a medicament for the treatment of a Kit-mediated
disease or condition as described herein, a Fms-mediated disease or
condition as described herein, a Fms-mediated and Kit-mediated
disease or condition as described herein, a Flt3-mediated disease
or condition as described herein or a Fms-mediated and
Flt3-mediated disease or condition as described herein, wherein the
Kit, Fms or Flt3 kinases can include any mutations thereof. In
other embodiments, the disclosure provides one or more compounds or
compositions as described herein for use in treating a Fms-mediated
and Kit-mediated disease or condition as described herein. In yet
other embodiments, the disclosure provides one or more compounds or
compositions as described herein for use in treating a Kit-mediated
disease or condition as described herein. In still other
embodiments, the disclosure provides one or more compounds or
compositions as described herein for use in treating a Fms-mediated
disease or condition as described herein.
[0195] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used in the
preparation of a medicament for the treatment of a disease or
condition selected from the group consisting of alopecia, baldness,
wound healing, androgenetic alopecia (AGA), epilepsy, traumatic
brain injury, tauopathies, Erdheim Chester Disease, Langerhans cell
histocytosis, hairy cell leukemia, non-small cell lung cancer,
cleroderma, anterior eye disease, posterior eye disease, lysosomal
storage disease, stem cell ablation and myelopreparation for stem
cell transplant, primary progressive multiple sclerosis, complex
regional pain syndrome, reflex sympathetic dystrophy, muscular
dystrophy, duchenne muscular dystrophy, causalgia,
neuro-inflammation, neuroinflammatory disorders, benign
forgetfulness, HIV, binswager type dementia, dementia with lewy
bodie, prosencephaly, microencepahy, cerebral palsy, congenital
hydrocephalus, abdominal dropsy, progressive supranuclear palsy,
glaucoma, addiction disorders, dependencies, alcoholism, tremors,
Wilson's disease, vascular dementias, multi infarct dementia,
fronto temporal dementia, pseudo-dementia, bladder cancer, ureter
cancer, urethra cancer, urachus cancer, basal cell carcinoma,
cholangiocarcinoma, colon cancer, endometrial cancer, esophageal
cancer, Ewing's sarcoma, gastric cancer, glioma, hepatocellular
carcinoma, Hodgkin lymphoma, laryngeal carcinoma, leukemia, liver
cancer, lung cancer, melanoma, mesothelioma, pancreatic cancer,
rectal cancer, renal cancer, squamous cell carcinoma, t cell
lymphoma, thyroid cancer, monocytic leukemia, pheochromocytoma,
malignant peripheral nerve cell tumors, malignant peripheral nerve
sheath tumors (MPNST), cutaneous and plexiform neurofibromas,
leiomyoadenomatoid tumor, fibroids, uterine fibroids,
leiomyosarcoma, papillary thyroid cancer, anaplastic thyroid
cancer, medullary thyroid cancer, follicular thyroid cancer,
hurthle cell carcinoma, thyroid cancer, angiosarcomas,
liposarcomas, ascites, malignant ascites, mesothelioma, salivary
gland tumors, mucoepidermoid carcinoma of the salivary gland,
acinic cell carcinoma of the salivary gland, gastrointestinal
stromal tumors (GIST--which includes, without limitation, 1.sup.st
line, 2.sup.nd line and neoadjuvant GIST), tumors that cause
effusions in potential spaces of the body, pleural effusions,
pericardial effusions, peritoneal effusions aka ascites, giant cell
tumors (GCT), GCT of bone, pigmented villonodular synovitis (PVNS),
tenosynovial giant cell tumor (TGCT), TCGT of tendon sheath
(TGCT-TS), other sarcomas; tumor angiogenesis and paracrine tumor
growth; and tumors that express aberrantly or otherwise Fms, CSF1R,
CSF1 or IL-34, or activating mutations or translocations of any of
the foregoing.
[0196] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are Kit inhibitors can be used, optionally in
combination with another therapeutic agent or therapy as described
herein, in the preparation of a medicament for the treatment of
neuro-inflammations, benign forgetfulness, HIV, binswager type
dementia, dementia with lewy bodie, prosencephaly, microencepahy,
cerebral palsy, congenital hydrocephalus, tremors, Wilson's
disease, vascular dementias/multi infarct dementia, fronto temporal
type, pseudo-dementia, papillary thyroid cancer, anaplastic thyroid
cancer, medullary thyroid cancer, follicular thyroid cancer,
hurthle cell carcinoma, thyroid cancer, ascites and malignant
ascites.
[0197] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are Fms inhibitors can be used, optionally in
combination with another therapeutic agent or therapy as described
herein, in the preparation of a medicament for the treatment of
neuro-inflammations, benign forgetfulness, HIV, binswager type
dementia, dementia with lewy bodie, prosencephaly, microencepahy,
cerebral palsy, congenital hydrocephalus, tremors, Wilson's
disease, vascular dementias/multi infarct dementia, fronto temporal
type, pseudo-dementia, papillary thyroid cancer, anaplastic thyroid
cancer, medullary thyroid cancer, follicular thyroid cancer,
hurthle cell carcinoma, thyroid cancer, ascites, and malignant
ascites.
[0198] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are Fms inhibitors that effectively cross the blood
brain barrier can be used, optionally in combination with another
therapeutic agent or therapy as described herein, in the
preparation of a medicament for the treatment of multiple
sclerosis, glioblastoma, Alzheimer's disease, or Parkinson's
disease.
[0199] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are Fms inhibitors that do not effectively cross the
blood brain barrier can be used, optionally in combination with
another therapeutic agent or therapy as described herein, in the
preparation of a medicament for the treatment of rheumatoid
arthritis, osteoarthritis, atherosclerosis, systemic lupus
erythematosus, glomerulonephritis, interstitial nephritis, Lupus
nephritis, tubular necrosis, diabetic nephropathy, or renal
hypertrophy.
[0200] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are dual Fms/Kit inhibitors can be used, optionally in
combination with another therapeutic agent or therapy as described
herein, in the preparation of a medicament for the treatment of
metastatic breast cancer, prostate cancer, multiple myeloma,
melanoma, acute myeloid leukemia, brain metastases,
neurofibromatosis, gastrointestinal stromal tumors, rheumatoid
arthritis, or multiple sclerosis.
[0201] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are dual Fms/Kit inhibitors can be used, optionally in
combination with another therapeutic agent or therapy as described
herein, in the preparation of a medicament for the treatment of
neuro-inflammations, benign forgetfulness, HIV, binswager type
dementia, dementia with lewy bodie, prosencephaly, microencepahy,
cerebral palsy, congenital hydrocephalus, primary progressive
multiple sclerosis, complex regional pain syndrome, reflex
sympathetic dystrophy, muscular dystrophy, duchenne muscular
dystrophy, causalgia, tremors, Wilson's disease, vascular
dementias/multi infarct dementia, fronto temporal type,
pseudo-dementia, papillary thyroid cancer, anaplastic thyroid
cancer, medullary thyroid cancer, follicular thyroid cancer,
hurthle cell carcinoma, thyroid cancer, ascites, and malignant
ascites.
[0202] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, that are dual Fms/Flt-3 inhibitors can be used, optionally
in combination with another therapeutic agent or therapy as
described herein, in the preparation of a medicament for the
treatment of acute myeloid leukemia. In some embodiments, the
disclosure provides a method for treating a subject suffering from
or at risk of acute myeloid leukemia comprising administering to
the subject a therapeutically effective amount of Compound I Form
A, Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II or a composition comprising Compound I Form
A, Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II and a pharmaceutically acceptable
carrier.
[0203] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II, or a composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein, can be used for the treatment of a Kit-mediated disease or
condition as described herein, a Fms-mediated disease or condition
as described herein, a Fms-mediated and Kit-mediated disease or
condition as described herein, a Flt3-mediated disease or condition
as described herein or a Fms-mediated and Flt3-mediated disease or
condition as described herein, wherein the Kit, Fms or Flt3 kinases
can include any mutations thereof. In other embodiments, the
disclosure provides one or more compounds or compositions as
described herein, and optionally in combination with another
therapeutic agent or therapy as described herein, for use in
treating a Fms-mediated and Kit-mediated disease or condition as
described herein. In yet other embodiments, the disclosure provides
one or more compounds or compositions as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein, for use in treating a Kit-mediated disease or
condition as described herein. In still other embodiments, the
disclosure provides one or more compounds or compositions as
described herein, and optionally in combination with another
therapeutic agent or therapy as described herein, for use in
treating a Fms-mediated disease or condition as described
herein.
[0204] In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein can be used for the treatment
of a disease or condition selected from the group consisting of
alopecia, baldness, wound healing, androgenetic alopecia (AGA),
epilepsy, traumatic brain injury, tauopathies, Erdheim Chester
Disease, Langerhans cell histocytosis, hairy cell leukemia,
non-small cell lung cancer, cleroderma, anterior eye disease,
posterior eye disease, lysosomal storage disease, stem cell
ablation and myelopreparation for stem cell transplant, primary
progressive multiple sclerosis, complex regional pain syndrome,
reflex sympathetic dystrophy, muscular dystrophy, duchenne muscular
dystrophy, causalgia, neuro-inflammation, neuroinflammatory
disorders, benign forgetfulness, HIV, binswager type dementia,
dementia with lewy bodie, prosencephaly, microencepahy, cerebral
palsy, congenital hydrocephalus, abdominal dropsy, progressive
supranuclear palsy, glaucoma, addiction disorders, dependencies,
alcoholism, tremors, Wilson's disease, vascular dementias, multi
infarct dementia, fronto temporal dementia, pseudo-dementia,
bladder cancer, ureter cancer, urethra cancer, urachus cancer,
basal cell carcinoma, cholangiocarcinoma, colon cancer, endometrial
cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, glioma,
hepatocellular carcinoma, Hodgkin lymphoma, laryngeal carcinoma,
leukemia, liver cancer, lung cancer, melanoma, mesothelioma,
pancreatic cancer, rectal cancer, renal cancer, squamous cell
carcinoma, t cell lymphoma, thyroid cancer, monocytic leukemia,
pheochromocytoma, malignant peripheral nerve cell tumors, malignant
peripheral nerve sheath tumors (MPNST), cutaneous and plexiform
neurofibromas, leiomyoadenomatoid tumor, fibroids, uterine
fibroids, leiomyosarcoma, papillary thyroid cancer, anaplastic
thyroid cancer, medullary thyroid cancer, follicular thyroid
cancer, hurthle cell carcinoma, thyroid cancer, angiosarcomas,
liposarcomas, ascites, malignant ascites, mesothelioma, salivary
gland tumors, mucoepidermoid carcinoma of the salivary gland,
acinic cell carcinoma of the salivary gland, gastrointestinal
stromal tumors (GIST--which includes, without limitation, 1.sup.st
line, 2.sup.nd line and neoadjuvant GIST), tumors that cause
effusions in potential spaces of the body, pleural effusions,
pericardial effusions, peritoneal effusions aka ascites, giant cell
tumors (GCT), GCT of bone, pigmented villonodular synovitis (PVNS),
tenosynovial giant cell tumor (TGCT), TCGT of tendon sheath
(TGCT-TS), other sarcomas, tumor angiogenesis and paracrine tumor
growth. In some embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein can be used for the treatment
of tumors that express aberrantly or otherwise Fms, CSF1R, CSF1 or
IL-34, or activating mutations or translocations of any of the
foregoing. In other embodiments, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of tumors that express aberrantly or otherwise Kit, SCFR, SCF, or
activating mutations or translocations of any of the foregoing. In
yet other embodiments, one or more solid, crystalline or polymorphs
of Compound I or solid or crystalline forms of Compound II as
described herein, or a composition thereof as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein can be used for the treatment of tumors that
express aberrantly or otherwise Flt3, Flt3 ligand, or activating
mutations or translocations of any of the foregoing.
[0205] In some embodiments, the disclosure provides a method for
regulating/modulating tumor associated macrophages (TAM), for
example, by depleting, inhibiting or reducing TAM or blocking
proliferation, migration or activation of TAM in a subject. The
method includes administering to the subject an effective amount of
one or more solid, crystalline or polymorphs of Compound I or solid
or crystalline forms of Compound II as described herein, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein. In certain embodiments, the disclosure provides a method
for treating a cancer mediated or modulated by TAM. The method
includes administering to the subject an effective amount one or
more solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II as described herein, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein. In other embodiments, the disclosure provides a method for
inhibiting infiltrating macrophages. The methods include
administering to the subject an effective amount of one or more
solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II as described herein, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein.
[0206] In some embodiments, the disclosure provides a method for
inhibiting, reducing, or blocking proliferation, migration or
activation of microglia in a subject. The method includes
administering to the subject an effective amount of one or more
solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II as described herein or a
composition thereof as described herein. In one embodiment, the
disclosure provides a method for depleting and/or eliminating
microglia in a subject. The method includes administering to the
subject an effective amount of one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein.
[0207] In some embodiments, the disclosure provides a method for
inhibiting, reducing, or blocking proliferation, migration or
activation of monocytes in a subject. In certain instances, the
monocytes are CD14+CD16++ monocytes. In another instance, the
monocytes are CD11b+ monocytes. The method includes administering
to the subject an effective amount of one or more solid,
crystalline or polymorphs of Compound I or solid or crystalline
forms of Compound II as described herein, or a composition as
described herein, and optionally in combination with another
therapeutic agent or therapy as described herein.
[0208] In some embodiments, the disclosure provides a method for
inhibiting, reducing, or blocking proliferation, migration or
activation of mast cells in a subject. The method includes
administering to the subject an effective amount of one or more
solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II as described herein, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein.
[0209] In some embodiments, the disclosure provides a method for
inhibiting, reducing, or blocking proliferation, migration or
activation of osteoclasts in a subject. The method includes
administering to the subject an effective amount of one or more
solid, crystalline or polymorphs of Compound I or solid or
crystalline forms of Compound II as described herein, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein.
[0210] In certain embodiments, the disclosure provides a method for
treating bone osteolysis and/or bone pain. The method includes
administering to the subject in need thereof an effective amount of
a compound, or a composition as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein.
[0211] In certain embodiments, the disclosure provides a method for
preventing bone and joint destruction and/or protecting bone
damages from tumor cells. The method includes administering to the
subject in need thereof an effective amount of one or more solid,
crystalline or polymorphs of Compound I or solid or crystalline
forms of Compound II as described herein, or a composition thereof
as described herein, and optionally in combination with another
therapeutic agent or therapy as described herein.
[0212] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of stem cell ablation and myelopreparation for stem cell
transplant.
[0213] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of monocytic leukemia.
[0214] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of acute myeloid leukemia.
[0215] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of melanoma.
[0216] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of malignant peripheral nerve cell tumors.
[0217] In another aspect, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of malignant peripheral nerve sheath tumors (MPNST).
[0218] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of pheochromocytomas cutaneous and plexiform neurofibromas. In
certain aspects, one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein can be used for the treatment of plexiform
neurofibromas.
[0219] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of neuro-inflammation.
[0220] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of benign forgetfulness.
[0221] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of binswager type dementia.
[0222] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of dementia with lewy bodie.
[0223] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of prosencephaly.
[0224] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of microencepahy.
[0225] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of cerebral palsy.
[0226] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of congenital hydrocephalus.
[0227] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of tremors.
[0228] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of Wilson's disease.
[0229] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of vascular dementias/multi infarct dementia.
[0230] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of fronto temporal type, pseudo-dementia.
[0231] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of thyroid cancer.
[0232] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of papillary thyroid cancer.
[0233] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of anaplastic thyroid cancer.
[0234] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of medullary thyroid cancer.
[0235] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of follicular thyroid cancer.
[0236] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of hurthle cell carcinoma.
[0237] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of ascites.
[0238] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of malignant ascites.
[0239] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of abdominal dropsy.
[0240] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of progressive supranuclear palsy.
[0241] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of glaucoma.
[0242] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of mesothelioma.
[0243] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of salivary gland tumors.
[0244] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of mucoepidermoid carcinoma of the salivary gland.
[0245] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of acinic cell carcinoma of the salivary gland, and others.
[0246] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of gastrointestinal stromal tumors (GIST--which includes, without
limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant GIST).
[0247] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of tumors that cause effusions in potential spaces of the body.
[0248] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of pleural effusions.
[0249] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of pericardial effusions.
[0250] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of peritoneal effusions aka ascites.
[0251] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of giant cell tumors (GCT).
[0252] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, optionally in combination with another
therapeutic agent or therapy as described herein, can be used for
the treatment of GCT of bone.
[0253] In certain aspects, one or more compounds or a composition
as described herein, optionally in combination with another
therapeutic agent or therapy as described herein, can be used for
the treatment of pigmented villonodular synovitis (PVNS).
[0254] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of tenosynovial giant cell tumor (TGCT).
[0255] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of TCGT of tendon sheath (TGCT-TS).
[0256] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of sarcomas.
[0257] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of glioblastoma.
[0258] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of breast cancer. In certain aspects, one or more solid,
crystalline or polymorphs of Compound I or solid or crystalline
forms of Compound II as described herein, or a composition thereof
as described herein, and optionally in combination with another
therapeutic agent or therapy as described herein, can be used for
the treatment of metastatic breast cancer.
[0259] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of ovarian cancer. In a certain embodiment, Compound I Form C can
be used for the treatment of ovarian cancer.
[0260] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of prion diseases. Non-limiting examples of prion diseases include
protein folding and aggregation disorders, and protein
accumulation/metabolism disorders Protein folding disorders are
classified as amyloidoses as well as other disorders associated
with abnormal protein folding. accumulation/metabolism disorders
include Gacuher, Niemann-Pick and lysosomal storage disorders. In a
certain embodiment, one or more solid, crystalline or polymorphs of
Compound I or solid or crystalline forms of Compound II as
described herein, or a composition thereof as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein, can be used for the treatment of prion
diseases. In a certain embodiment Compound I Form C, or a
composition thereof as described herein, and optionally in
combination with another therapeutic agent or therapy as described
herein, can be used for the treatment of prion diseases.
[0261] In certain aspects, one or more solid, crystalline or
polymorphs of Compound I or solid or crystalline forms of Compound
II as described herein, or a composition thereof as described
herein, and optionally in combination with another therapeutic
agent or therapy as described herein, can be used for the treatment
of Lysosomal Storage disorders. Non-limiting examples of lysosomal
storage disorders include mucolipodosis, alpha-mannosidosis,
aspartylglucosaminuria, Batten disease, beta-mannosidosis,
cystinosis, Danon disease, Fabry disease, Farber disease,
fucosidosis, galactosialidosis, Gaucher disease, gangliosidosis
(e.g., GM1 gangliosidosis and GM2-gangliosidosis AB variant),
Krabbe disease, metachromatic leukodystrophy, mucopolysaccharidoses
disorders (e.g., MPS 1--Hurler syndrome, MPS II--Hunter syndrome,
MPS III--Sanfilippo (A,B,C,D), MPS IVA--Morquio, MPS
IX--hyaluronidase, deficiency, MPS VI--Maroteaux-Lamy, or MPS
VII--Sly syndrome), mucolipidosis type I (Sialidosis),
Mucolipidosis type II (I-Cell disease); Mucolipidosis type III
(Pseudo-Hurler polydystrophy), Mucolipidosis type IV, multiple
sulfatase deficiency, Niemann-Pick types A, B, C, Pompe disease
(glycogen storage disease), pycnodysostosis, Sandhoff disease,
Schindler disease, Salla disease/sialic acid storage disease,
Tay-Sachs, and Wolman disease. In a certain embodiment, Compound I
Form C, or a composition thereof as described herein, and
optionally in combination with another therapeutic agent or therapy
as described herein, can be used for the treatment of Lysosomal
Storage disorders.
Combinations
[0262] In one aspect, the disclosure provides methods for treating
a Fms protein kinase mediated disease or condition in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
as described herein. In some embodiments, the method involves
administering to the subject a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D or crystalline Compound II. In one embodiment, the method
involves administering to the subject an effective amount of
subject a therapeutically effective amount of Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II as described herein in combination with one
or more other therapies for the disease or condition.
[0263] In another aspect, the disclosure provides methods for
treating a Kit protein kinase mediated disease or condition in an
animal subject in need thereof, wherein the method involves
administering to the subject an effective amount of any one or more
compound(s) as described herein. In some embodiments, the method
involves administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D or crystalline Compound II. In one embodiment,
the method involves administering to the subject a therapeutically
effective amount of Compound I Form A, Compound I Form B, Compound
I Form C, Compound I Form D or crystalline Compound II as described
herein in combination with one or more other therapies for the
disease or condition.
[0264] In another aspect, compositions are provided that include a
therapeutically effective amount of any one or more compound(s) as
described herein and at least one pharmaceutically acceptable
carrier, excipient, and/or diluent, including combinations of any
two or more compounds as described herein. The composition can
further include a plurality of different pharmacologically active
compounds, which can include a plurality of compounds as described
herein. In certain embodiments, the composition can include any one
or more compound(s) as described herein along with one or more
compounds that are therapeutically effective for the same disease
indication. In one aspect, the composition includes any one or more
compound(s) as described herein along with one or more compounds
that are therapeutically effective for the same disease indication,
wherein the compounds have a synergistic effect on the disease
indication. In one embodiment, the composition includes any one or
more compound(s) as described herein effective in treating a cancer
and one or more other compounds that are effective in treating the
same cancer, further wherein the compounds are synergistically
effective in treating the cancer. The compounds can be administered
simultaneously or sequentially.
[0265] In another aspect, methods are provided for modulating the
activity of a Fms and/or Kit and/or Flt-3 protein kinase, including
any mutations thereof, by contacting the protein kinase with an
effective amount of any one or more compound(s) as described
herein.
[0266] In another aspect, the disclosure provides methods for
treating a disease or condition mediated by Fms and/or Kit and/or
Flt-3, including any mutations thereof, in a subject in need
thereof by administering to the subject an effective amount of a
compound as described herein or a composition including any one or
more compound(s) as described herein. In one embodiment, the
disclosure provides methods for treating a disease or condition
mediated by Fms and/or Kit, including any mutations thereof, in a
subject in need thereof by administering to the subject an
effective amount of a compound as described herein or a composition
including any one or more compound(s) as described herein in
combination with one or more other suitable therapies for treating
the disease.
[0267] In another aspect, the disclosure provides methods for
treating a disease or condition mediated by Fms, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a compound as described herein
or a composition including any one or more compound(s) as described
herein. In one embodiment, the disclosure provides methods for
treating a disease or condition mediated by Fms, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a compound as described herein
or a composition including any one or more compound(s) as described
herein in combination with one or more other suitable therapies for
treating the disease.
[0268] In another aspect, the disclosure provides methods for
treating a disease or condition mediated by Kit, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a compound as described herein
or a composition including any one or more compound(s) as described
herein. In one embodiment, the disclosure provides methods for
treating a disease or condition mediated by Kit, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a compound as described herein
or a composition including any one or more compound(s) as described
herein in combination with one or more other suitable therapies for
treating the disease.
[0269] In another aspect, the disclosure provides methods for
treating a disease or condition mediated by Flt-3, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a compound as described herein
or a composition including any one or more compound(s) as described
herein. In one embodiment, the disclosure provides methods for
treating a disease or condition mediated by Flt-3, including any
mutations, such as an internal tandem duplication (ITD) mutation
thereof, in a subject in need thereof by administering to the
subject an effective amount of a composition including any one or
more compound(s) as described herein in combination with one or
more other suitable therapies for treating the disease. In some
embodiments, the Flt3 mutant encoded by Flt3 gene with ITD
mutations has one or more mutations at residues F691, D835, Y842 or
combinations thereof. In some embodiments, the Flt3 mutant has one
or more mutations selected from F691L, D835V/Y, Y842C/H or
combinations thereof.
[0270] In another aspect, the disclosure provides methods for
treating a disease or condition mediated by Fms and Flt-3,
including any mutations thereof, in a subject in need thereof by
administering to the subject an effective amount of a compound as
described herein or a composition including any one or more
compound(s) as described herein. In one embodiment, the disclosure
provides methods for treating a disease or condition mediated by
Fms and Flt-3, including any mutations thereof, in a subject in
need thereof by administering to the subject an effective amount of
a composition including any one or more compound(s) as described
herein in combination with one or more other suitable therapies for
treating the disease.
[0271] In another aspect, the disclosure provides methods for
treating a disease or condition mediated by Fms and Kit, including
any mutations thereof, in a subject in need thereof by
administering to the subject an effective amount of a compound as
described herein or a composition including any one or more
compound(s) as described herein. In one embodiment, the disclosure
provides methods for treating a disease or condition mediated by
Fms and Kit, including any mutations thereof, in a subject in need
thereof by administering to the subject an effective amount of a
composition including any one or more compound(s) as described
herein in combination with one or more other suitable therapies for
treating the disease.
[0272] In some embodiments, the disclosure provides a method of
treating a subject suffering from a disease or condition described
in this disclosure, said method comprising administering to the
subject an effective amount of Compound I Form A, Compound I Form
B, Compound I Form C, Compound I Form D or crystalline Compound II
or a composition including any one or more compound(s) as described
herein, in combination with immunotherapy such as i) a PD-L1
inhibitor (such as durvalumab, nivolumab, panitumumab, pertuzumab,
rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan,
ii) a PD-1 inhibitor or iii) an IDO inhibitor (such as indoximod).
In some embodiments, the method of treating a subject suffering
from a disease or condition described in this disclosure comprises
administering to the subject an effective amount of Compound I Form
C, or a composition thereof, in combination a therapeutically
effective amount of an IDO inhibitor (such as indoximod) for
treating an infectious disease. Non-limiting examples of infectious
diseases include a viral infections such as influenza, hepatitis C
virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV),
Epstein-Barr virus (EBV), poliovirus, varicella zoster virus,
coxsackie virus, and human immunodeficiency virus (HIV). In some
embodiments, the method of treating a subject suffering from a
disease or condition described in this disclosure comprises
administering to the subject an effective amount of Compound I Form
C, or a composition thereof, in combination a therapeutically
effective amount of PD-L1 inhibitor (such as durvalumab, nivolumab,
panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and
90 Y ibritumomab tiuxetan, for treating a c-Kit or c-Fms related
disease as described in this disclosure.
[0273] Compound I and II can deplete microglia which can inhibit
tau propagation. Exosome inhibitors halt tau propagation. In some
embodiments, the method of treating a subject suffering from a
disease or condition described in this disclosure comprises
administering to the subject an effective amount of Compound I Form
C, or a composition thereof, in combination with a therapeutically
effective amount of an exosome inhibitor wherein the disease or
condition is modulated by Tau propagation. Non-limiting examples of
diseases or conditions that are modulated by Tau propagation
include Alzheimers disease, Parkinson's disease and dementia.
[0274] In some embodiments, the disclosure provides a method of
treating a subject suffering from a disease or condition described
in this disclosure, said method comprising administering to the
subject an effective amount of Compound I Form A, Compound I Form
B, Compound I Form C, Compound I Form D or crystalline Compound II
or a composition including any one or more compound(s) as described
herein, in combination with a c-Kit protein kinase inhibitor or
mutant c-Kit protein kinase inhibitor. In another embodiment, the
mutant c-Kit protein kinase inhibitor is selected from
(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol,
(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone,
N-(3-carbamoylphenyl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,
2-phenyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,
4-bromo-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxam-
ide, ethyl
3-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamoylamino]propa-
noate,
3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-
-5-carboxamide,
4-methyl-3-phenyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole--
5-carboxamide,
3-cyclopropyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-ca-
rboxamide,
5-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-
-3-carboxamide,
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide,
3-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide-
,
3,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-4-carbo-
xamide,
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridazine-3-carboxamide-
,
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H-triazole-4-carboxamide,
3-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide-
,
4,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-carbo-
xamide or
N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-4-sulfona-
mide. In another embodiment, Compound I, Form C, is combined with
any of the mutant c-Kit mutant inhibitors described in this
specification for treating GIST--which includes, without
limitation, 1.sup.st line, 2.sup.nd line and neoadjuvant GIST.
[0275] In some embodiments, the disclosure provides a method of
treating a cancer in a subject in need thereof by administering to
the subject an effective amount of a compound or a composition
including any one or more compound(s) as described herein, in
combination with one or more other therapies or medical procedures
effective in treating the cancer. Other therapies or medical
procedures include suitable anticancer therapy (e.g. drug therapy,
vaccine therapy, gene therapy, photodynamic therapy) or medical
procedure (e.g. surgery, radiation treatment, hyperthermia heating,
bone marrow or stem cell transplant). In one embodiment, the one or
more suitable anticancer therapies or medical procedures is
selected from treatment with a chemotherapeutic agent (e.g.
chemotherapeutic drug), radiation treatment (e.g. X-ray,
.gamma.-ray, or electron, proton, neutron, or a particle beam),
hyperthermia heating (e.g. microwave, ultrasound, radiofrequency
ablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinoma
vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic
GM-CSF-secretion breast cancer vaccine, dendritic cell peptide
vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector
encoding MDA7, adenovirus 5-tumor necrosis factor alpha),
photodynamic therapy (e.g. aminolevulinic acid, motexafin
lutetium), oncolytic viral or bacterial therapy, surgery, or bone
marrow and stem cell transplantation. In certain embodiments, the
disclosure provides a method of treating a cancer in a subject in
need thereof by administering to the subject an effective amount of
a compound as described herein and applying a radiation treatment
as described herein either separately or simultaneously. In one
embodiment, the disclosure provides a method for treating a cancer
in a subject in need thereof by administering an effective amount
of a compound as described herein to the subject followed by a
radiation treatment (e.g. X-ray, .gamma.-ray, or electron, proton,
neutron, or a particle beam). In another embodiment, the disclosure
provides a method for treating a cancer in a subject in need
thereof by applying a radiation treatment (e.g. X-ray, g-ray, or
electron, proton, neutron, or a particle beam) to the subject
followed by administering an effective amount of a compound as
described herein to the subject. In yet another embodiment, the
disclosure provides a method for treating a cancer in a subject in
need thereof by administering a compound as described herein and a
radiation therapy (e.g. X-ray, .gamma.-ray, or electron, proton,
neutron, or a particle beam) to the subject simultaneously.
[0276] In some embodiments, the disclosure provides a method for
treating glioblastoma in a subject. In some embodiments, the method
of treating glioblastoma in a subject comprises administering to
the subject a therapeutically effective amount of Compound I Form
A, Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II or a composition comprising of Compound I
Form A, Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II and a pharmaceutically acceptable
excipient. In some embodiments, the method treating glioblastoma in
a subject further comprises administering a therapeutically
effective amount of a PD-1 inhibitor or a PD-L1 inhibitor to the
subject. In some embodiments, the method treating glioblastoma in a
subject further comprises administering to the subject a
therapeutically effective amount of Compound I Form C, or a
composition comprising of Compound I Form C, and a therapeutically
effective amount of a PD-1 inhibitor or an PD-L1 inhibitor. In some
embodiments, the method treating glioblastoma in a subject further
comprises applying an radiation therapy to the subject which may
occur before or after administering to the subject a compound or a
composition as described herein. In one instance, the treatment has
a single dose of 12 Gy ionizing radiation. In another instance, a
compound or a composition as described herein is administered to
the subject at a dose of about 600 to 1200 mg/day. In some
embodiments, such methods further comprise administering to the
subject a therapeutically effective amount of temozolomide. In
other instances, the method includes applying an ionizing radiation
treatment to the subject followed by administering to the subject
temozolomide (marketed as Temodar.RTM.) and a compound or a
composition as described herein. In some embodiments, the method of
treating glioblastoma in a subject comprises administering to the
subject a therapeutically effective amount of Compound I Form C, or
a composition comprising of Compound I Form C, and a
pharmaceutically acceptable excipient in combination with (1)
applying radiation therapy, and (2) administering a therapeutically
effective amount of temozolomide.
[0277] In another aspect, the disclosure provides a method for
treating a cancer in a subject in need thereof by administering to
the subject an effective amount of a compound or a composition
including any one or more compound(s) as described herein, in
combination with one or more suitable chemotherapeutic agents. The
compounds can be administered simultaneously or sequentially. In
some embodiments, the cancer is any cancer mediated by a protein
kinases selected from c-Fms, c-Kit, Flt3 or combinations thereof
and/or macrophages or microglia or a cancer as described herein. In
one embodiment, the one or more suitable chemotherapeutic agents is
selected from an alkylating agent, including, but not limited to,
adozelesin, altretamine, bendamustine, bizelesin, busulfan,
carboplatin, carboquone, carmofur, carmustine, chlorambucil,
cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid,
fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven,
lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol,
nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine,
procarbazine, ranimustine, satraplatin, semustine, streptozocin,
temozolomide, thiotepa, treosulfan, triaziquone,
triethylenemelamine, triplatin tetranitrate, trofosphamide, and
uramustine; an antibiotic, including, but not limited to,
aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,
doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril,
mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin,
valrubicin, and zorubicin; an antimetabolite, including, but not
limited to, aminopterin, azacitidine, azathioprine, capecitabine,
cladribine, clofarabine, cytarabine, decitabine, floxuridine,
fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea,
mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed,
tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and
vidarabine; an immunotherapy, an antibody therapy, including, but
not limited to, alemtuzumab, bevacizumab, cetuximab, galiximab,
gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab,
tositumomab, trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab,
tremelimumab and anti-CTLA-4 antibodies; a hormone or hormone
antagonist, including, but not limited to, anastrozole, androgens,
buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant,
goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene,
tamoxifen, and toremifene; a taxane, including, but not limited to,
DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel,
DHA-paclitaxel, and tesetaxel; a retinoid, including, but not
limited to, alitretinoin, bexarotene, fenretinide, isotretinoin,
and tretinoin; an alkaloid, including, but not limited to,
demecolcine, homoharringtonine, vinblastine, vincristine,
vindesine, vinflunine, and vinorelbine; an antiangiogenic agent,
including, but not limited to, AE-941 (GW786034, Neovastat),
enzalutamide, ABT-510, 2-methoxyestradiol, lenalidomide, and
thalidomide; a topoisomerase inhibitor, including, but not limited
to, amsacrine, belotecan, edotecarin, etoposide, etoposide
phosphate, exatecan, irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not limited
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib,
sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib, and
vatalanib; a targeted signal transduction inhibitor including, but
not limited to bortezomib, geldanamycin, and rapamycin; a
biological response modifier, including, but not limited to,
imiquimod, interferon-.alpha., and interleukin-2; and other
chemotherapeutics, including, but not limited to 3-AP
(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,
aminoglutethimide, anagrelide, asparaginase, bryostatin-1,
cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone,
lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac,
testolactone, tiazofurin, mTOR inhibitors (e.g. sirolimus,
temsirolimus, everolimus, deforolimus), PI3K inhibitors (e.g.
BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors (e.g. PD-332991),
Akt inhibitors, Hsp90 inhibitors (e.g. geldanamycin, radicicol,
tanespimycin), farnesyltransferase inhibitors (e.g. tipifarnib),
and Aromatase inhibitors (anastrozole letrozole exemestane). In
some embodiments, the method of treating a cancer involves
administering to the subject an effective amount of a composition
including any compound as described herein in combination with a
chemotherapeutic agent selected from capecitabine, 5-fluorouracil,
carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel,
SN-38, temozolomide, vinblastine, bevacizumab, cetuximab,
interferon-.alpha., interleukin-2, or erlotinib. In another
embodiment, the chemotherapeutic agent is a Mek inhibitor.
Exemplary Mek inhibitors include, but are not limited to, AS703026,
AZD6244 (Selumetinib), AZD8330, BIX 02188, CI-1040 (PD184352),
GSK1120212 (JTP-74057), PD0325901, PD318088, binimetinib, PD98059,
RDEA119(BAY 869766), TAK-733 and U0126-EtOH. In another embodiment,
the chemotherapeutic agent is a tyrosine kinase inhibitor.
Exemplary tyrosine kinase inhibitors include, but are not limited
to, AEE788, AG-1478 (Tyrphostin AG-1478), AG-490, Apatinib
(YN968D1), AV-412, AV-951(Tivozanib), Axitinib, AZD8931, BIBF1120
(Vargatef), BIBW2992 (Afatinib), BMS794833, BMS-599626, Brivanib
(BMS-540215), Brivanib alaninate (BMS-582664), Cediranib (AZD2171),
Chrysophanic acid (Chrysophanol), Crenolanib (CP-868569), CUDC-101,
CYC116, Dovitinib Dilactic acid (TKI258 Dilactic acid), E7080,
Erlotinib Hydrochloride (Tarceva, CP-358774, OSI-774, NSC-718781),
Foretinib (GSK1363089, XL880), Gefitinib (ZD-1839 or Iressa),
Imatinib (Gleevec), Imatinib Mesylate, Ki8751, KRN 633, Lapatinib
(Tykerb), Linifanib (ABT-869), Masitinib (Masivet, AB1010),
MGCD-265, Motesanib (AMG-706), MP-470, Mubritinib (TAK 165),
Neratinib (HKI-272), NVP-BHG712, OSI-420 (Desmethyl
Erlotinib,CP-473420), OSI-930, Pazopanib HCl, PD-153035 HCl,
PD173074, Pelitinib (EKB-569), PF299804, Ponatinib (AP24534),
PP121, RAF265 (CHIR-265), Raf265 derivative, Regorafenib (BAY
73-4506), Sorafenib Tosylate (Nexavar), Sunitinib Malate (Sutent),
Telatinib (BAY 57-9352), TSU-68 (SU6668), Vandetanib (Zactima),
Vatalanib dihydrochloride (PTK787), WZ3146, WZ4002, WZ8040, XL-184
(Cabozantinib), XL647, EGFR siRNA, FLT4 siRNA, KDR siRNA,
Antidiabetic agents such as metformin, PPAR agonists
(rosiglitazone, pioglitazone, bezafibrate, ciprofibrate,
clofibrate, gemfibrozil, fenofibrate, indeglitazar), and DPP4
inhibitors (sitagliptin, vildagliptin, saxagliptin, dutogliptin,
gemigliptin, alogliptin). In another embodiment, the agent is an
EGFR inhibitor. Exemplary EGFR inhibitors include, but are not
limited to, AEE-788, AP-26113, BIBW-2992 (Tovok), CI-1033,
GW-572016, Iressa, LY2874455, RO-5323441, Tarceva (Erlotinib,
OSI-774), CUDC-101 and WZ4002.
[0278] In some embodiments, the disclosure provides a method of
treating a subject suffering from a disease or condition described
in this disclosure, said method comprising administering to the
subject an effective amount of Compound I Form A, Compound I Form
B, Compound I Form C, Compound I Form D or crystalline Compound II
or a composition including any one or more compound(s) as described
herein, in combination with a therapeutically effective amount of
another therapeutic agent, wherein the other therapeutic agent is:
i) an alkylating agent (such as adozelesin, altretamine, bizelesin,
busulfan, carboplatin, carboquone, carmustine, chlorambucil,
cisplatin, cyclophosphamide, dacarbazine, estramustine,
fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven,
lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan,
semustine, streptozocin, temozolomide, thiotepa, or treosulfan);
ii) an antibiotic (such as bleomycin, dactinomycin, daunorubicin,
doxorubicin, epirubicin, idarubicin, menogaril, mitomycin,
mitoxantrone, neocarzinostatin, pentostatin, or plicamycin); iii)
an antimetabolite (such as azacitidine, capecitabine, cladribine,
clofarabine, cytarabine, decitabine, floxuridine, fludarabine,
5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine,
methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, or
trimetrexate); iv) an antibody therapy agent selected from
alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab,
pembrolizumab, nivolumab, durvalumab, panitumumab, pertuzumab,
rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan;
v) a hormone or hormone antagonist (such as anastrozole, androgens,
buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant,
goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene,
tamoxifen, or toremifene); vi) a taxane (such as DJ-927, docetaxel,
TPI 287, paclitaxel or DHA-paclitaxel); vii) a retinoid (such as
alitretinoin, bexarotene, fenretinide, isotretinoin, or tretinoin);
viii) an alkaloid (such as etoposide, homoharringtonine,
teniposide, vinblastine, vincristine, vindesine, or vinorelbine);
ix) an antiangiogenic agent (such as AE-941 (GW786034, Neovastat),
ABT-510, 2-methoxyestradiol, lenalidomide, or thalidomide); x) a
topoisomerase inhibitor (such as amsacrine, edotecarin, exatecan,
irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, or
9-aminocamptothecin; xi) a kinase inhibitor [such as PI3K
inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors
(e.g. PD-332991), Akt inhibitors, a Mek inhibitor (such as
AS703026, AZD6244 (Selumetinib), AZD8330, BIX 02188, CI-1040
(PD184352), GSK1120212 (JTP-74057), PD0325901, PD318088,
binimetinib, PD98059, RDEA119(BAY 869766), TAK-733 or U0126-EtOH),
an EGFR inhibitor, erlotinib, gefitinib, flavopiridol, imatinib
mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788,
AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib,
cobimetinib, cabozantinib, selumetinib, dovitinib, or vatalanib];
xii) a targeted signal transduction inhibitor (such as bortezomib,
geldanamycin, or rapamycin); xiii) a biological response modifier
(such as imiquimod, interferon-alpha, or interleukin-2); xiv) a
chemotherapeutic agent (such as 3-amino-2-carboxyaldehyde
thiosemicarbazone, mTOR inhibitors (such. as sirolimus,
temsirolimus, everolimus, deforolimus), altrasentan,
aminoglutethimide, anagrelide, asparaginase, bryostatin-1,
cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone,
lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac,
testolactone, or tiazofurin); xv) an Hsp90 inhibitor (e.g.
geldanamycin, radicicol, tanespimycin); xvi) a farnesyltransferase
inhibitors (e.g. tipifarnib); xvii) an aromatase inhibitor (such as
anastrozole, letrozole or exemestane); xviii) an IDO inhibitor;
xix) a histone acetyltransferase (HAT) inhibitor; xx) histone
deacetylase (HDAC) inhibitor; xxi) a sirtuin (SIRT) inhibitor;
xxii) a BET inhibitor (such as BRD2, BRD3, BRD4 and/or BRDT); or
xxiii) an antiangiogenic agent, (such as AE-941 (GW786034,
Neovastat), enzalutamide, ABT-510, 2-methoxyestradiol, lenalidomide
or thalidomide.
[0279] Bromodomains (e.g., BET proteins, such as BRD2, BRD3, BRD4,
and/or BRDT), and e.g., diseases related to abnormal expression of
bromodomains, including cell proliferative disorders, cancers,
chronic autoimmune, inflammatory conditions, among others.
Non-limiting examples of BET inhibitors include GSK1210151A and
GSK525762.
[0280] The histone deacetylase inhibitors (HDAC inhibitors) are
cytostatic agents that inhibit the proliferation of tumor cells in
culture and in vivo by inducing cell cycle arrest, differentiation
and/or apoptosis. HDAC inhibitors exert their anti-tumor effects
via the induction of expression changes of oncogenes or tumour
suppressor, through modulating that the acetylation/deactylation of
histones and/or non-histone proteins such as transcription factors.
Histone acetylation and deacetylation play important roles in the
modulation of chromatin topology and the regulation of gene
transcription. Non-limiting examples of HDAC inhibitors include
vorinostat, romidepsin, chidamide, panobinostat, belinostat,
valproic acid, mocetinostat, abexinostat, entinostat, resminostat,
givinostat, and quisinostat. HDAC inhibitors have been used
extensively in psychiatry and neurology as mood stabilzers and
anti-epileptics. One example of this is valproic acid, marketed as
a drug under the trade names Depakene, Depakote, and Divalproex.
HDAC inhibitors are also being used as a mitigator for
neurodegenerative diseases such as Alzheimer's disease and
Huntington's disease.
[0281] In some embodiments, the disclosure provides a composition,
which includes (i) a compound as described herein and (ii) a
chemotherapeutic agent as described herein. The composition can be
used for treating a disease or condition mediated by a protein
kinases selected from c-Fms, c-Kit, Flt3 or combinations thereof
and/or macrophages or microglia. Exemplary diseases or conditions
include, but are not limited to, alopecia, baldness, wound healing,
androgenetic alopecia (AGA), epilepsy, traumatic brain injury,
tauopathies, Erdheim Chester Disease, Langerhans cell histocytosis,
hairy cell leukemia, non-small cell lung cancer, cleroderma,
anterior eye disease, posterior eye disease, lysosomal storage
disease, stem cell ablation and myelopreparation for stem cell
transplant, primary progressive multiple sclerosis, complex
regional pain syndrome, reflex sympathetic dystrophy, muscular
dystrophy, duchenne muscular dystrophy, causalgia,
neuro-inflammation, neuroinflammatory disorders, benign
forgetfulness, HIV, binswager type dementia, dementia with lewy
bodie, prosencephaly, microencepahy, cerebral palsy, congenital
hydrocephalus, abdominal dropsy, progressive supranuclear palsy,
glaucoma, addiction disorders, dependencies, alcoholism, tremors,
Wilson's disease, vascular dementias, multi infarct dementia,
fronto temporal dementia, pseudo-dementia, bladder cancer, ureter
cancer, urethra cancer, urachus cancer, basal cell carcinoma,
cholangiocarcinoma, colon cancer, endometrial cancer, esophageal
cancer, Ewing's sarcoma, gastric cancer, glioma, hepatocellular
carcinoma, Hodgkin lymphoma, laryngeal carcinoma, leukemia, liver
cancer, lung cancer, melanoma, mesothelioma, pancreatic cancer,
rectal cancer, renal cancer, squamous cell carcinoma, t cell
lymphoma, thyroid cancer, monocytic leukemia, pheochromocytoma,
malignant peripheral nerve cell tumors, malignant peripheral nerve
sheath tumors (MPNST), cutaneous and plexiform neurofibromas,
leiomyoadenomatoid tumor, fibroids, uterine fibroids,
leiomyosarcoma, papillary thyroid cancer, anaplastic thyroid
cancer, medullary thyroid cancer, follicular thyroid cancer,
hurthle cell carcinoma, thyroid cancer, angiosarcomas,
liposarcomas, ascites, malignant ascites, mesothelioma, salivary
gland tumors, mucoepidermoid carcinoma of the salivary gland,
acinic cell carcinoma of the salivary gland, gastrointestinal
stromal tumors (GIST--which includes, without limitation, 1.sup.st
line, 2.sup.nd line and neoadjuvant GIST), tumors that cause
effusions in potential spaces of the body, pleural effusions,
pericardial effusions, peritoneal effusions aka ascites, giant cell
tumors (GCT), GCT of bone, pigmented villonodular synovitis (PVNS),
tenosynovial giant cell tumor (TGCT), TCGT of tendon sheath
(TGCT-TS), other sarcomas, tumor angiogenesis, or paracrine tumor
growth. In some embodiments, the compositions can be used to treat
tumors that express aberrantly or otherwise Fms, CSF1R, CSF1 or
IL-34, or activating mutations or translocations of any of the
foregoing; or tumors that express aberrantly or otherwise Kit,
SCFR, SCF, or activating mutations or translocations of any of the
foregoing; or and tumors that express aberrantly or otherwise Flt3,
Flt3 ligand, or activating mutations or translocations of any of
the foregoing.
[0282] In some embodiments, the disclosure provides a composition
including a Raf inhibitor and a compound described herein. In
certain embodiments, the disclosure provides a composition
including vemurafenib and a compound or a composition as described
herein. In certain embodiments, the disclosure provides a
composition including dabrafenib and a compound described herein.
In certain embodiments, the Raf inhibitor is a B-raf inhibitor as
disclosed in U.S. Pat. No. 7,863,288, which is incorporated herein
by reference in its entirety.
[0283] In some embodiments, the disclosure provides a composition
including taxol and a compound described herein.
[0284] In some embodiments, the disclosure provides a method for
treating mesothelioma in a subject. The method includes
administering a composition comprising taxol and a compound as
described herein. In some embodiments, the method includes
administering to the subject a therapeutically effective amount of
Compound I Form A, Compound I Form B, Compound I Form C or Compound
I Form D, crystalline Compound II or a composition comprising of
Compound I Form A, Compound I Form B, Compound I Form C, Compound I
Form D or crystalline Compound II and a pharmaceutically acceptable
excipient. In such embodiments, the method further comprises
administering to the subject a therapeutically effective amount of
taxol. In certain embodiments, the method includes administering to
the subject in need thereof an effective amount of a composition
comprising taxol and a therapeutically effective amount of Compound
I Form A, Compound I Form B, Compound I Form C, Compound I Form D
or crystalline Compound II or a composition comprising of Compound
I Form A, Compound I Form B, Compound I Form C, Compound I Form D
or crystalline Compound II and a pharmaceutically acceptable
excipient. In certain embodiments, the method includes
administering to the subject in need thereof an effective amount of
a composition comprising taxol and a compound or a composition as
described herein. In some embodiments, taxol and a compound
described herein can be administered simultaneously or separately.
In certain embodiments, the disclosure provides a method for
treating mesothelioma in a subject. The method includes
administering to the subject in need thereof taxol followed by
administering to the subject a compound or a composition as
described herein. In certain embodiments, the disclosure provides a
method for treating a mesothelioma in a subject, wherein the method
includes administering to the subject in need thereof a compound or
a composition as described herein followed by administering taxol
to the subject.
[0285] In some embodiments, the disclosure provides a method for
treating a melanoma or a metastatic melanoma in a subject. In
certain embodiments, the disclosure provides a method for treating
melanoma with a KIT mutation in a subject. In certain embodiments,
the disclosure provides a method for treating melanoma with a BRAF
mutation in a subject. In some embodiments, the method of treating
unresectable or metastatic melanoma with a KIT mutation in a
subject, or unresectable or metastatic melanoma with a BRAF
mutation in a subject, includes administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C or Compound I Form D, crystalline
Compound II or a composition comprising of Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II and a pharmaceutically acceptable
excipient. In some embodiments, the method of treating unresectable
or metastatic melanoma with a KIT mutation in a subject includes
administering to the subject a therapeutically effective amount of
Compound I Form C, or a composition comprising of Compound I Form C
and a pharmaceutically acceptable excipient. The method of treating
unresectable or metastatic melanoma with a BRAF mutation may
further comprises administering to the subject a therapeutically
effective amount of vemurafenib. In some embodiments, vemurafenib
and a compound described herein can be administered simultaneously
or separately. In certain instances, the melanoma is mediated by a
mutant B-raf protein kinase. In other instances, the melanoma is
mediated by a V600 mutant B-raf. In yet other instances, the
melanoma is mediated by a V600A, V600M, V600R, V600E, V600K or
V600G B-raf mutant. In other instances, the melanoma is mediated by
a V600E mutant B-raf.
[0286] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk of malignant
peripheral nerve sheath tumors (MPNST). In some embodiments, the
method of treating a subject suffering from or at risk of MPNST
includes administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D or crystalline Compound II or a composition
comprising of Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D or crystalline Compound II and a
pharmaceutically acceptable excipient. In such embodiments, the
method of treating a subject suffering from or at risk of MPNST
further comprises administering to the subject a therapeutically
effective amount of sirolimus. In certain embodiments, the method
of treating a subject suffering from or at risk of MPNST includes
administering to the subject in need thereof an effective amount of
a composition comprising sirolimus and a compound or a composition
as described herein. In certain embodiments, the method of treating
a subject suffering from or at risk of MPNST includes administering
to the subject in need thereof an effective amount of a composition
comprising sirolimus and Compound I Form C, or a composition
thereof, as described herein. In some embodiments, sirolimus and a
compound or composition described herein can be administered
simultaneously or separately.
[0287] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk of breast cancer. In
some embodiments, the breast cancer is metastatic breast cancer. In
some embodiments, the method of treating a subject suffering from
or at risk of breast cancer includes administering to the subject a
therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D or crystalline
Compound II or a composition comprising of Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II and a pharmaceutically acceptable
excipient. In some embodiments, the method of treating a subject
suffering from or at risk of breast cancer further comprises
administering to the subject a therapeutically effective amount of
eribulin. In some embodiments, the method of treating a subject
suffering from or at risk of breast cancer further comprises
administering to the subject a therapeutically effective amount of
paclitaxel. In certain embodiments, the method of treating a
subject suffering from or at risk of breast cancer includes
administering to the subject in need thereof an effective amount of
a composition comprising eribulin and a compound or a composition
as described herein. In certain embodiments, the method of treating
a subject suffering from or at risk of breast cancer includes
administering to the subject in need thereof an effective amount of
a composition comprising paclitaxel and a compound or a composition
as described herein. In certain embodiments, the method of treating
a subject suffering from or at risk of breast cancer includes
administering to the subject in need thereof an effective amount of
a composition comprising eribulin and Compound I Form C, or a
composition thereof, as described herein. In certain embodiments,
the method of treating a subject suffering from or at risk of
metastatic breast cancer includes administering to the subject in
need thereof an effective amount of a composition comprising
eribulin and Compound I Form C, or a composition thereof, as
described herein. In certain embodiments, the method of treating a
subject suffering from or at risk of metastatic breast cancer
includes administering to the subject in need thereof an effective
amount of a composition comprising paclitaxel and Compound I Form
C, or a composition thereof, as described herein. In some
embodiments, eribulin and a compound or composition described
herein can be administered simultaneously or separately. In certain
embodiments, the method includes administering to the subject in
need thereof an effective amount of a composition comprising
paclitaxel and a compound or a composition as described herein. In
some embodiments, paclitaxel and a compound or composition
described herein can be administered simultaneously or
separately.
[0288] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk of ovarian cancer. In
some embodiments, the method of treating a subject suffering from
or at risk of ovarian cancer comprises administering to the subject
a therapeutically effective amount of Compound I Form A, Compound I
Form B, Compound I Form C, Compound I Form D or crystalline
Compound II or a composition comprising of Compound I Form A,
Compound I Form B, Compound I Form C, Compound I Form D or
crystalline Compound II and a pharmaceutically acceptable
excipient. In some embodiments, the method of treating a subject
suffering from or at risk of ovarian cancer further comprises
administering to the subject a therapeutically effective amount of
paclitaxel. In certain embodiments, the method of treating a
subject suffering from or at risk of ovarian cancer includes
administering to the subject in need thereof an effective amount of
a composition comprising paclitaxel and a compound or a composition
as described herein. In certain embodiments, the method of treating
a subject suffering from or at risk of ovarian cancer includes
administering to the subject in need thereof an effective amount of
a composition comprising paclitaxel and Compound I Form C, or a
composition thereof, as described herein. In some embodiments,
paclitaxel and a compound or composition as described herein can be
administered to the subject in need thereof simultaneously or
separately. In some embodiments, paclitaxel and Compound I Form C
can be administered to the subject in need thereof simultaneously
or separately.
[0289] In some embodiments, the disclosure provides a method for
treating a subject suffering from or at risk solid tumors,
comprising administering to the subject a therapeutically effective
amount of Compound I Form A, Compound I Form B, Compound I Form C,
Compound I Form D or crystalline Compound II or a composition
comprising of Compound I Form A, Compound I Form B, Compound I Form
C, Compound I Form D or crystalline Compound II and a
pharmaceutically acceptable excipient. In some embodiments, the
method of treating a subject suffering from or at risk of melanoma
further comprises administering to the subject a therapeutically
effective amount of pembrolizumab. In certain embodiments, the
method of treating a subject suffering from or at risk of melanoma
includes administering to the subject in need thereof an effective
amount of a composition comprising pembrolizumab and a compound or
a composition as described herein. In certain embodiments, the
method of treating a subject suffering from or at risk of melanoma
includes administering to the subject in need thereof an effective
amount of a composition comprising pembrolizumab and Compound I
Form C, or a composition thereof, as described herein. In some
embodiments, pembrolizumab and a compound or composition described
herein can be administered simultaneously or separately.
Kinase Activity Assays
[0290] A number of different assays for kinase activity can be
utilized for assaying for active modulators and/or determining
specificity of a modulator for a particular kinase or group of
kinases, such as those described in U.S. Pat. Pub. No.
2014/0037617, which is hereby incorporated by reference in its
entirety. One of ordinary skill in the art can readily identify
other assays that can be utilized and can modify an assay for a
particular application. For example, numerous papers concerning
kinases describe assays that can be used.
[0291] Additional alternative assays can employ binding
determinations. For example, this sort of assay can be formatted
either in a fluorescence resonance energy transfer (FRET) format,
or using an AlphaScreen (amplified/uminescentproximity homogeneous
assay) format by varying the donor and acceptor reagents that are
attached to streptavidin or the phosphor-specific antibody.
EXAMPLES
A. Experimental Methods
Approximate Solubility--Solvent Addition Method
[0292] A weighed sample was treated with aliquots of the test
solvent at room temperature. The mixture was sonicated between
additions to facilitate dissolution. Complete dissolution of the
test material was determined by visual inspection. Solubility was
estimated based on the total solvent used to provide complete
dissolution. The actual solubility may be greater than the value
calculated because of the use of solvent aliquots that were too
large or due to a slow rate of dissolution. If complete dissolution
was achieved as a result of only one aliquot addition, the
solubility is expressed as "greater than."
Crystallization Screen
[0293] Both thermodynamic and kinetic crystallization techniques
were employed. These techniques are described in more detail below.
Once solid samples were harvested from crystallization attempts,
they were either examined under a microscope for birefringence and
morphology or observed with the naked eye. Solid samples were then
analyzed by XRPD, and the crystalline patterns compared to each
other to identify new crystalline forms.
Ambient Solution (AS)
[0294] Solutions were prepared in various solvents at ambient
temperature. The solution was filtered through a 0.2-.mu.m filter.
An antisolvent was added until turbidity was achieved or until a
maximum volume was obtained. Solutions were capped and then allowed
to sit at ambient.
Crash Cool (CC)
[0295] Saturated solutions were prepared in various solvents at
elevated temperature. The solutions were filtered through a
pre-warmed 0.2-.mu.m filter and then placed directly into a
freezer.
Fast Evaporation (FE)
[0296] Solutions were prepared in various solvents and sonicated
between aliquot additions to assist in dissolution. Once a mixture
reached complete dissolution, as judged by visual observation, the
solution was filtered through a 0.2-.mu.m filter. The filtered
solution was allowed to evaporate at ambient in an uncapped
vial.
Grinding (Mixer Mill)
[0297] A solid sample was placed into a ceramic grinding jar with a
grinding ball. A small amount of solvent may have also been added.
The sample was then ground at 30 Hz on a Retesh type MM220 mixer
mill for 20 minutes. The solids were isolated and analyzed.
Rotary Evaporation (RE)
[0298] Solutions prepared in various solvents were placed on the
rotary evaporator and removed when dry. Some samples were further
dried in a vacuum oven at elevated temperature.
Slow Cool (SC)
[0299] Saturated solutions were prepared in various solvents at
elevated temperatures and filtered through a 0.2-.mu.m filter into
a vial while still warm. The vial was sealed and allowed to cool
slowly to room temperature (some samples started directly from
ambient temperature). The presence or absence of solids was noted.
If there were no solids present, or if the amount of solids was
judged too small for XRPD analysis, the vial was placed in a
refrigerator. Again, the presence or absence of solids was noted
and if there were none, the vial was placed in a freezer. Solids
that formed were isolated by filtration and allowed to dry prior to
analysis.
Slow Evaporation (SE)
[0300] Solutions were prepared in various solvents and sonicated
between aliquot additions to assist in dissolution. Once a mixture
reached complete dissolution, as judged by visual observation, the
solution was filtered through a 0.2 .mu.m filter. The solution was
allowed to evaporate at ambient in a vial covered with aluminum
foil perforated with pinholes unless otherwise noted.
Slurry Experiments
[0301] Solutions were prepared by adding enough solids to a given
solvent so that excess solids were present. The mixture was then
agitated in a sealed vial at either ambient or a set
temperature.
Solid Vapor Stress (VS)
[0302] A solid sample was placed into a small glass vial, and then
placed into a large capped vial containing solvent. The vials were
left vertically and undisturbed at ambient.
Stress Experiments
[0303] Solids were stressed under different temperature and/or
relative humidity (RH) environments for a measured time period.
Specific RH values were achieved by placing the sample inside
sealed chambers containing saturated salt solutions. The salt
solutions were selected and prepared following an ASTM standard
procedure.
B. Instrumental Techniques
Differential Scanning Calorimetry (DSC)
[0304] The data acquisition parameters are displayed on each
thermogram in the Data section of this report. Each sample was
placed into an aluminum DSC pan, and the weight accurately
recorded. Indium metal was used as the calibration standard.
Dynamic Vapor Sorption/Desorption (DVS)
[0305] Moisture sorption/desorption data were collected on a VTI
SGA-100 Vapor Sorption Analyzer under a nitrogen purge. Equilibrium
criteria and the relative humidity (RH) range used for analysis are
displayed on each spreadsheet record in the Data section of this
report. Data were not corrected for the initial moisture content of
the samples. Sodium chloride and polyvinylpyrrolidine were used as
calibration standards.
Hot Stage Microscopy
[0306] Hot stage microscopy was performed using a Linkam hot stage
(model FTIR 600) mounted on a Leica DM LP microscope equipped with
a SPOT Insight.TM. color digital camera. Temperature calibrations
were performed using USP melting point standards. Samples were
placed on a cover glass, and a second cover glass was placed on top
of the sample. As the stage was heated, each sample was visually
observed using a 20.times. objective with crossed polarizers and a
first order red compensator. Images were captured using SPOT
software (v. 4.5.9).
Coulometric Karl-Fischer Analysis (KF)
[0307] Coulometric Karl Fischer (KF) analysis for water
determination was performed using a Mettler Toledo DL39 Karl
Fischer titrator. The sample was placed in the KF titration vessel
containing of Hydranal--Coulomat AD and mixed for 60 seconds to
ensure dissolution. The sample was then titrated by means of a
generator electrode which produces iodine by electrochemical
oxidation: 2 I-=>I.sub.2+2e. The sample size was optimized by
performing a scoping experiment. Two replicates were obtained to
ensure reproducibility. The value reported is the average of the
two replicates.
Infrared Spectroscopy (IR)
[0308] IR spectra were acquired on a Magna-IR 860.RTM. Fourier
transform infrared (FT-IR) spectrophotometer (Thermo Nicolet)
equipped with an Ever-Glo mid/far IR source, an extended range
potassium bromide (KBr) beamsplitter, and a deuterated triglycine
sulfate (DTGS) detector. An attenuated total reflectance (ATR)
accessory (Thunderdome.TM., Thermo Spectra-Tech), with a germanium
(Ge) crystal was used for data acquisition. The data acquisition
parameters for each spectrum are displayed above the image in the
Data section of this report. A background data set was acquired
with a clean Ge crystal. A Log 1IR (R=reflectance) spectrum was
acquired by taking a ratio of these two data sets against each
other. Wavelength verification was performed using NIST SRM 1921b
(polystyrene).
Nuclear Magnetic Resonance (NMR)
[0309] The solution phase .sup.1H NMR spectra were collected at
Spectra Data Services, Inc. The spectra acquisition parameters are
printed on each spectrum in the Data section of this report.
Spectra were referenced to internal tetramethylsilane at 0.0
ppm.
Raman Spectroscopy
[0310] Raman spectra were acquired on a Raman accessory module
interfaced to a Magna-IR 860.RTM. Fourier transform infrared
(FT-IR) spectrophotometer (Thermo Nicolet) equipped with an indium
gallium arsenide (InGaAs) detector. Wavelength verification was
performed using sulfur and cyclohexane. Each sample was prepared
for analysis by pressing into a pellet and placing it into a pellet
holder. The data acquisition parameters for each spectrum are
displayed above the image in the Data section of this report.
Thermogravimetry (TG)
[0311] The data acquisition parameters are displayed on each
thermogram in the Data section of this report. The sample was
placed in an aluminum sample pan and inserted into the TG furnace.
Nickel and Alumel.TM. were used as the calibration standards.
X-Ray Powder Diffraction (XRPD)
[0312] XRPD patterns of some forms of Compound I were collected
with a PANalytical X'Pert PRO MPD diffractometer using the
following experimental setting: 45 kV, 40 mA, Kal=1.5406 .ANG.,
scan range 1.01-39.98.degree. 2.theta., step size 0.017.degree.
2.theta., collection time: 1936 s. XRPD patterns of some other
forms of Compound I were collected with a Intel XRG-3000
Diffractometer using the following experimental setting: 40 kV, 30
mA, step size 0.03.degree. 2.theta., collection time: 300 s.
[0313] XRPD data shown in FIGS. 1, 6 and 10 was collected using
PANalytical X'Pert Pro Diffractometer and the XRPD data shown in
FIG. 17 was collected using Intel XRG-3000 Diffractometer.
[0314] The data presented contain X-ray diffraction patterns with
tables with peak lists. The range of data collected is instrument
dependent. Under most circumstances, peaks within the range of up
to about 30.degree. 20 were selected. Rounding algorithms were used
to round each peak to the nearest 0.1.degree. or 0.01.degree.
2.theta., depending upon the instrument used to collect the data
and/or the inherent peak resolution. The location of the peaks
along the x-axis (.degree. 2.theta.) in both the figures and the
tables were determined using proprietary software (TRIADS, version
2) and rounded to one or two significant figures after the decimal
point based upon the above criteria. Peak position variabilities
are given to within .+-.0.2.degree. 2.theta. based upon
recommendations outlined in the USP discussion of variability in
X-ray powder diffraction (United States Pharmacopeia, USP 37, NF
32, through S2<941>, 503, Dec. 1, 2014). The accuracy and
precision associated with any particular measurement reported
herein has not been determined. Moreover, third party measurements
on independently prepared samples on different instruments may lead
to variability which is greater than .+-.0.2.degree. 2.theta.. For
d-space listings, the wavelength used to calculate d-spacings was
1.5405929 .ANG., the Cu-K.sub..alpha.1 wavelength (Phys. Rev.
A56(6) 4554-4568 (1997). Variability associated with d-spacing
estimates was calculated from the USP recommendation, at each
d-spacing, and provided in the respective data tables.
[0315] Per USP guidelines, variable hydrates and solvates may
display peak variances greater than 0.2.degree. 2.theta. and
therefore peak variances of 0.2.degree. 2.theta. are not applicable
to these materials.
[0316] If multiple diffraction patterns are available, then
assessments of particle statistics (PS) and/or preferred
orientation (PO) are possible. Reproducibility among XRPD patterns
from multiple samples analyzed on a single diffractometer indicates
that the particle statistics are adequate. Consistency of relative
intensity among XRPD patterns from multiple diffractometers
indicates good orientation statistics. Alternatively, the observed
XRPD pattern may be compared with a calculated XRPD pattern based
upon a single crystal structure, if available. Two-dimensional
scattering patterns using area detectors can also be used to
evaluate PS/PO. If the effects of both PS and PO are determined to
be negligible, then the XRPD pattern is representative of the
powder average intensity for the sample and prominent peaks may be
identified as "Representative Peaks". In general, the more data
collected to determine Representative Peaks, the more confident one
can be of the classification of those peaks.
[0317] "Characteristic peaks", to the extent they exist, are a
subset of Representative Peaks and are used to differentiate one
crystalline polymorph from another crystalline polymorph
(polymorphs being crystalline forms having the same chemical
composition). Characteristic peaks are determined by evaluating
which representative peaks, if any, are present in one crystalline
polymorph of a compound against all other known crystalline
polymorphs of that compound to within .+-.0.2.degree. 2.theta.. Not
all crystalline polymorphs of a compound necessarily have at least
one characteristic peak.
[0318] Intel XRG-3000 Diffractometer
[0319] XRPD patterns were collected using an Inel XRG-3000
diffractometer equipped with a curved position sensitive detector
with a 20 range of 120.degree.. Prior to the analysis, a silicon
standard (NIST SRM 640c) was analyzed to verify the Si 111 peak
position. Samples were prepared for analysis by packing them into
thin-walled glass capillaries. Each capillary was mounted onto a
goniometer head and rotated during data acquisition.
[0320] PANalytical X'Pert Pro Diffractometer
[0321] The specimen was analyzed using Cu radiation produced using
an Optix long fine-focus source. An elliptically graded multilayer
mirror was used to focus the Cu K.alpha. X-rays of the source
through the specimen and onto the detector. The specimen was
sandwiched between 3-micron thick films, analyzed in transmission
geometry, and rotated to optimize orientation statistics. A
beam-stop was used to minimize the background generated by air
scattering. Soller slits were used for the incident and diffracted
beams to minimize axial divergence. Diffraction patterns were
collected using a scanning position-sensitive detector
(X'Celerator) located 240 mm from the specimen. Prior to the
analysis a silicon specimen (NIST SRM 640c) was analyzed to verify
the position of the silicon 111 peak.
[0322] Light Microscopy
[0323] Light microscopy was performed using a Leica DM LP
microscope equipped with Spot Insight color camera (model 3.2.0). A
10.times., 20.times., or 40.times. objective was used with cross
polarizers and a first order red compensator in place to view
samples. Samples were placed on a glass slide, then a cover glass
was then placed over each sample. Samples were analyzed as a dry
mount and suspended in mineral oil. Images were acquired at ambient
temperature using Spot software (v.4.5.9 for Windows). Micron bars
were inserted onto the images as a reference for particle size.
Example 1: Preparation of
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I Form
A)
[0324] Compound I Form A was obtained via recrystallization of
Compound I from methanol and water. Compound I (100 gm) was charged
into a flask and 800 mL methanol was added. The reaction mixtures
was heated to 65.degree. C. and 600 mL water was added as a steady
steam maintaining the temperature at 60.degree. C. The solution was
filtered while hot (60.degree. C.) to remove the insolubles.
Heating was discontinued and the filtrate was cooled to room
temperature stirring for at least four hours. White solid
precipitated out that was filtered, washed with water (2.times.200
mL) and dried under high vacuum at 60.degree. C. to provide 78 gm
of Compound I Form A with a purity of 99.8% by HPLC.
[0325] Compound I Form A was also obtained from the desolvation of
Form D under mild heating conditions.
[0326] The XRPD pattern for Compound I Form A is shown in FIG. 1.
The differential scanning calorimetry (DSC) curve of Form A is
shown in FIG. 2. The thermogravimetric analysis (TGA) of Form A
comprising a thermogram is shown in FIG. 3. The dynamic vapor
sorption (DVS) of Form A is shown in FIG. 4. The Raman spectrum of
Form A is shown in FIG. 5. The nuclear magnetic resonance spectrum
CH NMR) of Form A is shown in shown in FIG. 14. The IR spectrum of
form A is shown in FIG. 15.
Example 2: Preparation of
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I Form
B)
[0327] Compound I Form B was obtained by converting the Compound I
free base to hydrochloride salt.
[0328] The XRPD pattern for Compound I Form B is shown in FIG. 6.
The differential scanning calorimetry (DSC) curve of Form B is
shown in FIG. 7. The thermogravimetric analysis (TGA) of Form B
comprising a thermogram is shown in FIG. 8. The Raman spectrum of
Form B is shown in FIG. 9. The nuclear magnetic resonance spectrum
CH NMR) of Form B is shown in shown in FIG. 14. The IR spectrum of
form B is shown in FIG. 16.
Example 3: Preparation of
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine HCl salt (Compound I Forms C
and D)
[0329] Compound I Forms C and D were obtained via recrystallization
of Compound I Form A from a variety of solvents under a variety of
conditions. The following table summarizes the crystallization
experiments of Compound I Form A.
TABLE-US-00009 TABLE 1 Crystallization Experiments of Compound I
Form A Solvent (v/v) Conditions.sup.1 Description.sup.2 XRPD
Result.sup.3 Acetone VS White solid C Slurry (55.degree. C./1d)
White solid Amorph + pks 1,4-Dioxane VS White solid C EtOH SE White
solid, C B, UM VS White solid C CC (60.degree. C. to fzr) White
solid C SC (60.degree. C. to RT) White solid C Slurry (RT/21d)
White solid C MeOH SE White solid, A no B/E, UM VS White solid D
Slurry (RT/21d) White solid C Acetone/MeOH SC (60.degree. C. to
rfg) White solid, D (88:12) B, needles IPA/water (88:12) FE White
solid C SC (60.degree. C. to rfg) White solid, C B, needles
MeOH/water (10:90) Slurry (RT/21d) White solid Amorph + pks
MeOH/water (57:43) Slurry (60.degree. C./1d) White solid Disordered
Water VS White solid A + C .sup.1CC = Crash Cool, SC = Slow Cool,
SE = Slow evaporation, FE = Fast evaporation, VS = Vapor stress, d
= days, RT = Room temperature, fzr = freezer, rfg = refrigerator,
times and temperatures are approximate. .sup.2B = birefringent, B/E
= birefringence with extinction, UM = unknown morphology,
.sup.3Amorph = X-ray amorphous.
TABLE-US-00010 TABLE 2 Ambient Solution Crystallization of Compound
I Form A Solvent Antisolvent Description XRPD Result EtOH EtOAc
White solid A + C EtOH EtOAc.sup.1 White solid, not C birefringent,
needles. MeOH EtOAc White solid C .sup.1Precooled in freezer for
about 20 minutes.
TABLE-US-00011 TABLE 3 Solvent Grinding of Compound I Form A
Solvent Description XRPD Result EtOH White solid C MeOH White solid
A + C + D IPA White solid C Water White solid A + C
[0330] The XRPD pattern for Compound I Form C is shown in FIG. 10.
The differential scanning calorimetry (DSC) curve of Form C is
shown in FIG. 11. The thermogravimetric analysis (TGA) of Form C
comprising a thermogram is shown in FIG. 12. The dynamic vapor
sorption (DVS) of Form C is shown in FIG. 13. The nuclear magnetic
resonance spectrum (.sup.1H NMR) of Form C is shown in shown in
FIG. 14.
[0331] The XRPD pattern for Compound I Form D is shown in FIG. 17.
The thermogravimetric analysis (TGA) of Form B comprising a
thermogram is shown in FIG. 23.
Example 4: Preparation of Crystalline
[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-triflu-
oromethyl-pyridin-3-ylmethyl)-amine (Free Base of Compound I)
[0332] Compound II was prepared as disclosed above in Scheme I.
* * * * *