U.S. patent application number 17/347709 was filed with the patent office on 2022-03-31 for salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof.
This patent application is currently assigned to Sunovion Pharmaceuticals Inc.. The applicant listed for this patent is Sunovion Pharmaceuticals Inc.. Invention is credited to Nandkumar Nivritti BHOGLE, Takahiko HASHIZUKA, Robert Joseph PRYTKO, John R. SNOONIAN, Harold Scott WILKINSON, Haitao ZHANG.
Application Number | 20220098163 17/347709 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-31 |
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United States Patent
Application |
20220098163 |
Kind Code |
A1 |
BHOGLE; Nandkumar Nivritti ;
et al. |
March 31, 2022 |
SALTS OF A HETEROCYCLIC COMPOUND AND CRYSTALLINE FORMS, PROCESSES
FOR PREPARING, THERAPEUTIC USES, AND PHARMACEUTICAL COMPOSITIONS
THEREOF
Abstract
The present disclosure relates to salts of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, crystalline
forms thereof, and methods of preparation thereof, which are useful
in the treatment of CNS disorders.
Inventors: |
BHOGLE; Nandkumar Nivritti;
(North Reading, MA) ; HASHIZUKA; Takahiko; (Osaka,
JP) ; PRYTKO; Robert Joseph; (Millbury, MA) ;
SNOONIAN; John R.; (Bolton, MA) ; WILKINSON; Harold
Scott; (Westboro, MA) ; ZHANG; Haitao;
(Shrewsbury, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Pharmaceuticals Inc. |
Marlborough |
MA |
US |
|
|
Assignee: |
Sunovion Pharmaceuticals
Inc.
Marlborough
MA
|
Appl. No.: |
17/347709 |
Filed: |
June 15, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16817749 |
Mar 13, 2020 |
11136304 |
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17347709 |
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62818256 |
Mar 14, 2019 |
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International
Class: |
C07D 311/76 20060101
C07D311/76 |
Claims
1. A salt, which is:
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate
(Compound 1 L-Tartrate);
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate
(Compound 1 Fumarate); or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate
(Compound 1 Citrate); or a hydrate or solvate thereof.
2. The salt of claim 1, wherein the salt is a solid form.
3-12. (canceled)
13. The salt of claim 1, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate
(Compound 1 L-Tartrate).
14. The salt of claim 13, wherein Compound 1 L-tartrate is
crystalline.
15. The salt of claim 14 having Form LA, Form LB, or Form LC.
16. The salt of claim 15, wherein: A) Form LA has: characteristic
XRPD peaks in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree., and
24.2.degree..+-.0.2.degree.; an XRPD pattern with characteristic
peaks as substantially shown in FIG. 10 (FIG. 10); endotherm peaks
at temperatures of about 89.degree. C. and/or about 138.degree. C.;
a DSC thermogram substantially as depicted in FIG. 11 (FIG. 11); a
TGA thermogram substantially as depicted in FIG. 12 (FIG. 12); or a
DVS isotherm substantially as depicted in FIG. 13 (FIG. 13); or B)
Form LB has: characteristic XRPD peaks in terms of 2.theta.
selected from 18.7.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., and 31.4.degree..+-.0.2.degree.; an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 14 (FIG. 14); or a DVS isotherm substantially as depicted in
FIG. 15 (FIG. 15); or C) Form LC has: characteristic XRPD peaks in
terms of 2.theta. selected from 12.2.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., and 24.8.degree..+-.0.2.degree.; an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 16 (FIG. 16); an endotherm peak at a temperature of about
137.degree. C.; a DSC thermogram substantially as depicted in FIG.
17 (FIG. 17); a TGA thermogram substantially as depicted in FIG. 18
(FIG. 18); or a DVS isotherm substantially as depicted in FIG. 19
(FIG. 19).
17-27. (canceled)
28. The salt of claim 1, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate
(Compound 1 L-Fumarate).
29. The salt of claim 28, wherein Compound 1 Fumarate is
crystalline.
30. The salt of claim 29, having Form FA or Form FB.
31. The salt of claim 30, wherein: A) Form FA has: characteristic
XRPD peaks in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree., and
15.2.degree..+-.0.2.degree.; an XRPD pattern with characteristic
peaks as substantially shown in FIG. 22 (FIG. 22); an endotherm
peak at a temperature of about 147.degree. C.; a DSC thermogram
substantially as depicted in FIG. 23 (FIG. 23); a TGA thermogram
substantially as depicted in FIG. 24 (FIG. 24); or a DVS isotherm
substantially as depicted in FIG. 25 (FIG. 25); or B) Form FB has:
characteristic XRPD peaks in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.8.degree..+-.0.2.degree., and
20.2.degree..+-.0.2.degree., an XRPD pattern with characteristic
peaks as substantially shown in FIG. 26 (FIG. 26); an endotherm
peak at a temperature of about 96.degree. C., about 139.degree. C.,
and/or about 146.degree. C.; a DSC thermogram substantially as
depicted in FIG. 27 (FIG. 27); a TGA thermogram substantially as
depicted in FIG. 28 (FIG. 28); or a DVS isotherm substantially as
depicted in FIG. 29 (FIG. 29).
32-35. (canceled)
36. The salt of claim 1, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate
(Compound 1 Citrate).
37. The salt of claim 36, wherein Compound 1 Citrate is
crystalline.
38. The salt of claim 37, wherein the salt has: characteristic XRPD
peaks in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 15.5.degree..+-.0.2.degree., and
20.4.degree..+-.0.2.degree.; an XRPD pattern with characteristic
peaks as substantially shown in FIG. 30 (FIG. 30); an endotherm
peak at a temperature of about 142.degree. C.; a DSC thermogram
substantially as depicted in FIG. 31 (FIG. 31); a TGA thermogram
substantially as depicted in FIG. 32 (FIG. 32); or a DVS isotherm
substantially as depicted in FIG. 33 (FIG. 33).
39-74. (canceled)
75. A pharmaceutical composition comprising the salt of claim 1 and
a pharmaceutically acceptable excipient.
76. A method for treating a neurological or psychiatric disease or
disorder in a subject in need thereof, comprising administering to
said subject an effective amount of the salt of claim 1.
77. The method according to claim 76, wherein the neurological or
psychiatric disease or disorder is depression, bipolar disorder,
pain, schizophrenia, or other psychotic diseases, obsessive
compulsive disorder, addiction, social disorder, attention deficit
hyperactivity disorder, an anxiety disorder, a movement disorder,
epilepsy, autism or cognitive disease or disorder.
78. The method according to claim 76, wherein the neurological or
psychiatric disease or disorder is depression.
79. The method according to claim 78, wherein the depression is
treatment-resistant depression (TRD), major depressive disorder
(MDD), unipolar depression, bipolar depression or depression
associated with another disease or disorder.
80. The method according to claim 76, wherein said neurological
disease or disorder is selected from Alzheimer's disease and
Parkinson's disease.
81. The method according to claim 80, wherein said Alzheimer's
disease is Alzheimer's disease with agitation, Alzheimer's disease
with aggression, Alzheimer's disease agitation or Alzheimer's
disease with agitation aggression.
82. A method of treating agitation in a subject in need thereof,
comprising administering to said subject an effective amount of the
salt of claim 1.
83. A method of treating agitation associated with a neurological
or psychiatric disease or disorder in a subject in need thereof,
comprising administering to said subject an effective amount of the
salt claim 1.
84-129. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
application 62/818,256, filed Mar. 14, 2019, the entire disclosure
of which is hereby incorporated herein by reference.
FIELD
[0002] This application relates to salts of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1),
and crystalline forms, processes for preparing, therapeutic uses,
and pharmaceutical compositions thereof.
BACKGROUND
[0003] Central nervous system diseases and disorders affect a wide
range of the population with differing severity. Neurological and
psychiatric diseases and disorders include major depression,
schizophrenia, bipolar disorder, obsessive compulsive disorder
(OCD), panic disorder, and posttraumatic stress disorder (PTSD),
among others. These diseases and disorders affect a person's
thoughts, mood, behavior and social interactions and can
significantly impair daily functioning. See, e.g., Diagnostic and
Statistical Manual of Mental Disorders, 4.sup.th Ed., American
Psychiatric Association (2000) ("DSM-IV-TR"); Diagnostic and
Statistical Manual of Mental Disorders, 5.sup.th Ed., American
Psychiatric Association (2013) ("DSM-5"). Furthermore,
neuropsychiatric symptoms such as apathy, depression, anxiety,
cognitive impairment, psychosis, aggression, agitation, impulse
control and sleep disruption are now recognized as core impairments
of neurological diseases and disorders such as Alzheimer's and
Parkinson's diseases.
[0004] Various drugs are currently being developed for the
treatment of CNS disorders. For example,
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, which is
reported in U.S. Pat. No. 10,196,403, the entirety of which is
incorporated herein by reference, is useful in the treatment of CNS
disorders. There is a need for salts and new forms of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine for
facilitating the manufacture of safe, effective, and high quality
drug products.
SUMMARY
[0005] Provided herein are salts of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine and crystalline
forms thereof. Compound
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1)
has the following structure:
##STR00001##
[0006] In some embodiments, provided are processes of preparing
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1),
or salts or crystalline forms thereof.
[0007] In some embodiments, provided are methods of using
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1),
or salts or crystalline forms thereof, in the treatment of CNS
disorders.
[0008] In some embodiments, provided are pharmaceutical
compositions comprising
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1),
or salts or crystalline forms thereof, as described herein, and one
or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of
Compound 1 Hydrochloride Form HA.
[0010] FIG. 2 shows a differential scanning calorimetry (DSC)
thermogram of Compound 1 Hydrochloride Form HA.
[0011] FIG. 3 shows a thermogravimetric analysis (TGA) thermogram
of Compound 1 Hydrochloride Form HA.
[0012] FIG. 4 shows a dynamic vapor sorption (DVS) isotherm of
Compound 1 Hydrochloride Form HA.
[0013] FIG. 5 shows an XRPD pattern of Compound 1 Hydrochloride
Form HB.
[0014] FIG. 6 shows an XRPD pattern of Compound 1 Phosphate.
[0015] FIG. 7 shows a DSC thermogram of Compound 1 Phosphate.
[0016] FIG. 8 shows a TGA thermogram of Compound 1 Phosphate.
[0017] FIG. 9 shows a DVS isotherm of Compound 1 Phosphate.
[0018] FIG. 10 shows an XRPD pattern of Compound 1 L-Tartrate Form
LA.
[0019] FIG. 11 shows a DSC thermogram of Compound 1 L-Tartrate Form
LA.
[0020] FIG. 12 shows a TGA thermogram of Compound 1 L-Tartrate Form
LA.
[0021] FIG. 13 shows a DVS isotherm of Compound 1 L-Tartrate Form
LA.
[0022] FIG. 14 shows an XRPD pattern of Compound 1 L-Tartrate Form
LB.
[0023] FIG. 15 shows a DVS isotherm of Compound 1 L-Tartrate Form
LB.
[0024] FIG. 16 shows an XRPD pattern of Compound 1 L-Tartrate Form
LC.
[0025] FIG. 17 shows a DSC thermogram of Compound 1 L-Tartrate Form
LC.
[0026] FIG. 18 shows a TGA thermogram of Compound 1 L-Tartrate Form
LC.
[0027] FIG. 19 shows a DVS isotherm of Compound 1 L-Tartrate Form
LC.
[0028] FIG. 20 shows an XRPD pattern of Compound 1 D-Tartrate.
[0029] FIG. 21 shows a DVS isotherm of Compound 1 D-Tartrate.
[0030] FIG. 22 shows an XRPD pattern of Compound 1 Fumarate Form
FA.
[0031] FIG. 23 shows a DSC thermogram of Compound 1 Fumarate Form
FA.
[0032] FIG. 24 shows a TGA thermogram of Compound 1 Fumarate Form
FA.
[0033] FIG. 25 shows a DVS isotherm of Compound 1 Fumarate Form
FA.
[0034] FIG. 26 shows an XRPD pattern of Compound 1 Fumarate Form
FB.
[0035] FIG. 27 shows a DSC thermogram of Compound 1 Fumarate Form
FB.
[0036] FIG. 28 shows a TGA thermogram of Compound 1 Fumarate Form
FB.
[0037] FIG. 29 shows a DVS isotherm of Compound 1 Fumarate Form
FB.
[0038] FIG. 30 shows an XRPD pattern of Compound 1 Citrate.
[0039] FIG. 31 shows a DSC thermogram of Compound 1 Citrate.
[0040] FIG. 32 shows a TGA thermogram of Compound 1 Citrate.
[0041] FIG. 33 shows a DVS isotherm of Compound 1 Citrate.
[0042] FIG. 34 shows an XRPD pattern of Compound 1 Succinate.
[0043] FIG. 35 shows a DSC thermogram of Compound 1 Succinate.
[0044] FIG. 36 shows a TGA thermogram of Compound 1 Succinate.
[0045] FIG. 37 shows a DVS isotherm of Compound 1 Succinate.
[0046] FIG. 38 shows an XRPD pattern of Compound 1 Glutarate.
[0047] FIG. 39 shows a DVS isotherm of Compound 1 Glutarate.
[0048] FIG. 40 shows an XRPD pattern of Compound 1 L-Malate.
[0049] FIG. 41 shows a DSC thermogram of Compound 1 L-Malate.
[0050] FIG. 42 shows a TGA thermogram of Compound 1 L-Malate.
[0051] FIG. 43 shows a DVS isotherm of Compound 1 L-Malate.
[0052] FIG. 44 shows an XRPD pattern of Compound 1 Besylate.
[0053] FIG. 45 shows a DSC thermogram of Compound 1 Besylate.
[0054] FIG. 46 shows a TGA thermogram of Compound 1 Besylate.
[0055] FIG. 47 shows a DVS isotherm of Compound 1 Besylate.
DETAILED DESCRIPTION
[0056] The methods of the disclosure relate to the use of compounds
and compositions disclosed herein to treat neurological or
psychiatric diseases, disorders or impairments. In some
embodiments, the neurological or psychiatric disease or disorder is
depression, bipolar disorder, pain, schizophrenia, obsessive
compulsive disorder, psychostimulation, addiction, social disorder,
attention deficit hyperactivity disorder, an anxiety disorder, a
movement disorder, epilepsy, autism, Alzheimer's disease,
Parkinson's disease or cognitive impairments. In one embodiment,
the disease or disorder is depression, particularly
treatment-resistant depression (TRD), major depressive disorder
(MDD), unipolar depression, bipolar depression or depression
associated with another disease or disorder. In some embodiments,
the impairments in neurological diseases or disorders such as
Alzheimer's and Parkinson's diseases include neuropsychiatric
symptoms such as apathy, depression, anxiety, cognitive impairment,
psychosis, aggression, agitation, impulse control disorders, and/or
sleep disorders.
[0057] The description herein sets forth details to provide an
understanding of various embodiments of the disclosure, and is made
with the understanding that the provided disclosures are an
exemplification of the claimed subject matter without intending to
limit the claims to specific embodiments. Accordingly, specific
embodiments disclosed herein may be combined with other specific
embodiments disclosed herein, including specific embodiments under
various headings, which are provided for convenience and
organization, but are not to be construed to limit the claims in
any way.
[0058] All published documents cited herein are hereby incorporated
by reference in their entirety.
Definitions
[0059] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art.
[0060] As used herein, the singular forms "a", "an" and "the" are
intended to include the plural forms as well, unless the context
clearly indicates otherwise.
[0061] As used herein, and unless otherwise specified, the term
"about", when used in connection with a numeric value or range of
values which is provided to describe a particular solid form (e.g.,
a specific temperature or temperature range, such as describing a
melting, dehydration, or glass transition; a mass change, such as a
mass change as a function of temperature or humidity; a solvent or
water content, in terms of, for example, mass or a percentage; or a
peak position, such as in analysis by, for example, .sup.13C NMR,
DSC, TGA and XRPD), indicate that the value or range of values may
deviate to an extent deemed reasonable to one of ordinary skill in
the art while still describing the particular solid form.
Specifically, the term "about", when used in this context,
indicates that the numeric value or range of values may vary by 5%,
4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or
0.1% of the recited value or range of values while still describing
the particular solid form. In some embodiments, the values can vary
by about 5%. The term "about", when used in reference to a degree
2-theta value refers to .+-.0.3 degrees 2-theta or .+-.0.2 degrees
2-theta. In some embodiments, "about" refers to a degree 2-theta
value of .+-.0.2 degrees 2-theta. In some embodiments, "about"
refers to a temperature of .+-.3.degree. C.
[0062] As used herein, the phrase "alkali metal bicarbonate,"
employed alone or in combination with other terms, refers to a base
having formula M(HCO.sub.3), wherein M refers to an alkali metal
(e.g. lithium, sodium, or potassium). Example alkali metal
bicarbonate include, but are not limited to, lithium bicarbonate,
sodium bicarbonate, and potassium bicarbonate.
[0063] As used herein, the phrase "alkali metal alkoxide," employed
alone or in combination with other terms, refers to a base having
formula M(O-alkyl), wherein M refers to an alkali metal (e.g.
lithium, sodium, or potassium). Examples alkali metal alkoxide
include, but are not limited to lithium alkoxide, sodium alkoxide,
and potassium alkoxide.
[0064] As used herein, the phrase "metal hydroxide base," employed
alone or in combination with other terms, refers to a base having
formula MOH, wherein M refers to a metal such as an alkali metal
(e.g. lithium, sodium, or potassium). Example alkali metal
hydroxide bases include, but are not limited to lithium hydroxide,
sodium hydroxide, and potassium hydroxide.
[0065] As used herein, the terms "comprising" and "including" or
grammatical variants thereof are to be taken as specifying the
stated features, integers, steps or components but do not preclude
the addition of one or more additional features, integers, steps,
components or groups thereof. These terms encompass the term
"consisting of".
[0066] The expressions, "ambient temperature" and "room
temperature," as used herein, are understood in the art, and refer
generally to a temperature, e.g., a reaction temperature, that is
about the temperature of the room in which the reaction is carried
out, for example, a temperature from about 20.degree. C. to about
30.degree. C.
[0067] As used herein, the term "amorphous" or "amorphous form" is
intended to mean that the substance, component, or product in
question is not crystalline as determined, for instance, by XRPD or
where the substance, component, or product in question, for example
is not birefringent when viewed microscopically. For example,
amorphous means essentially without regularly repeating arrangement
of molecules or lacks the long range order of a crystal, i.e.,
amorphous form is non-crystalline. An amorphous form does not
display a defined x-ray diffraction pattern with sharp maxima. In
certain embodiments, a sample comprising an amorphous form of a
substance can be substantially free of other amorphous forms and/or
crystalline forms. For example, an amorphous substance can be
identified by an XRPD spectrum having an absence of readily
distinguishable reflections.
[0068] As used herein, the term "chemical purity" or "purity"
refers to a measurement of purity compound. In some embodiments,
the compound described herein can be isolated with a purity of at
least about 80%, about 85%, about 90%, about 95%, about 96%, about
97%, about 98%, or about 99%. In some embodiments, the compound
described herein can be isolated with an enantiomeric purity
greater than about 90%. In some embodiments, the compound described
herein can be isolated with an enantiomeric purity greater than
about 95%. In some embodiments, the compound described herein can
be isolated with an enantiomeric purity greater than about 99%. The
measurement can be determined by methods well-known in the art,
e.g., by elemental analysis, column chromatography, NMR
spectroscopy, and the like.
[0069] As used herein, the term "crystalline" or "crystalline form"
refers to a crystalline solid form of a chemical compound,
including, but not limited to, a single-component or
multiple-component crystal form, e.g., including solvates,
hydrates, clathrates, and a co-crystal. For example, crystalline
means having a regularly repeating and/or ordered arrangement of
molecules, and possessing a distinguishable crystal lattice. The
term "crystalline form" is meant to refer to a certain lattice
configuration of a crystalline substance. Different crystalline
forms of the same substance typically have different crystalline
lattices (e.g., unit cells), typically have different physical
properties attributed to their different crystalline lattices, and
in some instances, have different water or solvent content. The
different crystalline lattices can be identified by solid state
characterization methods such as by X-ray powder diffraction
(XRPD). Other characterization methods such as differential
scanning calorimetry (DSC), thermogravimetric analysis (TGA),
dynamic vapor sorption (DVS), and the like further help identify
the crystalline form as well as help determine stability and
solvent/water content.
[0070] As used herein, the term "% crystallinity" or "crystalline
purity," means percentage of a crystalline form in a preparation or
sample, which may contain other forms such as an amorphous form of
the same compound, or at least one other crystalline form of the
compound, or mixtures thereof. In some embodiments, the crystalline
forms can be isolated with a purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, the crystalline forms can be
isolated with a purity greater than about 90%. In some embodiments,
the crystalline forms can be isolated with a purity greater than
about 95%. In some embodiments, the crystalline forms can be
isolated with a purity greater than about 99%.
[0071] As used herein, "delaying" development of a disorder mean to
defer, hinder, slow, stabilize, and/or postpone development of the
disorder. Delay can be of varying lengths of time, depending on the
history of the disease and/or the individual being treated.
[0072] As used herein, the term "disorder" or specifically
identified disorders disclosed herein, (e.g. CNS disorders) refer
to the disorder as defined in the Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition (DSM-5).
[0073] As used herein, the term "enantiomeric purity" refers to a
measurement of purity for a chiral compound. In some embodiments,
the compound described herein can be isolated with an enantiomeric
purity of at least about 80%, about 85%, about 90%, about 95%,
about 96%, about 97%, about 98%, or about 99%. In some embodiments,
the compound described herein can be isolated with an enantiomeric
purity greater than about 99%. In some embodiments, the compound
described herein can be isolated with an enantiomeric purity
greater than about 90%. In some embodiments, the compound described
herein can be isolated with an enantiomeric purity greater than
about 95%. The measurement can be determined by methods well-known
in the art, e.g., by specific optical rotation, chiral column
chromatography, NMR spectroscopy, and the like.
[0074] The term "hydrate," as used herein, is meant to refer to a
solid form (e.g., crystalline form) of Compound 1 and its salts
that includes water. The water in a hydrate can be present in a
stoichiometric amount with respect to the amount of salt in the
solid, or can be present in varying amounts, such as can be found
in connection with channel hydrates.
[0075] The reactions of the processes described herein can be
carried out in suitable solvents which can be readily selected by
one of skill in the art of organic synthesis. Suitable solvents can
be substantially nonreactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected. In some embodiments, reactions can
be carried out in the absence of solvent, such as when at least one
of the reagents is a liquid or gas. As used herein, the term
"organic solvent" refers to carbon-based solvents (i.e., they
contain carbon in their structure) that are employed to dissolve or
disperse one or more compounds described herein.
[0076] Suitable solvents can include halogenated solvents such as
carbon tetrachloride, bromodichloromethane, dibromochloromethane,
bromoform, chloroform, bromochloromethane, dibromomethane, butyl
chloride, dichloromethane (methylene chloride),
tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane,
1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane,
I,I,I-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane,
hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene,
chlorobenzene, fluorobenzene, mixtures thereof and the like.
[0077] Suitable solvents can include ether solvents include
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan,
tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl
ether, ethylene glycol diethyl ether, diethylene glycol dimethyl
ether (diglyme), diethylene glycol diethyl ether, triethylene
glycol dimethyl ether, anisole, tert-butyl methyl ether, mixtures
thereof and the like.
[0078] Suitable solvents can include protic solvents (e.g., polar
protic solvents) can include, by way of example and without
limitation, water, methanol, ethanol, 2-nitroethanol,
2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol,
iso-butyl alcohol, tert-butyl alcohol, 2-ethoxyethanol, diethylene
glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, tert-pentyl
alcohol, diethylene glycol monomethyl ether, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or
glycerol.
[0079] Suitable solvents can include aprotic solvents can include,
by way of example and without limitation, N,N-dimethylformamide
(DMF), N,N-dimethylacetamide (DMA),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),
formamide, N-methylacetamide, N-methylformamide, acetonitrile,
dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate,
hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,
sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,
nitrobenzene, or hexamethylphosphoramide.
[0080] Suitable solvents can include hydrocarbon solvents include
benzene, cyclohexane, pentane, hexane, toluene, cycloheptane,
methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene,
octane, indane, nonane, or naphthalene.
[0081] As used herein, the term "peak" or "characteristic peak"
refers to a reflection having a relative height/intensity of at
least about 3% of the maximum peak height/intensity.
[0082] As used herein, "pharmaceutically acceptable" or
"physiologically acceptable" refer to compounds (e.g., solid
forms), compositions, dosage forms and other materials, which are
useful in preparing a pharmaceutical composition that is suitable
for veterinary or human pharmaceutical use.
[0083] The term "pharmaceutically acceptable excipient" refers to a
non-toxic binder, filler, adjuvant, carrier, excipient, glidant,
sweetening agent, diluent, preservative, dye/colorant, flavor
enhancer, surfactant, wetting agent, dispersing agent, suspending
agent, stabilizer, isotonic agent, solvent, emulsifier, anti-caking
agent, flavor, desiccant, plasticizer, vehicle, disintegrant, or
lubricant that does not destroy the pharmacological activity of the
compound with which it is formulated. Pharmaceutically acceptable
excipients that can be used in the compositions include ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, potassium sorbate, partial glyceride mixtures
of saturated vegetable fatty acids, water, salts or electrolytes,
such as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0084] As used herein, "prevention" or "preventing" refers to a
regimen that protects against the onset of the disorder such that
the clinical symptoms of the disorder do not develop. Accordingly,
"prevention" relates to administration of a therapy, including
administration of a compound disclosed herein, to a subject before
signs of the diseases are detectable in the subject (for example,
administration of a compound disclosed herein to a subject in the
absence of a detectable syndrome of the disorder). The subject may
be at risk of developing the disorder. As used herein, an "at risk"
subject is one who is at risk of developing a disorder to be
treated. This may be shown, for example, by one or more risk
factors, which are measurable parameters that correlate with
development of a disorder and are known in the art.
[0085] Preparation of compounds can involve the protection and
deprotection of various chemical groups. The need for protection
and deprotection, and the selection of appropriate protecting
groups (PG) can be readily determined by one skilled in the art.
The chemistry of protecting groups can be found, for example, in
Wuts and Greene, Greene's Protective Groups in Organic Synthesis,
4.sup.th Ed., John Wiley & Sons: New York, 2006, which is
incorporated herein by reference in its entirety. Preparation of
compounds can also include leaving group (LG), which is a molecular
fragment that leaves in bond cleavage. Leaving groups can be anions
or neutral fragment and is able to stabilize the additional
electron density that results from bond cleavage. Typical leaving
groups are halides such as Cl, Br, and I, and sulfonate esters such
as tosylate (TsO), triflate (TfO), mesylate (MsO), and the
like.
[0086] As used herein, the term "reacting," "contacting" or
"treating" when describing a certain process is used as known in
the art and generally refers to the bringing together of chemical
reagents in such a manner so as to allow their interaction at the
molecular level to achieve a chemical or physical transformation.
In some embodiments, the reacting involves two reagents, wherein
one or more equivalents of second reagent are used with respect to
the first reagent. The reacting steps of the processes described
herein can be conducted for a time and under conditions suitable
for preparing the identified product.
[0087] As used herein, the term "salt" refers to a substance that
results from the combination of a compound and an acid or a base.
For example, the free base Compound 1 can be combined with the
desired acid in a solvent or in a melt to generate a salt of
Compound 1. In some embodiments, acid addition salt of Compound 1
can be converted to a different acid addition salt by anion
exchange. Salts which are prepared in a solvent system can be
isolated by precipitation from the solvent. Precipitation and/or
crystallization can be induced, for example, by evaporation,
reduction of temperature, addition of anti-solvent, or combinations
thereof.
[0088] As used herein, the term "solid form" refers to a compound
provided herein in either an amorphous state or a crystalline state
(e.g., crystalline form), whereby a compound provided herein in a
crystalline state may optionally include solvent or water within
the crystalline lattice, for example, to form a solvated or
hydrated crystalline form. In some embodiments, the compound
provided herein is in a crystalline state as described herein.
[0089] A "solvate" as used herein is formed by the interaction of a
solvent and a compound.
[0090] As used herein, the term "subject," to which administration
is contemplated includes, but is not limited to, humans (i.e., a
male or female of any age group, e.g., a pediatric subject (e.g.,
infant, child, adolescent) or adult subject (e.g., young adult,
middle-aged adult or senior adult)) and/or other primates (e.g.,
cynomolgus monkeys, rhesus monkeys); mammals, including
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs; and/or birds, including commercially
relevant birds such as chickens, ducks, geese, quail, and/or
turkeys. The "subject" may have independently been diagnosed with a
disorder as defined herein, may currently be experiencing symptoms
associated with disorders or may have experienced symptoms in the
past, may be at risk of developing a disorder, or may be reporting
one or more of the symptoms of a disorder, even though a diagnosis
may not have been made. In some embodiments, the subject is a human
who may have independently been diagnosed with a disorder as
defined herein, may currently be experiencing symptoms associated
with disorders or may have experienced symptoms in the past, may be
at risk of developing a disorder, or may be reporting one or more
of the symptoms of a disorder, even though a diagnosis may not have
been made.
[0091] As used herein, the term "substantially" when referring to a
characteristic figure of a crystal form, such as an XRPD pattern, a
DSC thermogram, a TGA thermogram, or the like, means that a subject
figure can be non-identical to the reference depicted herein, but
it falls within the limits of experimental error and thus can be
deemed as derived from the same crystal form as disclosed herein,
as judged by a person of ordinary skill in the art. For example,
the term "substantially" as used in the context of XRPD herein is
meant to encompass variations disclosed herein (e.g., instrument
variation, measurement variation, etc.).
[0092] As used herein, the term "substantially amorphous" means a
majority of the weight of a sample or preparation (e.g., of a salt
of Compound 1) is amorphous and the remainder of the sample is a
crystalline form of the same compound. In some embodiments, a
substantially amorphous sample has less than about 5% crystallinity
(e.g., about 95% of the non-crystalline form of the same compound),
preferably less than about 4% crystallinity (e.g., about 96% of the
non-crystalline form of the same compound), more preferably less
than about 3% crystallinity (e.g., about 97% of the non-crystalline
form of the same compound), even more preferably less than about 2%
crystallinity (e.g., about 98% of the non-crystalline form of the
same compound), still more preferably less than about 1%
crystallinity (e.g., about 99% of the non-crystalline form of the
same compound), and most preferably about 0% crystallinity (e.g.,
about 100% of the non-crystalline form of the same compound). In
some embodiments, the term "fully amorphous" means less than about
99% or about 0% crystallinity.
[0093] As used herein, the term "substantially crystalline," means
a majority of the weight of a sample or preparation (e.g., of a
salt of Compound 1) is crystalline and the remainder of the sample
is a non-crystalline form (e.g., amorphous form) of the same
compound. In some embodiments, a substantially crystalline sample
has at least about 95% crystallinity (e.g., about 5% of the
non-crystalline form of the same compound), preferably at least
about 96% crystallinity (e.g., about 4% of the non-crystalline form
of the same compound), more preferably at least about 97%
crystallinity (e.g., about 3% of the non-crystalline form of the
same compound), even more preferably at least about 98%
crystallinity (e.g., about 2% of the non-crystalline form of the
same compound), still more preferably at least about 99%
crystallinity (e.g., about 1% of the non-crystalline form of the
same compound), and most preferably about 100% crystallinity (e.g.,
about 0% of the non-crystalline form of the same compound). In some
embodiments, the term "fully crystalline" means at least about 99%
or about 100% crystallinity.
[0094] The term "substantially isolated" is meant that the compound
is at least partially or substantially separated from the
environment in which it was formed or detected. Partial separation
can include, e.g., a composition enriched in the compound, salts,
hydrates, solvates, or solid forms provided herein. Substantial
separation can include compositions containing at least about 50%,
at least about 60%, at least about 70%, at least about 80%, at
least about 90%, at least about 95%, at least about 97%, or at
least about 99% by weight of the compound, salts, hydrates,
solvates, or solid forms provided herein.
[0095] As used herein, the term "therapeutically effective amount"
or "effective amount" refers to an amount that is effective to
elicit the desired biological or medical response, including the
amount of a compound that, when administered to a subject for
treating a disorder, is sufficient to effect such treatment of the
disorder. The effective amount will vary depending on the compound,
the disorder, and its severity, and the age, weight, etc. of the
subject to be treated. The effective amount may be in one or more
doses (for example, a single dose or multiple doses may be required
to achieve the desired treatment endpoint). An effective amount may
be considered to be given in an effective amount if, in conjunction
with one or more other agents, a desirable or beneficial result may
be or is achieved. Suitable doses of any co-administered compounds
may optionally be lowered due to the combined action, additive or
synergistic, of the compound.
[0096] As used herein, the terms "treatment," "treat," and
"treating" refer to an approach for obtaining beneficial or desired
results including, but not limited to, therapeutic benefit.
Therapeutic benefit includes eradication and/or amelioration of the
underlying disorder being treated; it also includes the eradication
and/or amelioration of one or more of the symptoms associated with
the underlying disorder such that an improvement is observed in the
subject, notwithstanding that the subject may still be afflicted
with the underlying disorder. In some embodiments, "treatment" or
"treating" includes one or more of the following: (a) inhibiting
the disorder (for example, decreasing one or more symptoms
resulting from the disorder, and/or diminishing the extent of the
disorder); (b) slowing or arresting the development of one or more
symptoms associated with the disorder (for example, stabilizing the
disorder and/or delaying the worsening or progression of the
disorder); and/or (c) relieving the disorder (for example, causing
the regression of clinical symptoms, ameliorating the disorder,
delaying the progression of the disorder, and/or increasing quality
of life). In some embodiments, treatment can be administered after
one or more symptoms have developed. In other embodiments,
treatment can be administered in the absence of symptoms. For
example, treatment can be administered to a susceptible individual
prior to the onset of symptoms (e.g., in light of a history of
symptoms and/or in light of genetic or other susceptibility
factors). Treatment may also be continued after symptoms have
resolved, for example to prevent or delay their recurrence.
[0097] As used herein, the term "treatment-resistant depression,"
which is also known as "treatment-refractory depression," refers to
major depressive disorder (MDD) situations where the subject shows
inadequate responses to treatment with at least two antidepressants
(e.g., standard antidepressant treatments that are commercially
available). Inadequate response can be no response. Inadequate
response can also be when the subject does not show full remission
of symptoms, or when the physician or clinician does not deem the
subject's response to be adequate. Treatment-resistant depression
symptoms can range from mild to severe. Factors that can contribute
to inadequate response include, but not limited to, early
discontinuation of treatment, insufficient dosage of medication,
patient noncompliance, misdiagnosis, and concurrent psychiatric
disorders.
[0098] EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HCl
(hydrochloric acid); M (molar); MeCN (acetonitrile); MeOH
(methanol); mg (milligram(s)); min. (minutes(s)); mL
(milliliter(s)); mmol (millimole(s)); NaHCO.sub.3 (sodium
bicarbonate); NaOH (sodium hydroxide); nM (nanomolar); Ph (phenyl);
.mu.g (microgram(s)); .mu.L (microliter(s)); .mu.M (micromolar); wt
% (weight percent).
Salts and Crystalline Forms Thereof
[0099] Provided herein are salts of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1),
and crystalline forms thereof. Compound
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1)
has the structure:
##STR00002##
[0100] Compound 1 is described in U.S. patent application Ser. No.
15/663,688 (allowed), the entirety of which is incorporated herein
by reference.
[0101] Compound 1
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine is named or
identified using other commonly recognized nomenclature systems.
For example, the compound may be named or identified with common
names, systematic names, or non-systematic names. The nomenclature
systems that are commonly recognized in the art of chemistry
include, but are not limited to, Chemical Abstract Service (CAS)
and International Union of Pure and Applied Chemistry (IUPAC). The
IUPAC name provided by ChemDraw Professional 15.0 has been used
herein for Compound 1.
[0102] Compound 1 may be prepared as a salt. In some embodiments,
Compound 1 may be prepared as a pharmaceutically acceptable salt.
Non-limiting examples of pharmaceutically acceptable salts include
malates, tartrates, citrates, phosphates, sulfates, pyrosulfates,
bisulfates, sulfites, bisulfites, monohydrogen-phosphates,
dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,
bromides, iodides, acetates, propionates, decanoates, caprylates,
acrylates, formates, isobutyrates, caproates, heptanoates,
propiolates, oxalates, malonates, succinates, suberates, sebacates,
fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,
benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
methylsulfonates, propylsulfonates, besylates, tosylates,
xylenesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, phenylacetates, phenylpropionates,
phenylbutyrates, lactates, gamma-hydroxybutyrates, glycolates, and
mandelates. Lists of other suitable pharmaceutically acceptable
salts are found in Remington: The Science and Practice of Pharmacy,
21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa.,
2006.
[0103] In some embodiments, the salt is a hydrochloric acid salt of
Compound 1. The hydrochloric acid salt form of Compound 1 is
referred to herein as "Compound 1 Hydrochloride." An alternative
name for the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride
or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloric
acid salt.
[0104] In some embodiments, the salt is a phosphoric acid salt of
Compound 1. The phosphoric acid salt form of Compound 1 is referred
to herein as "Compound 1 Phosphate." An alternative name for the
salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
phosphate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
phosphoric acid salt.
[0105] In some embodiments, the salt is a L-tartaric acid salt of
Compound 1. The L-tartaric acid salt form of Compound 1 is referred
to herein as "Compound 1 L-Tartrate." An alternative name for the
salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartaric acid
salt.
[0106] In some embodiments, the salt is a D-tartaric acid salt of
Compound 1. The D-tartaric acid salt form of Compound 1 is referred
to herein as "Compound 1 D-Tartrate." An alternative name for the
salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
D-tartrate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
D-tartaric acid salt.
[0107] In some embodiments, the salt is a fumaric acid salt of
Compound 1. The fumaric acid salt form of Compound 1 is referred to
herein as "Compound 1 Fumarate." An alternative name for the salt
is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumaric acid
salt.
[0108] In some embodiments, the salt is a citric acid salt of
Compound 1. The citric acid salt form of Compound 1 is referred to
herein as "Compound 1 Citrate." An alternative name for the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citric acid
salt.
[0109] In some embodiments, the salt is a succinic acid salt of
Compound 1. The succinic acid salt form of Compound 1 is referred
to herein as "Compound 1 Succinate." An alternative name for the
salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
succinate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
succinic acid salt.
[0110] In some embodiments, the salt is a glutaric acid salt of
Compound 1. The citric acid salt form of Compound 1 is referred to
herein as "Compound 1 Glutarate." An alternative name for the salt
is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutaric acid
salt.
[0111] In some embodiments, the salt is a L-malic acid salt of
Compound 1. The L-malic acid salt form of Compound 1 is referred to
herein as "Compound 1 L-malate." An alternative name for the salt
is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malate or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malic acid
salt.
[0112] In some embodiments, the salt is a benzenesulfonic acid salt
of Compound 1. The benzenesulfonic acid salt form of Compound 1 is
referred to herein as "Compound 1 Besylate." An alternative name
for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
besylate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
benzenesulfonic acid salt.
[0113] In some embodiments, the salt is a p-toluenesulfonic acid
salt of Compound 1. The p-toluenesulfonic acid salt form of
Compound 1 is referred to herein as "Compound 1 Tosylate." An
alternative name for the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate or
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
p-toluenesulfonic acid salt.
[0114] The salts described herein can have about half, about 1,
about 2, about 3 equivalents, etc. of acid to Compound 1. In some
embodiments, the salts described herein comprises about half
equivalent of acid to Compound 1. In some embodiments, the salts
described herein comprise about 1 equivalent of acid to Compound 1.
In some embodiments, the salts described herein comprise about 2
equivalents of acid to Compound 1. In some embodiments, the salts
described herein comprise about 3 equivalents of acid to Compound
1. A person skilled in the art would recognize that there is an
equilibrium between the acid and Compound 1 in which the protons
may reside, which depends on the conditions (e.g., solvents,
temperature, etc.) and the strength of the acids. For example, in
some conditions, the acid becomes a counter-anion by losing one or
more protons to Compound 1, and Compound 1 becomes a
counter-cation. In some conditions, the protons of the acids may
form a weak interaction with the basic sites of Compound 1 and
thus, the protons are shared between the acid and Compound 1.
[0115] The salts described herein can have less than about 1, about
2, about 3, about 4, about 5, or greater than about 6 equivalents
of solvent or hydrate to the salt. In some embodiments, the salts
described have less than about 1 equivalent of solvent or hydrate
to the salt. In some embodiments, the salts described have less
than about 1 equivalent of hydrate to the salt. In some
embodiments, the salts described have about 2 equivalents of
solvent or hydrate to the salt. In some embodiments, the salts
described have about 2 equivalent of hydrate to the salt. In some
embodiments, the salts described have about 3 equivalents of
solvent or hydrate to the salt. In some embodiments, the salts
described have about 3 equivalents of hydrate to the salt.
[0116] In some embodiments, the salts described herein are
anhydrous.
[0117] Salts of Compound 1 can be isolated as one or more
crystalline forms. Different crystalline forms of the same
substance may have different bulk properties relating to, for
example, hygroscopicity, solubility, stability, and the like.
Crystalline forms with high melting points may have good
thermodynamic stability, which may be advantageous in prolonging
shelf-life drug formulations containing the crystalline form.
Crystalline forms with lower melting points may be less
thermodynamically stable, but may be advantageous in having
increased water solubility, which may translate to increased drug
bioavailability. Crystalline forms that are weakly hygroscopic may
be desirable for stability to heat or humidity and may be resistant
to degradation during long storage. The crystalline forms described
herein have many advantages, for example they have desirable
properties. Moreover, the crystalline forms disclosed herein may be
useful for improving the performance characteristics of a
pharmaceutical product such as dissolution profile, shelf-life and
bioavailability.
[0118] Different crystalline forms of a particular substance, such
as Compound 1 as described herein, can include both anhydrous forms
of that substance and solvated/hydrated forms of that substance,
where each of the anhydrous forms and solvated/hydrated forms are
distinguished from each other by different XRPD patterns, or other
solid state characterization methods, thereby signifying different
crystalline lattices. In some instances, a single crystalline form
(e.g., identified by a unique XRPD pattern) can have variable water
or solvent content, where the lattice remains substantially
unchanged (as does the XRPD pattern) despite the compositional
variation with respect to water and/or solvent.
[0119] An XRPD pattern of reflections (peaks) is typically
considered a fingerprint of a particular crystalline form. It is
well known that the relative intensities of the XRPD peaks can
widely vary depending on, inter alia, the sample preparation
technique, crystal size distribution, filters used, the sample
mounting procedure, and the particular instrument employed. In some
instances, new peaks can be observed or existing peaks may
disappear, depending on the type of the machine or the settings
(for example, whether a Ni filter is used or not). Moreover,
instrument variation and other factors can affect the 2-theta
(2.theta.) values. Thus, peak assignments, such as those reported
herein, can vary by plus or minus (.+-.) about 0.2.degree.
(2-theta) or about 0.3.degree. (2-theta).
[0120] In the same way, temperature readings in connection with
DSC, TGA, or other thermal experiments can vary about .+-.3.degree.
C. depending on the instrument, particular settings, sample
preparation, etc. Accordingly, a crystalline form reported herein
having a DSC thermogram "substantially" as shown in any of the
Figures is understood to accommodate such variation.
[0121] Crystalline forms of a substance can be obtained by a number
of methods, as known in the art. Such methods include, but are not
limited to, melt recrystallization, melt cooling, solvent
recrystallization, recrystallization in confined spaces such as,
e.g., in nanopores or capillaries, recrystallization on surfaces or
templates such as, e.g., on polymers, recrystallization in the
presence of additives, such as, e.g., co-crystal counter-molecules,
desolvation, dehydration, rapid evaporation, rapid cooling, slow
cooling, vapor diffusion, sublimation, exposure to moisture,
grinding and solvent-drop grinding.
[0122] Compound 1 and its salts can be prepared in batches referred
to as batches, samples, or preparations. The batches, samples, or
preparations can include Compound 1 and its salts in any of the
crystalline or non-crystalline forms described herein, including
hydrated and non-hydrated forms, and mixtures thereof.
[0123] Compounds provided herein (e.g., salts of Compound 1) can
also include all isotopes of atoms occurring in the intermediates
or final compounds. Isotopes include those atoms having the same
atomic number but different mass numbers. For example, isotopes of
hydrogen include tritium and deuterium. One or more constituent
atoms of the compounds provided herein can be replaced or
substituted with isotopes of the atoms in natural or non-natural
abundance. In some embodiments, the compound includes at least one
deuterium atom. For example, one or more hydrogen atoms in a
compound of the present disclosure can be replaced or substituted
by deuterium. In some embodiments, the compound includes two or
more deuterium atoms. In some embodiments, the compound includes 1,
2, 3, 4, 5, 6, 7 or 8 deuterium atoms. Synthetic methods for
including isotopes into organic compounds are known in the art.
Examples of isotopes that can be incorporated into the compounds
disclosed herein include isotopes of hydrogen, carbon, nitrogen,
oxygen, phosphorus, fluorine, chlorine, and iodine (e.g., .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, .sup.123I, and .sup.125I).
[0124] In some embodiments, Compound 1 or its salts and crystalline
forms thereof are substantially isolated.
[0125] Compound 1 can be observed and/or isolated as various salt
forms and polymorphs thereof, including, e.g., hydrochloride salt
(form HA and form HB), phosphate salt, L-tartrate salt (form LA,
form LB, and form LC), D-tartrate salt, fumarate (form FA and form
FB), citrate, succinate, glutarate, L-malate, besylate, and
tosylate.
Compound 1 Hydrochloride
[0126] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride
(Compound 1 Hydrochloride). In some embodiments, Compound 1
Hydrochloride is crystalline.
[0127] Compound 1 Hydrochloride can be prepared according to the
procedure provided in U.S. Pat. No. 10,196,403. In some
embodiments, provided is Compound 1 Hydrochloride prepared by
isolating Compound 1 Hydrochloride Form HA from a mixture of
Compound 1, HCl, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In some
embodiments, S1 is C.sub.1-6 alkyl acetate. In some embodiments, S1
is methanol. In some embodiments, S1 is THF. In some embodiments,
S1 is ethyl acetate.
Compound 1 Hydrochloride Form HA
[0128] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride
Form HA (Compound 1 hydrochloride Form HA). In some embodiments,
Compound 1 Hydrochloride Form HA is crystalline.
[0129] In some embodiments, Compound 1 Hydrochloride Form HA has
characteristic XRPD peak in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree., and
15.1.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HA has a characteristic XRPD peak in terms of
2.theta. at 9.4.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Hydrochloride Form HA has a characteristic XRPD peak in
terms of 2.theta. at 11.4.degree..+-.0.2.degree.. In some
embodiments, Compound 1 Hydrochloride Form HA has a characteristic
XRPD peak in terms of 2.theta. at 15.1.degree..+-.0.2.degree..
[0130] In some embodiments, Compound 1 Hydrochloride Form HA has
characteristic XRPD peaks in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree., and
17.6.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HA has at least one characteristic XRPD peak in
terms of 2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.+-.0.2.degree., 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., and 17.6.degree..+-.0.2.degree..
[0131] In some embodiments, Compound 1 Hydrochloride Form HA has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 9.4.degree..+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., 17.6.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HA has at least one characteristic XRPD peak in
terms of 2.theta. selected from 9.4.degree..+-.0.2.degree.
11.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree.,
17.6.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 24.3.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree..
[0132] In some embodiments, Compound 1 Hydrochloride Form HA has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 9.4.degree..+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., 17.6.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HA has at least two characteristic XRPD peaks in
terms of 2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree.,
17.6.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 24.3.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree..
[0133] In some embodiments, Compound 1 Hydrochloride Form HA has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 9.4.degree..+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., 17.6.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HA has at least three characteristic XRPD peaks
in terms of 2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree.,
17.6.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 24.3.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree..
[0134] In some embodiments, Compound 1 Hydrochloride Form HA has an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 1 (FIG. 1).
[0135] In some embodiments, Compound 1 Hydrochloride Form HA has
endotherm peaks at temperatures of about 99.degree. C. and about
187.degree. C. In some embodiments, Compound 1 Hydrochloride Form
HA has an endotherm peak at a temperature of about 99.degree. C. In
some embodiments, Compound 1 Hydrochloride Form HA has an endotherm
peak at a temperature of about 187.degree. C. In some embodiments,
Compound 1 Hydrochloride Form HA has a DSC thermogram substantially
as depicted in FIG. 2 (FIG. 2). In some embodiments, Compound 1
Hydrochloride Form HA has a TGA thermogram substantially as
depicted in FIG. 3 (FIG. 3). In some embodiments, Compound 1
Hydrochloride Form HA has a DVS isotherm substantially as depicted
in FIG. 4 (FIG. 4).
[0136] In some embodiments, Compound 1 Hydrochloride Form HA has
characteristic XRPD peaks in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree., and
15.1.degree..+-.0.2.degree.; and has endotherm peaks at
temperatures of about 99.degree. C. and about 187.degree. C. In
some embodiments, Compound 1 Hydrochloride Form HA has
characteristic XRPD peaks in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree., and
15.1.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 99.degree. C. In some embodiments, Compound 1
Hydrochloride Form HA has characteristic XRPD peaks in terms of
2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.+-.0.2.degree., and 15.1.degree..+-.0.2.degree.; and an
endotherm peak at a temperature of about 187.degree. C. In some
embodiments, Compound 1 Hydrochloride Form HA has characteristic
XRPD peaks in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree., and
15.1.degree..+-.0.2.degree.; and a DSC thermogram substantially as
depicted in FIG. 2 (FIG. 2). In some embodiments, Compound 1
Hydrochloride Form HA has characteristic XRPD peaks in terms of
2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.+-.0.2.degree., and 15.1.degree..+-.0.2.degree.; and a DVS
isotherm substantially as depicted in FIG. 4 (FIG. 4).
[0137] In some embodiments, Compound 1 Hydrochloride Form HA can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 Hydrochloride Form HA
can be isolated with a crystalline purity greater than about 99%.
In some embodiments, Compound 1 Hydrochloride Form HA can be
isolated with a crystalline purity greater than about 99.9%.
[0138] In some embodiments, provided is Compound 1 Hydrochloride
Form HA prepared by isolating Compound 1 Hydrochloride Form HA from
a mixture of Compound 1, HCl, and S1, wherein S1 is a solvent. In
some embodiments, S1 is an organic solvent. In some embodiments, S1
is ether. In some embodiments, S1 is C.sub.1-6 alkyl acetate. In
some embodiments, S1 is THF. In some embodiments, S1 is ethyl
acetate.
Compound 1 Hydrochloride Form HB
[0139] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine Hydrochloride
Form HB (Compound 1 hydrochloride Form HB). In some embodiments,
Compound 1 Hydrochloride HB is crystalline.
[0140] In some embodiments, Compound 1 Hydrochloride Form HB has
characteristic XRPD peaks in terms of 2.theta. selected from
8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree., and
10.3.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HB has a characteristic XRPD peak in terms of
2.theta. at 8.6.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Hydrochloride Form HB has a characteristic XRPD peak in
terms of 2.theta. at 9.6.degree..+-.0.2.degree.. In some
embodiments, Compound 1 Hydrochloride HB has a characteristic XRPD
peak in terms of 2.theta. at 10.3.degree..+-.0.2.degree..
[0141] In some embodiments, Compound 1 Hydrochloride Form HB has
characteristic XRPD peaks in terms of 2.theta. selected from
8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., and 17.3.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Hydrochloride Form HB has at least one
characteristic XRPD peak in terms of 2.theta. selected from
8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., and 17.3.degree..+-.0.2.degree..
[0142] In some embodiments, Compound 1 Hydrochloride Form HB has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., 12.6.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree., and
23.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HB has at least one characteristic XRPD peak in
terms of 2.theta. selected from 8.6.degree..+-.0.2.degree.,
9.6.degree..+-.0.2.degree., 10.3.degree..+-.0.2.degree.,
12.6.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree.
18.3.degree..+-.0.2.degree., 23.8.degree..+-.0.2.degree.,
24.4.degree..+-.0.2.degree., 26.9.degree..+-.0.2.degree., and
27.1.degree..+-.0.2.degree..
[0143] In some embodiments, Compound 1 Hydrochloride Form HB has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., 12.6.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree., and
23.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HB has at least two characteristic XRPD peaks in
terms of 2.theta. selected from 8.6.degree..+-.0.2.degree.,
9.6.degree..+-.0.2.degree., 10.3.degree..+-.0.2.degree.,
12.6.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree.,
18.3.degree..+-.0.2.degree., 23.8.degree..+-.0.2.degree.,
24.4.degree..+-.0.2.degree., 26.9.degree..+-.0.2.degree., and
27.1.degree..+-.0.2.degree..
[0144] In some embodiments, Compound 1 Hydrochloride Form HB has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., 12.6.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree., and
23.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Hydrochloride Form HB has at least three characteristic XRPD peaks
in terms of 2.theta. selected from 8.6.degree..+-.0.2.degree.,
9.6.degree..+-.0.2.degree., 10.3.degree..+-.0.2.degree.,
12.6.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree.,
18.3.degree..+-.0.2.degree., 23.8.degree..+-.0.2.degree.,
24.4.degree..+-.0.2.degree., 26.9.degree..+-.0.2.degree., and
27.1.degree..+-.0.2.degree..
[0145] In some embodiments, Compound 1 Hydrochloride Form HB has an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 5 (FIG. 5).
[0146] In some embodiments, Compound 1 Hydrochloride Form HB can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 Hydrochloride Form HB
can be isolated with a crystalline purity greater than about 99%.
In some embodiments, Compound 1 Hydrochloride Form HB can be
isolated with a crystalline purity greater than about 99.9%.
[0147] In some embodiments, provided is Compound 1 hydrochloride
Form HB prepared by isolating Compound 1 hydrochloride Form HA from
a mixture of Compound 1, HCl, and S1, wherein S1 is a solvent. In
some embodiments, S1 comprises water. In some embodiments, Form HB
is prepared by exposing Form HA to high humidity. In some
embodiments, Form HB is prepared by exposing Form HA to about 75%
relative humidity.
Compound 1 Phosphate
[0148] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine Phosphate. In
some embodiments, Compound 1 Phosphate is crystalline.
[0149] In some embodiments, Compound 1 Phosphate has characteristic
XRPD peaks in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree., and
18.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
Phosphate has a characteristic XRPD peak in terms of 2.theta. at
4.6.degree..+-.0.2.degree.. In some embodiments, Compound 1
Phosphate has a characteristic XRPD peak in terms of 2.theta. at
9.1.degree..+-.0.2.degree.. In some embodiments, Compound 1
Phosphate has a characteristic XRPD peak in terms of 2.theta. at
18.2.degree..+-.0.2.degree..
[0150] In some embodiments, Compound 1 Phosphate has characteristic
XRPD peaks in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 22.8.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Phosphate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 22.8.degree..+-.0.2.degree..
[0151] In some embodiments, Compound 1 Phosphate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
15.7.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Phosphate has at least one characteristic XRPD peak in terms of
2.theta. selected from 4.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., 15.7.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree.,
24.8.degree..+-.0.2.degree., 26.0.degree..+-.0.2.degree.,
27.4.degree..+-.0.2.degree., and 30.1.degree..+-.0.2.degree..
[0152] In some embodiments, Compound 1 Phosphate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
15.7.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Phosphate has at least two characteristic XRPD peaks in terms of
2.theta. selected from 4.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., 15.7.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree.,
24.8.degree..+-.0.2.degree., 26.0.degree..+-.0.2.degree.,
27.4.degree..+-.0.2.degree., and 30.1.degree..+-.0.2.degree..
[0153] In some embodiments, Compound 1 Phosphate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
15.7.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Phosphate has at least three characteristic XRPD peaks in terms of
2.theta. selected from 4.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., 15.7.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree.,
24.8.degree..+-.0.2.degree., 26.0.degree..+-.0.2.degree.,
27.4.degree..+-.0.2.degree., and 30.1.degree..+-.0.2.degree..
[0154] In some embodiments, Compound 1 Phosphate has an XRPD
pattern with characteristic peaks as substantially shown in FIG. 6
(FIG. 6).
[0155] In some embodiments, Compound 1 Phosphate has an endotherm
peak at a temperature of about 213.degree. C. In some embodiments,
Compound 1 Phosphate has a DSC thermogram substantially as depicted
in FIG. 7 (FIG. 7). In some embodiments, Compound 1 Phosphate has a
TGA thermogram substantially as depicted in FIG. 8 (FIG. 8). In
some embodiments, Compound 1 Phosphate has a DVS isotherm
substantially as depicted in FIG. 9 (FIG. 9).
[0156] In some embodiments, Compound 1 Phosphate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 22.8.degree..+-.0.2.degree.; and
an endotherm peak at a temperature of about 213.degree. C. In some
embodiments, Compound 1 Phosphate has at least one characteristic
XRPD peak in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 22.8.degree..+-.0.2.degree.; and a
DSC thermogram substantially as depicted in FIG. 7 (FIG. 7). In
some embodiments, Compound 1 Phosphate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 22.8.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 9 (FIG. 9).
[0157] In some embodiments, Compound 1 Phosphate can be isolated
with a crystalline purity of at least about 80%, about 85%, about
90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In
some embodiments, Compound 1 Phosphate can be isolated with a
crystalline purity greater than about 99%. In some embodiments,
Compound 1 phosphate can be isolated with a crystalline purity
greater than about 99.9%.
[0158] In some embodiments, provided is Compound 1 phosphate
prepared by isolating Compound 1 phosphate from a mixture of
Compound 1, phosphoric acid, and S1, wherein S1 is a solvent. In
some embodiments, S1 is an organic solvent. In some embodiments, S1
is C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In
some embodiments, S1 is C.sub.1-6 alkyl acetate. In some
embodiments, S1 is a mixture of organic solvents. In some
embodiments, S1 is a mixture of C.sub.1-6 alkyl alcohol and
C.sub.1-6 alkyl acetate. In some embodiments, S1 is THF. In some
embodiments, S1 is ethyl acetate. In some embodiments, S1 is a
mixture of methanol and acetone. In some embodiments, S1 is a
mixture of methanol and ethyl acetate.
[0159] Compound 1 L-Tartrate
[0160] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate
(Compound 1 L-Tartrate). In some embodiments, Compound 1 L-Tartrate
is crystalline.
[0161] In some embodiments, provided is Compound 1 L-Tartrate
prepared by isolating Compound 1 L-Tartrate from a mixture of
Compound 1, tartaric acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In some
embodiments, S1 is C.sub.1-6 alkyl acetate. In some embodiments, S1
is C.sub.1-6 alkyl ketone. In some embodiments, S1 is a mixture of
C.sub.1-6 alkyl alcohol and C.sub.1-6 alkyl ketone. In some
embodiments, S1 is a mixture of C.sub.1-6 alkyl alcohol and
C.sub.1-6 alkyl acetate. In some embodiments, S1 is methanol. In
some embodiments, S1 is THF. In some embodiments, S1 is ethyl
acetate. In some embodiments, S1 is a mixture of methanol and
acetone. In some embodiments, S1 is a mixture of methanol and ethyl
acetate.
Compound 1 L-Tartrate Form LA
[0162] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-Tartrate Form
LA (Compound 1 L-Tartrate Form LA). In some embodiments, Compound 1
L-Tartrate Form LA is crystalline.
[0163] In some embodiments, Compound 1 L-Tartrate Form LA has
characteristic XRPD peaks in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree., and
24.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Tartrate Form LA has a characteristic XRPD peak in terms of
2.theta. at 12.1.degree..+-.0.2.degree.. In some embodiments,
Compound 1 L-Tartrate Form LA has a characteristic XRPD peak in
terms of 2.theta. at 18.1.degree..+-.0.2.degree.. In some
embodiments, Compound 1 L-Tartrate Form LA has a characteristic
XRPD peak in terms of 2.theta. at 24.2.degree..+-.0.2.degree..
[0164] In some embodiments, Compound 1 L-Tartrate Form LA has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 12.1.degree..+-.0.2.degree., 15.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., and 24.2.degree..+-.0.2.degree.. In
some embodiments, Compound 1 L-Tartrate Form LA has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 15.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
19.3.degree..+-.0.2.degree., 23.9.degree..+-.0.2.degree.,
24.2.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
27.2.degree..+-.0.2.degree..
[0165] In some embodiments, Compound 1 L-Tartrate Form LA has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 12.1.degree..+-.0.2.degree., 15.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., and 24.2.degree..+-.0.2.degree.. In
some embodiments, Compound 1 L-Tartrate Form LA has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 15.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
19.3.degree..+-.0.2.degree., 23.9.degree..+-.0.2.degree.,
24.2.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
27.2.degree..+-.0.2.degree..
[0166] In some embodiments, Compound 1 L-Tartrate Form LA has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 12.1.degree..+-.0.2.degree., 15.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., and 24.2.degree..+-.0.2.degree.. In
some embodiments, Compound 1 L-Tartrate Form LA has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 15.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
19.3.degree..+-.0.2.degree., 23.9.degree..+-.0.2.degree.,
24.2.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
27.2.degree..+-.0.2.degree..
[0167] In some embodiments, Compound 1 L-Tartrate Form LA has an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 10 (FIG. 10).
[0168] In some embodiments, Compound 1 L-Tartrate Form LA has
endotherm peaks at temperatures of about 89.degree. C. and about
138.degree. C. In some embodiments, Compound 1 L-Tartrate Form LA
has an endotherm peak at a temperature of about 89.degree. C. In
some embodiments, Compound 1 L-Tartrate Form LA has an endotherm
peak at a temperature of about 138.degree. C. In some embodiments,
Compound 1 L-Tartrate Form LA has a DSC thermogram substantially as
depicted in FIG. 11 (FIG. 11). In some embodiments, Compound 1
L-Tartrate Form LA has a TGA thermogram substantially as depicted
in FIG. 12 (FIG. 12). In some embodiments, Compound 1 L-Tartrate
Form LA has a DVS isotherm substantially as depicted in FIG. 13
(FIG. 13).
[0169] In some embodiments, Compound 1 L-Tartrate Form LA has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 12.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree., and
24.2.degree..+-.0.2.degree.; and has endotherm peaks at
temperatures of about 89.degree. C. and about 138.degree. C. In
some embodiments, Compound 1 L-Tartrate Form LA has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree., and
24.2.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 89.degree. C. In some embodiments, Compound 1 L-Tartrate
Form LA has at least one characteristic XRPD peak in terms of
2.theta. selected from 12.1.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., and 24.2.degree..+-.0.2.degree.; and
an endotherm peak at a temperature of about 138.degree. C. In some
embodiments, Compound 1 L-Tartrate Form LA has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.1.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree., and
24.2.degree..+-.0.2.degree.; and a DSC thermogram substantially as
depicted in FIG. 11 (FIG. 11). In some embodiments, Compound 1
L-Tartrate Form LA has at least one characteristic XRPD peak in
terms of 2.theta. selected from 12.1.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., and 24.2.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 13 (FIG. 13).
[0170] In some embodiments, Compound 1 L-Tartrate Form LA can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 L-Tartrate Form LA can
be isolated with a crystalline purity greater than about 99%. In
some embodiments, Compound 1 L-Tartrate Form LA can be isolated
with a crystalline purity greater than about 99.9%.
[0171] In some embodiments, provided is Compound 1 L-tartrate Form
LA prepared by isolating Compound 1 L-tartrate Form LA from a
mixture of Compound 1, L-tartaric acid, and S1, wherein S1 is a
solvent. In some embodiments, S1 is an organic solvent. In some
embodiments, S1 is ether. In some embodiments, S1 is C.sub.1-6
alkyl acetate. In some embodiments, S1 is THF. In some embodiments,
S1 is ethyl acetate.
Compound 1 L-Tartrate Form LB
[0172] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-Tartrate Form
LB (Compound 1 L-tartrate Form LB). In some embodiments, Compound 1
L-Tartrate Form LB is crystalline.
[0173] In some embodiments, Compound 1 L-Tartrate Form LB has
characteristic XRPD peaks in terms of 2.theta. selected from
18.7.degree..+-.0.2.degree., 25.0.degree..+-.0.2.degree., and
31.4.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Tartrate Form LB has a characteristic XRPD peak in terms of
2.theta. at 18.7.degree..+-.0.2.degree.. In some embodiments,
Compound 1 L-Tartrate Form LB has a characteristic XRPD peak in
terms of 2.theta. at 25.0.degree..+-.0.2.degree.. In some
embodiments, Compound 1 L-Tartrate Form LB has a characteristic
XRPD peak in terms of 2.theta. at 31.4.degree..+-.0.2.degree..
[0174] In some embodiments, Compound 1 L-Tartrate Form LB has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 6.3.degree..+-.0.2.degree., 12.5.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., 25.0.degree..+-.0.2.degree., and
31.4.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Tartrate Form LB has at least one characteristic XRPD peak in
terms of 2.theta. selected from 6.3.degree..+-.0.2.degree.,
12.5.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
18.7.degree..+-.0.2.degree., 20.0.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., 24.2.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., and 31.4.degree..+-.0.2.degree..
[0175] In some embodiments, Compound 1 L-Tartrate Form LB has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 6.3.degree..+-.0.2.degree., 12.5.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., 25.0.degree..+-.0.2.degree., and
31.4.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Tartrate Form LB has at least two characteristic XRPD peaks in
terms of 2.theta. selected from 6.3.degree..+-.0.2.degree.,
12.5.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
18.7.degree..+-.0.2.degree., 20.0.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., 24.2.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., and 31.4.degree..+-.0.2.degree..
[0176] In some embodiments, Compound 1 L-Tartrate Form LB has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 6.3.degree..+-.0.2.degree., 12.5.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., 25.0.degree..+-.0.2.degree., and
31.4.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Tartrate Form LB has at least three characteristic XRPD peaks in
terms of 2.theta. selected from 6.3.degree..+-.0.2.degree.,
12.5.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
18.7.degree..+-.0.2.degree., 20.0.degree..+-.0.2.degree.,
23.9.degree..+-.0.2.degree., 24.2.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., and 31.4.degree..+-.0.2.degree..
[0177] In some embodiments, Compound 1 L-Tartrate Form LB has an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 14 (FIG. 14). In some embodiments, Compound L-Tartrate Form LB
has a DVS isotherm as substantially shown in FIG. 15 (FIG. 15).
[0178] In some embodiments, Compound 1 L-Tartrate Form LB can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 L-Tartrate Form LB can
be isolated with a crystalline purity greater than about 99%. In
some embodiments, Compound 1 L-Tartrate Form LB can be isolated
with a crystalline purity greater than about 99.9%.
[0179] In some embodiments, provided is Compound 1 L-tartrate Form
LB prepared by isolating Compound 1 L-tartrate Form LB from a
mixture of Compound 1, L-tartaric acid, and S1, wherein S1 is a
solvent. In some embodiments, S1 is an organic solvent. In some
embodiments, S1 is C.sub.1-6 alkyl alcohol. In some embodiments, S1
is a C.sub.1-6 alkyl ketone. In some embodiments, S1 is a mixture
of organic solvents. In some embodiments, S1 is a mixture of a
C.sub.1-6 alkyl alcohol and a C.sub.1-6 alkyl ketone. In some
embodiments, S1 is a mixture of methanol and acetone.
Compound 1 L-Tartrate Form LC
[0180] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-Tartrate Form
LC (Compound 1 L-tartrate Form LC). In some embodiments, Compound 1
L-Tartrate Form LC is crystalline.
[0181] In some embodiments, Compound 1 L-Tartrate Form LC has
characteristic XRPD peaks in terms of 2.theta. selected from
12.2.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Tartrate Form LC has a characteristic XRPD peak in terms of
2.theta. at 12.2.degree..+-.0.2.degree.. In some embodiments,
Compound 1 L-Tartrate Form LC has a characteristic XRPD peak in
terms of 2.theta. at 16.5.degree..+-.0.2.degree.. In some
embodiments, Compound 1 L-Tartrate Form LC has a characteristic
XRPD peak in terms of 2.theta. at 24.8.degree..+-.0.2.degree..
[0182] In some embodiments, Compound 1 L-Tartrate Form LC has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 12.2.degree..+-.0.2.degree., 15.4.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., 22.6.degree..+-.0.2.degree.,
24.8.degree..+-.0.2.degree., and 25.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 L-Tartrate Form LC has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.2.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
15.4.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
18.7.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
20.0.degree..+-.0.2.degree., 22.4.degree..+-.0.2.degree.,
22.6.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., 25.5.degree..+-.0.2.degree., and
27.1.degree..+-.0.2.degree..
[0183] In some embodiments, Compound 1 L-Tartrate Form LC has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 12.2.degree..+-.0.2.degree., 15.4.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., 22.6.degree..+-.0.2.degree.,
24.8.degree..+-.0.2.degree., and 25.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 L-Tartrate Form LC has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
12.2.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
15.4.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
18.7.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
20.0.degree..+-.0.2.degree., 22.4.degree..+-.0.2.degree.,
22.6.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., 25.5.degree..+-.0.2.degree., and
27.1.degree..+-.0.2.degree..
[0184] In some embodiments, Compound 1 L-Tartrate Form LC has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 12.2.degree..+-.0.2.degree., 15.4.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., 22.6.degree..+-.0.2.degree.,
24.8.degree..+-.0.2.degree., and 25.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 L-Tartrate Form LC has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
12.2.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
15.4.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
18.7.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
20.0.degree..+-.0.2.degree., 22.4.degree..+-.0.2.degree.,
22.6.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree.,
25.0.degree..+-.0.2.degree., 25.5.degree..+-.0.2.degree., and
27.1.degree..+-.0.2.degree..
[0185] In some embodiments, Compound 1 L-Tartrate Form LC has an
XRPD pattern with characteristic peaks as substantially shown in
FIG. 16 (FIG. 16).
[0186] In some embodiments, Compound 1 L-Tartrate Form LC has an
endotherm peak at a temperature of about 137.degree. C. In some
embodiments, Compound 1 L-Tartrate Form LC has a DSC thermogram
substantially as depicted in FIG. 17 (FIG. 17). In some
embodiments, Compound 1 L-Tartrate Form LC has a TGA thermogram
substantially as depicted in FIG. 18 (FIG. 18). In some
embodiments, Compound 1 L-Tartrate Form LC has a DVS isotherm
substantially as depicted in FIG. 19 (FIG. 19).
[0187] In some embodiments, Compound 1 L-Tartrate Form LC has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 12.2.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 137.degree. C. In some embodiments, Compound 1 L-Tartrate
Form LC has at least one characteristic XRPD peak in terms of
2.theta. selected from 12.2.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., and 24.8.degree..+-.0.2.degree.; and a
DSC thermogram substantially as depicted in FIG. 17 (FIG. 17). In
some embodiments, Compound 1 L-Tartrate Form LC has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.2.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.; and a DVS isotherm substantially as
depicted in FIG. 19 (FIG. 19).
[0188] In some embodiments, Compound 1 L-Tartrate Form LC can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 L-Tartrate Form LC can
be isolated with a crystalline purity greater than about 99%. In
some embodiments, Compound 1 L-Tartrate Form LC can be isolated
with a crystalline purity greater than about 99.9%.
[0189] In some embodiments, provided is Compound 1 L-tartrate Form
LB prepared by isolating Compound 1 L-tartrate Form LB from a
mixture of Compound 1, L-tartaric acid, and S1, wherein S1 is a
solvent. In some embodiments, S1 is an organic solvent. In some
embodiments, S1 is C.sub.1-6 alkyl alcohol. In some embodiments, S1
is C.sub.1-6 alkyl acetate. In some embodiments, S1 is a mixture of
organic solvents. In some embodiments, S1 is a mixture of a
C.sub.1-6 alkyl alcohol and a C.sub.1-6 alkyl acetate. In some
embodiments, S1 is a mixture of methanol and ethyl acetate.
Compound 1 D-Tartrate
[0190] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-Tartrate
(Compound 1 D-Tartrate). In some embodiments, Compound 1 D-tartrate
is crystalline.
[0191] In some embodiments, Compound 1 D-Tartrate has
characteristic XRPD peaks in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree., and
17.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
D-Tartrate has a characteristic XRPD peak in terms of 2.theta. at
11.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
D-Tartrate has a characteristic XRPD peak in terms of 2.theta. at
16.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
D-Tartrate has a characteristic XRPD peak in terms of 2.theta. at
17.9.degree..+-.0.2.degree..
[0192] In some embodiments, Compound 1 D-Tartrate has
characteristic XRPD peaks in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., and 23.9.degree..+-.0.2.degree.. In
some embodiments, Compound 1 D-Tartrate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., and 23.9.degree..+-.0.2.degree..
[0193] In some embodiments, Compound 1 D-Tartrate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
16.1.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree., and
23.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
D-Tartrate has at least one characteristic XRPD peak in terms of
2.theta. selected from 6.0.degree..+-.0.2.degree.,
11.9.degree..+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
13.4.degree..+-.0.2.degree., 14.9.degree..+-.0.2.degree.,
16.1.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree.,
21.6.degree..+-.0.2.degree., 23.9.degree..+-.0.2.degree., and
24.6.degree..+-.0.2.degree..
[0194] In some embodiments, Compound 1 D-Tartrate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
16.1.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree., and
23.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
D-Tartrate has at least two characteristic XRPD peaks in terms of
2.theta. selected from 6.0.degree..+-.0.2.degree.,
11.9.degree..+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
13.4.degree..+-.0.2.degree., 14.9.degree..+-.0.2.degree.,
16.1.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree.,
21.6.degree..+-.0.2.degree., 23.9.degree..+-.0.2.degree., and
24.6.degree..+-.0.2.degree..
[0195] In some embodiments, Compound 1 D-Tartrate has at least
three characteristic XRPD peaks in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
16.1.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree., and
23.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
D-Tartrate has at least three characteristic XRPD peaks in terms of
2.theta. selected from 6.0.degree..+-.0.2.degree.,
11.9.degree..+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
13.4.degree..+-.0.2.degree., 14.9.degree..+-.0.2.degree.,
16.1.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.1.degree..+-.0.2.degree.,
21.6.degree..+-.0.2.degree., 23.9.degree..+-.0.2.degree., and
24.6.degree..+-.0.2.degree..
[0196] In some embodiments, Compound 1 D-Tartrate has an XRPD
pattern with characteristic peaks as substantially shown in FIG. 20
(FIG. 20).
[0197] In some embodiments, Compound 1 D-Tartrate has endotherm
peaks at temperatures of about 76.degree. C. and about 153.degree.
C. In some embodiments, Compound 1 D-Tartrate has an endotherm peak
at a temperature of about 76.degree. C. In some embodiments,
Compound 1 D-Tartrate has an endotherm peak at a temperature of
about 153.degree. C. In some embodiments, Compound 1 D-Tartrate has
a DVS isotherm substantially as depicted in FIG. 21 (FIG. 21).
[0198] In some embodiments, Compound 1 D-Tartrate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., and 23.9.degree..+-.0.2.degree.; and
has endotherm peaks at temperatures of about 76.degree. C. and
about 153.degree. C. In some embodiments, Compound 1 D-Tartrate has
at least one characteristic XRPD peak in terms of 2.theta. selected
from 11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., and 23.9.degree..+-.0.2.degree.; and
an endotherm peak at a temperature of about 76.degree. C. In some
embodiments, Compound 1 D-Tartrate has at least one characteristic
XRPD peak in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., and 23.9.degree..+-.0.2.degree.; and
an endotherm peak at a temperature of about 153.degree. C. In some
embodiments, Compound 1 D-Tartrate has at least one characteristic
XRPD peak in terms of 2.theta. selected from
11.9.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., and 23.9.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 21 (FIG. 21).
[0199] In some embodiments, Compound 1 D-Tartrate can be isolated
with a crystalline purity of at least about 80%, about 85%, about
90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In
some embodiments, Compound 1 D-Tartrate can be isolated with a
crystalline purity greater than about 99%. In some embodiments,
Compound D-Tartrate can be isolated with a crystalline purity
greater than about 99.9%.
[0200] In some embodiments, provided is Compound 1 D-Tartrate
prepared by isolating Compound 1 D-Tartrate from a mixture of
Compound 1, D-tartaric acid, and S1, wherein S1 is a solvent. In
some embodiments, S1 is an organic solvent. In some embodiments, S1
is ether. In some embodiments, S1 is C.sub.1-6 alkyl acetate. In
some embodiments, S1 is THF. In some embodiments, S1 is ethyl
acetate.
Compound 1 Fumarate
[0201] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate
(Compound 1 Fumarate). In some embodiments, Compound 1 Fumarate is
crystalline.
[0202] In some embodiments, provided is Compound 1 Fumarate
prepared by isolating Compound 1 Fumarate from a mixture of
Compound 1, fumaric acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In some
embodiments, S1 is C.sub.1-6 alkyl acetate. In some embodiments, S1
is a C.sub.1-6 alkyl ketone. In some embodiments, S1 is a mixture
of organic solvents. In some embodiments, S1 is a mixture of a
C.sub.1-6 alkyl alcohol and a C.sub.1-6 alkyl ketone. In some
embodiments, S1 is methanol. In some embodiments, S1 is THF. In
some embodiments, S1 is ethyl acetate. In some embodiments, S1 is a
mixture of methanol and acetone.
Compound 1 Fumarate Form FA
[0203] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine Fumarate Form
FA (Compound 1 fumarate Form FA). In some embodiments, Compound 1
Fumarate Form FA is crystalline.
[0204] In some embodiments, Compound 1 Fumarate Form FA has
characteristic XRPD peaks in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree., and
15.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
Fumarate Form FA has a characteristic XRPD peak in terms of
2.theta. at 7.7.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Fumarate Form FA has a characteristic XRPD peak in terms
of 2.theta. at 14.2.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Fumarate Form FA has a characteristic XRPD peak in terms
of 2.theta. at 15.2.degree..+-.0.2.degree..
[0205] In some embodiments, Compound 1 Fumarate Form FA has
characteristic XRPD peaks in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FA has at least one
characteristic XRPD peak in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree..
[0206] In some embodiments, Compound 1 Fumarate Form FA has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 7.7.degree..+-.0.2.degree., 13.0.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 24.6.degree..+-.0.2.degree.,
26.0.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FA has at least one
characteristic XRPD peak in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 12.1.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
14.6.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 24.6.degree..+-.0.2.degree.,
26.0.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree..
[0207] In some embodiments, Compound 1 Fumarate Form FA has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 7.7.degree..+-.0.2.degree., 13.0.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 24.6.degree..+-.0.2.degree.,
26.0.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FA has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 12.1.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
14.6.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 24.6.degree..+-.0.2.degree.,
26.0.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree..
[0208] In some embodiments, Compound 1 Fumarate Form FA has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 7.7.degree..+-.0.2.degree., 13.0.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 24.6.degree..+-.0.2.degree.,
26.0.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FA has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 12.1.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
14.6.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 24.6.degree..+-.0.2.degree.,
26.0.degree..+-.0.2.degree., and 30.7.degree..+-.0.2.degree..
[0209] In some embodiments, Compound 1 Fumarate Form FA has an XRPD
pattern with characteristic peaks as substantially shown in FIG. 22
(FIG. 22).
[0210] In some embodiments, Compound 1 Fumarate Form FA has an
endotherm peak at a temperature of about 138.degree. C. In some
embodiments, Compound 1 Fumarate Form FA has a DSC thermogram
substantially as depicted in FIG. 23 (FIG. 23). In some
embodiments, Compound 1 L-Fumarate Form FA has a TGA thermogram
substantially as depicted in FIG. 24 (FIG. 24). In some
embodiments, Compound 1 Fumarate Form FA has a DVS isotherm
substantially as depicted in FIG. 25 (FIG. 25).
[0211] In some embodiments, Compound 1 Fumarate Form FA has
characteristic XRPD peaks in terms of 2.theta. selected from
7.7.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree., and
15.2.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 147.degree. C. In some embodiments, Compound 1 Fumarate
Form FA has characteristic XRPD peaks in terms of 2.theta. selected
from 7.7.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree., and
15.2.degree..+-.0.2.degree.; and a DSC thermogram substantially as
depicted in FIG. 23 (FIG. 23). In some embodiments, Compound 1
Fumarate Form FA has characteristic XRPD peaks in terms of 2.theta.
selected from 7.7.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., and 15.2.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 25 (FIG. 25).
[0212] In some embodiments, Compound 1 Fumarate Form FA can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 Fumarate Form FA can be
isolated with a crystalline purity greater than about 99%. In some
embodiments, Compound 1 Fumarate Form FA can be isolated with a
crystalline purity greater than about 99.9%.
[0213] In some embodiments, provided is Compound 1 Fumarate Form FA
prepared by isolating Compound 1 Fumarate Form FA from a mixture of
Compound 1, fumaric acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In some
embodiments, S1 is a C.sub.1-6 alkyl ketone. In some embodiments,
S1 is a mixture of organic solvents. In some embodiments, S1 is a
mixture of a C.sub.1-6 alkyl alcohol and a C.sub.1-6 alkyl ketone.
In some embodiments, S1 is methanol. In some embodiments, S1 is
THF. In some embodiments, S1 is a mixture of methanol and
acetone.
Compound 1 Fumarate FB
[0214] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine Fumarate Form
FB (Compound 1 fumarate Form FB). In some embodiments, Compound 1
Fumarate Form FB is crystalline.
[0215] In some embodiments, Compound 1 Fumarate Form FB has
characteristic XRPD peaks in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.8.degree..+-.0.2.degree., and
20.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
Fumarate Form FB has a characteristic XRPD peak in terms of
2.theta. at 6.7.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Fumarate Form FB has a characteristic XRPD peak in terms
of 2.theta. at 13.8.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Fumarate Form FB has a characteristic XRPD peak in terms
of 2.theta. at 20.2.degree..+-.0.2.degree.. In some embodiments,
Compound 1 Fumarate Form FB has a characteristic XRPD peak in terms
of 2.theta. at 27.0.degree..+-.0.2.degree..
[0216] In some embodiments, Compound 1 Fumarate Form FB has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 6.7.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 20.2.degree..+-.0.2.degree.,
23.5.degree..+-.0.2.degree., 25.1.degree..+-.0.2.degree.,
27.0.degree..+-.0.2.degree., and 29.6.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FB has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 20.2.degree..+-.0.2.degree.,
23.1.degree..+-.0.2.degree., 23.5.degree..+-.0.2.degree.,
24.2.degree..+-.0.2.degree., 25.1.degree..+-.0.2.degree.,
27.0.degree..+-.0.2.degree., and 29.6.degree..+-.0.2.degree..
[0217] In some embodiments, Compound 1 Fumarate Form FB has at
least two characteristic XRPD peaks in terms of 2.theta. selected
from 6.7.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 20.2.degree..+-.0.2.degree.,
23.5.degree..+-.0.2.degree., 25.1.degree..+-.0.2.degree.,
27.0.degree..+-.0.2.degree., and 29.6.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FB has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 20.2.degree..+-.0.2.degree.,
23.1.degree..+-.0.2.degree., 23.5.degree..+-.0.2.degree.,
24.2.degree. .+-.0.2.degree., 25.1.degree..+-.0.2.degree.,
27.0.degree..+-.0.2.degree., and 29.6.degree..+-.0.2.degree..
[0218] In some embodiments, Compound 1 Fumarate Form FB has at
least three characteristic XRPD peaks in terms of 2.theta. selected
from 6.7.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 20.2.degree..+-.0.2.degree.,
23.5.degree..+-.0.2.degree., 25.1.degree..+-.0.2.degree.,
27.0.degree..+-.0.2.degree., and 29.6.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Fumarate Form FB has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.4.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 20.2.degree..+-.0.2.degree.,
23.1.degree..+-.0.2.degree., 23.5.degree..+-.0.2.degree.,
24.2.degree..+-.0.2.degree., 25.1.degree..+-.0.2.degree.,
27.0.degree..+-.0.2.degree., and 29.6.degree..+-.0.2.degree..
[0219] In some embodiments, Compound 1 Fumarate Form FB has an XRPD
pattern with characteristic peaks as substantially shown in FIG. 26
(FIG. 26).
[0220] In some embodiments, Compound 1 Fumarate Form FB has
endotherm peaks at temperatures of about 96.degree. C., about
139.degree. C., and about 146.degree. C. In some embodiments,
Compound 1 Fumarate Form FB has an endotherm peak at a temperature
of about 96.degree. C. In some embodiments, Compound 1 Fumarate
Form FB has an endotherm peak at a temperature of about 139.degree.
C. In some embodiments, Compound 1 Fumarate Form FB has an
endotherm peak at a temperature of about 146.degree. C. In some
embodiments, Compound 1 Fumarate Form FB has a DSC thermogram
substantially as depicted in FIG. 27 (FIG. 27). In some
embodiments, Compound 1 Fumarate Form FB has a TGA thermogram
substantially as depicted in FIG. 28 (FIG. 28). In some
embodiments, Compound 1 Fumarate Form FB has a DVS isotherm
substantially as depicted in FIG. 29 (FIG. 29).
[0221] In some embodiments, Compound 1 Fumarate Form FB has at
least one characteristic XRPD peak in terms of 2.theta. selected
from 6.7.degree..+-.0.2.degree., 13.8.degree..+-.0.2.degree., and
20.2.degree..+-.0.2.degree.; and endotherm peaks at temperatures of
about 96.degree. C., about 139.degree. C., and about 146.degree. C.
In some embodiments, Compound 1 Fumarate Form FB has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.8.degree..+-.0.2.degree., and
20.2.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 96.degree. C. In some embodiments, Compound 1 Fumarate
Form FB has at least one characteristic XRPD peak in terms of
2.theta. selected from 6.7.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., and 20.2.degree..+-.0.2.degree.; and
an endotherm peak at a temperature of about 139.degree. C. In some
embodiments, Compound 1 Fumarate Form FB has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.8.degree..+-.0.2.degree., and
20.2.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 146.degree. C. In some embodiments, Compound 1 Fumarate
Form FB has at least one characteristic XRPD peak in terms of
2.theta. selected from 6.7.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., and 20.2.degree..+-.0.2.degree.; and a
DSC thermogram substantially as depicted in FIG. 27 (FIG. 27). In
some embodiments, Compound 1 Fumarate Form FB has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.7.degree..+-.0.2.degree., 13.8.degree..+-.0.2.degree., and
20.2.degree..+-.0.2.degree.; and a DVS isotherm substantially as
depicted in FIG. 29 (FIG. 29).
[0222] In some embodiments, Compound 1 Fumarate Form FB can be
isolated with a crystalline purity of at least about 80%, about
85%, about 90%, about 95%, about 96%, about 97%, about 98%, or
about 99%. In some embodiments, Compound 1 Fumarate Form FB can be
isolated with a crystalline purity greater than about 99%. In some
embodiments, Compound 1 Fumarate Form FB can be isolated with a
crystalline purity greater than about 99.9%.
[0223] In some embodiments, provided is Compound 1 Fumarate Form FB
prepared by isolating Compound 1 Fumarate Form FB from a mixture of
Compound 1, fumaric acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl acetate. In some embodiments, S1 is ethyl
acetate.
Compound 1 Citrate
[0224] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate. In
some embodiments, Compound 1 Citrate is crystalline. In some
embodiments, Compound 1 citrate has characteristic XRPD peaks in
terms of 2.theta. selected from 6.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., and 20.4.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Citrate has a characteristic XRPD peak
in terms of 2.theta. at 6.5.degree..+-.0.2.degree.. In some
embodiments, Compound 1 Citrate has a characteristic XRPD peak in
terms of 2.theta. at 15.5.degree..+-.0.2.degree.. In some
embodiments, Compound 1 Citrate has a characteristic XRPD peak in
terms of 2.theta. at 20.4.degree..+-.0.2.degree..
[0225] In some embodiments, Compound 1 Citrate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 10.2.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., 17.8.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., and 20.4.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Citrate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 10.2.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
17.3.degree..+-.0.2.degree., 17.8.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., 20.4.degree..+-.0.2.degree.,
20.8.degree..+-.0.2.degree., 21.2.degree..+-.0.2.degree.,
21.5.degree..+-.0.2.degree., 22.0.degree..+-.0.2.degree.,
23.1.degree..+-.0.2.degree., and 26.0.degree..+-.0.2.degree..
[0226] In some embodiments, Compound 1 Citrate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 10.2.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., 17.8.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., and 20.4.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Citrate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 10.2.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
17.3.degree..+-.0.2.degree., 17.8.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., 20.4.degree..+-.0.2.degree.,
20.8.degree..+-.0.2.degree., 21.2.degree..+-.0.2.degree.,
21.5.degree..+-.0.2.degree., 22.0.degree..+-.0.2.degree.,
23.1.degree..+-.0.2.degree., and 26.0.degree..+-.0.2.degree..
[0227] In some embodiments, Compound 1 Citrate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 10.2.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., 17.8.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., and 20.4.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Citrate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 10.2.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 14.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
17.3.degree..+-.0.2.degree., 17.8.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., 20.4.degree..+-.0.2.degree.,
20.8.degree..+-.0.2.degree., 21.2.degree..+-.0.2.degree.,
21.5.degree..+-.0.2.degree., 22.0.degree..+-.0.2.degree.,
23.1.degree..+-.0.2.degree., and 26.0.degree..+-.0.2.degree..
[0228] In some embodiments, Compound 1 Citrate has an XRPD pattern
with characteristic peaks as substantially shown in FIG. 30 (FIG.
30).
[0229] In some embodiments, Compound 1 Citrate has an endotherm
peak at a temperature of about 142.degree. C. In some embodiments,
Compound 1 Citrate has a DSC thermogram substantially as depicted
in FIG. 31 (FIG. 31). In some embodiments, Compound 1 Citrate has a
TGA thermogram substantially as depicted in FIG. 32 (FIG. 32). In
some embodiments, Compound 1 citrate has a DVS isotherm
substantially as depicted in FIG. 33 (FIG. 33).
[0230] In some embodiments, Compound 1 Citrate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.5.degree..+-.0.2.degree., 15.5.degree..+-.0.2.degree., and
20.4.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 142.degree. C. In some embodiments, Compound 1 Citrate has
at least one characteristic XRPD peak in terms of 2.theta. selected
from 6.5.degree..+-.0.2.degree., 15.5.degree..+-.0.2.degree., and
20.4.degree..+-.0.2.degree.; and a DSC thermogram substantially as
depicted in FIG. 31 (FIG. 31). In some embodiments, Compound 1
Citrate has at least one characteristic XRPD peak in terms of
2.theta. selected from 6.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., and 20.4.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 33 (FIG. 33).
[0231] In some embodiments, Compound 1 Citrate can be isolated with
a crystalline purity of at least about 80%, about 85%, about 90%,
about 95%, about 96%, about 97%, about 98%, or about 99%. In some
embodiments, Compound 1 Citrate can be isolated with a crystalline
purity greater than about 99%. In some embodiments, Compound 1
Citrate can be isolated with a crystalline purity greater than
about 99.9%.
[0232] In some embodiments, provided is Compound 1 Citrate prepared
by isolating Compound 1 citrate from a mixture of Compound 1,
citric acid, and S1, wherein S1 is a solvent. In some embodiments,
S1 is an organic solvent. In some embodiments, S1 is C.sub.1-6
alkyl alcohol. In some embodiments, S1 is ether. In some
embodiments, S1 is C.sub.1-6 alkyl acetate. In some embodiments, S1
is a C.sub.1-6 alkyl ketone. In some embodiments, S1 is a mixture
of organic solvents. In some embodiments, S1 is a mixture of a
C.sub.1-6 alkyl alcohol and a C.sub.1-6 alkyl ketone. In some
embodiments, S1 is a mixture of a C.sub.1-6 alkyl alcohol and a
C.sub.1-6 alkyl acetate. In some embodiments, S1 is ethyl acetate.
In some embodiments, S1 is a mixture of methanol and acetone. In
some embodiments, S1 is THF. In some embodiments, S1 is a mixture
of methanol and ethyl acetate.
Compound 1 Succinate
[0233] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate. In
some embodiments, Compound 1 Succinate is crystalline.
[0234] In some embodiments, Compound 1 Succinate has characteristic
XRPD peaks in terms of 2.theta. selected from
6.6.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree., and
13.9.degree..+-.0.2.degree.. In some embodiments, Compound 1
Succinate has a characteristic XRPD peak in terms of 2.theta. at
6.6.degree..+-.0.2.degree.. In some embodiments, Compound 1
Succinate has a characteristic XRPD peak in terms of 2.theta. at
12.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
Succinate has a characteristic XRPD peak in terms of 2.theta. at
13.9.degree..+-.0.2.degree..
[0235] In some embodiments, Compound 1 Succinate has characteristic
XRPD peaks in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Succinate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree..
[0236] In some embodiments, Compound 1 Succinate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
16.0.degree..+-.0.2.degree., 19.2.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., 21.1.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 23.3.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Succinate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.6.degree..+-.0.2.degree., 9.0.degree..+-.0.2.degree.,
11.5.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
13.9.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
21.1.degree..+-.0.2.degree., 22.9.degree..+-.0.2.degree.,
23.3.degree..+-.0.2.degree., 25.2.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree..
[0237] In some embodiments, Compound 1 Succinate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
16.0.degree..+-.0.2.degree., 19.2.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., 21.1.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 23.3.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Succinate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
6.6.degree..+-.0.2.degree., 9.0.degree..+-.0.2.degree.,
11.5.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
13.9.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
21.1.degree..+-.0.2.degree., 22.9.degree..+-.0.2.degree.,
23.3.degree..+-.0.2.degree., 25.2.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree..
[0238] In some embodiments, Compound 1 Succinate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
16.0.degree..+-.0.2.degree., 19.2.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., 21.1.degree..+-.0.2.degree.,
22.9.degree..+-.0.2.degree., 23.3.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Succinate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
6.6.degree..+-.0.2.degree., 9.0.degree..+-.0.2.degree.,
11.5.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
13.9.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
21.1.degree..+-.0.2.degree., 22.9.degree..+-.0.2.degree.,
23.3.degree..+-.0.2.degree., 25.2.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree..
[0239] In some embodiments, Compound 1 Succinate has an XRPD
pattern with characteristic peaks as substantially shown in FIG. 34
(FIG. 34).
[0240] In some embodiments, Compound 1 Succinate has an endotherm
peak at a temperature of about 153.degree. C. In some embodiments,
Compound 1 Succinate has a DSC thermogram substantially as depicted
in FIG. 35 (FIG. 35). In some embodiments, Compound 1 Succinate has
a TGA thermogram substantially as depicted in FIG. 36 (FIG. 36). In
some embodiments, Compound 1 Succinate has a DVS isotherm
substantially as depicted in FIG. 37 (FIG. 37).
[0241] In some embodiments, Compound 1 Succinate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.; and
an endotherm peak at a temperature of about 153.degree. C. In some
embodiments, Compound 1 succinate has at least one characteristic
XRPD peak in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.; and a
DSC thermogram substantially as depicted in FIG. 35 (FIG. 35). In
some embodiments, Compound 1 Succinate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
12.8.degree..+-.0.2.degree., 13.9.degree..+-.0.2.degree.,
19.8.degree..+-.0.2.degree., and 26.5.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 37 (FIG. 37).
[0242] In some embodiments, Compound 1 Succinate can be isolated
with a crystalline purity of at least about 80%, about 85%, about
90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In
some embodiments, Compound 1 Succinate can be isolated with a
crystalline purity greater than about 99%. In some embodiments,
Compound 1 Succinate can be isolated with a crystalline purity
greater than about 99.9%.
[0243] In some embodiments, provided is Compound 1 Succinate
prepared by isolating Compound 1 succinate from a mixture of
Compound 1, succinic acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
ether. In some embodiments, S1 is C.sub.1-6 alkyl acetate. In some
embodiments, S1 is THF. In some embodiments, S1 is ethyl
acetate.
Compound 1 Glutarate
[0244] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine Glutarate. In
some embodiments, Compound 1 Glutarate is crystalline.
[0245] In some embodiments, Compound 1 Glutarate has characteristic
XRPD peaks in terms of 2.theta. selected from
9.1.degree..+-.0.2.degree., 10.6.degree..+-.0.2.degree., and
18.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
Glutarate has a characteristic XRPD peak in terms of 2.theta. at
9.1.degree..+-.0.2.degree.. In some embodiments, Compound 1
Glutarate has a characteristic XRPD peak in terms of 2.theta. at
10.6.degree..+-.0.2.degree.. In some embodiments, Compound 1
Glutarate has a characteristic XRPD peak in terms of 2.theta. at
18.2.degree..+-.0.2.degree..
[0246] In some embodiments, Compound 1 Glutarate has characteristic
XRPD peaks in terms of 2.theta. selected from
9.1.degree..+-.0.2.degree., 10.6.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 19.0.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Glutarate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
9.1.degree..+-.0.2.degree., 10.6.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., and 19.0.degree..+-.0.2.degree..
[0247] In some embodiments, Compound 1 Glutarate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
9.1.degree..+-.0.2.degree., 10.6.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 19.0.degree..+-.0.2.degree.,
22.5.degree..+-.0.2.degree., 27.4.degree..+-.0.2.degree., and
28.0.degree..+-.0.2.degree.. In some embodiments, Compound 1
Glutarate has at least one characteristic XRPD peak in terms of
2.theta. selected from 9.1.degree..+-.0.2.degree.,
10.6.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 21.8.degree..+-.0.2.degree.,
21.9.degree..+-.0.2.degree., 22.5.degree..+-.0.2.degree.,
25.8.degree..+-.0.2.degree., 27.4.degree..+-.0.2.degree., and
28.0.degree..+-.0.2.degree..
[0248] In some embodiments, Compound 1 Glutarate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
9.1.degree..+-.0.2.degree., 10.6.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 19.0.degree..+-.0.2.degree.,
22.5.degree..+-.0.2.degree., 27.4.degree..+-.0.2.degree., and
28.0.degree..+-.0.2.degree.. In some embodiments, Compound 1
Glutarate has at least two characteristic XRPD peaks in terms of
2.theta. selected from 9.1.degree..+-.0.2.degree.,
10.6.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 21.8.degree..+-.0.2.degree.,
21.9.degree..+-.0.2.degree., 22.5.degree..+-.0.2.degree.,
25.8.degree..+-.0.2.degree., 27.4.degree..+-.0.2.degree., and
28.0.degree..+-.0.2.degree..
[0249] In some embodiments, Compound 1 Glutarate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
9.1.degree..+-.0.2.degree., 10.6.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 19.0.degree..+-.0.2.degree.,
22.5.degree..+-.0.2.degree., 27.4.degree..+-.0.2.degree., and
28.0.degree..+-.0.2.degree.. In some embodiments, Compound 1
Glutarate has at least three characteristic XRPD peaks in terms of
2.theta. selected from 9.1.degree..+-.0.2.degree.,
10.6.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 21.8.degree..+-.0.2.degree.,
21.9.degree..+-.0.2.degree., 22.5.degree..+-.0.2.degree.,
25.8.degree..+-.0.2.degree., 27.4.degree..+-.0.2.degree., and
28.0.degree..+-.0.2.degree..
[0250] In some embodiments, Compound 1 Glutarate has an XRPD
pattern with characteristic peaks as substantially shown in FIG. 38
(FIG. 38). In some embodiments, Compound 1 Glutarate has a DVS
isotherm as substantially shown in FIG. 39 (FIG. 39).
[0251] In some embodiments, Compound 1 Glutarate can be isolated
with a crystalline purity of at least about 80%, about 85%, about
90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In
some embodiments, Compound 1 Glutarate can be isolated with a
crystalline purity greater than about 99%. In some embodiments,
Compound 1 Glutarate can be isolated with a crystalline purity
greater than about 99.9%.
[0252] In some embodiments, provided is Compound 1 Glutarate
prepared by isolating Compound 1 glutarate from a mixture of
Compound 1, glutaric acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl alcohol. In some embodiments, S1 is C.sub.1-6 alkyl
acetate. In some embodiments, S1 is a C.sub.1-6 alkyl ketone. In
some embodiments, S1 is a mixture of organic solvents. In some
embodiments, S1 is a mixture of a C.sub.1-6 alkyl alcohol and a
C.sub.1-6 alkyl ketone. In some embodiments, S1 is a mixture of
methanol and acetone. In some embodiments, S1 is THF. In some
embodiments, S1 is ethyl acetate.
Compound 1 L-Malate
[0253] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-Malate. In
some embodiments, Compound 1 L-Malate is crystalline.
[0254] In some embodiments, Compound 1 L-Malate has characteristic
XRPD peaks in terms of 2.theta. selected from
13.5.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Malate has a characteristic XRPD peak in terms of 2.theta. at
13.5.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Malate has a characteristic XRPD peak in terms of 2.theta. at
18.8.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Malate has a characteristic XRPD peak in terms of 2.theta. at
25.2.degree..+-.0.2.degree..
[0255] In some embodiments, Compound 1 L-Malate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
13.5.degree..+-.0.2.degree., 14.4.degree..+-.0.2.degree.,
15.2.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
23.8.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Malate has at least one characteristic XRPD peak in terms of
2.theta. selected from 13.5.degree..+-.0.2.degree.,
14.4.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
17.7.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
22.4.degree..+-.0.2.degree., 23.8.degree..+-.0.2.degree.,
24.6.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree..
[0256] In some embodiments, Compound 1 L-Malate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
13.5.degree..+-.0.2.degree., 14.4.degree..+-.0.2.degree.,
15.2.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
23.8.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Malate has at least two characteristic XRPD peaks in terms of
2.theta. selected from 13.5.degree..+-.0.2.degree.,
14.4.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
17.7.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
22.4.degree..+-.0.2.degree., 23.8.degree..+-.0.2.degree.,
24.6.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree..
[0257] In some embodiments, Compound 1 L-Malate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
13.5.degree..+-.0.2.degree., 14.4.degree..+-.0.2.degree.,
15.2.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
23.8.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree.. In some embodiments, Compound 1
L-Malate has at least three characteristic XRPD peaks in terms of
2.theta. selected from 13.5.degree..+-.0.2.degree.,
14.4.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
17.7.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree.,
22.4.degree..+-.0.2.degree., 23.8.degree..+-.0.2.degree.,
24.6.degree..+-.0.2.degree., 24.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree..
[0258] In some embodiments, Compound 1 L-Malate has an XRPD pattern
with characteristic peaks as substantially shown in FIG. 40 (FIG.
40).
[0259] In some embodiments, Compound 1 L-Malate has an endotherm
peak at a temperature of about 82.degree. C. In some embodiments,
Compound 1 L-Malate has a DSC thermogram substantially as depicted
in FIG. 41 (FIG. 41). In some embodiments, Compound 1 L-L-Malate
has a TGA thermogram substantially as depicted in FIG. 42 (FIG.
42). In some embodiments, Compound 1 L-Malate has a DVS isotherm
substantially as depicted in FIG. 43 (FIG. 43).
[0260] In some embodiments, Compound 1 L-Malate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
13.5.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 82.degree. C. In some embodiments, Compound 1 L-Malate has
at least one characteristic XRPD peak in terms of 2.theta. selected
from 13.5.degree..+-.0.2.degree., 18.8.degree..+-.0.2.degree., and
25.2.degree..+-.0.2.degree.; and a DSC thermogram substantially as
depicted in FIG. 41 (FIG. 41). In some embodiments, Compound 1
L-Malate has at least one characteristic XRPD peak in terms of
2.theta. selected from 13.5.degree..+-.0.2.degree.,
18.8.degree..+-.0.2.degree., and 25.2.degree..+-.0.2.degree.; and a
DVS isotherm substantially as depicted in FIG. 43 (FIG. 43).
[0261] In some embodiments, Compound 1 L-Malate can be isolated
with a crystalline purity of at least about 80%, about 85%, about
90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In
some embodiments, Compound 1 L-Malate can be isolated with a
crystalline purity greater than about 99%. In some embodiments,
Compound 1 L-Malate can be isolated with a crystalline purity
greater than about 99.9%.
[0262] In some embodiments, provided is Compound 1 L-Malate
prepared by isolating Compound 1 L-malate from a mixture of
Compound 1, L-malic acid, and S1, wherein S1 is a solvent. In some
embodiments, S1 is an organic solvent. In some embodiments, S1 is
C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In some
embodiments, S1 is C.sub.1-6 alkyl acetate. In some embodiments, S1
is methanol. In some embodiments, S1 is THF. In some embodiments,
S1 is ethyl acetate.
Compound 1 Besylate
[0263] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine Besylate. In
some embodiments, Compound 1 Besylate is crystalline. In some
embodiments, Compound 1 Besylate has characteristic XRPD peaks in
terms of 2.theta. selected from 6.0.degree..+-.0.2.degree.,
12.0.degree..+-.0.2.degree., and 24.1.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Besylate has a characteristic XRPD
peak in terms of 2.theta. at 6.0.degree..+-.0.2.degree.. In some
embodiments, Compound 1 Besylate has a characteristic XRPD peak in
terms of 2.theta. at 12.0.degree..+-.0.2.degree.. In some
embodiments, Compound 1 Besylate has a characteristic XRPD peak in
terms of 2.theta. at 24.1.degree..+-.0.2.degree..
[0264] In some embodiments, Compound 1 Besylate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree.,
16.6.degree..+-.0.2.degree., 24.1.degree..+-.0.2.degree.,
26.8.degree..+-.0.2.degree., and 30.3.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Besylate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.6.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 21.2.degree..+-.0.2.degree.,
22.2.degree..+-.0.2.degree., 23.2.degree..+-.0.2.degree.,
24.1.degree..+-.0.2.degree., 26.8.degree..+-.0.2.degree., and
30.3.degree..+-.0.2.degree..
[0265] In some embodiments, Compound 1 Besylate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree.,
16.6.degree..+-.0.2.degree., 24.1.degree..+-.0.2.degree.,
26.8.degree..+-.0.2.degree., and 30.3.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Besylate has at least two
characteristic XRPD peaks in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.6.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 21.2.degree..+-.0.2.degree.,
22.2.degree..+-.0.2.degree., 23.2.degree..+-.0.2.degree.,
24.1.degree..+-.0.2.degree., 26.8.degree..+-.0.2.degree., and
30.3.degree..+-.0.2.degree..
[0266] In some embodiments, Compound 1 Besylate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree.,
16.6.degree..+-.0.2.degree., 24.1.degree..+-.0.2.degree.,
26.8.degree..+-.0.2.degree., and 30.3.degree..+-.0.2.degree.. In
some embodiments, Compound 1 Besylate has at least three
characteristic XRPD peaks in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree.,
16.4.degree..+-.0.2.degree., 16.6.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 21.2.degree..+-.0.2.degree.,
22.2.degree..+-.0.2.degree., 23.2.degree..+-.0.2.degree.,
24.1.degree..+-.0.2.degree., 26.8.degree..+-.0.2.degree., and
30.3.degree..+-.0.2.degree..
[0267] In some embodiments, Compound 1 Besylate has an XRPD pattern
with characteristic peaks as substantially shown in FIG. 44 (FIG.
44).
[0268] In some embodiments, Compound 1 Besylate has an endotherm
peak at a temperature of about 136.degree. C. In some embodiments,
Compound 1 Besylate has a DSC thermogram substantially as depicted
in FIG. 45 (FIG. 45). In some embodiments, Compound 1 Besylate has
a TGA thermogram substantially as depicted in FIG. 46 (FIG. 46). In
some embodiments, Compound 1 Besylate has a DVS isotherm
substantially as depicted in FIG. 47 (FIG. 47).
[0269] In some embodiments, Compound 1 Besylate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree., and
24.1.degree..+-.0.2.degree.; and an endotherm peak at a temperature
of about 136.degree. C. In some embodiments, Compound 1 Besylate
has at least one characteristic XRPD peak in terms of 2.theta.
selected from 6.0.degree..+-.0.2.degree.,
12.0.degree..+-.0.2.degree., and 24.1.degree..+-.0.2.degree.; and a
DSC thermogram substantially as depicted in FIG. 45 (FIG. 45). In
some embodiments, Compound 1 Besylate has at least one
characteristic XRPD peak in terms of 2.theta. selected from
6.0.degree..+-.0.2.degree., 12.0.degree..+-.0.2.degree., and
24.1.degree..+-.0.2.degree.; and a DVS isotherm substantially as
depicted in FIG. 47 (FIG. 47).
[0270] In some embodiments, Compound 1 Besylate can be isolated
with a crystalline purity of at least about 80%, about 85%, about
90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In
some embodiments, Compound 1 Besylate can be isolated with a
crystalline purity greater than about 99%. In some embodiments,
Compound 1 Besylate can be isolated with a crystalline purity
greater than about 99.9%.
[0271] In some embodiments, provided is Compound 1 Besylate
prepared by isolating Compound 1 Besylate from a mixture of
Compound 1, benzenesulfonic acid, and S1, wherein S1 is a solvent.
In some embodiments, S1 is an organic solvent. In some embodiments,
S1 is C.sub.1-6 alkyl alcohol. In some embodiments, S1 is ether. In
some embodiments, S1 is C.sub.1-6 alkyl acetate. In some
embodiments, S1 is a C.sub.1-6 alkyl ketone. In some embodiments,
S1 is a mixture of organic solvents. In some embodiments, S1 is a
mixture of a C.sub.1-6 alkyl alcohol and a C.sub.1-6 alkyl ketone.
In some embodiments, S1 is ethyl acetate. In some embodiments, S1
is THF. In some embodiments, S1 is a mixture of methanol and
acetone.
Compound 1 Tosylate
[0272] In some embodiments, provided is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate
(Compound 1 Tosylate).
[0273] In some embodiments, provided is Compound 1 Tosylate
prepared by isolating Compound 1 Tosylate from a mixture of
Compound 1, p-toluenesulfonic acid, and S1, wherein S1 is a
solvent. In some embodiments, S1 is an organic solvent. In some
embodiments, S1 is C.sub.1-6 alkyl alcohol. In some embodiments, S1
is ether. In some embodiments, S1 is C.sub.1-6 alkyl acetate. In
some embodiments, S1 is a C.sub.1-6 alkyl ketone. In some
embodiments, S1 is a mixture of organic solvents. In some
embodiments, S1 is a mixture of a C.sub.1-6 alkyl alcohol and a
C.sub.1-6 alkyl ketone. In some embodiments, S1 is methanol. In
some embodiments, S1 is THF. In some embodiments, S1 is ethyl
acetate. In some embodiments, S1 is a mixture of methanol and
acetone.
Process for Preparation of Compound 1 and Compound 1 Phosphate
[0274] Provided herein are also processes for preparing Compound 1
or a salt thereof. A process of preparing Compound 1 is described
in U.S. Pat. No. 10,196,403, the entirety of which is incorporated
herein by reference. The processes for preparing Compound 1 or a
salt thereof provided herein have certain advantages over the
processes currently disclosed in the art. For example, the
processes described herein demonstrate good scalability, yields,
and stereochemical selectivity. The processes described herein
include a chiral resolution by crystallization, which avoids chiral
separation by HPLC, and is therefore more amenable for manufacture
on a multi-kilogram scale.
[0275] Provided herein is a process of preparing
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate
(Compound 1 Phosphate), having the structure:
##STR00003##
wherein the process comprises:
[0276] (a) reacting a compound of Formula III having the
structure:
##STR00004##
or a salt thereof, wherein X is halo, with
N-methylaminoacetaldehyde dimethylacetal (Compound 4) having the
structure:
##STR00005##
in the presence of A1, wherein A1 is an acid, to provide a compound
of Formula II, having the structure:
##STR00006##
or a salt thereof, wherein X is halo;
[0277] (b) hydrogenating a compound of Formula II, or a salt
thereof, in the presence of a metal catalyst to provide
1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Racemic Compound
1) having the structure:
##STR00007##
[0278] (c) reacting Racemic Compound 1 with dibenzoyl-L-tartaric
acid in the presence of S3, wherein S3 is a solvent, to provide
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate) having the
structure:
##STR00008##
[0279] (d) reacting Compound 1 dibenzoyl-L-tartrate with B1,
wherein B1 is a base, to provide Compound 1 having the
structure:
##STR00009##
and
[0280] (e) reacting Compound 1 with phosphoric acid to provide
Compound 1 Phosphate.
[0281] Provided herein is a process of preparing Compound 1 having
the structure:
##STR00010##
wherein the process comprises:
[0282] (a) reacting a compound of Formula III having the
structure:
##STR00011##
or a salt thereof, wherein X is halo, with
N-methylaminoacetaldehyde dimethylacetal (Compound 4) having the
structure:
##STR00012##
in the presence of A1, wherein A1 is an acid, to provide a compound
of Formula II, having the structure:
##STR00013##
or a salt thereof, wherein X is halo;
[0283] (b) hydrogenating a compound of Formula II, or a salt
thereof, in the presence of a metal catalyst to provide
1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Racemic Compound
1) having the structure:
##STR00014##
[0284] (c) reacting Racemic Compound 1 with dibenzoyl-L-tartaric
acid in the presence of S3, wherein S3 is a solvent, to provide
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate) having the
structure:
##STR00015##
and
[0285] (d) reacting Compound 1 dibenzoyl-L-tartrate with B1,
wherein B1 is a base, to provide Compound 1.
[0286] In some embodiments, provided is a process of preparing
Compound 1, wherein the process comprises:
[0287] (a) hydrogenating a compound of Formula II, or a salt
thereof, in the presence of a metal catalyst to provide Racemic
Compound 1;
[0288] (b) reacting Racemic Compound 1 with dibenzoyl-L-tartaric
acid in the presence of S3, wherein S3 is a solvent, to provide
Compound 1 dibenzoyl-L-tartrate; and
[0289] (c) reacting Compound 1 dibenzoyl-L-tartrate with B1,
wherein B1 is a base, to provide Compound 1.
[0290] In some embodiments, provided is a process of preparing
Compound 1, wherein the process comprises:
[0291] (a) reacting Racemic Compound 1 with dibenzoyl-L-tartaric
acid in the presence of S3, wherein S3 is a solvent, to provide
Compound 1 dibenzoyl-L-tartrate; and
[0292] (c) reacting Compound 1 dibenzoyl-L-tartrate with B1,
wherein B1 is a base, to provide Compound 1.
[0293] Provided herein is a process of preparing
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate
(Compound 1 Phosphate), having the structure:
##STR00016##
comprising reacting
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1)
having the structure:
##STR00017##
with phosphoric acid. In some embodiments, Compound 1 phosphate is
crystalline.
[0294] In some embodiments, the phosphoric acid is an aqueous
solution of phosphoric acid. In some embodiments, the aqueous
solution of phosphoric acid is about 80% to about 95% aqueous
solution of phosphoric acid by weight. In some embodiments, the
aqueous solution of phosphoric acid is about 87% aqueous solution
of phosphoric acid by weight.
[0295] In some embodiments, the reacting of Compound 1 with
phosphoric acid is carried out in the presence of Sla, wherein Sla
is a solvent. In some embodiments, Sla is a polar aprotic solvent,
water, or a mixture thereof. In some embodiments, the polar aprotic
solvent of S1 is acetonitrile. In some embodiments, S1a is a
mixture of acetonitrile and water.
[0296] In some embodiments, the reacting of Compound 1 with
phosphoric acid is carried out at a temperature between about
15.degree. C. and about 25.degree. C. In some embodiments, the
reacting of Compound 1 with phosphoric acid is carried out at about
20.degree. C. In some embodiments, between about 1 and about 5
molar equivalents of phosphoric acid are used per molar equivalent
of Compound 1. In some embodiments, about 1 molar equivalent of
phosphoric acid is used per molar equivalent of Compound 1.
[0297] Compound 1 can be prepared by a process comprising reacting
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate) having the
structure:
##STR00018##
wherein B1 is a base.
[0298] In some embodiments, B1 is an alkali hydroxide base. In some
embodiments, B1 is potassium hydroxide. In some embodiments, B1 is
an aqueous solution of potassium hydroxide. In some embodiments,
the aqueous solution of potassium hydroxide is about 10% to about
20% aqueous solution of potassium hydroxide by weight. In some
embodiments, the aqueous solution of potassium hydroxide is about
14% aqueous solution of potassium hydroxide by weight.
[0299] In some embodiments, the reacting of Compound 1
dibenzoyl-L-tartrate and the base is carried out in the presence of
S2, wherein S2 is a solvent. In some embodiments, S2 is a polar
aprotic solvent. In some embodiments, the polar aprotic solvent is
an ether. In some embodiments, S2 is tert-butyl methyl ether.
[0300] In some embodiments, the reacting of Compound 1
dibenzoyl-L-tartrate and B1 is carried out at a temperature between
about 20.degree. C. and about 30.degree. C. In some embodiments,
the reacting of Compound 1 dibenzoyl-L-tartrate and the base is
carried out at a temperature of about 23.degree. C. In some
embodiments, between about 0.5 and about 5 molar equivalents of B1
are used per molar equivalent of Compound 1 dibenzoyl-L-tartrate.
In some embodiments, between about 1 and about 3 molar equivalents
of B1 are used per molar equivalent of Compound 1
dibenzoyl-L-tartrate. In some embodiments, between about 1 and
about 2 molar equivalents of B1 are used per molar equivalent of
Compound 1 dibenzoyl-L-tartrate. In some embodiments, about 1 molar
equivalent of B1 is used per molar equivalent of Compound 1
dibenzoyl-L-tartrate.
[0301] In some embodiments, the reacting of Compound 1
dibenzoyl-L-tartrate with B1 is further carried out in the presence
of sodium chloride. In some embodiments, about 1 to about 10 molar
equivalents of sodium chloride are used per molar equivalent of
Compound 1 dibenzoyl-L-tartrate. In some embodiments, about 5 molar
equivalents of sodium chloride are used per molar equivalent of
Compound 1 dibenzoyl-L-tartrate.
[0302] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate) can be
prepared by a process comprising reacting
1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Racemic Compound
1) having the structure:
##STR00019##
with dibenzoyl-L-tartaric acid, in the presence of S3, wherein S3
is a solvent.
[0303] In some embodiments, S3 is a polar protic solvent. In some
embodiments, S3 is C.sub.1-6 alkyl-OH. In some embodiments, S3 is
methanol. In some embodiments, S3 is a mixture of methanol and
water. In some embodiments, the reacting is carried out at a
temperature from about 20.degree. C. to about 70.degree. C. In some
embodiments, the precipitating is carried out at a temperature of
about 20.degree. C. In some embodiments, about 1 to about 5 molar
equivalents of dibenzoyl-L-tartaric acid are used per molar
equivalent of Racemic Compound 1. In some embodiments, about 1
molar equivalent of dibenzoyl-L-tartaric acid is used per molar
equivalent of Racemic Compound 1.
[0304] The process of preparing Compound 1 dibenzoyl L-tartrate can
further comprise precipitating Compound 1 dibenzoyl-L-tartrate from
a mixture comprising: Racemic Compound 1, dibenzoyl-L-tartaric
acid, and S3. In some embodiments, S3 is methanol. In some
embodiments, S3 is a mixture of methanol and water.
[0305] The process of preparing Compound 1 dibenzoyl L-tartrate can
further comprise isolating Compound 1 dibenzoyl-L-tartrate from
S3a, wherein S3a is a solvent. In some embodiments, S3a is polar
protic solvent. In some embodiments, S3a is C.sub.1-6 alkyl-OH. In
some embodiments, S3a is methanol. In some embodiments, the
isolating of Compound 1 dibenzoyl-L-tartrate is carried out at a
temperature of about 10.degree. C. to about 65.degree. C.
[0306] 1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Racemic
Compound 1) can be prepared by a process comprising hydrogenating a
compound of Formula II, having the structure:
##STR00020##
or a salt thereof, wherein X is halo, in the presence of a metal
catalyst.
[0307] In some embodiments, the compound of Formula II is Compound
2 is 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine
trifluoromethanesulfonate (Compound 2) having the structure:
##STR00021##
[0308] In some embodiments, the metal catalyst is palladium on
activated carbon. In some embodiments, the hydrogenating of a
compound of Formula II is carried out at a hydrogen pressure of
about 2 to about 10 bar. In some embodiments, the hydrogenating of
a compound of Formula II is carried out at a hydrogen pressure of
about 5 bar.
[0309] In some embodiments, the hydrogenating of a compound of
Formula II is carried out at a temperature between about 20.degree.
C. and about 30.degree. C. In some embodiments, the hydrogenating
of a compound of Formula II is carried out at a temperature of
about 25.degree. C.
[0310] In some embodiments, the hydrogenating of a compound of
Formula II is carried out in the presence of S4, wherein S4 is a
solvent. In some embodiments, S4 is a polar protic solvent, In some
embodiments, S4 is C.sub.1-6 alkyl-OH. In some embodiments, S4 is
methanol.
[0311] In some embodiments, the hydrogenating of a compound of
Formula II is carried out in the presence of B2, wherein B2 is a
base. In some embodiments, B2 is a carbonate base. In some
embodiments, B2 is potassium carbonate. In some embodiments, B2 is
an aqueous solution of potassium carbonate. In some embodiments,
the aqueous solution of potassium carbonate is about 5% potassium
carbonate by weight.
[0312] The compound of Formula II can be prepared by reacting a
compound of Formula III having the structure:
##STR00022##
or a salt thereof, wherein X is halo, with
N-methylaminoacetaldehyde dimethylacetal (Compound 4) having the
structure:
##STR00023##
in the presence of A1, wherein A1 is an acid.
[0313] In some embodiments, the compound of Formula III is
2-(2-bromo-5-fluorophenyl)ethan-1-ol (Compound 3) having the
structure:
##STR00024##
[0314] In some embodiments, A1 is trifluoromethanesulfonic acid. In
some embodiments, the reacting of the compound of Formula III and
Compound 4 is carried out in the presence of S5, wherein S5 is a
solvent. In some embodiments, S5 is a halogenated solvent. In some
embodiments, S5 is dichloromethane.
[0315] In some embodiments, the reacting of the compound of Formula
III and Compound 4 is carried out a temperature between about
0.degree. C. and about 35.degree. C. In some embodiments, the
reacting of the compound of Formula III and Compound 4 is carried
out a temperature of about 30.degree. C. In some embodiments, about
1.2 molar equivalents of Compound 4 are used per molar equivalent
of the compound of Formula III. In some embodiments, about 4 molar
equivalents of A1 are used per molar equivalent of the compound of
Formula III.
[0316] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, can also be provided in combination in a single
embodiment (while the embodiments are intended to be combined as if
written in multiply dependent form). Conversely, various features
of the invention which are, for brevity, described in the context
of a single embodiment, can also be provided separately or in any
suitable subcombination.
[0317] The reactions of the processes described herein can be
carried out in air or under an inert atmosphere. Typically,
reactions containing reagents or products that are substantially
reactive with air can be carried out using air-sensitive synthetic
techniques that are well known to the skilled artisan.
[0318] The processes described herein can be monitored according to
any suitable method known in the art. For example, product
formation can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e.g., .sup.1H or .sup.13C),
infrared spectroscopy, spectrophotometry (e.g., UV-visible), or
mass spectrometry; or by chromatography such as high performance
liquid chromatography (HPLC) or thin layer chromatography. The
compounds obtained by the reactions can be purified by any suitable
method known in the art. For example, chromatography (medium
pressure) on a suitable adsorbent (e.g., silica gel, alumina and
the like), HPLC, or preparative thin layer chromatography;
distillation; sublimation, trituration, or recrystallization. The
purity of the compounds, in general, are determined by physical
methods such as measuring the melting point (in case of a solid),
obtaining a NMR spectrum, or performing a HPLC separation. If the
melting point decreases, if unwanted signals in the NMR spectrum
are decreased, or if extraneous peaks in an HPLC trace are removed,
the compound can be said to have been purified. In some
embodiments, the compounds are substantially purified.
Method of Use
[0319] In some embodiments, the disclosure provides a method for
treating a neurological or psychiatric disease or disorder in a
subject, comprising administering to the subject an effective
amount of a compound of this disclosure (or its pharmaceutically
acceptable salt), or composition comprising a compound of this
disclosure (or its pharmaceutically acceptable salt). Neurological
and/or psychiatric diseases and disorders can exhibit a variety of
psychiatric and behavioral symptoms, including apathy, depression,
anxiety, cognitive impairment, psychosis, aggression, agitation,
poor impulse control and sleep disruptions.
[0320] In one embodiment, the neurological or psychiatric disease
or disorder is bipolar disorder, anxiety, depression, Alzheimer's
disease with agitation, Alzheimer's disease with aggression,
Alzheimer's disease agitation or Alzheimer's disease with agitation
aggression.
[0321] In one embodiment, the neurological or psychiatric disease
or disorder is bipolar disorder, anxiety, depression, dementia,
Alzheimer's disease, Alzheimer's disease with agitation,
Alzheimer's disease with aggression, Alzheimer's disease agitation
or Alzheimer's disease with agitation aggression, a neurocognitive
disorder, a neurocognitive disorder with behavioral and
psychological symptoms.
[0322] In one embodiment, the neurological or psychiatric disease
or disorder are behavioral and psychological symptoms of a
neurocognitive disorder including dementia and Alzheimer's disease.
The behavioral and psychological symptoms include disturbances in
perception, thought content, mood, or behaviors including delusions
(distressing beliefs), hallucinations, psychoses, agitation (easily
upset, repeating questions, arguing or complaining, hoarding,
pacing, inappropriate screaming, crying out, disruptive sounds,
rejection of care leaving home), aggression (physical or verbal),
depression or dysphoria, anxiety (worrying, shadowing), apathy or
indifference, disinhibition (socially inappropriate behavior,
sexually inappropriate behavior, irritability or lability, motor
disturbance (repetitive activities without purpose, wandering,
rummaging, night-time behaviors (waking and getting up at night)
impulsivity, attentional deficits, executive dysfunction.
[0323] Assays were used herein to identify representative candidate
treatments. Examples of candidate treatments include, without
limitation, treatment of Alzheimer's disease with agitation,
Alzheimer's disease with aggression, Alzheimer's disease agitation
and Alzheimer's disease with agitation aggression. Aggression and
agitation are common symptoms in neurological and psychiatric
diseases and disorders. Aggression and agitation have been
associated with hyperactivity in subcortical brain regions, which
can be modelled in animals using psychostimulants (e.g., PCP,
Amphetamine). For example, psychostimulants induce hyperlocomotor
activity (HLA) in animals. Antipsychotics (e.g., haloperidol,
clozapine and risperidone) have been shown to reduce
psychostimulant-induced HLA and are efficacious against agitation
in Alzheimer's disease. Other drugs used off-label, or are
currently under study in clinical trials, for agitation in
Alzheimer's disease are mood stabilizers, such as lithium (which
also decreases Amphetamine-induced HLA), and antidepressants (e.g.,
citalopram). Antidepressants demonstrate activity in assays such as
the forced swim and tail suspension tests. Therefore, the
aforementioned assays were helpful in identifying candidate
treatments for agitation in Alzheimer's disease and
agitation/aggression in other neurological and psychiatric diseases
and disorders.
[0324] In one embodiment, provided is a method of treating a
bipolar disorder in a subject in need thereof, comprising the step
of administering to said subject an effective amount of the
compound according to formula I or a pharmaceutically acceptable
salt thereof.
[0325] In one embodiment, provided is a method of treating anxiety
in a subject in need thereof, comprising the step of administering
to said subject an effective amount of the compound according to
formula I or a pharmaceutically acceptable salt thereof.
[0326] In some embodiments, the neurological or psychiatric disease
or disorder is selected from a psychosis, including schizophrenia
(paranoid, disorganized, catatonic or undifferentiated),
schizophreniform disorder, schizoaffective disorder, delusional
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorder due to a general medical condition and
substance-induced or drug-induced (e.g., phencyclidine, ketamine
and other dissociative anesthetics, amphetamine and other
psychostimulants and cocaine) psychosis, psychotic disorder,
psychosis associated with affective disorders, brief reactive
psychosis, schizoaffective psychosis, "schizophrenia-spectrum"
disorders such as schizoid or schizotypal personality disorders, or
illness associated with psychosis (such as major depression, manic
depressive (bipolar) disorder, Alzheimer's disease and
post-traumatic stress syndrome), including both positive, negative,
and cognitive symptoms of schizophrenia and other psychoses;
cognitive disorders including dementia (semantic dementia,
frontotemporal dementia, dementia with depressive features,
persisting, subcortical dementia, dementia with Lewy Bodies,
Parkinsonism-ALS Dementia Complex, and dementia associated with
Alzheimer's disease, ischemia, multi-infarct dementia, trauma,
vascular problems, stroke, HIV disease, Parkinson's disease,
Huntington's disease, Down syndrome, Pick's disease,
Creutzfeldt-Jacob disease, perinatal hypoxia, or substance abuse),
delirium, amnestic disorders or age related cognitive decline;
anxiety disorders including acute stress disorder, agoraphobia,
generalized anxiety disorder, obsessive-compulsive disorder, panic
attack, panic disorder, post-traumatic stress disorder, separation
anxiety disorder, social phobia, specific phobia, substance-induced
anxiety disorder and anxiety due to a general medical condition;
substance-related disorders and addictive behaviors (including
substance-induced delirium, persisting dementia, persisting
amnestic disorder, psychotic disorder or anxiety disorder;
tolerance, dependence or withdrawal from substances including
alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,
nicotine, opioids, phencyclidine, sedatives, hypnotics or
anxiolytics); eating disorders such as obesity, bulimia nervosa,
pica and compulsive eating disorders; bipolar disorders, including
bipolar I disorder, bipolar II disorder, cyclothymic disorder,
substance/medication-induced bipolar and related disorders, bipolar
and related disorder due to another medical condition, other
specified bipolar and related disorder, and unspecified bipolar and
related disorders, depressive disorders including unipolar
depression, seasonal depression and post-partum depression,
atypical depression, catatonic depression, elderly depression,
endogenous depression, melancholic depression, perinatal
depression, situational depression, chronic depression,
premenstrual syndrome (PMS) and premenstrual dysphoric disorder
(PDD), mood disorders due to a general medical condition, and
substance-induced mood disorders; attention, learning and
development disorders such as pervasive developmental disorder
including autistic disorder, attention disorders including
attention-deficit hyperactivity disorder (ADHD) and conduct
disorder, disorders such as autism and autism spectrum disorders
(including Asperger's syndrome, pervasive developmental disorder,
Rett Syndrome and Fragile X Syndrome), depression, benign
forgetfulness, childhood learning disorders, specific learning
disorders, intellectual development disorders, and closed head
injury; movement disorders and symptoms, including tremors,
dyskinesia, dystonia, tics, dysphonia, ataxia, myoclonus, Essential
Tremor, Tardive Dyskinesia, Restless Leg Syndrome, Tourette
Syndrome, Multiple System Atrophy, Multiple Sclerosis, Huntington's
Disease, Parkinson's Disease and Atypical Parkinsonisms; epilepsy;
urinary incontinence; neuronal damage including ocular damage,
retinopathy or macular degeneration of the eye, tinnitus, hearing
impairment and loss, and brain edema; emesis; and sleep disorders
including insomnia, disturbed sleep, jet lag, hypersomnia,
cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behavior
disorder, Restless Leg Syndrome, periodic limb movement disorder,
circadian rhythm sleep disorders, delayed sleep phase disorder,
sleepwalking, night terrors, bed wetting, rapid eye movement sleep
behavior disorder, shift work sleep disorder, excessive daytime
sleepiness, non-24-hour sleep-wake disorder, sleep paralysis and
narcolepsy.
[0327] In some embodiments, the neurological or psychiatric disease
or disorder is Alzheimer's disease, Parkinson's disease,
depression, cognitive impairment, stroke, schizophrenia, Down
syndrome, or Fetal Alcohol Syndrome. In some embodiments, the
neurological or psychiatric disorder is Alzheimer's disease. In
some embodiments, the neurological or psychiatric disorder is
Parkinson's disease. In some embodiments, the neurological or
psychiatric disorder is depression. In some embodiments, the
neurological or psychiatric disorder is cognitive impairment. In
some embodiments, the cognitive impairment is cognitive dysfunction
associated with depression, for example, major depressive disorder.
In some embodiments, the neurological or psychiatric disorder is
stroke. In some embodiments, the neurological or psychiatric
disorder is schizophrenia. In some embodiments, the neurological or
psychiatric disorder is Down syndrome. In some embodiments, the
neurological or psychiatric disorder is Fetal Alcohol Syndrome.
[0328] In some embodiments, the neurological or psychiatric disease
or disorder is bipolar disorder. Bipolar disorders (including both
bipolar I and bipolar II) are serious psychiatric disorders that
have a prevalence of approximately 2% of the population, and
affects both genders alike. It is a relapsing-remitting condition
characterized by cycling between elevated (i.e., manic) and
depressed moods, which distinguishes it from other disorders such
as major depressive disorder and schizophrenia. Bipolar I is
defined by the occurrence of a full manic episode, although most
individuals experience significant depression. Symptoms of mania
include elevated or irritable mood, hyperactivity, grandiosity,
decreased need for sleep, racing thoughts and in some cases,
psychosis. The depressive episodes are characterized by anhedonia,
sad mood, hopelessness, poor self-esteem, diminished concentration
and lethargy. Bipolar II is defined as the occurrence of a major
depressive episode and hypomanic (less severe mania) episode
although subjects spend considerably more time in the depressive
state. Other related conditions include cyclothymic disorder.
[0329] In some embodiments, the neurological or psychiatric disease
or disorder is schizophrenia. Schizophrenia is a disorder of
unknown origin, which usually appears for the first time in early
adulthood and is marked by characteristics such as psychotic
symptoms, phasic progression and development, and/or deterioration
in social behavior and professional capability. Characteristic
psychotic symptoms are disorders of thought content (e.g.,
multiple, fragmentary, incoherent, implausible or simply delusional
contents, or ideas of persecution) and of mentality (e.g., loss of
association, flight of imagination, incoherence up to
incomprehensibility), as well as disorders of perceptibility (e.g.,
hallucinations), emotions (e.g., superficial or inadequate
emotions), self-perceptions, intentions, impulses, and/or
inter-human relationships, and psychomotoric disorders (e.g.,
catatonia). Other symptoms are also associated with this disorder.
Schizophrenia is classified into subgroups: the paranoid type,
characterized by delusions and hallucinations and absence of
thought disorder, disorganized behavior, and affective flattening;
the disorganized type, also named "hebephrenic schizophrenia," in
which thought disorder and flat affect are present together; the
catatonic type, in which prominent psychomotor disturbances are
evident, and symptoms may include catatonic stupor and waxy
flexibility; and the undifferentiated type, in which psychotic
symptoms are present but the criteria for paranoid, disorganized,
or catatonic types have not been met. The symptoms of schizophrenia
normally manifest themselves in three broad categories: positive,
negative and cognitive symptoms. Positive symptoms are those which
represent an "excess" of normal experiences, such as hallucinations
and delusions. Negative symptoms are those where the subject
suffers from a lack of normal experiences, such as anhedonia and
lack of social interaction. The cognitive symptoms relate to
cognitive impairment in schizophrenics, such as lack of sustained
attention and deficits in decision making.
[0330] In some embodiments, the neurological or psychiatric disease
or disorder is anxiety disorder. Anxiety disorders are
characterized by fear, worry, and uneasiness, usually generalized
and unfocused as an overreaction to a situation. Anxiety disorders
differ in the situations or types of objects that induce fear,
anxiety, or avoidance behavior, and the associated cognitive
ideation. Anxiety differs from fear in that anxiety is an emotional
response to a perceived future threat while fear is associated with
a perceived or real immediate threat. They also differ in the
content of the associated thoughts or beliefs. Examples of anxiety
disorders include separation anxiety disorder, selective mutism,
specific phobia, social anxiety disorder (social phobia), panic
disorder, panic attack specifier, agoraphobia, generalized anxiety
disorder, substance/medication-induced anxiety disorder, anxiety
disorder due to another medical condition, illness anxiety
disorder, social (pragmatic) communication disorder, other
specified anxiety disorder, and unspecified anxiety disorder;
stressor-related disorders, including reactive attachment disorder,
disinhibited social engagement disorder, posttraumatic stress
disorder (PTSD), acute stress disorder, and adjustment
disorders.
[0331] Cognitive impairment includes a decline in cognitive
functions or cognitive domains, e.g., working memory, attention and
vigilance, verbal learning and memory, visual learning and memory,
reasoning and problem solving (e.g., executive function, speed of
processing and/or social cognition). In particular, cognitive
impairment may indicate deficits in attention, disorganized
thinking, slow thinking, difficulty in understanding, poor
concentration, impairment of problem solving, poor memory,
difficulties in expressing thoughts, and/or difficulties in
integrating thoughts, feelings and behavior, or difficulties in
extinction of irrelevant thoughts.
[0332] In some embodiments, the neurological or psychiatric disease
or disorder involves a deficit in cognition (cognitive domains as
defined by the DSM-5 are: complex attention, executive function,
learning and memory, language, perceptual-motor, social cognition).
In some embodiments, the neurological or psychiatric disorder is
associated with a deficit in dopamine signaling. In some
embodiments, the neurological or psychiatric disorder is associated
with basal ganglia dysfunction. In some embodiments, the
neurological or psychiatric disorder is associated with
dysregulated locomotor activity. In some embodiments, the
neurological or psychiatric disorder is associated with impairment
of prefrontal cortex functioning.
[0333] In some embodiments, the present disclosure provides a
method of treating one or more symptoms of a neurological and/or
psychiatric disease or disorder provided herein. Such diseases or
disorders include mood disorders, including bipolar I disorder,
bipolar II disorder, mania, cyclothymic disorder,
substance/medication-induced bipolar and related disorders, bipolar
and related disorder due to another medical condition, other
specified bipolar and related disorder, and unspecified bipolar and
related disorders; psychotic disorders, including schizophrenia,
schizophrenia spectrum disorder, acute schizophrenia, chronic
schizophrenia, NOS schizophrenia, schizoid personality disorder,
schizotypal personality disorder, delusional disorder, psychosis,
psychotic disorder, brief psychotic disorder, shared psychotic
disorder, psychotic disorder due to a general medical condition,
drug-induced psychosis (e.g., cocaine, alcohol, amphetamine),
schizoaffective disorder, agitation, aggression, delirium,
catalepsy, catatonia, dissociative identity disorder, paranoid
personality disorder, psychotic depression, Schizotypical
Personality Disorder, Childhood Disintegrative Disorder (Heller's
Syndrome), Disintegrative Psychosis, Dissociative Amnesia, Somatic
Symptom Disorder, Parkinson's psychosis, excitative psychosis,
Tourette's syndrome, and organic or NOS psychosis; depressive
disorders, including disruptive mood dysregulation disorder, major
depressive disorder (MDD) (including major depressive episode),
dysthymia, persistent depressive disorder (dysthymia), treatment
resistant depression, premenstrual dysphoric disorder,
substance/medication-induced depressive disorder, depressive
disorder due to another medical condition, other specified
depressive disorder, and unspecified depressive disorder; anxiety
disorders; and other disorders including substance abuse or
dependency (e.g., nicotine, alcohol, cocaine), addiction, internet
gaming disorder, eating disorders, behavior disorder, seizure,
vertigo, epilepsy, agitation, aggression, neurodegenerative
disease, Alzheimer's disease, Parkinson's disease, dyskinesias,
Huntington's disease, dementia, premenstrual dysphoria, attention
deficit disorder (ADD) and attention deficit hyperactivity disorder
(ADHD)), hyperkinetic syndrome, autism, autism spectrum disorder,
obsessive-compulsive disorder, pain, fibromyalgia, migraine,
cognitive impairment, movement disorder, restless leg syndrome
(RLS), multiple sclerosis, Primary Progressive Multiple Sclerosis,
Parkinson's disease, Huntington's disease, dyskinesias multiple
sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive
daytime sleepiness, jet lag, drowsy side effect of medications,
insomnia, sexual dysfunction, hypertension, emesis, Lesche-Nyhane
disease, Wilson's disease, Rett syndrome, and Huntington's chorea.
In some embodiments, the neurological and/or psychiatric disorders
include agitation and aggression.
[0334] In some embodiments, the agitation and aggression are
associated with Alzheimer's disease, Parkinson's disease, and/or
autism.
[0335] In some embodiments, the agitation is associated with
psychiatric disorders such as depression and schizophrenia.
[0336] In some embodiments, the neurological and/or psychiatric
disease or disorders are obsessive-compulsive disorder and related
disorders (e.g., body dysmorphic disorder, hoarding disorder,
trichotillomania, excoriation disorder).
[0337] In some embodiments, the neurological and/or psychiatric
diseases or disorders are disruptive, impulse-control, and conduct
disorders including oppositional defiant disorder, intermittent
explosive disorder, conduct disorder, antisocial personality
disorder, pyromania, kleptomania, other specified disruptive,
impulse-control, and conduct disorder, unspecified disruptive,
impulse-control, and conduct disorder.
[0338] Depressive disorders include major depressive disorder and
dysthymia, and are associated with depressed mood (sadness), poor
concentration, insomnia, fatigue, appetite disturbances, excessive
guilt and thoughts of suicide.
[0339] In some embodiments, the present disclosure provides a
method of treating one or more symptoms including depression (e.g.,
major depressive disorder or dysthymia); bipolar disorder, seasonal
affective disorder; cognitive deficit; sleep related disorder
(e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including
those sleep disorders which are produced by psychiatric conditions;
chronic fatigue syndrome; anxieties (e.g., general anxiety
disorder, social anxiety disorder, panic disorder); obsessive
compulsive disorder; post-menopausal vasomotor symptoms (e.g., hot
flashes, night sweats); neurodegenerative disease (e.g.,
Parkinson's disease, Alzheimer's disease, amyotrophic lateral
sclerosis, primary lateral sclerosis, progressive muscular atrophy,
progressive bulbar (atrophy) palsy, pseudobulbar palsy spinal
muscular atrophy diseases (e.g., SMA type I, also called
Werdnig-Hoffmann disease, SMA type II, SMA type III, also called
Kugelberg-Welander disease, and Kennedy Disease, also called
progressive spinobulbar muscular atrophy), Hallervorden-Spatz
disease, Seitelberger disease (Infantile Neuroaxonal Dystrophy),
adrenoleukodystrophy, Alexander Disease, autosomal dominant
cerebellar ataxia (ADCA), pure autonomic failure
(Bradbury-Eggleston Syndrome), CADASIL Syndrome, and neuronal
ceroids lipofuscinose disorders such as Batten Disease
(Spielmeyer-Vogt-Sjogren)); manic disorder; dysthymic disorder; and
obesity.
[0340] In some embodiments, a depressive disorder is associated
with acute suicidality or suicide ideation. The United States Food
and Drug Administration has adopted a "black box" label warning
indicating that antidepressants may increase the risk of suicidal
thinking and behavior in some children, adolescents and young
adults (up to age 24) with a depressive disorder such as MDD. In
some embodiments, a provided compound does not increase the risk of
suicidal thinking and/or behavior in children, adolescents and/or
young adults with a depressive disorder, e.g., with MDD. In some
embodiments, the present disclosure provides a method of treating
one or more symptoms of a depressive disorder (e.g., MDD) in
children, adolescents and/or young adults without increasing the
risk of suicidal thinking and/or behavior.
[0341] In some embodiments, the present disclosure provides a
method of treating one or more symptoms including senile dementia,
Early Onset Alzheimer's disease, Alzheimer's type dementia,
cognition, memory loss, amnesia/amnestic syndrome, disturbances of
consciousness, coma, lowering of attention, speech disorder,
agnosia, aphasia, apraxia, Mild Cognitive Impairment (MCI), benign
forgetfulness, mild neurocognitive disorder, major neurocognitive
disorder, neurocognitive disorder due to disease (e.g.,
Huntington's Disease, Parkinson's disease, Prion Disease, Traumatic
Brain Injury, HIV or AIDS), Binswanger's Disease (subcortical
leukoencephalopathy), and Capgras Syndrome.
[0342] In some embodiments, the present disclosure provides a
method of treating one or more symptoms of pain, e.g., neuropathic
pain, sensitization accompanying neuropathic pain, or inflammatory
pain. In some embodiments, the pain is neuropathic pain, including
post herpetic (or post-shingles) neuralgia, reflex sympathetic
dystrophy/causalgia or nerve trauma, phantom limb pain, carpal
tunnel syndrome, and peripheral neuropathy (such as diabetic
neuropathy or neuropathy arising from chronic alcohol use). In some
embodiments, the pain is acute pain, nociceptive pain, arthritis
pain, rheumatoid arthritis, osteoarthritis, joint pain,
muscoskeletal pain, back pain, dorsalgia, bulging disc, hip pain,
visceral pain, headache, tension headache, acute tension headache,
chronic tension headache, chronic cluster headache, common
migraine, classic migraine, cluster headache, mixed headache,
posttraumatic headache, eye strain headache, Short-lasting
Unilateral Neuralgiform (SUNCT) headache, SUNCT Syndrome, herpes
zoster, acute herpes zoster, shingles, postherpetic neuralgia
(shingles), causalgia, central pain, central pain syndrome, chronic
back pain, neuralgia, neuropathic pain syndrome, neuropathy,
diabetic neuropathy, diabetes-related neuropathy, diabetes-related
nerve pain, fibrositis, peripheral neuropathy caused by
chemotherapy, peripheral nerve disease, peripheral neuropathy,
nerve pain, nerve trauma, sensitization accompanying neuropathic
pain, complex regional pain syndrome, compression neuropathy,
craniofacial pain, chronic joint pain, chronic knee pain, chronic
pain syndrome, cancer pain, trigeminal neuralgia, tic doloreaux,
reflex sympathetic causalgia, painful peripheral neuropathy, spinal
nerve injury, arachnoiditis, spinal pain, Bernhardt-Roth Syndrome
(meralgia parasthetica), carpal tunnel syndrome, cerebrospinal
fluid syndrome, Charcot-Marie-tooth disease, hereditary motor and
sensory neuropathy, peroneal muscular atrophy, cluster-tic
syndrome, coccygeal pain syndromes, compartment syndrome,
degenerative disc disease, failed back surgery syndrome,
genito-pelvic pain/penetration disorder, gout, inflammatory pain,
lumbar radiculopathy, neuroma (painful scar), pain associated with
multiple sclerosis, pelvic floor disorders, phantom limb pain,
piriformis syndrome, psychogenic pain, radicular pain syndrome,
Raeder's syndrome, referred pain, reflex sympathetic dystrophy
syndrome, sciatica, sciatica pain, scoliosis, slipped disc, somatic
pain, spinal stenosis, stiff-person syndrome/stiff-man syndrome,
stump pain, sympathetically maintained pain, tolosa-hunt syndrome,
whiplash, or pain associated with Lyme disease.
[0343] In some embodiments, the present disclosure provides a
method of treating one or more symptoms including obesity; migraine
or migraine headache; and sexual dysfunction, in men or women,
including without limitation sexual dysfunction caused by
psychological and/or physiological factors, erectile dysfunction,
premature ejaculation, vaginal dryness, lack of sexual excitement,
inability to obtain orgasm, and psycho-sexual dysfunction,
including without limitation, inhibited sexual desire, inhibited
sexual excitement, inhibited female orgasm, inhibited male orgasm,
functional dyspareunia, functional vaginismus, and atypical
psychosexual dysfunction.
[0344] In some embodiments, the present disclosure provides a
method of suppressing rapid eye movement (REM) during both sleep
and daytime equivalent.
[0345] In some embodiments, the present disclosure provides a
method of suppressing or eliminating pathological or excessive REM
during the night or daytime equivalent.
[0346] In some embodiments, the present disclosure provides a
method of treating one or more symptoms including cataplexy (sudden
involuntary transient bouts of muscle weakness or paralysis while
awake); nighttime sleep disturbance/sleep fragmentation associated
with narcolepsy or other conditions; sleep paralysis associated
with narcolepsy or other conditions; hypnagogic and hypnapompic
hallucinations associated with narcolepsy or other conditions; and
excessive daytime sleepiness associated with narcolepsy, sleep
apnea or shift work disorder and other medical conditions such as
cancer, chronic fatigue syndrome and fibromyalgia.
[0347] In some embodiments, the present disclosure provides a
method of treating one or more symptoms of movement diseases or
disorders, including akinesias, akinetic-rigid syndromes,
dyskinesias and dystonias. Examples of akinesias and akinetic-rigid
syndromes include Parkinson's disease, drug-induced Parkinsonism,
postencephalitic Parkinsonism, secondary Parkinsonism, Parkinson
plus syndromes, atypical Parkinsonism, idiopathic Parkinsonism,
progressive supranuclear palsy, multiple system atrophy,
corticobasal degeneration, Parkinsonism-ALS dementia complex and
basal ganglia calcification, medication-induced Parkinsonism (such
as neuroleptic-induced parkinsonism, neuroleptic malignant
syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced
acute akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremor), Gilles de la Tourette's
syndrome, epilepsy, muscular spasms and disorders associated with
muscular spasticity or weakness including tremors. Examples of
dyskinesias include drug (e.g. L-DOPA) induced dyskinesia tremor
(such as rest tremor, postural tremor, intention tremor), chorea
(such as Sydenham's chorea, Huntington's disease, benign hereditary
chorea, neuroacanthocytosis, symptomatic chorea, drug-induced
chorea and hemiballism), myoclonus (including generalized myoclonus
and focal myoclonus), tics (including simple tics, complex tics and
symptomatic tics). Examples of dystonias include generalized
dystonia, idiopathic dystonia, drug-induced dystonia, symptomatic
dystonia, paroxymal dystonia, focal dystonia, blepharospasm,
oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,
axial dystonia, dystonic writer's cramp and hemiplegic dystonia.
Other examples of movement diseases or disorders include
stereotypic movement disorder, persistent (chronic) motor disorder,
medication-Induced movement disorder, psychogenic movement
disorders, substance/medication-induced movement disorder,
extrapyramidal movement disorders, hyperkinetic movement disorders,
hypokinetic movement disorders, alternating hemiplegia, Angelman
syndrome, Hallervorden-Spatz Disease, ataxia, dentate cerebellar
ataxia, ataxia telangiectasia (Louis-Bar syndrome), Friedreich's
Ataxia, hereditary spinal ataxia, hereditary spinal sclerosis,
Machado-Joseph Disease, spinocerebellar ataxia, progressive
myoclonic ataxia, athetosis, ballismus, blepharospasm (eye
twitching), cerebral palsy, tardive dystonia, tardive dyskinesia,
idiopathic torsion dystonia, torsion dystonia, focal dystonia,
idiopathic familial dystonia, Idiopathic nonfamilial dystonia,
cervical dystonia (spasmodic torticollis), primary dystonia,
orofacial dystonia, developmental coordination disorder,
bulbospinal muscular atrophy (Kennedy's Disease), Shy-Drager
Syndrome, and Stiff-Person (Stiff-Man) Syndrome.
[0348] In some embodiments, the present disclosure provides a
method of treating one or more symptoms of epilepsy and/or
seizures, including abdominal epilepsy, absence seizure, acquired
epilepsy, acquired epileptiform aphasia, Aicardi syndrome, Alpers'
disease, Alpers-Huttenlocher syndrome, Angelman syndrome, benign
focal epilepsy, benign focal epilepsy of childhood, benign
intracranial hypertension, benign rolandic epilepsy (BRE), CDKL5
disorder, childhood absence epilepsy, dentate cerebellar ataxia,
Doose syndrome, Dravet syndrome, dyscognitive focal seizure,
epilepsy with grand mal seizures, epilepsy with myoclonic-absences,
epileptic hemiplegia, febrile seizures, focal seizure, frontal lobe
epilepsy, generalized tonic-clonic seizures, genetic epilepsy,
Glutl deficiency syndrome, hypothalamic hamartoma, idiopathic
epilepsy, idiopathic generalized epilepsy, idiopathic
localization-related epilepsies, idiopathic partial epilepsy,
idiopathic seizure, juvenile absence epilepsy, juvenile myoclonic
epilepsy, Lafora disease, Lafora progressive myoclonus epilepsy,
Landau-Kleffner syndrome, Lassueur-Graham-Little syndrome, Lennox
syndrome, Lennox-Gastaut syndrome, medically refractory epilepsy,
mesial-temporal lobe sclerosis, myoclonic seizure, neonatal
epilepsy, occipital lobe epilepsy, Ohtahara syndrome,
Panayiotopoulos syndrome, parietal lobe epilepsy, PCDH19 epilepsy,
photosensitive epilepsy, progressive myoclonic epilepsies,
Rasmussen's encephalitis, Rasmussen's syndrome, refractory
epilepsy, seizure disorder, status epilepticus, Sturge-Weber
syndrome, symptomatic generalized epilepsy, symptomatic partial
epilepsy, TBCK-related ID syndrome, temporal lobe epilepsy,
temporal lobe seizures, tonic-clonic seizure, West syndrome,
tremor, cerebellar tremor, cerebellar outflow tremor, intention
tremor, essential tremor, benign essential tremor, Parkinsonian
tremor, and medication-induced postural tremor.
Pharmaceutical Compositions
[0349] According to an embodiment, the disclosure provides a
composition comprising Compound 1 or salts thereof (or crystalline
forms, hydrates, or solvates thereof) and a pharmaceutically
acceptable carrier, adjuvant, or vehicle. In some embodiments, the
amount of Compound 1 in compositions of this disclosure is such
that is effective to treat, prevent, and/or manage various
neurological and/or psychiatric diseases, disorders and/or symptoms
in a subject. In some embodiments, a composition of this disclosure
is formulated for administration to a subject in need of such
composition. In some embodiments, a composition of this disclosure
is formulated for oral administration to a subject.
[0350] As used herein, the term "subject" to which administration
is contemplated includes, but is not limited to, humans (i.e., a
male or female of any age group, e.g., a pediatric subject (e.g.,
infant, child, adolescent) or adult subject (e.g., young adult,
middle-aged adult or senior adult)) and/or other primates (e.g.,
cynomolgus monkeys, rhesus monkeys); mammals, including
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs; and/or birds, including commercially
relevant birds such as chickens, ducks, geese, quail, and/or
turkeys.
[0351] In certain embodiments, provided herein is a composition
(e.g., a pharmaceutical composition) comprising Compound 1 or salts
thereof (or crystalline forms, hydrates, or solvates thereof) and a
pharmaceutically acceptable excipient or carrier. In some
embodiments, provided herein is a method of treating neurological
or psychiatric diseases and disorders in a subject in need thereof
in a subject, comprising administering an effective amount of
Compound 1 or salts thereof (or crystalline forms, hydrates, or
solvates thereof) or a pharmaceutical composition described herein.
Examples of carriers and excipients are well known to those skilled
in the art and are described in detail in, e.g., Ansel, Howard C,
et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery
Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;
Gennaro, Alfonso R., et al. Remington: The Science and Practice of
Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000;
and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.
Chicago, Pharmaceutical Press, 2005. The formulations may also
include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents,
diluents and other known additives to provide an elegant
presentation of the drug (i.e., a compound of the present
disclosure or pharmaceutical composition thereof) or aid in the
manufacturing of the pharmaceutical product (i.e., medicament).
[0352] Compositions of the present disclosure may be administered
orally, parenterally, by inhalation, topically, rectally, nasally,
buccally, sublingually, vaginally or via an implanted reservoir.
The term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques. Preferably, the
compositions are administered orally, intraperitoneally or
intravenously. Sterile injectable forms of the compositions of this
disclosure may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium.
Pharmaceutically acceptable compositions of this disclosure may be
orally administered in any orally acceptable dosage form including
capsules, tablets, aqueous suspensions or solutions.
[0353] The amount of Compound 1 or salts thereof (or crystalline
forms, hydrates, or solvates thereof) that may be combined with the
carrier materials to produce a composition in a single dosage form
will vary depending upon a variety of factors, including the host
treated and the particular mode of administration. It should also
be understood that a specific dosage and treatment regimen for any
particular subject will depend upon a variety of factors, including
the activity of the specific form of Compound 1 employed, the age,
body weight, general health, sex, diet, time of administration,
rate of excretion, drug combination, and the judgment of the
treating physician and the severity of the particular disease being
treated.
Combination Therapies
[0354] In some embodiments, the present disclosure provides a
method of treating a neurological and/or psychiatric disease or
disorder described herein, comprising administering a compound of
the disclosure in conjunction with one or more pharmaceutical
agents. Suitable pharmaceutical agents that may be used in
combination with Compound 1 or salts thereof (or crystalline forms,
hydrates, or solvates thereof) include anti-Parkinson's drugs,
anti-Alzheimer's drugs, antidepressants, anti-psychotics,
anti-ischemics, CNS depressants, anti-cholinergics, nootropics,
epilepsy medication, attention (e.g., ADD/ADHD) medications,
sleep-promoting medications, wakefulness-promoting medications, and
pain medications. In some embodiments, suitable pharmaceutical
agents are anxiolytics.
[0355] Suitable anti-Parkinson's drugs include dopamine replacement
therapy (e.g. L-DOPA, carbidopa, COMT inhibitors such as entacapone
or tolcapone), dopamine agonists (e.g. D1 agonists, D2 agonists,
mixed D1/D2 agonists, bromocriptine, pergolide, cabergoline,
ropinirole, pramipexole, piribedil, or apomorphine in combination
with domperidone), histamine H2 antagonists, monoamine oxidase
inhibitors (such as selegiline, rasagiline, safinamide and
tranylcypromine), certain atypical antipsychotics such as
pimavanserin (a non-dopaminergic atypical antipsychotic and inverse
agonist of the serotonin 5-HT2A receptor), and amantadine.
[0356] In some embodiments, Compound 1 or salts thereof (or
crystalline forms, hydrates, or solvates thereof) can be used in
combination with levodopa (with or without a selective
extracerebral decarboxylase inhibitor such as carbidopa or
benserazide), anticholinergics such as biperiden (optionally as its
hydrochloride or lactate salt) and
trihexyphenidyl(benzhexyl)hydrochloride, COMT inhibitors such as
entacapone or tolcapone, MAO AB inhibitors, antioxidants, A2a
adenosine receptor antagonists, cholinergic agonists, MDA receptor
antagonists, serotonin receptor antagonists and dopamine receptor
agonists such as alentemol, bromocriptine, fenoldopam, lisuride,
naxagolide, pergolide and pramipexole. It will be appreciated that
the dopamine agonist may be in the form of a pharmaceutically
acceptable salt, for example, alentemol hydrobromide, bromocriptine
mesylate, fenoldopam mesylate, naxagolide hydrochloride and
pergolide mesylate. Lisuride and pramipexole are commonly used in a
non-salt form.
[0357] Suitable anti-Alzheimer's drugs include beta-secretase
inhibitors, gamma-secretase inhibitors, cholinesterase inhibitors
such as donepezil, galantamine or rivastigmine, HMG-CoA reductase
inhibitors, NSAID's including ibuprofen, vitamin E, and
anti-amyloid antibodies. In some embodiments, an anti-Alzheimer's
drug is memantine.
[0358] Suitable anti-depressants and anti-anxiety agents include
norepinephrine reuptake inhibitors (including tertiary amine
tricyclics and secondary amine tricyclics), selective serotonin
reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs),
reversible inhibitors of monoamine oxidase (RIMAs), serotonin and
noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing
factor (CRF) antagonists, a-adrenoreceptor antagonists,
neurokinin-1 receptor antagonists, atypical anti-depressants,
benzodiazepines, 5-HT1 A agonists or antagonists, especially 5-HT1
A partial agonists, and corticotropin releasing factor (CRF)
antagonists.
[0359] Specific suitable anti-depressant and anti-anxiety agents
include amitriptyline, clomipramine, doxepin, imipramine and
trimipramine; amoxapine, desipramine, citalopram, escitalopram,
maprotiline, nortriptyline and protriptyline; fluoxetine,
fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine,
tranylcypromine and selegiline; moclobemide: venlafaxine;
desvenlafaxine, duloxetine; aprepitant; bupropion, vilazodone,
mirtazapine, lithium, nefazodone, trazodone and viloxazine;
alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,
halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan,
gepirone and ipsapirone, reboxetine, vortioxetine, clorazepate, and
ketamine and pharmaceutically acceptable salts thereof. In some
embodiments, suitable anti-depressant and anti-anxiety agents are
tianeptine, or pharmaceutically acceptable salts thereof.
[0360] Suitable anti-psychotic and mood stabilizer agents include
D2 antagonists, 5HT2A antagonists, atypical antipsychotics,
lithium, and anticonvulsants.
[0361] Specific suitable anti-psychotic and mood stabilizer agents
include chlorpromazine, fluphenazine, haloperidol, amisulpride,
perphenazine, thioridazine, trifluoperazine, aripiprazole,
asenapine, clozapine, olanzapine, paliperidone, brexpiprazole,
paliperidone, cariprazine, pimavanserin, illoperidone,
lumateperone, MIN-101, quetiapine, risperidone, ziprasidone,
lurasidone, flupentixol, levomepromazine, pericyazine,
perphenazine, pimozide, prochlorperazine, zuclopenthixol,
olanzapine and fluoxetine, lithium, carbamazepine, lamotrigine,
valproic acid, iloperidone, thiothixene, gabapentin, tiagabine and
pharmaceutically acceptable salts thereof.
[0362] Suitable epilepsy medications include levetiracetam,
oxcarbazepine, clobazam, retigabine, zonisamide, felbamate,
esclicarbazepine acetate, lacosamide, carbamazepine, tiagabine,
methsuximide, progabide, valproic acid, lamotrigine, brivaracetam,
rufinamide, topiramate and perampanel.
[0363] Suitable attention medications include methyl phenidate,
atomoxetine, guanfacine, D-amphetamine, lisdexamphetamine,
methylamphetamine, and clonidine.
[0364] Suitable sleep-promoting medications include ramelteon,
triazolam, zopiclone, eszopiclone, Zolpidem, temazepam, and
trazodone.
[0365] Suitable wakefulness-promoting medications include
Modafinil, D-Amphetamine, caffeine, and armodafinil.
[0366] Suitable pain medications include dextromethorphan,
tapentadol, buprenorphine, codeine, fentanyl, hydrocodone,
hydromorphone, morphine, naloxegol, oxycodone, tramadol,
gabapentil, difluprednate, pregabalin, acetyl salicyclic acid,
bromfenac, diclofenac, diflunisal, indomethacin, ketorolac,
meoxican, and naproxen.
[0367] In some embodiments, compounds and compositions of the
disclosure may be used in combination with other therapies.
Suitable therapies include psychotherapy, cognitive behavioral
therapy, electroconvulsive therapy, transcranial magnetic
stimulation, vagus nerve stimulation, and deep-brain
stimulation.
[0368] The exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the condition, the particular agent, its
mode of administration, and the like. The compounds and
compositions of the disclosure are preferably formulated in dosage
unit form for ease of administration and uniformity of dosage. The
expression "dosage unit form" as used herein refers to a physically
discrete unit of agent appropriate for the subject to be treated.
It will be understood, however, that the total daily usage of the
compounds and compositions of the present disclosure will be
decided by the attending physician within the scope of sound
medical judgment.
[0369] The pharmaceutically acceptable compositions of this
disclosure can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, sublingually, as an oral or nasal spray, or the like,
depending on the severity of the infection being treated. In some
embodiments, Compound 1 or salts thereof (or crystalline forms,
hydrates, or solvates thereof) may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0370] In some embodiments, a combination of two or more
therapeutic agents may be administered together with Compound 1 or
salts thereof (or crystalline forms, hydrates, or solvates
thereof). In some embodiments, a combination of three or more
therapeutic agents may be administered with Compound 1 or salts
thereof (or crystalline forms, hydrates, or solvates thereof).
[0371] Other examples of agents the compounds and compositions of
this disclosure may also be combined with include: vitamins and
nutritional supplements, antiemetics (e.g. 5-HT3 receptor
antagonists, dopamine antagonists, K1 receptor antagonists,
histamine receptor antagonists, cannabinoids, benzodiazepines, or
anticholinergics), agents for treating Multiple Sclerosis (MS) such
as beta interferon (e.g., Avonex.RTM. and Rebif.RTM.,
dalfampridine, alemtuzumab), Copaxone.RTM., and mitoxantrone;
treatments for Huntington's disease such as tetrabenazine;
treatments for asthma such as albuterol and Singulair.RTM.;
anti-inflammatory agents such as corticosteroids, T F blockers,
IL-1 RA, azathioprine, and sulfasalazine; immunomodulatory and
immunosuppressive agents such as cyclosporin, tacrolimus,
rapamycin, mycophenolate mofetil, interferons, corticosteroids,
cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic
factors such as acetylcholinesterase inhibitors, MAO inhibitors,
interferons, anti-convulsants, ion channel blockers, riluzole,
agents for treating cardiovascular disease such as beta-blockers,
ACE inhibitors, diuretics, nitrates, calcium channel blockers, and
statins, fibrates, cholesterol absorption inhibitors, bile acid
sequestrants, and niacin; agents for treating liver disease such as
corticosteroids, cholestyramine, interferons, and anti-viral
agents; agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth factors; agents
for treating immunodeficiency disorders such as gamma globulin; and
anti-diabetic agents such as biguanides (metformin, phenformin,
buformin), thiazolidinediones (rosiglitazone, pioglitazone,
troglitazone), sulfonylureas (tolbutamide, acetohexamide,
tolazamide, chlorpropamide, glipizide, glyburide, glimepiride,
gliclazide), meglitinides (repaglinide, nateglinide),
alpha-glucosidase inhibitors (miglitol, acarbose), incretin
mimetics (exenatide, liraglutide, taspoglutide), gastric inhibitory
peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin,
saxagliptin, linagliptin, alogliptin), amylin analogs
(pramlintide), and insulin and insulin analogs.
[0372] In some embodiments, Compound 1 or salts thereof (or
crystalline forms, hydrates, or solvates thereof) are administered
in combination with an antisense agent, a monoclonal or polyclonal
antibody, or an siRNA therapeutic.
[0373] Those additional agents may be administered separately from
an inventive compound-containing composition, as part of a multiple
dosage regimen. Alternatively, those agents may be part of a single
dosage form, mixed together with a compound of this disclosure in a
single composition. If administered as part of a multiple dosage
regime, the two active agents may be submitted simultaneously,
sequentially or within a period of time from one another, normally
within five hours from one another.
[0374] As used herein, the term "combination," "combined," and
related terms refers to the simultaneous or sequential
administration of therapeutic agents in accordance with this
disclosure. For example, Compound 1 or salts thereof (or
crystalline forms, hydrates, or solvates thereof) may be
administered with another therapeutic agent simultaneously or
sequentially in separate unit dosage forms or together in a single
unit dosage form. Accordingly, the present disclosure provides a
single unit dosage form comprising Compound 1 or salts thereof (or
crystalline forms, hydrates, or solvates thereof), an additional
therapeutic agent, and a pharmaceutically acceptable carrier,
adjuvant, or vehicle.
[0375] The amount of both, an inventive compound and additional
therapeutic agent (in those compositions which comprise an
additional therapeutic agent as described above) that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Preferably, compositions of this disclosure
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of an inventive can be administered.
[0376] In those compositions which comprise an additional
therapeutic agent, that additional therapeutic agent and Compound 1
or salts thereof (or crystalline forms, hydrates, or solvates
thereof) may act synergistically. Therefore, the amount of
additional therapeutic agent in such compositions will be less than
that required in a monotherapy utilizing only that therapeutic
agent. In such compositions a dosage of between 0.01-100 mg/kg body
weight/day of the additional therapeutic agent can be
administered.
[0377] The amount of additional therapeutic agent present in the
compositions of this disclosure will be no more than the amount
that would normally be administered in a composition comprising
that therapeutic agent as the only active agent. Preferably the
amount of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0378] In some embodiments, the present disclosure provides a
medicament comprising Compound 1 or salts thereof (or crystalline
forms, hydrates, or solvates thereof), and a pharmaceutically
acceptable carrier, adjuvant, or vehicle.
[0379] In some embodiments, the present disclosure provides the use
of Compound 1 or salts thereof (or crystalline forms, hydrates, or
solvates thereof) in the manufacture of a medicament for the
treatment of a neurological and/or psychiatric disease or
disorder.
EXAMPLES
Example 1: Preparation of Salts of Compound 1
[0380] The free base of Compound 1 (500 mg) was dissolved in MeOH
(34 mL). The solution was divided into 33 vials (resulting in a 15
mg scale of Compound 1). To each vial, the appropriate counter ion
(0.95 equivalents) was added and dissolved by the screening solvent
listed in Table 1. The solution was heated at 60.degree. C. for 1 h
and then allowed to cool undisturbed at room temperature. Each vial
was opened and allowed to stand at room temperature (slow
evaporation). In several cases, acetone or EtOAc additive were
added to vials and allowed to stand at room temperature, allowing
for slow evaporation. Results of the solvent screen are shown below
in Table 1. Further, certain experiments were performed on a larger
scale, as shown in Table 1.
TABLE-US-00001 TABLE 1 Solvent screen Solvent Acid (0.95 Scale
Additive equivalents rel. (amount for slow En- to Compound of Com-
Screening evapora- Notes On try 1) pound 1) Solvent tion Product 1
HCl 15 mg MeOH -- -- 2 HCl 15 mg THF -- Crystalline - Form HA 3 HCl
15 mg EtOAc -- Crystalline - Form HA 4 H.sub.3PO.sub.4 15 mg MeOH +
-- Crystalline Acetone 5 H.sub.3PO.sub.4 15 mg THF -- Crystalline 6
H.sub.3PO.sub.4 15 mg EtOAc -- Crystalline 7 H.sub.3PO.sub.4 200 mg
MeOH (1 mL) acetone Crystalline + EtOAc (5 mL) 8 H.sub.3PO.sub.4
1000 mg MeOH (7 mL) acetone Crystalline + EtOAc (35 mL) 9
L-Tartaric acid 15 mg MeOH + Crystalline - acetone Form LB 10
L-Tartaric acid 15 mg THF Crystalline - Form LA 11 L-Tartaric acid
15 mg EtOAc Crystalline - Form LA 12 L-Tartaric acid 100 mg MeOH (1
mL) acetone Crystalline - + EtOAc (5 Form LC mL), 100 mg scale 13
L-Tartaric acid 100 mg MeOH (1 mL) EtOAc Crystalline - + EtOAc (5
Form LC mL); 100 mg scale 14 D-Tartaric acid 15 mg MeOH + --
acetone 15 D-Tartaric acid 15 mg THF Crystalline 16 D-Tartaric acid
15 mg EtOAc Crystalline 17 Fumaric acid 15 mg MeOH Crystalline -
Form FA 18 Fumaric acid 15 mg THF Crystalline - Form FA 19 Fumaric
acid 15 mg EtOAc Crystalline - Form FB 20 Fumaric acid 200 mg MeOH
(1 mL) Acetone Crystalline - + Acetone (5 Form FA mL) 21 Citric
Acid 15 mg MeOH + Crystalline acetone 22 Citric Acid 15 mg THF --
23 Citric Acid 15 mg EtOAc Crystalline 24 Citric Acid 100 mg MeOH
(1 mL) Acetone Crystalline + EtOAc (5 mL); 25 TsOH 15 mg MeOH + --
acetone 26 TsOH 15 mg THF -- 27 TsOH 15 mg EtOAc -- 28 Succinic
acid 15 mg MeOH + -- acetone 29 Succinic acid 15 mg THF Crystalline
30 Succinic acid 15 mg EtOAc Crystalline 31 Glutaric acid 15 mg
MeOH + Crystalline acetone 32 Glutaric acid 15 mg THF -- 33
Glutaric acid 15 mg EtOAc -- 34 L-malic acid 15 mg MeOH Crystalline
35 L-malic acid 15 mg THF Crystalline 36 L-malic acid 15 mg EtOAC
Crystalline 37 BsOH 15 mg MeOH + -- acetone 38 BsOH 15 mg THF -- 39
BsOH 15 mg EtOAc Crystalline
Example 2. Synthesis of Free Base
[0381] Saturated sodium bicarbonate water (15 ml) and water (5 ml)
was added to Compound 1 hydrochloride (600 mg). The solution was
extracted with chloroform (15 mL, 3 times). The organic extract was
washed with brine (20 ml) and evaporated. The free base of Compound
1 was isolated as an oil (approx. 500 mg).
Example 3. Compound 1 Hydrochloride Form HA
[0382] The XRPD spectrum for Compound 1 Hydrochloride HA is
provided in FIG. 1 (FIG. 1) and the corresponding peak data is
provided below in Table 2.
TABLE-US-00002 TABLE 2 XRPD Peak Data for Compound 1 Hydrochloride
Form HA FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 6.7 0.1 7.0 13.1 43.1 0.6 8.6 0.2 46.6 10.3 214.3
2.7 9.4 0.1 1072.7 9.4 7887.4 100.0 10.3 0.2 24.8 8.6 91.1 1.2 11.4
0.1 196.4 7.7 1443.9 18.3 12.5 0.3 16.7 7.1 38.4 0.5 13.6 0.2 11.6
6.5 53.1 0.7 14.2 0.1 192.1 6.2 1412.5 17.9 15.1 0.1 328.7 5.9
2417.1 30.6 16.0 0.2 9.9 5.5 45.7 0.6 17.2 0.1 329.2 5.2 2420.3
30.7 17.6 0.1 442.4 5.0 2710.9 34.4 17.9 0.2 16.6 5.0 76.4 1.0 18.8
0.1 87.4 4.7 535.5 6.8 19.2 0.1 116.1 4.6 609.6 7.7 20.1 0.2 57.1
4.4 262.4 3.3 20.6 0.1 30.9 4.3 189.5 2.4 20.9 0.2 37.8 4.3 173.5
2.2 21.5 0.2 25.4 4.1 93.5 1.2 22.1 0.1 49.6 4.0 303.9 3.9 23.1 0.1
55.2 3.8 405.7 5.1 23.6 0.1 21.2 3.8 129.9 1.7 24.3 0.1 204.0 3.7
1250.3 15.9 24.8 0.1 41.2 3.6 303.0 3.8 25.2 0.1 24.4 3.5 149.6 1.9
25.6 0.1 76.5 3.5 562.3 7.1 25.8 0.1 170.3 3.4 894.7 11.3 26.2 0.2
269.3 3.4 824.9 10.5 27.0 0.1 615.1 3.3 3768.7 47.8 27.7 0.1 66.1
3.2 405.1 5.1 28.0 0.1 38.5 3.2 283.1 3.6 28.3 0.1 90.9 3.2 668.5
8.5 28.6 0.1 99.9 3.1 734.3 9.3 29.8 0.1 27.2 3.0 166.4 2.1 30.1
0.1 31.8 3.0 195.0 2.5 30.5 0.1 79.8 2.9 488.7 6.2 31.7 0.1 83.3
2.8 612.1 7.8 32.2 0.2 58.9 2.8 270.7 3.4 32.8 0.2 40.3 2.7 148.3
1.9 33.0 0.1 8.7 2.7 53.1 0.7 33.5 0.2 22.6 2.7 69.3 0.9 34.0 0.2
20.0 2.6 73.6 0.9 34.5 0.1 17.1 2.6 104.6 1.3 35.6 0.1 174.9 2.5
1286.0 16.3 36.4 0.1 16.7 2.5 102.1 1.3 38.3 0.2 42.6 2.3 195.5 2.5
38.6 0.2 41.2 2.3 189.3 2.4 39.5 0.1 16.5 2.3 100.9 1.3
[0383] A DSC thermogram for Form HA is shown in FIG. 2 (FIG. 2).
The thermogram is characterized by endotherm peaks at temperatures
of about 99.degree. C. and about 187.degree. C. FIG. 3 (FIG. 3)
shows a thermogravimetric analysis (TGA) thermogram of Form HA.
FIG. 4 (FIG. 4) shows a dynamic vapor sorption (DVS) isotherm of
Form HA.
Example 4. Compound 1 Hydrochloride Form HB
[0384] The XRPD spectrum for Compound 1 Hydrochloride HB is
provided in FIG. 5 (FIG. 5) and the corresponding peak data is
provided below in Table 3.
TABLE-US-00003 TABLE 3 XRPD Peak Data for Compound 1 Hydrochloride
Form HB FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 8.6 0.2 139.5 10.2 640.9 28.7 9.6 0.1 189.2 9.2
1391.2 62.3 10.3 0.1 364.2 8.6 2231.9 100.0 12.6 0.1 146.9 7.0
1079.8 48.4 13.6 0.2 57.1 6.5 174.8 7.8 14.7 0.2 314.0 6.0 1442.9
64.7 16.5 0.1 99.9 5.4 524.9 23.5 17.3 0.1 296.0 5.1 2176.4 97.5
17.6 0.2 80.4 5.0 369.3 16.6 18.3 0.1 67.1 4.8 493.1 22.1 19.5 0.1
45.3 4.6 277.8 12.5 19.7 0.1 44.1 4.5 269.9 12.1 20.1 0.2 75.8 4.4
278.7 12.5 21.1 0.2 45.3 4.2 208.2 9.3 22.0 0.3 82.6 4.0 216.9 9.7
23.1 0.2 55.5 3.9 255.0 11.4 23.8 0.1 188.1 3.7 988.1 44.3 24.4 0.2
239.1 3.6 732.6 32.8 25.3 0.1 98.4 3.5 516.6 23.1 26.3 0.2 116.7
3.4 536.5 24.0 26.6 0.1 60.5 3.4 370.5 16.6 26.9 0.1 151.8 3.3
1116.3 50.0 27.1 0.1 154.7 3.3 1137.6 51.0 27.4 0.1 102.1 3.3 625.5
28.0 28.9 0.2 112.0 3.1 514.8 23.1 29.7 0.2 38.9 3.0 119.2 5.3 30.3
0.2 52.0 2.9 238.7 10.7 31.7 0.2 75.6 2.8 278.1 12.5 32.6 0.2 45.0
2.7 165.5 7.4 33.3 0.5 87.3 2.7 133.7 6.0 34.8 0.3 85.5 2.6 196.5
8.8 35.6 0.2 59.0 2.5 271.3 12.2 38.8 0.2 42.7 2.3 130.8 5.9
[0385] FIG. 6 (FIG. 6) shows a dynamic vapor sorption (DVS)
isotherm of Form HB.
Example 5. Compound 1 Phosphate
[0386] The XRPD spectrum for Compound 1 Phosphate is provided in
FIG. 7 (FIG. 7) and the corresponding peak data is provided below
in Table 4.
TABLE-US-00004 TABLE 4 XRPD Peak Data for Compound 1 Phosphate d-
Rel. FWHM Area spacing Height Int. Pos. [.degree.2.theta.] Left
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [cts] [%] 4.6 0.1
1876.4 19.4 13796.8 99.4 9.1 0.1 665.0 9.7 4890.0 35.2 13.6 0.1
36.5 6.5 335.3 2.4 14.0 0.1 40.3 6.3 296.0 2.1 15.2 0.1 10.6 5.8
97.6 0.7 15.7 0.1 79.4 5.6 583.5 4.2 16.2 0.1 28.8 5.5 264.9 1.9
18.2 0.1 1887.7 4.9 13880.4 100.0 19.1 0.1 59.7 4.6 548.4 4.0 19.8
0.1 9.5 4.5 87.6 0.6 21.2 0.1 20.5 4.2 187.9 1.4 22.3 0.1 77.0 4.0
707.8 5.1 22.8 0.1 1005.6 3.9 9242.6 66.6 23.1 0.1 44.5 3.8 408.6
2.9 23.4 0.1 24.7 3.8 181.9 1.3 24.0 0.1 12.4 3.7 75.8 0.6 24.8 0.1
82.3 3.6 605.3 4.4 25.2 0.1 33.0 3.5 242.5 1.8 25.5 0.1 16.6 3.5
152.6 1.1 26.0 0.1 121.0 3.4 1111.9 8.0 26.8 0.1 12.3 3.3 150.8 1.1
27.0 0.1 17.7 3.3 130.0 0.9 27.4 0.1 154.5 3.3 1419.7 10.2 27.7 0.1
20.0 3.2 183.7 1.3 28.2 0.1 14.7 3.2 134.9 1.0 29.4 0.1 10.5 3.0
64.5 0.5 29.6 0.1 9.1 3.0 55.9 0.4 30.1 0.1 103.4 3.0 760.0 5.5
30.7 0.1 14.0 2.9 128.2 0.9 31.0 0.1 59.6 2.9 438.6 3.2 31.3 0.1
12.9 2.9 79.2 0.6 32.1 0.1 41.8 2.8 384.3 2.8 33.5 0.2 9.1 2.7 28.0
0.2 34.1 0.1 24.0 2.6 176.4 1.3 34.9 0.1 32.7 2.6 300.7 2.2 35.2
0.1 16.5 2.5 151.3 1.1 36.4 0.1 8.2 2.5 50.3 0.4 36.8 0.1 25.9 2.4
190.1 1.4 37.8 0.1 18.5 2.4 135.8 1.0 38.3 0.1 16.1 2.3 118.0 0.9
38.8 0.1 62.1 2.3 456.3 3.3 39.0 0.1 75.9 2.3 558.4 4.0 39.3 0.1
11.0 2.3 101.0 0.7 40.9 0.1 13.5 2.2 123.9 0.9 41.3 0.1 10.5 2.2
64.1 0.5 41.6 0.2 13.7 2.2 63.0 0.5 43.4 0.1 22.4 2.1 205.8 1.5
45.1 0.1 13.6 2.0 125.1 0.9 45.5 0.2 9.5 2.0 34.8 0.3 45.9 0.1 23.7
2.0 174.3 1.3 46.5 0.1 9.0 2.0 82.8 0.6 48.0 0.1 31.5 1.9 289.5 2.1
49.0 0.1 15.2 1.9 93.1 0.7 49.4 0.1 14.1 1.8 86.3 0.6 50.8 0.2 10.8
1.8 33.0 0.2 51.5 0.1 13.6 1.8 124.9 0.9 52.3 0.1 10.8 1.7 99.0 0.7
52.5 0.1 13.7 1.7 126.1 0.9 52.9 0.1 72.9 1.7 446.8 3.2 53.9 0.1
9.2 1.7 112.4 0.8 56.3 0.1 6.4 1.6 33.5 0.2 57.3 0.1 9.1 1.6 55.7
0.4 58.6 0.1 17.9 1.6 109.4 0.8 60.3 0.2 8.9 1.5 27.3 0.2 62.4 0.4
16.0 1.5 29.4 0.2 63.9 0.2 5.7 1.5 17.6 0.1 64.4 0.1 5.9 1.4 36.1
0.3
[0387] A DSC thermogram for Compound 1 Phosphate is shown in FIG. 8
(FIG. 8). The thermogram is characterized by an endotherm peak at a
temperature of about 213.degree. C. FIG. 9 (FIG. 9) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1
Phosphate. FIG. 10 (FIG. 10) shows a dynamic vapor sorption (DVS)
isotherm of Compound 1 Phosphate.
Example 6. Compound 1 L-Tartrate Form LA
[0388] The XRPD spectrum for Compound 1 Form LA is provided in FIG.
11 (FIG. 11) and the corresponding peak data is provided below in
Table 5.
TABLE-US-00005 TABLE 5 XRPD Peak Data for Compound 1 L-Tartrate
Form LA FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 4.7 0.5 15.1 18.8 23.2 0.1 5.1 0.2 7.5 17.3 27.6
0.1 6.1 0.2 91.6 14.6 336.6 1.2 9.1 0.2 55.6 9.8 255.4 0.9 12.1 0.2
570.4 7.3 2621.2 9.5 12.4 0.2 161.8 7.2 743.5 2.7 12.8 0.2 55.3 6.9
203.4 0.7 13.4 0.2 65.3 6.6 240.0 0.9 14.1 0.2 85.6 6.3 314.8 1.1
15.0 0.2 286.0 5.9 1051.5 3.8 15.9 0.1 58.1 5.6 427.5 1.6 16.4 0.3
407.9 5.4 1071.2 3.9 16.9 0.1 170.1 5.2 1042.1 3.8 17.1 0.1 177.0
5.2 1301.4 4.7 18.1 0.2 7483.7 4.9 27513.5 100.0 19.3 0.1 182.5 4.6
958.4 3.5 19.9 0.1 96.3 4.5 590.0 2.1 20.5 0.3 192.8 4.3 506.3 1.8
21.1 0.1 23.5 4.2 144.1 0.5 21.7 0.2 172.9 4.1 635.8 2.3 22.1 0.2
74.1 4.0 340.4 1.2 22.5 0.2 34.9 3.9 160.3 0.6 23.0 0.2 144.9 3.9
443.8 1.6 23.9 0.2 910.0 3.7 4182.2 15.2 24.2 0.1 1554.5 3.7
11430.2 41.5 24.8 0.1 381.4 3.6 2003.3 7.3 25.8 0.2 92.7 3.5 426.0
1.6 26.2 0.1 60.4 3.4 370.1 1.4 27.0 0.1 361.4 3.3 1897.9 6.9 27.2
0.1 306.0 3.3 2249.8 8.2 27.6 0.2 162.1 3.2 744.8 2.7 28.4 0.1
220.1 3.1 1156.1 4.2 29.0 0.2 220.8 3.1 811.7 3.0 29.4 0.2 94.4 3.0
433.8 1.6 29.8 0.1 166.3 3.0 1019.1 3.7 30.3 0.1 236.2 2.9 1736.9
6.3 30.7 0.2 142.4 2.9 523.6 1.9 31.2 0.2 76.2 2.9 280.3 1.0 31.8
0.2 52.2 2.8 191.8 0.7 32.7 0.2 94.2 2.7 346.3 1.3 33.1 0.2 83.3
2.7 255.2 0.9 33.5 0.2 67.1 2.7 246.6 0.9 34.1 0.2 120.2 2.6 441.8
1.6 34.4 0.1 74.6 2.6 457.2 1.7 34.9 0.1 21.1 2.6 129.4 0.5 35.6
0.2 163.1 2.5 749.4 2.7 36.6 0.2 239.8 2.5 1101.8 4.0 37.1 0.1
171.4 2.4 900.0 3.3 38.3 0.1 63.9 2.3 391.6 1.4 38.6 0.1 134.4 2.3
823.8 3.0 39.0 0.2 50.3 2.3 154.1 0.6
[0389] A DSC thermogram for Form LA is shown in FIG. 12 (FIG. 12).
The thermogram is characterized by endotherm peaks at temperatures
of about 89.degree. C. and about 138.degree. C. FIG. 13 (FIG. 13)
shows a thermogravimetric analysis (TGA) thermogram of Compound 1
L-Tartrate Form LA. FIG. 14 (FIG. 14) shows a dynamic vapor
sorption (DVS) isotherm of Form LA.
Example 7. Compound 1 L-Tartrate Form LB
[0390] The XRPD spectrum for Compound 1 L-Tartrate Form LB is
provided in FIG. 15 (FIG. 15) and the corresponding peak data is
provided below in Table 6.
TABLE-US-00006 TABLE 6 XRPD Peak Data for Compound 1 L-Tartrate
Form LB FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 4.3 0.5 9.5 20.7 14.6 0.0 6.3 0.1 269.5 14.1
1651.3 4.2 8.9 0.7 33.5 9.9 38.4 0.1 11.9 0.1 66.9 7.4 410.0 1.1
12.1 0.2 221.2 7.3 813.2 2.1 12.5 0.1 302.4 7.1 1853.2 4.7 12.8 0.1
60.1 6.9 368.0 0.9 13.4 0.2 19.1 6.6 58.5 0.2 14.1 0.1 8.5 6.3 51.9
0.1 14.9 0.2 82.8 5.9 253.6 0.7 15.5 0.1 222.5 5.7 1363.3 3.5 15.9
0.1 28.6 5.6 175.2 0.5 16.3 0.2 186.9 5.4 763.5 2.0 16.5 0.1 65.6
5.4 402.0 1.0 16.9 0.1 63.5 5.2 389.1 1.0 18.1 0.1 717.7 4.9 5276.8
13.5 18.7 0.1 6395.4 4.7 39187.7 100.0 19.2 0.2 34.3 4.6 157.5 0.4
19.6 0.1 65.8 4.5 403.0 1.0 19.9 0.1 146.2 4.5 1074.9 2.7 20.0 0.1
227.2 4.4 1391.9 3.6 20.5 0.2 30.5 4.3 93.6 0.2 22.0 0.2 38.5 4.0
118.1 0.3 22.5 0.1 59.3 4.0 435.9 1.1 22.6 0.1 50.8 3.9 373.3 1.0
23.9 0.2 459.3 3.7 2110.9 5.4 24.2 0.1 224.6 3.7 1651.5 4.2 24.6
0.1 154.1 3.6 1132.8 2.9 25.0 0.1 3586.6 3.6 21976.5 56.1 27.1 0.2
123.6 3.3 568.0 1.5 28.4 0.1 12.9 3.1 78.7 0.2 28.8 0.3 94.4 3.1
247.9 0.6 29.4 0.1 114.3 3.0 700.1 1.8 29.8 0.2 43.4 3.0 199.5 0.5
30.3 0.1 61.7 2.9 323.9 0.8 30.7 0.2 137.7 2.9 632.9 1.6 31.0 0.2
64.8 2.9 298.0 0.8 31.4 0.1 1318.4 2.8 8078.3 20.6 33.1 0.2 28.4
2.7 104.5 0.3 33.8 0.2 48.9 2.6 149.7 0.4 34.0 0.1 10.2 2.6 74.8
0.2 34.1 0.2 25.3 2.6 77.6 0.2 34.6 0.1 29.1 2.6 178.5 0.5 35.1 0.1
77.6 2.6 475.3 1.2 35.9 0.2 99.2 2.5 364.7 0.9 36.4 0.1 38.0 2.5
232.9 0.6 36.7 0.2 173.5 2.4 797.3 2.0 37.0 0.1 79.1 2.4 484.8 1.2
37.7 0.2 23.6 2.4 108.3 0.3 37.9 0.1 279.5 2.4 2055.0 5.2 38.9 0.2
1.6 2.3 5.8 0.0 39.6 0.1 18.1 2.3 110.8 0.3
[0391] FIG. 16 (FIG. 16) shows a dynamic vapor sorption (DVS)
isotherm of Form LB.
Example 8. Compound 1 L-Tartrate Form LC
[0392] The XRPD spectrum for Compound 1 L-Tartrate Form LC is
provided in FIG. 17 (FIG. 17) and the corresponding peak data is
provided below in Table 7.
TABLE-US-00007 TABLE 7 XRPD Peak Data for Compound 1 L-Tartrate
Form LC FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 6.3 0.2 57.4 14.1 175.8 3.0 12.2 0.2 908.8 7.3
4176.6 70.7 12.8 0.2 389.8 6.9 1791.5 30.3 15.0 0.1 168.1 5.9 882.8
15.0 15.4 0.1 420.8 5.7 3093.9 52.4 16.5 0.2 1001.8 5.4 4092.4 69.3
18.7 0.2 825.8 4.7 3373.2 57.1 19.5 0.1 179.9 4.5 1102.1 18.7 19.8
0.1 646.7 4.5 3396.4 57.5 20.0 0.1 557.8 4.4 2929.7 49.6 22.4 0.1
290.2 4.0 1777.9 30.1 22.6 0.2 614.3 3.9 2822.9 47.8 23.7 0.3 107.2
3.8 246.2 4.2 24.2 0.3 211.4 3.7 555.1 9.4 24.8 0.1 963.6 3.6
5904.1 100.0 25.0 0.1 697.9 3.6 3665.6 62.1 25.5 0.2 1163.6 3.5
5347.3 90.6 26.2 0.2 97.8 3.4 449.6 7.6 26.5 0.1 99.7 3.4 611.0
10.4 27.1 0.1 356.3 3.3 1871.2 31.7 27.8 0.1 83.2 3.2 509.6 8.6
28.0 0.1 85.6 3.2 524.7 8.9 29.0 0.2 286.3 3.1 1315.9 22.3 29.4 0.1
102.3 3.0 752.4 12.7 29.9 0.2 259.2 3.0 1191.2 20.2 30.8 0.2 282.3
2.9 1037.7 17.6 31.4 0.1 199.3 2.8 1465.7 24.8 32.9 0.1 68.5 2.7
419.4 7.1 33.4 0.7 131.0 2.7 150.5 2.6 33.8 0.1 86.4 2.7 529.2 9.0
34.6 0.1 75.8 2.6 557.2 9.4 35.0 0.2 121.9 2.6 373.3 6.3 35.4 0.1
52.4 2.5 385.6 6.5 36.0 0.1 273.1 2.5 1673.6 28.4 36.6 0.1 104.7
2.5 641.3 10.9 37.0 0.1 139.8 2.4 856.8 14.5 37.6 0.2 277.9 2.4
1135.3 19.2 39.6 0.1 114.0 2.3 598.9 10.1
[0393] A DSC thermogram for Form LC is shown in FIG. 18 (FIG. 18).
The thermogram is characterized by an endotherm peak at a
temperature of about 137.degree. C. FIG. 19 (FIG. 19) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1
L-Tartrate Form LC. FIG. 20 (FIG. 20) shows a dynamic vapor
sorption (DVS) isotherm of Form LC.
Example 9. Compound 1 D-Tartrate
[0394] The XRPD spectrum for Compound 1 D-Tartrate is provided in
FIG. 22 (FIG. 22) and the corresponding peak data is provided below
in Table 8.
TABLE-US-00008 TABLE 8 XRPD Peak Data for Compound 1 D-Tartrate
FWHM d- Rel. Pos. Left Area spacing Int. [.degree.2.theta.]
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [%] 6.0 0.2 71.0
14.8 4.0 11.9 0.1 286.4 7.4 25.7 12.3 0.1 129.2 7.2 11.6 13.4 0.2
115.0 6.6 6.5 14.9 0.1 57.0 5.9 4.3 16.1 0.1 120.8 5.5 9.1 16.9 0.1
432.0 5.3 32.4 17.9 0.1 1112.7 4.9 100.0 19.1 0.1 202.7 4.6 15.2
20.6 0.1 41.3 4.3 3.1 21.2 0.1 32.2 4.2 2.4 21.6 0.1 125.1 4.1 9.4
22.1 0.2 37.8 4.0 2.1 23.4 0.1 57.1 3.8 4.3 23.9 0.1 523.8 3.7 33.6
24.6 0.1 102.0 3.6 9.2 25.1 0.2 167.0 3.5 8.3 25.9 0.1 86.3 3.4 6.5
26.8 0.1 87.1 3.3 7.8 27.2 0.2 59.7 3.3 2.7 28.7 0.2 78.5 3.1 3.5
29.6 0.1 106.2 3.0 8.0 30.1 0.1 84.6 3.0 7.6 30.4 0.2 96.6 2.9 4.3
31.5 0.3 31.9 2.8 0.9 32.4 0.2 57.6 2.8 3.2 33.8 0.2 22.5 2.7 1.3
34.2 0.2 43.8 2.6 1.6 35.3 0.1 150.3 2.5 9.7 36.3 0.2 62.3 2.5 3.5
36.9 0.1 33.8 2.4 2.5 38.3 0.2 35.1 2.3 2.0 38.8 0.2 45.1 2.3
2.5
[0395] A DSC thermogram for Compound 1 D-Tartrate is shown in FIG.
23 (FIG. 23). The thermogram is characterized by endotherm peaks at
temperatures of about 76.degree. C. and about 153.degree. C. FIG.
23 (FIG. 23) shows a thermogravimetric analysis (TGA) thermogram of
Compound 1 D-Tartrate. FIG. 24 (FIG. 24) shows a dynamic vapor
sorption (DVS) isotherm of Compound 1 D-Tartrate.
Example 10. Compound 1 Fumarate Form FA
[0396] The XRPD spectrum for Compound 1 Fumarate FA is provided in
FIG. 25 (FIG. 25) and the corresponding peak data is provided below
in Table 9.
TABLE-US-00009 TABLE 9 XRPD Peak Data for Compound 1 Fumarate Form
FA FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 5.0 0.3 7.1 17.7 16.4 0.0 7.7 0.2 2022.3 11.5
9293.7 21.3 11.3 0.2 8.6 7.8 26.3 0.1 12.1 0.2 161.3 7.3 741.3 1.7
13.0 0.1 429.8 6.8 2633.3 6.0 14.2 0.1 911.3 6.2 4786.2 11.0 14.6
0.1 339.9 6.0 1784.9 4.1 15.2 0.1 1404.9 5.8 10330.0 23.7 15.9 0.2
13.6 5.6 62.5 0.1 16.2 0.2 18.9 5.5 69.5 0.2 17.1 0.2 22.9 5.2
105.2 0.2 18.1 0.2 183.7 4.9 844.4 1.9 18.8 0.1 126.3 4.7 928.9 2.1
19.1 0.1 6.2 4.6 38.1 0.1 19.3 0.1 5.6 4.6 34.3 0.1 19.9 0.3 32.9
4.5 75.5 0.2 20.8 0.1 15.2 4.3 92.9 0.2 21.8 0.2 115.7 4.1 531.7
1.2 22.4 0.1 135.0 4.0 993.0 2.3 22.6 0.1 162.7 3.9 996.7 2.3 22.9
0.1 4216.3 3.9 25835.4 59.3 23.9 0.2 85.0 3.7 390.4 0.9 24.2 0.1
42.2 3.7 258.7 0.6 24.6 0.1 1727.3 3.6 10583.8 24.3 25.0 0.1 5.0
3.6 30.7 0.1 25.5 0.1 2.0 3.5 12.0 0.0 26.0 0.2 500.3 3.4 2299.2
5.3 26.5 0.2 193.7 3.4 890.0 2.0 27.0 0.1 61.1 3.3 374.5 0.9 27.2
0.1 16.6 3.3 101.5 0.2 27.6 0.2 55.7 3.2 170.6 0.4 28.2 0.1 22.4
3.2 164.6 0.4 28.6 0.1 25.1 3.1 153.9 0.4 29.0 0.1 27.7 3.1 203.7
0.5 29.3 0.2 74.8 3.0 343.9 0.8 30.1 0.1 4.5 3.0 33.2 0.1 30.7 0.1
7109.3 2.9 43561.8 100.0 31.6 0.2 441.0 2.8 2026.5 4.7 32.2 0.1
27.6 2.8 169.2 0.4 32.8 0.4 93.0 2.7 170.9 0.4 33.3 0.1 68.3 2.7
418.2 1.0 34.6 0.2 48.2 2.6 177.1 0.4 35.2 0.1 165.4 2.5 1013.5 2.3
35.9 0.2 20.1 2.5 74.0 0.2 37.0 0.1 35.8 2.4 263.0 0.6 37.9 0.1
175.8 2.4 1077.3 2.5 38.6 0.2 1019.2 2.3 4684.0 10.8 39.7 0.2 24.5
2.3 112.4 0.3
[0397] A DSC thermogram for Form FA is shown in FIG. 26 (FIG. 26).
The thermogram is characterized by an endotherm peak at a
temperature of about 147.degree. C. FIG. 27 (FIG. 27) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1 Fumarate
Form FA. FIG. 28 (FIG. 28) shows a dynamic vapor sorption (DVS)
isotherm of Form FA.
Example 11. Compound 1 Fumarate Form FB
[0398] The XRPD spectrum for Compound 1 Fumarate FB is provided in
FIG. 29 (FIG. 29) and the corresponding peak data is provided below
in Table 10.
TABLE-US-00010 TABLE 10 XRPD Peak Data for Compound 1 Fumarate Form
FB FWHM d- Rel. Pos. Left Area spacing Height Int.
[.degree.2.theta.] [.degree.2.theta.] [cts*.degree.2.theta.]
[.ANG.] [cts] [%] 4.7 0.5 18.2 18.9 27.9 0.0 6.7 0.1 2225.1 13.1
13634.5 9.2 9.0 0.1 118.6 9.8 871.7 0.6 9.7 0.1 5.6 9.1 41.3 0.0
11.1 0.1 7.2 8.0 44.1 0.0 11.7 0.2 49.6 7.6 182.4 0.1 12.1 0.1 31.3
7.3 191.5 0.1 12.5 0.2 152.2 7.1 699.5 0.5 13.0 0.2 207.1 6.8 634.3
0.4 13.4 0.1 868.4 6.6 5321.2 3.6 13.8 0.1 3273.3 6.4 20057.1 13.6
14.7 0.1 30.2 6.0 185.3 0.1 15.9 0.1 7.8 5.6 48.0 0.0 16.2 0.1 52.0
5.5 318.6 0.2 17.8 0.2 506.6 5.0 2328.1 1.6 18.4 0.1 102.2 4.8
626.3 0.4 19.3 0.1 85.3 4.6 448.1 0.3 20.2 0.1 24120.6 4.4 147797.7
100.0 20.7 0.1 135.2 4.3 828.2 0.6 21.1 0.1 104.2 4.2 638.7 0.4
21.2 0.1 85.5 4.2 628.5 0.4 22.3 0.2 38.0 4.0 174.6 0.1 23.1 0.1
270.2 3.8 1655.6 1.1 23.5 0.1 1093.1 3.8 8037.4 5.4 24.2 0.1 316.6
3.7 2328.0 1.6 25.1 0.1 1032.5 3.5 7592.1 5.1 26.1 0.1 85.6 3.4
629.7 0.4 26.3 0.1 246.2 3.4 1508.5 1.0 27.0 0.1 22016.7 3.3
134906.2 91.3 27.7 0.2 408.1 3.2 1250.3 0.9 28.6 0.2 73.0 3.1 335.3
0.2 29.2 0.2 47.6 3.1 218.9 0.2 29.6 0.1 1056.9 3.0 6476.2 4.4 30.2
0.1 28.5 3.0 174.7 0.1 31.0 0.1 102.4 2.9 537.6 0.4 31.7 0.1 256.7
2.8 1573.0 1.1 32.6 0.1 24.5 2.7 150.0 0.1 32.8 0.1 122.3 2.7 749.7
0.5 33.1 0.1 111.4 2.7 819.1 0.6 33.9 0.1 395.1 2.6 2905.2 2.0 34.4
0.1 257.4 2.6 1893.0 1.3 35.0 0.2 25.8 2.6 95.0 0.1 35.3 0.1 37.1
2.5 194.8 0.1 35.6 0.2 95.5 2.5 438.8 0.3 36.1 0.1 112.4 2.5 688.5
0.5 36.5 0.2 168.2 2.5 773.1 0.5 36.8 0.2 107.5 2.4 493.8 0.3 37.4
0.2 58.1 2.4 213.8 0.1 37.9 0.1 132.2 2.4 809.9 0.6 38.6 0.2 42.2
2.3 129.3 0.1 39.0 0.1 60.0 2.3 367.4 0.3
[0399] A DSC thermogram for Form FB is shown in FIG. 30 (FIG. 30).
The thermogram is characterized by endotherm peaks at temperatures
of about 96.degree. C., about 139.degree. C., and about 146.degree.
C. FIG. 31 (FIG. 31) shows a thermogravimetric analysis (TGA)
thermogram of Compound 1 Fumarate Form FB. FIG. 32 (FIG. 32) shows
a dynamic vapor sorption (DVS) isotherm of Form FB.
Example 12. Compound 1 Citrate
[0400] The XRPD spectrum for Compound 1 Citrate is provided in FIG.
33 (FIG. 33) and the corresponding peak data is provided below in
Table 11.
TABLE-US-00011 TABLE 11 XRPD Peak Data for Compound 1 Citrate FWHM
d- Rel. Pos. Left Area spacing Height Int. [.degree.2.theta.]
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [cts] [%] 6.5 0.1
638.9 13.6 3915.0 91.1 10.2 0.1 70.4 8.7 517.3 12.0 11.5 0.2 41.4
7.7 126.8 3.0 13.0 0.2 226.0 6.8 1038.5 24.2 13.9 0.2 43.2 6.4
198.5 4.6 14.5 0.1 160.4 6.1 1179.6 27.5 15.5 0.2 1052.1 5.7 4297.6
100.0 16.5 0.1 152.9 5.4 936.6 21.8 17.3 0.1 272.8 5.1 1671.6 38.9
17.8 0.1 414.1 5.0 3044.9 70.9 18.9 0.1 103.1 4.7 541.2 12.6 19.4
0.1 472.0 4.6 3470.7 80.8 20.4 0.1 778.0 4.3 4086.1 95.1 20.8 0.1
226.2 4.3 1385.8 32.3 21.2 0.1 511.2 4.2 3132.6 72.9 21.5 0.2 290.8
4.1 1336.5 31.1 22.0 0.2 416.0 4.0 1699.3 39.5 23.1 0.1 249.5 3.9
1528.8 35.6 24.3 0.2 85.8 3.7 394.4 9.2 24.6 0.1 87.3 3.6 641.8
14.9 25.1 0.1 161.9 3.5 992.2 23.1 26.0 0.1 569.5 3.4 3489.4 81.2
27.0 0.1 39.3 3.3 241.0 5.6 27.2 0.1 40.4 3.3 247.3 5.8 27.5 0.1
195.6 3.2 1198.4 27.9 27.9 0.1 85.5 3.2 523.6 12.2 28.5 0.2 91.5
3.1 420.3 9.8 29.2 0.1 184.4 3.1 1129.8 26.3 30.4 0.2 90.1 2.9
413.9 9.6 30.8 0.2 47.3 2.9 217.4 5.1 31.4 0.1 124.7 2.8 763.9 17.8
32.5 0.1 56.1 2.8 412.5 9.6 33.3 0.1 211.8 2.7 1297.9 30.2 33.8 0.1
46.2 2.7 283.3 6.6 34.8 0.2 91.0 2.6 278.6 6.5 35.3 0.1 138.9 2.5
850.8 19.8 36.5 0.1 136.9 2.5 1006.8 23.4 36.8 0.1 89.2 2.4 656.2
15.3 37.4 0.2 118.6 2.4 435.9 10.1 38.3 0.1 50.5 2.3 309.5 7.2
[0401] A DSC thermogram for Compound 1 Citrate is shown in FIG. 34
(FIG. 34). The thermogram is characterized by an endotherm peak at
a temperature of about 142.degree. C. FIG. 35 (FIG. 35) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1 Citrate.
FIG. 36 (FIG. 36) shows a dynamic vapor sorption (DVS) isotherm of
Compound 1 Citrate.
Example 13. Compound 1 Succinate
[0402] The XRPD spectrum for Compound 1 Succinate is provided in
FIG. 37 (FIG. 37) and the corresponding peak data is provided below
in Table 12.
TABLE-US-00012 TABLE 12 XRPD Peak Data for Compound 1 Succinate
FWHM d- Rel. Pos. Left Area spacing Height Int. [.degree.2.theta.]
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [cts] [%] 6.6 0.1
78.4 13.3 576.5 11.0 9.0 0.2 59.6 9.8 273.7 5.2 11.5 0.1 79.6 7.7
487.5 9.3 12.8 0.1 223.3 6.9 1641.8 31.4 13.9 0.1 690.8 6.4 5079.1
97.2 14.2 0.1 47.7 6.2 292.3 5.6 16.0 0.1 81.8 5.5 501.4 9.6 16.4
0.1 40.7 5.4 249.1 4.8 16.8 0.1 40.4 5.3 247.3 4.7 17.2 0.1 35.5
5.1 217.3 4.2 17.7 0.2 87.6 5.0 268.5 5.1 18.3 0.1 39.8 4.9 243.6
4.7 19.2 0.1 79.4 4.6 417.1 8.0 19.8 0.1 852.5 4.5 5223.5 100.0
21.1 0.1 97.2 4.2 595.9 11.4 22.9 0.1 343.9 3.9 2528.7 48.4 23.3
0.1 304.5 3.8 1599.1 30.6 23.8 0.1 80.9 3.7 594.6 11.4 24.5 0.1
73.2 3.6 448.7 8.6 25.0 0.1 148.6 3.6 910.6 17.4 25.2 0.1 177.8 3.5
1307.4 25.0 25.4 0.1 340.4 3.5 1787.6 34.2 25.9 0.1 50.0 3.4 306.3
5.9 26.1 0.1 84.1 3.4 618.3 11.8 26.5 0.1 913.2 3.4 4796.2 91.8
27.2 0.2 118.0 3.3 542.4 10.4 28.3 0.1 69.6 3.1 426.7 8.2 29.3 0.1
184.3 3.0 1129.3 21.6 30.4 0.2 50.7 2.9 155.2 3.0 31.7 0.1 45.2 2.8
277.0 5.3 32.3 0.2 51.0 2.8 234.3 4.5 33.2 0.1 53.2 2.7 325.9 6.2
33.4 0.1 47.8 2.7 293.1 5.6 33.9 0.2 40.5 2.6 186.3 3.6 34.8 0.2
52.5 2.6 160.9 3.1 35.8 0.2 61.6 2.5 188.8 3.6 36.5 0.2 62.0 2.5
285.0 5.5 37.4 0.2 81.7 2.4 250.3 4.8 38.9 0.1 43.8 2.3 268.1 5.1
39.6 0.2 51.2 2.3 235.1 4.5
[0403] A DSC thermogram for Compound 1 Succinate is shown in FIG.
38 (FIG. 38). The thermogram is characterized by an endotherm peak
at a temperature of about 153.degree. C. FIG. 39 (FIG. 39) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1
Succinate. FIG. 40 (FIG. 40) shows a dynamic vapor sorption (DVS)
isotherm of Compound 1 Succinate.
Example 14. Compound 1 Glutarate
[0404] The XRPD spectrum for Compound 1 Glutarate is provided in
FIG. 41 (FIG. 41) and the corresponding peak data is provided below
in Table 13.
TABLE-US-00013 TABLE 13 XRPD Peak Data for Compound 1 Glutarate
FWHM d- Rel. Pos. Left Area spacing Height Int. [.degree.2.theta.]
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [cts] [%] 9.1 0.1
487.6 9.7 3585.4 21.0 9.7 0.2 4.3 9.1 13.1 0.1 10.6 0.1 409.4 8.4
2150.4 12.6 11.3 0.2 7.3 7.8 33.6 0.2 11.9 0.2 28.2 7.4 129.6 0.8
12.7 0.1 7.5 7.0 55.1 0.3 14.2 0.1 37.5 6.2 230.0 1.4 15.0 0.2 31.0
5.9 142.4 0.8 15.9 0.1 74.0 5.6 388.5 2.3 16.8 0.1 85.0 5.3 520.6
3.1 18.2 0.1 2781.0 4.9 17040.5 100.0 18.6 0.1 18.4 4.8 134.9 0.8
19.0 0.1 503.2 4.7 3700.2 21.7 19.6 0.1 96.8 4.5 593.4 3.5 20.8 0.1
33.4 4.3 204.5 1.2 21.8 0.1 110.8 4.1 678.8 4.0 21.9 0.1 136.5 4.1
836.7 4.9 22.5 0.1 209.4 4.0 1539.6 9.0 23.1 0.2 58.2 3.8 214.0 1.3
23.6 0.1 17.4 3.8 106.3 0.6 25.0 0.2 97.3 3.6 446.9 2.6 25.3 0.1
39.1 3.5 239.3 1.4 25.8 0.1 135.9 3.4 999.2 5.9 26.4 0.1 74.2 3.4
545.5 3.2 27.4 0.1 368.3 3.2 2256.9 13.2 28.0 0.1 451.6 3.2 2767.2
16.2 28.5 0.1 25.9 3.1 190.2 1.1 29.5 0.1 19.8 3.0 121.5 0.7 30.0
0.1 56.1 3.0 412.6 2.4 30.3 0.1 10.1 3.0 61.6 0.4 31.5 0.2 27.9 2.8
85.5 0.5 32.9 0.2 40.1 2.7 123.0 0.7 33.8 0.1 32.2 2.6 197.0 1.2
35.2 0.1 42.2 2.6 258.5 1.5 35.6 0.2 26.2 2.5 80.1 0.5 36.8 0.1
148.0 2.4 1088.0 6.4 37.2 0.2 65.1 2.4 299.2 1.8 37.9 0.1 33.6 2.4
246.9 1.5 38.5 0.1 59.6 2.3 365.3 2.1 39.5 0.1 8.8 2.3 54.1 0.3
[0405] FIG. 42 (FIG. 42) shows a dynamic vapor sorption (DVS)
isotherm of Compound 1 Glutarate.
Example 15. Compound 1 L-Malate
[0406] The XRPD spectrum for Compound 1 L-Malate is provided in
FIG. 43 (FIG. 43) and the corresponding peak data is provided below
in Table 14.
TABLE-US-00014 TABLE 14 XRPD Peak Data for Compound 1 L-Malate FWHM
d- Rel. Pos. Left Area spacing Height Int. [.degree.2.theta.]
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [cts] [%] 11.9
0.1 37.7 7.4 231.0 2.6 13.1 0.1 93.8 6.8 689.9 7.8 13.5 0.2 1102.0
6.5 5064.2 57.0 14.4 0.1 97.7 6.2 718.5 8.1 15.2 0.2 171.4 5.8
787.6 8.9 16.0 0.1 59.5 5.5 312.4 3.5 16.6 0.1 58.5 5.3 429.9 4.8
17.0 0.1 69.6 5.2 512.0 5.8 17.7 0.1 121.5 5.0 744.3 8.4 18.1 0.1
73.3 4.9 449.4 5.1 18.8 0.2 1935.1 4.7 8893.1 100.0 19.8 0.1 49.1
4.5 300.6 3.4 20.9 0.1 43.5 4.3 320.2 3.6 22.4 0.2 179.9 4.0 826.6
9.3 22.9 0.2 105.8 3.9 486.1 5.5 23.8 0.1 539.5 3.7 2833.7 31.9
24.6 0.1 138.8 3.6 1020.8 11.5 24.8 0.2 856.5 3.6 3148.9 35.4 25.2
0.2 1082.7 3.5 4422.7 49.7 25.6 0.1 241.8 3.5 1269.7 14.3 26.2 0.1
217.6 3.4 1142.8 12.9 26.8 0.2 89.7 3.3 274.7 3.1 27.2 0.1 61.3 3.3
450.6 5.1 27.7 0.1 134.8 3.2 826.1 9.3 28.0 0.2 105.8 3.2 486.4 5.5
28.6 0.2 75.7 3.1 347.8 3.9 28.9 0.1 39.8 3.1 244.1 2.7 29.4 0.4
74.8 3.0 137.4 1.6 30.5 0.1 104.3 2.9 767.2 8.6 32.3 0.1 36.3 2.8
222.7 2.5 33.1 0.2 75.5 2.7 277.5 3.1 33.4 0.2 74.1 2.7 272.6 3.1
34.4 0.2 58.7 2.6 269.7 3.0 34.8 0.3 51.2 2.6 117.6 1.3 35.4 0.2
63.3 2.5 194.1 2.2 35.9 0.2 123.8 2.5 568.9 6.4 37.1 0.3 124.8 2.4
286.8 3.2 37.5 0.3 49.2 2.4 113.1 1.3 38.2 0.3 157.5 2.4 361.9 4.1
39.5 0.2 18.1 2.3 83.2 0.9
[0407] A DSC thermogram for Compound 1 L-Malate is shown in FIG. 44
(FIG. 44). The thermogram is characterized by an endotherm peak at
a temperature of about 82.degree. C. FIG. 45 (FIG. 45) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1 L-Malate.
FIG. 46 (FIG. 46) shows a dynamic vapor sorption (DVS) isotherm of
Compound 1 L-Malate.
Example 16. Compound 1 Besylate
[0408] The XRPD spectrum for Compound 1 Besylate is provided in
FIG. 47 (FIG. 47) and the corresponding peak data is provided below
in Table 15.
TABLE-US-00015 TABLE 15 XRPD Peak Data for Compound 1 Besylate FWHM
d- Rel. Pos. Left Area spacing Height Int. [.degree.2.theta.]
[.degree.2.theta.] [cts*.degree.2.theta.] [.ANG.] [cts] [%] 6.0 0.1
9260.8 14.6 56745.2 100.0 12.0 0.2 3664.6 7.4 16841.2 29.7 13.0 0.2
42.2 6.8 155.1 0.3 13.8 0.2 58.7 6.4 179.7 0.3 14.7 0.2 67.1 6.0
246.6 0.4 16.4 0.1 90.9 5.4 668.0 1.2 16.6 0.2 711.3 5.3 3269.0 5.8
16.9 0.1 54.1 5.2 331.6 0.6 18.1 0.1 73.6 4.9 451.0 0.8 18.6 0.1
81.6 4.8 600.1 1.1 19.0 0.1 102.1 4.7 750.5 1.3 19.4 0.1 70.5 4.6
518.7 0.9 20.3 0.2 91.9 4.4 281.6 0.5 21.2 0.1 101.0 4.2 742.6 1.3
21.4 0.1 94.2 4.1 692.3 1.2 22.2 0.1 126.7 4.0 931.6 1.6 23.2 0.1
160.2 3.8 1177.8 2.1 24.1 0.1 7880.7 3.7 48288.4 85.1 24.9 0.2 54.1
3.6 165.6 0.3 25.5 0.2 77.2 3.5 236.6 0.4 26.0 0.2 58.2 3.4 267.6
0.5 26.8 0.1 450.2 3.3 3310.2 5.8 28.6 0.2 31.5 3.1 115.8 0.2 29.6
0.2 24.0 3.0 110.1 0.2 30.3 0.1 1661.3 2.9 10179.2 17.9 31.9 0.2
174.8 2.8 803.5 1.4 34.0 0.1 47.0 2.6 345.3 0.6 34.6 0.2 26.0 2.6
119.4 0.2 35.5 0.1 52.8 2.5 323.7 0.6 36.0 0.1 67.0 2.5 410.6 0.7
36.6 0.2 108.9 2.5 333.6 0.6 37.4 0.1 119.7 2.4 880.4 1.6 38.4 0.1
107.9 2.3 661.2 1.2
[0409] A DSC thermogram for Compound 1 Besylate is shown in FIG. 48
(FIG. 48). The thermogram is characterized by an endotherm peak at
a temperature of about 136.degree. C. FIG. 49 (FIG. 49) shows a
thermogravimetric analysis (TGA) thermogram of Compound 1 Besylate.
FIG. 50 (FIG. 50) shows a dynamic vapor sorption (DVS) isotherm of
Compound 1 Besylate.
Example 17. Stability Study
[0410] Each sample was stored at 60.degree. C. and 60.degree. C.
75% RH for 1 month. Each sample was measured at 20 days and 1 month
by HPLC. HPLC conditions are described below.
[0411] Column: Waters XSelect CSH C18, 4.6.times.150 mm, 3.5
.mu.m
[0412] MPA: 50 mM HClO4 in water (pH=3)
[0413] MPB: MeOH/acetonitrile (9:1)
[0414] Wavelength: 215 nm
[0415] Column Temp: 40.degree. C.
[0416] Flow: 1 mL/min
[0417] Gradient:
TABLE-US-00016 0 min 10% MPB 12 min 24% MPB 20 min 90% MPB 20 min
90% MPB 21 min 10% MPB 31 min 10% MPB
[0418] The results of the stability are shown in Table 16
below.
TABLE-US-00017 TABLE 16 Stability Study Results L- Fumaric Citric
Free- HCl H.sub.3PO.sub.4 Tartaric acid acid base Initial 98.94
99.20 99.10 99.48 99.08 98.28 20 day at 60.degree. C. 98.50 99.20
99.13 99.54 99.10 76.57 1 month at 60.degree. C. 98.89 99.23 99.14
99.60 99.16 62.18 20 days at 60.degree. C. 99.07 99.20 99.23 99.67
98.34 -- 75% RH 1 month at 60.degree. C. 99.05 99.24 99.23 99.64
97.73 5.83 75% RH
The freebase (amorphous) of Compound 1 was unstable at 60.degree.
C. and 60.degree. C. 75% RH. The other salts (Hydrochloride,
Phosphate, L-tartrate, Fumarate, citrate) were stable.
Example 18. Phosphate Polymorph Screen
[0419] Compound 1 Phosphate was subjected to three forms of
polymorph screening: solvent screening, slurry screening, and rapid
cool screening. The procedures for each screening are provided
below.
[0420] Solvent Screening: Compound 1 Phosphate (5 mg) was put into
a small glass vial and solvents were added until the sample was
dissolved at 90.degree. C. or boiling point. Maximum volume of
solvent was 500 .mu.L. The solution or suspension was heated for 1
h, allowed to cool undisturbed at room temperature overnight, and
cooled at 5.degree. C. for 3 days. Un-precipitated samples were
opened and allowed to stand at room temperature until dryness (slow
evaporation). The precipitated solids were filtered by sintering
filter plate, and measured directly by XRPD on the plate.
[0421] Slurry Screening: Compound 1 Phosphate (10 mg) was put into
a small glass vial and organic solvents mixed with water were
added. The samples were then suspended at room temperature or
50.degree. C. and shaken for 4 to 10 days. The suspensions were
filtered. The collected solids were analyzed by XRPD to determine
polymorphic form.
[0422] Rapid Cool Screening: Compound 1 Phosphate (10 mg) was
dissolved at 90.degree. C. or boiling point. The solution was
cooled at 0.degree. C. rapidly. After 1 h, solution was cooled at
-20.degree. C. for 3 days. The precipitated crystals were filtered.
Recovered solids were analyzed by XRPD to determine polymorphic
form.
[0423] From the screening studies (over 75 trials), only one
polymorph (Compound 1 Phosphate as described in Example 5) was
identified.
Example 19. Synthesis of Compound 1 and Compound 1 Phosphate
Step 1. Preparation of
1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine
trifluoromethanesulfonate
##STR00025##
[0425] A solution of 2-(2-bromo-5-fluorophenyl)ethan-1-ol (200 g,
913 mmol) and N-methylaminoacetaldehyde dimethylacetal (130 g, 1091
mmol) in dichloromethane (300 mL) was cooled to 0.degree. C. and
trifluoromethanesulfonic acid (554 g, 3691 mmol) was added over 1 h
while maintaining the temperature below 35.degree. C. with external
cooling. The mixture was warmed to 30.degree. C. and stirred at
30.degree. C. for 23 h. The mixture was cooled to 20.degree. C. and
methanol (33 mL), dichloromethane (1275 mL) and tert-butyl methyl
ether (1358 mL) were added. The precipitate was collected by
suction filtration. The solids were washed with a solution
consisting of 1:1 (v/v) dichloromethane and tert-butyl methyl ether
(1830 mL) and dried under vacuum (>28'' Hg) at 45.degree. C. for
21 h to give
1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine
trifluoromethanesulfonate (339 g, 87% yield) as a tan powder. MS
(ESI): m/z 274, 276 [M+H].sup.+; .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): [ppm 8.65 (br s, 1H), 8.54 (br s, 1H), 7.67 (dd,
J=8.80, 5.28 Hz, 1H), 7.15 (dd, J=9.98, 8.80 Hz, 1H), 5.21 (dd,
J=9.78, 2.35 Hz, 1H), 4.06 (dt, J=12.03, 5.92 Hz, 1H), 3.89 (dt,
J=11.93, 5.18 Hz, 1H), 3.50-3.38 (m, 1H), 3.31 (br s, 1H), 2.73 (t,
J=5.67 Hz, 2H), 2.64 (br s, 3H); .sup.13C-NMR (100 MHz,
DMSO-d.sub.6): [ppm 158.91, 156.48, 136.20, 136.16, 132.57, 132.48,
123.37, 123.20, 119.20, 119.17, 115.34, 115.10, 66.59, 59.63,
49.09, 49.04, 33.01, 28.75, 28.73.
Step 2. Preparation of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium
(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate
##STR00026##
[0427] A solution of
1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine
trifluoromethanesulfonate (300 g, 707 mmol), palladium, 10 wt. %
(dry basis) on activated carbon, 50% water (1.2 g), methanol (1006
mL) and 5 wt. % aq. potassium carbonate (1059 g) was hydrogenated
at 25.degree. C., 5 bar hydrogen pressure, for 1 h. The pressure
was released, and the solution was filtered through a 5-micron
disposable polypropylene in-line filter cartridge which was rinsed
with a solution consisting of 1:1 (v/v) methanol and water (540 g).
The solution was concentrated under reduced pressure to a final
volume of 1200 mL. To the mixture was added tert-butyl methyl ether
(893 mL) and 20 wt. % aq. potassium hydroxide (185 mL). The mixture
was stirred for 10 minutes at 20.degree. C. The stirring was
stopped and the phases were separated. The aqueous phase was
extracted with tert-butyl methyl ether (649 mL). The combined
organic layers were concentrated under reduced pressure to a final
volume of 450 mL. To the solution was added SDA (specially
denatured alcohol) 3A ethanol (851 mL). The solution was
concentrated under reduced pressure to a final volume of 675 mL.
The solution (solution A) was held for further processing. In a
separate vessel was added dibenzoyl-L-tartaric acid (252 g, 703
mmol), SDA 3A ethanol (2704 mL) and deionized water (69 mL). The
mixture was heated to approximately 70.degree. C. and solution A
was added over 9 minutes, which resulted in precipitation. The
mixture was stirred at approximately 70.degree. C. for 45 minutes
then cooled to 20.degree. C. over approximately 2.5 h. The
precipitate was collected by suction filtration. The solids were
washed with SDA 3A ethanol (960 mL) and dried under vacuum
(>28'' Hg) at 45.degree. C. for 17 h to give
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium
(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (181 g, 46% yield)
as a white solid.
[0428] Alternative resolving agents, other than
dibenzoyl-L-tartaric acid were explored, but most were found to not
be suitable or practical for various reasons (e.g., availability,
cost, performance). Such resolving agents include (R)-mandelic
acid, L-tartaric acid, and L-malic acid. However,
N-acetyl-D-leucine was found to provide the desired (R)-isomer in
approximately 91:9 ratio and approximately 17% yield.
[0429] The optical purity of intermediate
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium
(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate was enriched to
96.4% de by performing the following recrystallization
procedure.
[0430] To (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium
(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (177 g, 320 mmol)
was added methanol (3578 mL) and the solution was concentrated at
atmospheric pressure to a final volume of 1326 mL which resulted in
crystallization. The temperature of the slurry was adjusted to
approximately 62.degree. C. and stirring was continued for 20 min.
The slurry was cooled to 10.degree. C. over 2 h and the solids were
collected by suction filtration. The solids were washed with cold
(10.degree. C.) methanol (675 mL) and dried under vacuum (>28''
Hg) at 45.degree. C. overnight to give
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium
(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (136 g, 77% yield)
as a white solid. MS (ESI): m/z 196 [M+H].sup.+; .sup.1H-NMR (400
MHz, DMSO-d.sub.6): [ppm 8.03-7.85 (m, 4H), 7.70-7.55 (m, 2H),
7.54-7.43 (m, 4H), 7.27 (td, J=7.92, 6.06 Hz, 1H), 7.11-6.89 (m,
2H), 5.67 (s, 2H), 5.15 (dd, J=9.98, 2.93 Hz, 1H), 3.92 (ddd,
J=11.84, 7.34, 4.70 Hz, 1H), 3.69 (dt, J=11.54, 4.99 Hz, 1H),
3.36-3.24 (m, 1H), 3.22-3.04 (m, 1H), 2.80-2.61 (m, 2H), 2.54 (s,
3H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6): [ppm 168.21, 164.89,
159.56, 157.13, 136.87, 136.82, 133.37, 129.60, 129.23, 128.88,
128.80, 128.65, 125.10, 125.07, 120.58, 120.43, 114.57, 113.07,
112.87, 72.47, 66.71, 59.65, 49.22, 49.17, 32.62, 27.28, 27.26.
Step 3. Preparation of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate
##STR00027##
[0432] To a mixture of compound
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium
(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (75 g, 135.5 mmol)
and tert-butyl methyl ether (223 mL) was added a solution
consisting of 14 wt. % aq. potassium hydroxide (120 mL) and sodium
chloride (15 g). The mixture was stirred for 10 minutes at
23-25.degree. C. The stirring was stopped and the phases were
separated. The aqueous phase was extracted with tert-butyl methyl
ether (2.times.78 mL). The combined organic layers were
concentrated under reduced pressure to a final volume of 90 mL. The
solution was cooled to approximately 48.degree. C. and acetonitrile
(288 ml) was added. The solution was concentrated at atmospheric
pressure to a final volume of approx. 210 mL. The mixture was
cooled to 20.degree. C. and acetonitrile (97 mL) and DI water (23
mL) were added. To this was added at 20.degree. C. a solution
consisting of 87% by weight aq. H.sub.3PO.sub.4 (16.9 g) and
acetonitrile (81 mL). The product precipitated during the addition.
The slurry was stirred for 3 h at 20.degree. C. and the solids were
collected by suction filtration. The solids were washed with a
solution consisting of acetonitrile (135 mL) and DI water (8 mL)
and dried under vacuum (>28'' Hg) at 55.degree. C. overnight to
give (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate
(36 g, 89% yield) as a white crystalline solid, which is Compound 1
Phosphate as characterized in Example 5. MS (ESI): m/z 196
[M+H].sup.+; .sup.1H-NMR (400 MHz, D.sub.2O): [ppm 7.27 (td,
J=7.83, 5.87 Hz, 1H), 7.03 (d, J=7.25 Hz, 1H), 6.97 (dd, J=10.37,
8.80 Hz, 1H), 5.25 (t, J=5.87 Hz, 1H), 4.04 (dt, J=11.74, 5.87 Hz,
1H), 3.91-3.80 (m, 1H), 3.47 (d, J=5.87 Hz, 2H); 2.83 (t, J=5.48
Hz, 2H), 2.75 (s, 3H); .sup.13C-NMR (100 MHz, D.sub.2O with 5%
methanol-d.sub.4): [ppm 161.09, 158.67, 138.10, 138.07, 130.51,
130.42, 126.19, 126.16, 120.28, 120.13, 114.37, 114.17, 68.33,
62.15, 51.39, 51.34, 34.05, 28.38, 28.35.
Step 4. Recrystallization of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate using
water/acetone
##STR00028##
[0434] 19.5 g of the product of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate from
step 3 was dissolved in 70 g water at 20.degree. C., and then 30 g
acetone was charged into the process stream to make the 16.3 wt %
starting solution. The solution passed through the polish filter to
remove any insoluble matters. Then dosing 600 g acetone into the
solution within around 1 hour. The product crystallized out during
the addition. The slurry was stirred at least 30 min at 20.degree.
C. and the solids were collected by suction filtration. The solids
were washed with a binary solvents acetone (54 g) and DI water (6
g) and dried under vacuum (>28'' Hg) at 55.degree. C. overnight
to give (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
phosphate (18.1 g, 93% yield) as a white crystalline solid.
Step 4. Recrystallization of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate using
water/acetonitrile
##STR00029##
[0436] 35.0 g of the product of
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate from
step 3 was dissolved in 70 g water at 20.degree. C., and then 30 g
acetonitrile was charged into the process stream to make the 25.9
wt % starting solution. The solution passed through the polish
filter to remove any insoluble matters. Then dosing 600 g
acetonitrile into the solution within around 1 hour. The product
crystallized out during the addition. The slurry was stirred at
least 30 min at 20.degree. C. and the solids were collected by
suction filtration. The solids were washed with a binary solvents
acetonitrile (90 g) and DI water (10 g) and dried under vacuum
(>28'' Hg) at 55.degree. C. overnight to give
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (31.2
g, 89% yield) as a white crystalline solid.
[0437] Various preferred embodiments [A] to [DY] of the invention
can be described in the text below:
[Embodiment A] A salt, which is: [0438]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate
(Compound 1 Phosphate); [0439]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate
(Compound 1 L-Tartrate); [0440]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate
(Compound 1 D-Tartrate); [0441]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate
(Compound 1 Fumarate); [0442]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate
(Compound 1 Citrate); [0443]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate
(Compound 1 Succinate); [0444]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate
(Compound 1 Glutarate); [0445]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malate
(Compound 1 L-Malate); [0446]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine besylate
(Compound 1 Besylate); or [0447]
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate
(Compound 1 Tosylate); or a hydrate or solvate thereof. [Embodiment
B] The salt of Embodiment [B] above, or according to other
embodiments of the invention, wherein the salt is a solid form.
[Embodiment C] The salt of Embodiment [A] or [B] above, or
according to other embodiments of the invention, wherein the salt
is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate
(Compound 1 Phosphate). [Embodiment D] The salt of Embodiment [C]
above, or according to other embodiments of the invention, wherein
Compound 1 Phosphate is crystalline. [Embodiment E] The salt of
Embodiment [D] above, or according to other embodiments of the
invention, wherein the salt has characteristic XRPD peaks in terms
of 2.theta. selected from 4.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., and 18.2.degree..+-.0.2.degree..
[Embodiment F] The salt of Embodiment [D] above, or according to
other embodiments of the invention, wherein the salt has at least
one characteristic XRPD peak in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
15.7.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.. [Embodiment G] The salt of Embodiment
[D] above, or according to other embodiments of the invention,
wherein the salt has at least two characteristic XRPD peaks in
terms of 2.theta. selected from 4.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., 15.7.degree..+-.0.2.degree.,
18.2.degree..+-.0.2.degree., 22.3.degree..+-.0.2.degree.,
22.8.degree..+-.0.2.degree., and 24.8.degree..+-.0.2.degree..
[Embodiment H] The salt of Embodiment [D] above, or according to
other embodiments of the invention, wherein the salt has at least
three characteristic XRPD peaks in terms of 2.theta. selected from
4.6.degree..+-.0.2.degree., 9.1.degree..+-.0.2.degree.,
15.7.degree..+-.0.2.degree., 18.2.degree..+-.0.2.degree.,
22.3.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree., and
24.8.degree..+-.0.2.degree.. [Embodiment I] The salt of any one of
Embodiments [D] through [H] above, or according to other
embodiments of the invention, wherein the salt has an XRPD pattern
with characteristic peaks as substantially shown in FIG. 6 (FIG.
6). [Embodiment J] The salt of any one of Embodiments [D] through
[I] above, or according to other embodiments of the invention,
wherein the salt has an endotherm peak at a temperature of about
213.degree. C. [Embodiment K] The salt of any one of Embodiments
[D] through [J] above, or according to other embodiments of the
invention, wherein the salt has a DSC thermogram substantially as
depicted in FIG. 7 (FIG. 7). [Embodiment L] The salt of any one of
Embodiments [D] through [K] above, or according to other
embodiments of the invention, wherein the salt has a DVS isotherm
substantially as depicted in FIG. 9 (FIG. 9). [Embodiment M] The
salt of Embodiment [A] or [B] above, or according to other
embodiments of the invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate
(Compound 1 L-Tartrate). [Embodiment N] The salt of Embodiment [M]
above, or according to other embodiments of the invention, wherein
Compound 1 L-tartrate is crystalline. [Embodiment 0] The salt of
Embodiment [N] above, or according to other embodiments of the
invention, having Form LA. [Embodiment P] The salt of Embodiment
[0] above, or according to other embodiments of the invention,
wherein Form LA has characteristic XRPD peaks in terms of 2.theta.
selected from 12.1.degree..+-.0.2.degree.,
18.1.degree..+-.0.2.degree., and 24.2.degree..+-.0.2.degree..
[Embodiment Q] The salt of Embodiment [N] or [0] above, or
according to other embodiments of the invention, wherein Form LA
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 10 (FIG. 10). [Embodiment R] The salt of Embodiment
[N] above, or according to other embodiments of the invention,
having Form LB. [Embodiment S] The salt of Embodiment [R] above, or
according to other embodiments of the invention, wherein Form LB
has characteristic XRPD peaks in terms of 2.theta. selected from
18.7.degree..+-.0.2.degree., 25.0.degree..+-.0.2.degree., and
31.4.degree..+-.0.2.degree.. [Embodiment T] The salt of Embodiment
[R] or [S] above, or according to other embodiments of the
invention, wherein Form LB has an XRPD pattern with characteristic
peaks as substantially shown in FIG. 14 (FIG. 14). [Embodiment U]
The salt of Embodiment [N] above, or according to other embodiments
of the invention, having Form LC. [Embodiment V] The salt of
Embodiment [U] above, or according to other embodiments of the
invention, wherein Form LC has characteristic XRPD peaks in terms
of 2.theta. selected from 12.2.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., and 24.8.degree..+-.0.2.degree..
[Embodiment W] The salt of Embodiment [U] or [V] above, or
according to other embodiments of the invention, wherein Form LC
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 16 (FIG. 16). [Embodiment X] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate
(Compound 1 D-tartrate). [Embodiment Y] The salt of Embodiment [X]
above, or according to other embodiments of the invention, wherein
Compound 1 D-tartrate is crystalline. [Embodiment Z] The salt of
Embodiment [Y] above, or according to other embodiments of the
invention, wherein the salt has characteristic XRPD peaks in terms
of 2.theta. selected from 11.9.degree..+-.0.2.degree.,
16.9.degree..+-.0.2.degree., and 17.9.degree..+-.0.2.degree..
[Embodiment AA] The salt of Embodiment [Y] or [Z] above, or
according to other embodiments of the invention, wherein the salt
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 20 (FIG. 20). [Embodiment AB] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate
(Compound 1 L-Fumarate). [Embodiment AC] The salt of Embodiment
[AB] above, or according to other embodiments of the invention,
wherein Compound 1 Fumarate is crystalline. [Embodiment AD] The
salt of Embodiment [AC] above, or according to other embodiments of
the invention, having Form FA. [Embodiment AE] The Embodiment [AD]
above, or according to other embodiments of the invention, wherein
Form FA has characteristic XRPD peaks in terms of 2.theta. selected
from 7.7.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree., and
15.2.degree..+-.0.2.degree.. [Embodiment AF] The salt of Embodiment
[AD] or [AE] above, or according to other embodiments of the
invention, wherein Form FA has an XRPD pattern with characteristic
peaks as substantially shown in FIG. 22 (FIG. 22). [Embodiment AG]
The salt of Embodiment [AC] above, or according to other
embodiments of the invention, having Form FB. [Embodiment AH] The
salt of Embodiment [AG] above, or according to other embodiments of
the invention, wherein Form FB has characteristic XRPD peaks in
terms of 2.theta. selected from 6.7.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., and 20.2.degree..+-.0.2.degree..
[Embodiment AI] The salt of Embodiment [AG] or [AH] above, or
according to other embodiments of the invention, wherein Form FB
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 26 (FIG. 26). [Embodiment AJ] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate
(Compound 1 Citrate). [Embodiment AK] The salt of Embodiment [AJ]
above, or according to other embodiments of the invention, wherein
Compound 1 Citrate is crystalline. [Embodiment AL] The Embodiment
[AK] above, or according to other embodiments of the invention,
wherein the salt has characteristic XRPD peaks in terms of 2.theta.
selected from 6.5.degree..+-.0.2.degree.,
15.5.degree..+-.0.2.degree., and 20.4.degree..+-.0.2.degree..
[Embodiment AM] The salt of Embodiment [AK] or [AL] above, or
according to other embodiments of the invention, wherein the salt
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 30 (FIG. 30). [Embodiment AN] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate
(Compound 1 Succinate). [Embodiment AO] The salt of Embodiment [AN]
above, or according to other embodiments of the invention, wherein
Compound 1 Succinate is crystalline. [Embodiment AP] The salt of
Embodiment [AO] above, or according to other embodiments of the
invention, wherein the salt has characteristic XRPD peaks in terms
of 2.theta. selected from 6.6.degree..+-.0.2.degree.,
12.8.degree..+-.0.2.degree., and 13.9.degree..+-.0.2.degree..
[Embodiment AQ] The salt of Embodiment [AO] or [AP] above, or
according to other embodiments of the invention, wherein the salt
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 34 (FIG. 34). [Embodiment AR] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate
(Compound 1 Glutarate). [Embodiment AS] The salt of Embodiment [AR]
above, or according to other embodiments of the invention, wherein
Compound 1 Glutarate is crystalline. [Embodiment AT] The salt of
Embodiment [AS] above, or according to other embodiments of the
invention, wherein the salt has characteristic XRPD peaks in terms
of 2.theta. selected from 9.1.degree..+-.0.2.degree.,
10.6.degree..+-.0.2.degree., and 18.2.degree..+-.0.2.degree..
[Embodiment AU] The salt of Embodiment [AS] or [AT] above, or
according to other embodiments of the invention, wherein the salt
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 38 (FIG. 38). [Embodiment AV] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malate
(Compound 1 L-Malate). [Embodiment AW] The salt of Embodiment [AV]
above, or according to other embodiments of the invention, wherein
Compound 1 L-Malate is crystalline. [Embodiment AX] The salt of
Embodiment [AW] above, or according to other embodiments of the
invention, wherein the salt has characteristic XRPD peaks in terms
of 2.theta. selected from 13.5.degree..+-.0.2.degree.,
18.8.degree..+-.0.2.degree., and 25.2.degree..+-.0.2.degree..
[Embodiment AY] The salt of Embodiment [AW] or [AX] above, or
according to other embodiments of the invention, wherein the salt
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 40 (FIG. 40). [Embodiment AZ] The salt of Embodiment
[A] or [B] above, or according to other embodiments of the
invention, wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine besylate
(Compound 1 Besylate). [Embodiment BA] The salt of Embodiment [AZ]
above, or according to other embodiments of the invention, wherein
Compound 1 Besylate is crystalline. [Embodiment BB] The salt of
Embodiment [BA] above, or according to other embodiments of the
invention, wherein the salt has characteristic XRPD peaks in terms
of 2.theta. selected from 6.0.degree..+-.0.2.degree.,
12.0.degree..+-.0.2.degree., and 24.1.degree..+-.0.2.degree..
[Embodiment BC] The salt of Embodiment [BA] or [BB] above, or
according to other embodiments of the invention, wherein the salt
has an XRPD pattern with characteristic peaks as substantially
shown in FIG. 44 (FIG. 44). [Embodiment BD] The salt of Embodiment
[A] above, or according to other embodiments of the invention,
wherein the salt is
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate
(Compound 1 Tosylate). [Embodiment BE] A salt, which is:
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride
(Compound 1 Hydrochloride); or a hydrate or solvate thereof,
wherein the salt is crystalline and having Form HA or Form HB.
[Embodiment BF] The salt of Embodiment [BE] above, or according to
other embodiments of the invention, having Form HA. [Embodiment BG]
The salt of Embodiment [BF] above, or according to other
embodiments of the invention, wherein Form HA has characteristic
XRPD peaks in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree., and
15.1.degree..+-.0.2.degree.. [Embodiment BH] The salt of Embodiment
[BF] above, or according to other embodiments of the invention,
wherein Form HA has characteristic XRPD peaks in terms of 2.theta.
selected from 9.4.degree..+-.0.2.degree., 11.4.+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree., and
17.6.degree..+-.0.2.degree.. [Embodiment BI] The salt of Embodiment
[BF] above, or according to other embodiments of the invention,
wherein Form HA has at least one characteristic XRPD peak in terms
of 2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree.,
17.6.degree..+-.0.2.degree., and 27.0.degree..+-.0.2.degree..
[Embodiment BJ] The salt of Embodiment [BF] above, or according to
other embodiments of the invention, wherein Form HA has at least
two characteristic XRPD peaks in terms of 2.theta. selected from
9.4.degree..+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 15.1.degree..+-.0.2.degree.,
17.2.degree..+-.0.2.degree., 17.6.degree..+-.0.2.degree., and
27.0.degree..+-.0.2.degree.. [Embodiment BK] The salt of Embodiment
[BF] above, or according to other embodiments of the invention,
wherein Form HA has at least three characteristic XRPD peaks in
terms of 2.theta. selected from 9.4.degree..+-.0.2.degree.,
11.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 17.2.degree..+-.0.2.degree.,
17.6.degree..+-.0.2.degree.
, and 27.0.degree..+-.0.2.degree.. [Embodiment BL] The salt of any
one of Embodiments [BE] to [BK] above, or according to other
embodiments of the invention, wherein Form HA has an XRPD pattern
with characteristic peaks as substantially shown in FIG. 1 (FIG.
1). [Embodiment BM] The salt of any one of Embodiments [BE] to [BL]
above, or according to other embodiments of the invention, wherein
Form HA has endotherm peaks at temperatures of about 99.degree. C.
and about 187.degree. C. [Embodiment BN] The salt of any one of
Embodiments [BE] to [BM] above, or according to other embodiments
of the invention, wherein Form HA has a DSC thermogram
substantially as depicted in FIG. 2 (FIG. 2). [Embodiment BO] The
salt of any one of Embodiments [BE] to [BN] above, or according to
other embodiments of the invention, wherein Form HA has a DVS
isotherm substantially as depicted in FIG. 4 (FIG. 4). [Embodiment
BP] The salt of Embodiment [BE] above, or according to other
embodiments of the invention, having Form HB. [Embodiment BQ] The
salt of Embodiment [BP] above, or according to other embodiments of
the invention, wherein Form HB has characteristic XRPD peaks in
terms of 2.theta. selected from 8.6.degree..+-.0.2.degree.,
9.6.degree..+-.0.2.degree., and 10.3.degree..+-.0.2.degree..
[Embodiment BR] The salt of Embodiment [BP] above, or according to
other embodiments of the invention, wherein Form HB has
characteristic XRPD peaks in terms of 2.theta. selected from
8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., and 17.3.degree..+-.0.2.degree..
[Embodiment BS] The salt of Embodiment [BP] above, or according to
other embodiments of the invention, wherein Form HB has at least
one characteristic XRPD peak in terms of 2.theta. selected from
8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., 12.6.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree., and
23.8.degree..+-.0.2.degree.. [Embodiment BT] The salt of Embodiment
[BP] above, or according to other embodiments of the invention,
wherein Form HB has at least two characteristic XRPD peaks in terms
of 2.theta. selected from 8.6.degree..+-.0.2.degree.,
9.6.degree..+-.0.2.degree., 10.3.degree..+-.0.2.degree.,
12.6.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree.,
17.3.degree..+-.0.2.degree., and 23.8.degree..+-.0.2.degree..
[Embodiment BU] The salt of Embodiment [BP] above, or according to
other embodiments of the invention, wherein Form HB has at least
three characteristic XRPD peaks in terms of 2.theta. selected from
8.6.degree..+-.0.2.degree., 9.6.degree..+-.0.2.degree.,
10.3.degree..+-.0.2.degree., 12.6.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree., 17.3.degree..+-.0.2.degree., and
23.8.degree..+-.0.2.degree.. [Embodiment BV] The salt of any one of
Embodiments [BP] to [BU] above, or according to other embodiments
of the invention, wherein Form HB has an XRPD pattern with
characteristic peaks as substantially shown in FIG. 5 (FIG. 5).
[Embodiment BW] A pharmaceutical composition comprising the salt of
any one of Embodiments [A] to [BV] above, or according to other
embodiments of the invention, and a pharmaceutically acceptable
excipient. [Embodiment BX] A method for treating a neurological or
psychiatric disease or disorder in a subject in need thereof,
comprising administering to said subject an effective amount of the
salt of any one of Embodiments [A] to [BV] above, or the
pharmaceutical composition of [Embodiment BW] above, or according
to other embodiments of the invention. [Embodiment BY] The method
according to Embodiment [BX] above, or according to other
embodiments of the invention, wherein the neurological or
psychiatric disease or disorder is depression, bipolar disorder,
pain, schizophrenia, or other psychotic diseases, obsessive
compulsive disorder, addiction, social disorder, attention deficit
hyperactivity disorder, an anxiety disorder, a movement disorder,
epilepsy, autism or cognitive disease or disorder. [Embodiment BZ]
The method according to Embodiment [BX] above, or according to
other embodiments of the invention, wherein the neurological or
psychiatric disease or disorder is depression. [Embodiment CA] The
method according to Embodiment [BZ] above, or according to other
embodiments of the invention, wherein the depression is
treatment-resistant depression (TRD), major depressive disorder
(MDD), unipolar depression, bipolar depression or depression
associated with another disease or disorder. [Embodiment CB] The
method according to Embodiment [BX] above, or according to other
embodiments of the invention, wherein said neurological disease or
disorder is selected from Alzheimer's disease and Parkinson's
disease. [Embodiment CC] The method according to Embodiment [CB]
above, or according to other embodiments of the invention, wherein
said Alzheimer's disease is Alzheimer's disease with agitation,
Alzheimer's disease with aggression, Alzheimer's disease agitation
or Alzheimer's disease with agitation aggression. [Embodiment CD] A
method of treating agitation in a subject in need thereof,
comprising administering to said subject an effective amount of the
salt of any one of Embodiments [A] to [BV] above, or the
pharmaceutical composition of [Embodiment BW] above, or according
to other embodiments of the invention. [Embodiment CE] A method of
treating agitation associated with a neurological or psychiatric
disease or disorder in a subject in need thereof, comprising
administering to said subject an effective amount of the salt of
any one of Embodiments [A] to [BV] above, or the pharmaceutical
composition of [Embodiment BW] above, or according to other
embodiments of the invention. [Embodiment CF] A process of
preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
phosphate (Compound 1 Phosphate), having the structure:
##STR00030##
[0447] comprising reacting
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1)
having the structure:
##STR00031##
with phosphoric acid. [Embodiment CG] The process of Embodiment
[CF] above, or according to other embodiments of the invention,
wherein the phosphoric acid is an aqueous solution of phosphoric
acid. [Embodiment CH] The process of Embodiment [CF] above, or
according to other embodiments of the invention, wherein the
aqueous solution of phosphoric acid is an about 80% to about 95%
aqueous solution of phosphoric acid by weight. [Embodiment CI] The
process of Embodiment [CF] above, or according to other embodiments
of the invention, wherein the aqueous solution of phosphoric acid
is an about 87% aqueous solution of phosphoric acid by weight.
[Embodiment CJ] The process of any one of Embodiments [CF] to [CI]
above, or according to other embodiments of the invention, wherein
the reacting of Compound 1 with phosphoric acid is carried out in
the presence of S1a, wherein S1a is a solvent. [Embodiment CK] The
process of Embodiment [CJ] above, or according to other embodiments
of the invention, wherein S1a is a mixture of acetonitrile and
water. [Embodiment CL] The process of Embodiment [CJ] above, or
according to other embodiments of the invention, wherein S1a is a
mixture of acetone and water. [Embodiment CM] The process of
Embodiment [CJ] above, or according to other embodiments of the
invention, wherein S1a is a polar aprotic solvent, water, or a
mixture thereof. [Embodiment CN] The process of any one of
Embodiments [CF] to [CM] above, or according to other embodiments
of the invention, wherein between about 1 and about 5 molar
equivalents of phosphoric acid are used per molar equivalent of
Compound 1. [Embodiment CO] The process of any one of Embodiments
[CF] to [CN] above, or according to other embodiments of the
invention, wherein Compound 1 is prepared by a process comprising
reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate) having the
structure:
##STR00032##
wherein B1 is a base. [Embodiment CP] A process of preparing
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1)
comprising reacting
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate) having the
structure:
##STR00033##
wherein B1 is a base. [Embodiment CQ] The process of Embodiment
[CO] or [CP] above, or according to other embodiments of the
invention, wherein B1 is an alkali hydroxide base. [Embodiment CR]
The process of Embodiment [CO] or [CP] above, or according to other
embodiments of the invention, wherein B1 is potassium hydroxide.
[Embodiment CS] The process of Embodiment [CO] or [CP] above, or
according to other embodiments of the invention, wherein B1 is an
aqueous solution of potassium hydroxide. [Embodiment CT] The
process of Embodiment [CS] above, or according to other embodiments
of the invention, wherein the aqueous solution of potassium
hydroxide is an about 10% to about 20% aqueous solution of
potassium hydroxide by weight. [Embodiment CU] The process of
Embodiment [CS] above, or according to other embodiments of the
invention, wherein the aqueous solution of potassium hydroxide is
an about 14% aqueous solution of potassium hydroxide by weight.
[Embodiment CV] The process of any one of Embodiments [CO] to [CU]
above, or according to other embodiments of the invention, wherein
the reacting of Compound 1 dibenzoyl-L-tartrate and the base is
carried out in the presence of S2, wherein S2 is a solvent.
[Embodiment CW] The process of Embodiment [CV] above, or according
to other embodiments of the invention, wherein S2 is a polar
aprotic solvent. [Embodiment CX] The process of any one of
Embodiments [CO] to [CW] above, or according to other embodiments
of the invention, wherein between about 0.5 and about 5 molar
equivalents of B1 are used per molar equivalent of Compound 1
dibenzoyl-L-tartrate. [Embodiment CY] The process of any one of
Embodiments [CO] to [CX] above, or according to other embodiments
of the invention, wherein the reacting of Compound 1
dibenzoyl-L-tartrate with B1 is further carried out in the presence
of sodium chloride. [Embodiment CZ] The process of any one of
Embodiments [CO] to [CY] above, or according to other embodiments
of the invention, wherein about 1 to about 10 molar equivalents of
sodium chloride are used per molar equivalent of Compound 1
dibenzoyl-L-tartrate. [Embodiment DA] A process for preparing
(R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine
dibenzoyl-L-tartrate (Compound 1 dibenzoyl-L-tartrate), comprising
reacting 1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Racemic
Compound 1) having the structure:
##STR00034##
with dibenzoyl-L-tartaric acid in the presence of S3, wherein S3 is
a solvent. [Embodiment DB] The process of Embodiment [DA] above, or
according to other embodiments of the invention, wherein S3 is a
polar protic solvent. [Embodiment DC] The process of Embodiment
[DA] above, or according to other embodiments of the invention,
wherein S3 is a mixture of methanol and water. [Embodiment DD] The
process of any one of Embodiments [DA] to [DC] above, or according
to other embodiments of the invention, wherein about 1 to about 5
molar equivalents of dibenzoyl-L-tartaric acid are used per molar
equivalent of Racemic Compound 1. [Embodiment DE] The process of
any one of Embodiments [DA] to [DD] above, or according to other
embodiments of the invention, further comprising precipitating
Compound 1 dibenzoyl-L-tartrate from a mixture comprising: Racemic
Compound 1, dibenzoyl-L-tartaric acid, and S3. [Embodiment DF] The
process of any one of Embodiments [DA] to [DE] above, or according
to other embodiments of the invention, further comprising isolating
Compound 1 dibenzoyl-L-tartrate from S3a, wherein S3a is a solvent.
[Embodiment DG] The process of Embodiment [DF] above, or according
to other embodiments of the invention, wherein S3a is methanol.
[Embodiment DH] The process of any one of Embodiments [DA] to [DG]
above, or according to other embodiments of the invention, wherein
1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Racemic Compound
1) is prepared by a process comprising hydrogenating a compound of
Formula II, having the structure:
##STR00035##
or a salt thereof, wherein X is halo, in the presence of a metal
catalyst. [Embodiment DI] The process of Embodiment [DH] above, or
according to other embodiments of the invention, wherein the
compound of Formula II is
1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine
trifluoromethanesulfonate (Compound 2) having the structure:
##STR00036##
[Embodiment DJ] The process of Embodiment [DH] or [DI] above, or
according to other embodiments of the invention, wherein the metal
catalyst is palladium on activated carbon. [Embodiment DK] The
process of any one of Embodiments [DH] to [DJ] above, or according
to other embodiments of the invention, wherein the hydrogenating of
the compound of Formula II is carried out at a hydrogen pressure of
about 2 to about 10 bar. [Embodiment DL] The process of any one of
Embodiments [DH] to [DK] above, or according to other embodiments
of the invention, wherein the hydrogenating of the compound of
Formula II is carried out at a hydrogen pressure of about 5 bar.
[Embodiment DM] The process of any one of Embodiments [DH] to [DL]
above, or according to other embodiments of the invention, wherein
the hydrogenating of the compound of Formula II is carried out in
the presence of S4, wherein S4 is a solvent. [Embodiment DN] The
process of Embodiment [DM] above, or according to other embodiments
of the invention, wherein S4 is a polar protic solvent. [Embodiment
DO] The process of any one of Embodiments [DH] to [DN] above, or
according to other embodiments of the invention, wherein the
hydrogenating of the compound of Formula II is carried out in the
presence of B2, wherein B2 is a base. [Embodiment DP] The process
of Embodiment [DO] above, or according to other embodiments of the
invention, wherein B2 is a carbonate base. [Embodiment DQ] The
process of Embodiment [DO] above, or according to other embodiments
of the invention, wherein B2 is potassium carbonate. [Embodiment
DR] The process of Embodiment [DO] above, or according to other
embodiments of the invention, wherein B2 is an aqueous solution of
potassium carbonate. [Embodiment DS] The process of any one of
Embodiments [DH] to [DR] above, or according to other embodiments
of the invention, wherein the compound of Formula II is prepared by
reacting a compound of Formula III having the structure:
##STR00037##
or a salt thereof, wherein X is halo, with
N-methylaminoacetaldehyde dimethylacetal (Compound 4) having the
structure:
##STR00038##
in the presence of A1, wherein A1 is an acid. [Embodiment DT] The
process of Embodiment [DS] above, or according to other embodiments
of the invention, wherein the compound of Formula III is
2-(2-bromo-5-fluorophenyl)ethan-1-ol (Compound 3) having the
structure:
##STR00039##
[Embodiment DU] The process of claim Embodiment [DS] or [DT] above,
or according to other embodiments of the invention, wherein A1 is
trifluoromethanesulfonic acid. [Embodiment DV] The process of any
one of Embodiments [DS] to [DU] above, or according to other
embodiments of the invention, wherein the reacting of the compound
of Formula III and Compound 4 is carried out in the presence of S5,
wherein S5 is a solvent. [Embodiment DW] The process of Embodiment
[DV] above, or according to other embodiments of the invention,
wherein S5 is a halogenated solvent. [Embodiment DX] The process of
any one of Embodiments [DS] to [DW] above, or according to other
embodiments of the invention, wherein about 1.2 molar equivalents
of Compound 4 are used per molar equivalent of the compound of
Formula III. [Embodiment DY] Compound 1 Phosphate prepared by the
process of any one of Embodiments [CF] to [CO] above, or according
to other embodiments of the invention, wherein Compound 1 Phosphate
is crystalline.
[0448] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference,
including all patent, patent applications, and publications, cited
in the present application is incorporated herein by reference in
its entirety.
* * * * *