NZ625511B2 - Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use - Google Patents
Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use Download PDFInfo
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- NZ625511B2 NZ625511B2 NZ625511A NZ62551112A NZ625511B2 NZ 625511 B2 NZ625511 B2 NZ 625511B2 NZ 625511 A NZ625511 A NZ 625511A NZ 62551112 A NZ62551112 A NZ 62551112A NZ 625511 B2 NZ625511 B2 NZ 625511B2
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- pyrazin
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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Abstract
Disclosed herein are compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, solid forms, isotopologues and metabolites thereof, stearic acid and lactose monohydrate and methods of their use for the treatment of a disease disorder, or condition such as cancer, especially solid tumours, non-Hodgkin lymphoma and glioblastoma multiforme, an inflammatory condition, an immunological condition, a neurodegenerative disease, diabetes, obesity, a neurological disorder, an age-related disease, or a cardiovascular condition. disorder, or condition such as cancer, especially solid tumours, non-Hodgkin lymphoma and glioblastoma multiforme, an inflammatory condition, an immunological condition, a neurodegenerative disease, diabetes, obesity, a neurological disorder, an age-related disease, or a cardiovascular condition.
Description
WO 82344
PHARMACEUTICAL COMPOSITIONS OF 7-(6-(2-HYDROXYPROPAN
YL)PYRIDINYL)—1-((TRANS)METHOXYCYCLOHEXYL)—3,4-
DIHYDROPYRAZINO [2,3-B]PYRAZIN-2(1H)—ONE, A SOLID FORM THEREOF
AND METHODS OF THEIR USE
This application claims the benefit of and priority to US. Provisional
Application No. 61/566,109, filed er 2, 201 1, US. Provisional Application No.
61/647,288, filed May 15, 2012, US. Provisional Application No.61/653,439, filed May 31,
2012 and US. Provisional Application No. 61/670,419, filed July 11, 2012, the entire ts
of each of which are incorporated herein by reference.
1. FIELD
Provided herein are compositions of 7-(6-(2-hydroxypropanyl)pyridinyl)-
1-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)—one, a solid form
thereof, isotopologues thereof, and s of their use for the treatment of a disease, disorder,
or condition.
2. BACKGROUND
The connection between abnormal protein phosphorylation and the cause or
consequence of diseases has been known for over 20 years. Accordingly, protein kinases have
become a very important group of drug targets. See Cohen, Nature, 1:309-315 (2002). s
protein kinase tors have been used clinically in treating a wide variety of diseases, such as
cancer, chronic inflammatory es, diabetes, and stroke. See Cohen, Eur. J. Biochem.,
268:5001-5010 (2001), n Kinase torsfor the Treatment osz'sease.‘ The Promise
and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167
(2005).
The elucidation of the intricacy of protein kinase pathways and the complexity
of the relationship and interaction among and between the various protein kinases and kinase
pathways highlights the importance of developing pharmaceutical agents capable of acting as
protein kinase modulators, regulators, or inhibitors that have ial actiVity on multiple
kinases or multiple kinase pathways. Accordingly, there remains a need for new kinase
modulators.
The protein named mTOR (mammalian target of rapamycin), also known as
FRAP, RAFTI or RAPTl , is a Ser/Thr protein kinase related to the lipid kinases of the
phosphoinositide 3-kinase (PI3K) . It functions as a sensor of mitogen, energy, and
nutrient levels; and is a central controller of cell growth. mTOR has been shown to be one of
the most critical proteins in the mTOlVPBK/Akt pathway that regulates cell growth and
eration. kis and Younes, Expert Rev. Anticancer Ther. 6(1): 13 1-140 (2006).
mTOR exists in two complexes, mammalian target of rapamycin x 1 l) which
complexes with raptor, and mammalian target of rapamycin complex 2 (mTORC2) which
complexes with rictor. While mTORCl is sensitive to rapamycin analogs (such as
olimus or imus), mTORC2 is largely rapamycin-insensitive (Kim et al., Cell
110(2): 163-175 (2002); Sarbassov et al., e 307: 1098-1 101 (2005)). .
l mTOR inhibitors have been or are being evaluated in clinical trials for
the treatment of cancer. For example, temsirolimus was approved for use in renal cell
carcinoma in 2007 and sirolimus was approved in 1999 for the prophylaxis of renal transplant
rejection. imus was approved in 2009 for renal cell carcinoma patients that have
progressed on vascular endothelial growth factor receptor inhibitors, in 2010 for
subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in
patients who require therapy but are not candidates for al resection, and in 2011 for
progressive neuroendocrine tumors of pancreatic origin (PNET) in patients
with unresectable, locally advanced or atic e. The interesting but limited clinical
success of these mTORCl compounds demonstrates the usefulness ofmTOR inhibitors in the
treatment of cancer and transplant rejection, and the increased potential for compounds with
both mTORCl and mTORC2 inhibitory actiVity.
The preparation and selection of a solid form of a pharmaceutical compound are
complex, given that a change in the solid form may affect a variety of physical and chemical
properties of the compound, which may in turn provide s or drawbacks in processing,
formulation, stability, and ilability of the compound. Potential pharmaceutical solids
include crystalline solids and amorphous solids. An amorphous solid is characterized by a lack
of long-range structural order, whereas a crystalline solid is characterized by ural
periodicity. The desired class of pharmaceutical solids depends upon the specific ation;
an amorphous solid is sometimes selected on the basis of, e.g., an enhanced dissolution profile,
while a crystalline solid may be desirable for properties, such as physical or chemical stability.
See Vippagunta et al., Adv. Drug. Deliv. Rev., 483-26 (2001); Yu, Adv. Drug. Deliv. Rev.,
48:27-42 (2001).
Whether crystalline or amorphous, potential solid forms of a pharmaceutical
compound may e single-component . A single-component solid contains
essentially the pharmaceutical compound in the absence of other compounds. y among
single-component lline materials may potentially arise, e.g. , from the phenomenon of
polymorphism, wherein multiple three-dimensional ements exist for a single
pharmaceutical compound. See Bym et al., Solid State Chemistry of Drugs, SSCI, West
Lafayette (1999). The importance of polymorphs in ceuticals was underscored by the
case of Ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About
two years after the product was launched, the unanticipated precipitation of a new, less soluble
polymorph in the formulation necessitated the withdrawal of the product from the market until a
more consistent formulation could be developed. See Chemburkar et al., Org. Process Res.
Dev., 4:413-417 (2000).
Notably, it is not possible to predict a priori if crystalline forms of a compound
even exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005,
“Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem.
Commun. :3635-3645 (with t to crystal ering, if instructions are not very e
and/or if other external factors affect the process, the result can be unpredictable); Jones et al.,
2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,”
MRS Bulletin 31:875-879 (At present it is not generally possible to computationally predict the
number of observable rphs of even the simplest molecules); Price, 2004, “The
4 (Followed by page 4A)
ational prediction of pharmaceutical crystal structures and polymorphism,” Advanced
Drug Delivery Reviews -319 (“Price”); and Bernstein, 2004, “Crystal Structure
Prediction and Polymorphism,” ACA Transactions 39:14-23 (a great deal still needs to be
learned and done before one can state with any degree of confidence the y to predict a
crystal structure, much less polymorphic forms)). The preparation of solid forms is of great
importance in the development of a safe, ive, stable, and marketable pharmaceutical
compound.
Citation or identification of any references in this disclosure is not to be
construed as an admission that the references are prior art to this disclosure.
1. SUMMARY
Provided herein are compositions of 7-(6-(2-hydroxypropanyl)pyridin
yl)((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, or a
pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof. In one
embodiment, the solid form is crystalline. In another embodiment, the solid form is a singlecomponent
crystalline form of 7-(6-(2-hydroxypropanyl)pyridinyl)((trans)
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. In yet another
embodiment, the solid form is crystalline Form A of 7-(6-(2-hydroxypropanyl)pyridin
yl)((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Solid
form A of 7-(6-(2-hydroxypropanyl)pyridinyl)((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(1H)-one is claimed in a divisional ation, and a
description of this form is retained herein for completeness.
] In a particular embodiment, provided is a ceutical composition
comprising an effective amount of 7 (6 (2 hydroxypropanyl)pyridinyl)((trans)
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form f, stearic acid and lactose
monohydrate, wherein the the metabolite is the ethyl metabolite having the structure:
4A (Followed by page 5)
OH 6)
|\ :
N/ NNo
Ilf\
In yet another embodiment, the solid form is a hydrate. In yet r
ment, the solid form is hydrate Form B of 7-(6-(2—hydroxypropan—2-yl)pyridin—3-yl)-
1-((Irans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)—one.
In yet another embodiment, the solid form is anhydrous. In yet another
embodiment, the solid form is anhydrous Form C of 7—(6-(2-hydroxypropan—2—yl)pyridin—3-
yl)((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In yet another embodiment, the solid form is a solvate. In yet another
embodiment, the solid form is methanol solvate Form D of 7-(6-(2-hydroxypropan
yl)pyridin-3—yl)((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-
one.
In yet another embodiment, the solid form is a pinacol co-crystal of 7-(6-(2-
hydroxypropanyl)pyridin-3 -yl)- l ns)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -
b]pyrazin-2(lH)—one.
In another embodiment, the isotopologue is enriched in C, 14C and/or 2H.
Without intending to be limited by any particular theory, a solid form provided
herein has particular advantageous physical and/or chemical properties making them useful,
e. g., for manufacturing, processing, formulation and/or storage, While also possessing
ularly advantageous biological properties, such as, e.g. , bioavailability and/or biological
activity.
Also provided herein are pharmaceutical compositions comprising
2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
opyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, and one or more pharmaceutically able excipients.
In one embodiment, the pharmaceutical ition comprises a solid form of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, and one or more pharmaceutically acceptable ents.
In one embodiment, the pharmaceutical composition comprises Form A of
2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, and one or more pharmaceutically acceptable excipients
In one ment, the pharmaceutical composition comprises Form B of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, and one or more pharmaceutically acceptable excipients.
In one embodiment, the pharmaceutical composition comprises Form C of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, and one or more pharmaceutically acceptable excipients.
In one embodiment, the pharmaceutical composition comprises Form D of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, and one or more pharmaceutically acceptable excipients.
WO 82344
In one embodiment, the pharmaceutical composition ses a pinacol co-
crystal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-
dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one, and one or more pharmaceutically acceptable
excipients.
In another embodiment, the pharmaceutical composition comprises an
isotopologue of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)—
3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one, and one ore more pharmaceutically acceptable
excipients. 13
In one embodiment, the isotopologue is enriched in C, 14C and/or 2H.
Additionally, provided herein are isotopologues of 7-(6-(2-hydroxypropan
idinyl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2(1H)-
one itself, ing isotopologues enriched in 13C, 14C and/or 2H, including those set forth
Additionally, provided herein is are methods of treating or preventing a disease,
disorder, or ion in a subject, which comprises administering to the subject a
eutically effective amount of a composition of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-
l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a
pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof In certain
embodiments, the disease, disorder, or condition is cancer, inflammatory conditions,
immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological
disorders, age-related es, and/or cardiovascular conditions, and/or conditions treatable or
table by tion of a kinase pathway. In one embodiment, the kinase pathway is the
mTOlVPI3K/Akt pathway.
Provided herein are methods of treating or preventing a disease, disorder, or
condition in a subject, which comprise inhibiting a kinase pathway in said subject with a
metabolite of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In certain ments, the metabolite is the
O-desmethyl metabolite (having the name l-((lr,4r)—4-hydroxycyclohexyl)(6-(2-
hydroxypropanyl)pyridinyl)-3 ,4-dihydropyrazino[2,3-b]pyrazin-2( l H)—one). In certain
embodiments, the disease, disorder, or condition is cancer, inflammatory conditions,
immunological conditions, neurodegenerative diseases, es, obesity, neurological
disorders, age-related diseases, and/or vascular conditions, and/or conditions treatable or
table by inhibition of a kinase y. In one embodiment, the kinase pathway is the
mTOlVPI3K/Akt y.
Provided herein are methods of ng or preventing a disease, disorder, or
condition in a subject, which comprise administering an effective amount of a compound that
provides a metabolite of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)—4-
ycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one upon administration to said
patient. In certain embodiments, the metabolite is the O-desmethyl lite (having the
name l-(( l r,4r)hydroxycyclohexyl)(6-(2-hydroxypropanyl)pyridin-3 -yl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one). In certain embodiments, the disease, disorder, or
condition is cancer, inflammatory conditions, immunological conditions, neurodegenerative
diseases, diabetes, obesity, neurological disorders, age-related diseases, and/or cardiovascular
conditions, and/or conditions ble or preventable by inhibition of a kinase pathway. In one
embodiment, the kinase pathway is the mTOlVPI3K/Akt pathway.
In one embodiment, the method comprises administering to the t a
therapeutically effective amount of Form A of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form B of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subj ect a
therapeutically effective amount of Form C of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one ment, the method comprises administering to the subj ect a
therapeutically effective amount of Form D of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of a pinacol co-crystal of 7-(6-(2-hydroxypropanyl)pyridinyl)— l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( lH)-one.
In another ment, the method comprises administering to the subject a
eutically effective amount of an isotopologue of 2-hydroxypropanyl)pyridin
yl)-l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one
embodiment, the isotopologue is enriched in 13 C, 14C and/or 2H.
Further provided herein is are methods of treating or preventing a proliferative
disease in a t, which comprises administering to the t a therapeutically effective
amount of a composition of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-((trans)—4-
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form thereof.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form A of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
s)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form B of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subj ect a
therapeutically effective amount of Form C of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method ses administering to the subj ect a
therapeutically effective amount of Form D of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of a pinacol co-crystal of 7-(6-(2-hydroxypropanyl)pyridinyl)— l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 azin-2( lH)-one.
In another ment, the method comprises administering to the subject a
therapeutically effective amount of an isotopologue of 7-(6-(2-hydroxypropanyl)pyridin
yl)-l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one
embodiment, the ologue is enriched in 13 C, 14C and/or 2H.
Provided herein are methods of treating or preventing an mTOR-mediated
e in a subject, which comprises administering to the subject a therapeutically effective
amount of a composition of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-((trans)—4-
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, ologue, metabolite or solid form thereof.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form A of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises stering to the subject a
therapeutically effective amount of Form B of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one ment, the method ses administering to the subj ect a
therapeutically effective amount of Form C of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subj ect a
therapeutically effective amount of Form D of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises stering to the subject a
therapeutically effective amount of a pinacol co-crystal of 7-(6-(2-hydroxypropanyl)pyridinyl)— l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 azin-2( lH)-one.
In another embodiment, the method comprises administering to the subject a
therapeutically effective amount of an isotopologue of 7-(6-(2-hydroxypropanyl)pyridin
yl)-l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one
embodiment, the isotopologue is enriched in 13 C, 14C and/or 2H.
Provided herein are methods of inhibiting the growth of a cell, comprising
ting the cell with a composition of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)—
4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a ceutically
acceptable salt, isotopologue, metabolite or solid form thereof.
In one embodiment, the method comprises contacting the cell with Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l ns)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises contacting the cell with Form B of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method ses contacting the cell with Form C of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises contacting the cell with Form D of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method ses contacting the cell with a pinacol co-
crystal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-
dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In another embodiment, the method comprises contacting a cell with an
isotopologue of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)—
3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one embodiment, the isotopologue is
enriched in 13C, 14C and/or 2H.
Provided herein are s of modulating the activity of TOR kinase,
comprising contacting TOR kinase with a composition of 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l ns)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino[2,3-b]pyrazin-2( e, or a
pharmaceutically acceptable salt, isotopologue, metabolite, or solid form thereof.
In one embodiment, the method comprises contacting TOR kinase with Form A
of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)— l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises contacting TOR kinase with Form B
of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
opyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises contacting TOR kinase with Form C
of 2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises contacting TOR kinase with Form D
of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method ses contacting TOR kinase with a pinacol
co-crystal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-
dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one.
In another embodiment, the method comprises the method comprises ting
TOR kinase with an isotopologue of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one embodiment, the
isotopologue is ed in 13C, 14C and/or 2H.
Provided herein are methods for treating or preventing a solid tumor, non-
Hodgkin ma or multiple myeloma comprising administering an effective amount of a
composition of 7-(6-(2-hydroxypropanyl)pyridinyl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, isotopologue, metabolite or a ceutically
acceptable salt or solid form thereof, to a subject having a solid tumor, non-Hodgkin lymphoma
or le myeloma.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form A of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form B of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form C of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
s)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises stering to the subj ect a
therapeutically effective amount of Form D of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of a pinacol co-crystal of 7-(6-(2-hydroxypropanyl)pyridinyl)— l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( lH)-one.
In another embodiment, the method comprises administering to the subject a
therapeutically effective amount of an isotopologue of 7-(6-(2-hydroxypropanyl)pyridin
yl)-l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one
embodiment, the isotopologue is ed in 13 C, 14C and/or 2H.
In certain ments, provided herein are methods for achieving a Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or
stable disease, ing the International Workshop Criteria (IWC) for NHL, International
Uniform Response Criteria for le Myeloma (IURC), Eastern Cooperative Oncology
Group Performance Status (ECOG) or Response ment for Oncology (RANO)
Working Group for GBM comprising administering an effective amount of a composition of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof to a t having a solid tumor, non-Hodgkin ma or
multiple myeloma
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form A of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of Form B of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically ive amount of Form C of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subj ect a
therapeutically effective amount of Form D of 7-(6-(2—hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In one embodiment, the method comprises administering to the subject a
therapeutically effective amount of a pinacol co-crystal of 7-(6-(2-hydroxypropanyl)pyridinyl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( lH)-one.
In another embodiment, the method comprises administering to the subject a
therapeutically ive amount of an isotopologue of 2-hydroxypropanyl)pyridin
yl)-l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In one
embodiment, the isotopologue is enriched in 13 C, 14C and/or 2H.
In certain embodiments, provided herein are methods for making Form A of
2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, comprising dissolving amorphous 7-(6-(2—hydroxypropan-
2-yl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydro-pyrazino [2,3 -b]pyrazin-2( lH)-
one in toluene, MTBE (methyl tert-butyl ether), DIPE (diisopropyl ether), THF
(tetrahydrofuran), DME hoxyethane), IPAc opyl acetate), EtOAc (ethyl e),
MIBK l isobutyl ketone), acetone, IPA (isopropyl alcohol), ethanol, ACN nitrile),
nitromethane, or IPA:water (95 :5) and allowing the resulting solution to evaporate at room
temperature.
In certain embodiments, provided herein are methods for making Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)- l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT (butylated hydroxytoluene), IPA and water, heating and then cooling to room
temperature.
2012/067172
In certain embodiments, provided herein are methods for making Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, sing dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT and MeOAc (methyl acetate), heating, cooling to room temperature, distilling
under vacuum and contacting with n-heptane.
In certain embodiments, provided herein are methods for making Form B of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT, IPA and water, g e and adding water, g the mixture,
collecting by ion, washing with IPA & water, and drying. In certain embodiments, this
process fiarther comprises adding a small amount of Form B in water to the mixture of 7-(6-(2-
hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -
b]pyrazin-2(lH)—one in BHT, IPA and water.
In certain embodiments, provided herein are s for making Form C of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT, MeOH, distilling to remove MeOH, further distillation with IPA, g the
mixture, collecting by filtration, washing with IPA and drying.
In certain embodiments, provided herein are methods for making Form D of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture ofBHT in MeOH, heating, then cooling with ng, collection by filtration, washing
and drying.
In certain embodiments, provided herein are methods for making a pinacol co-
crystal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, comprising mixing 7-(6-(2-hydroxypropan
yl)pyridinyl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2(1H)-
one with pinacol in solution, heating until solids are dissolved, distilling said solution and
seeding with a pinacol stal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-((trans)
ycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
In n embodiments, provided herein are methods for preparing a
composition provided herein, comprising: (i) ng out the desired amount of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof and the desired amount of ents; (ii) mixing or blending
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof and the excipients; (iii) passing the mixture of 7-(6-(2—
hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, ologue,
metabolite or solid form thereof and excipients through a screen; (iv) mixing or blending
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof and the excipients; (v) weighing out the desired amount of
lubricating agents; (vi) passing the lubricating agents through a screen; (vii) mixing or blending
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l ns)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the excipients and the lubricating agents; (viii) compressing
the mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the excipients and the lubricating agents; and (ix) coating the
compressed mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)—4-
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form thereof, the excipients and the
lubricating agents.
In n embodiments, ed herein are methods for preparing a
composition provided herein, comprising: (i) weighing out the desired amount of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof and the desired amount of excipients; (ii) g the excipients
through a ; (iii) mixing or blending 7-(6-(2-hydroxypropanyl)pyridinyl)—l-((trans)—
4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form thereof and the excipients; (iv) passing
the mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof and excipients through a screen; (v) mixing or blending
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a ceutically able salt, ologue,
metabolite or solid form thereof and the excipients; (vi) weighing out the desired amount of
lubricating agents; (vii) passing the lubricating agents through a screen; (viii) mixing or
blending 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a ceutically able salt, isotopologue,
metabolite or solid form thereof, the excipients and the lubricating agents; (ix) compressing the
mixture of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)— l ns)—4-methoxycyclohexyl)-3,4-
opyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the excipients and the lubricating agents; and (x) coating the
compressed mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)—4-
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form thereof, the excipients and the
lubricating agents.
4. BRIEF DESCRIPTION OF THE DRAWINGS
depicts an X-ray powder diffractogram of Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
opyrazino[2,3-b]pyrazin-2(lH)-one.
depicts polar light microscopy photographs of Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l ns)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
depicts a thermograVimetric thermogram (top) and a differential scanning
calorimetric thermogram (bottom) of Form A of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)—3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
depicts kinetic (top) and isotherm (bottom) DVS curves of Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
dipicts dissolution profiles of 20 mg s of Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)—one (Core vs Coated).
depicts a differential ng calorimetric (DSC) thermogram of a
pinacol co-crystal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
depicts an X-ray powder diffractogram of a pinacol co-crystal of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
provides plasma tration-time profiles in healthy adult males
administered a single 20 mg oral dose of Compound A.
depicts an X-ray powder diffractogram of Form B of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
depicts a differential scanning calorimetric (DSC) thermogram of Form
B of 2-hydroxypropanyl)pyridinyl)- l -((trans)—4-methoxycyclohexyl)—3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
FIG. ll depicts an X-ray powder diffractogram of Form C of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
depicts a differential ng calorimetric (DSC) thermogram of
Form C of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
depicts a differential scanning calorimetric (DSC) thermogram of
Form D of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
s an X-ray powder ctogram of Form D of
2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one.
. DETAILED DESCRIPTION
.1 DEFINITIONS
To facilitate understanding of the disclosure set forth herein, a number of terms
are defined below.
Generally, the nomenclature used herein and the laboratory procedures in
organic chemistry, nal chemistry, and cology described herein are those well
known and commonly employed in the art. Unless def1ned otherwise, all technical and
scientific terms used herein generally have the same meaning as commonly tood by one
of ordinary skill in the art to which this disclosure belongs.
It should be noted that if there is a discrepancy between a depicted structure and
a name given that structure, the depicted structure is to be accorded more weight. In addition, if
the stereochemistry of a structure or a portion of a structure is not indicated with, for e,
bold or dashed lines, the structure or portion of the structure is to be interpreted as
encompassing all stereoisomers of it.
The term “Compound A” refers to 7-(6-(2-hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, also haVing the
chemical names 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -(( lr,4r)—4-methoxycyclohexyl)-
3 ,4-dihydropyrazino[2,3 -b]pyrazin-2( l H)-one and 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -
(( l R* ,4R*)methoxycyclohexyl)—3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( l , which has
the following structure:
I :
N / N N o
I I T
N N
including pharmaceutically acceptable salts, isotopologues, solid forms and lites thereof.
Compound A can be prepared according to the methods described in US. Pat.
Appl. Publ. Nos. 2010/0216781 and 2011/0137028, the disclosure of each of which is
orated herein by reference in its entirety. Compound A can also be synthesized according
to other s apparent to those of skill in the art based upon the teaching herein.
The term “subject” refers to an animal, including, but not limited to, a primate
(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject”
and “patient” are used herein interchangeably in reference, for example, to a mammalian
subject, such as a human subject, in one ment, a human. In one embodiment, the subject
has or is susceptible to having a disease, disorder, or condition provided herein.
The term “treat,” “treating,” or “treatment” means an alleviation, in whole or in
part, of a e, disorder, or condition provided herein, or one or more symptoms associated
with the disease, disorder, or condition, or slowing, or halting of further progression or
worsening of the disease, disorder, or condition, or one or more symptoms associated with the
disease, er, or ion.
The term “prevent,” “preventing,” or ntion” means prevention of the
onset, ence, or spread of a disease, disorder, or condition ed herein, or one or more
symptoms associated with the disease, disorder, or condition, in a subject at risk for developing
the disease, disorder, or condition.
The term “effective amount” or “therapeutically effective amount” refers to, in
one embodiment, an amount of Compound A capable of alleviating, in whole or in part, one or
more symptoms associated with a disease, disorder, or condition provided herein, or slowing or
halting further progression or worsening of one or more of the symptoms of the disease,
er, or condition; in another embodiment, an amount capable of preventing or providing
prophylaxis for the disease, disorder, or condition in a t at risk for ping the disease,
disorder, or condition, such as cancer, inflammatory conditions, immunological conditions,
neurodegenerative diseases, es, obesity, neurological disorders, age-related diseases,
and/or cardiovascular conditions, and/or diseases, disorders, and conditions treatable or
preventable by inhibition of a kinase pathway, for example, the mTOlVPI3K/Akt pathway. In
one embodiment, an effective amount of a compound is an amount that inhibits a kinase in a
cell, such as, for example, in vitro or in vivo. In one embodiment the kinase is TOR kinase. In
certain embodiments, the effective amount of a compound ts the kinase in a cell by about
%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about
90%, or about 99%, ed to the activity of the kinase in an ted cell. In one
embodiment, “effective amount” refers to the amount of Compound A capable of alleviating, in
whole or in part, symptoms associated with a solid tumor (for example, a neuroendocrine
tumor, non-small cell lung cancer, glioblastoma multiforme, hepatocellular carcinoma, breast
cancer, colorectal cancer, ry cancer, pancreatic cancer, adenocystic cancer, adrenal
cancer, esophageal , renal , leiomyosarcoma, or paraganglioma, including
ed solid tumors), non-Hodgkin lymphoma or multiple myeloma, or slowing or halting
further progression or worsening of those symptoms, or treating or ting a solid tumor (for
example, a neuroendocrine tumor, all cell lung , glioblastoma multiforme,
hepatocellular carcinoma, breast cancer, colorectal cancer, salivary cancer, pancreatic cancer,
adenocystic cancer, adrenal cancer, esophageal , renal cancer, leiomyosarcoma, or
paraganglioma), non-Hodgkin lymphoma or multiple myeloma in a subject having or at risk for
having a solid tumor, non-Hodgkin lymphoma or multiple a. As will be apparent to
those skilled in the art, it is to be expected that the effective amount of a compound disclosed
herein may vary depending on the indication being treated, e.g. the effective amount of the
compound would likely be different for ng ts suffering from, or at risk for,
inflammatory conditions relative to the effective amount of the compound for treating patients
suffering from, or at risk of, a different disorder, e.g., a disorder provided herein.
In the context of a solid tumor (for e, a neuroendocrine tumor, non-small
cell lung cancer, glioblastoma multiforme, hepatocellular oma, breast cancer, colorectal
cancer, salivary , pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal
, renal cancer, leiomyosarcoma, or nglioma, including advanced solid tumors),
non-Hodgkin lymphoma or multiple myeloma, inhibition may be assessed by inhibition or
retarding of disease progression, inhibition of tumor growth, reduction or regression of primary
and/or secondary tumor (s), relief of tumor-related ms, improvement in quality of life,
inhibition of tumor ed s (including tumor secreted hormones, such as those that
contribute to carcinoid syndrome), ions in endocrine hormone markers (for example,
chromogranin, gastrin, serotonin, and/or glucagon), delayed appearance or recurrence of
primary or secondary tumors, slowed development of primary and/or secondary tumors,
decreased ence of primary and/or secondary tumors, slowed or decreased severity of
secondary effects of disease, arrested tumor growth and/or regression of tumors, increased Time
To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival
(OS), among others. OS as used herein means the time from randomization until death from
any cause, and is measured in the intent-to-treat population. TTP as used herein means the time
from randomization until objective tumor progression; TTP does not include deaths. As used
herein, PFS means the time from randomization until objective tumor ssion or death. In
one embodiment, PFS rates will be computed using the Kaplan-Meier estimates. In the
extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this
context, the term “prevention” includes either preventing the onset of clinically evident solid
tumor (for example, a neuroendocrine tumor, non-small cell lung cancer, glioblastoma
orme, hepatocellular oma, breast , colorectal cancer, salivary cancer,
pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal cancer, renal cancer,
leiomyosarcoma, or paraganglioma, including advanced solid tumors), non-Hodgkin lymphoma
or multiple myeloma ther or preventing the onset of a preclinically evident stage of a
solid tumor (for example, a neuroendocrine tumor, non-small cell lung cancer, astoma
multiforme, hepatocellular carcinoma, breast cancer, colorectal cancer, salivary cancer,
pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal cancer, renal cancer,
leiomyosarcoma, or paraganglioma, including advanced solid ), non-Hodgkin lymphoma
or multiple myeloma. Also intended to be encompassed by this definition is the prevention of
transformation into malignant cells or to arrest or reverse the progression of premalignant cells
to malignant cells. This includes prophylactic treatment of those at risk of developing a solid
tumor (for example, a neuroendocrine tumor, non-small cell lung cancer, glioblastoma
multiforme, hepatocellular carcinoma, breast cancer, colorectal cancer, salivary cancer,
pancreatic cancer, adenocystic , adrenal , esophageal cancer, renal cancer,
leiomyosarcoma, or paraganglioma, ing ed solid tumors), non-Hodgkin lymphoma
or multiple myeloma.
The term “cancer” refers to any of various malignant neoplasms characterized by
the proliferation of cells that can invade surrounding tissue and metastasize to new body sites.
Both benign and malignant tumors are classified according to the type of tissue in which they
are found. For example, f1bromas are neoplasms of fibrous tive , and melanomas
are abnormal growths of pigment (melanin) cells. Malignant tumors originating from epithelial
tissue, e.g., in skin, bronchi, and stomach, are termed carcinomas. Malignancies of epithelial
lar tissue such as are found in the breast, prostate, and colon, are known as
adenocarcinomas. ant growths of tive tissue, e.g., muscle, cartilage, lymph tissue,
and bone, are called sarcomas. mas and leukemias are malignancies arising among
white blood cells. Through the process of metastasis, tumor cell ion to other areas of the
body establishes sms in areas away from the site of initial appearance. Bone s are
one of the most favored sites of metastases of malignant tumors, occurring in about 30% of all
cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are
particularly known to be likely to metastasize to bone.
An “advanced solid tumor” as used herein, means a solid tumor that has spread
locally, or metastasized or spread to another part of the body.
] In certain embodiments, the treatment may be assessed by Response Evaluation
Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the
Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216
and Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid
tumours: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228—247).
Overall responses for all possible combinations of tumor ses in target and non-target
lesions with our t the appearance ofnew lesions are as follows:
Target lesions rget lesions Overall response
Incomplete No PR
response/SD
No SD
Yes or no PD
CR = complete response; PR = partial response; SD = stable disease; and PD = progressive
disease.
With respect to the evaluation of target lesions, complete se (CR) is the
disappearance of all target lesions, partial response (PR) is at least a 30% se in the sum of
the longest diameter of target lesions, taking as reference the ne sum longest diameter,
progressive disease (PD) is at least a 20% increase in the sum of the longest diameter of target
s, taking as reference the smallest sum longest er recorded since the treatment
started or the appearance of one or more new lesions and stable disease (SD) is neither
sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for
ssive disease, taking as reference the smallest sum longest diameter since the treatment
started.
WO 82344 2012/067172
With respect to the evaluation of non-target lesions, complete response (CR) is
the disappearance of all non-target lesions and normalization of tumor marker level; incomplete
response/stable disease (SD) is the persistence of one or more non-target lesion(s) and/or the
maintenance of tumor marker level above the normal limits, and progressive e (PD) is the
appearance of one or more new lesions and/or unequivocal progression of existing non-target
lesions.
In certain embodiments, the treatment of lymphoma may be assessed by the
International Workshop Criteria (IWC) for dgkin lymphoma (NHL) (see Cheson BD,
Pfistner B, Juweid, ME, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin.
Oncol: 2007: (25) 579-586), using the response and endpoint ions shown below:
Res n onse Definition Nodal Masses S leen, liver Bone Marrow
Disappearance (a) FDG-avid or PET Not palpable, Infiltrate
of all evidence positive prior to therapy; nodules cleared on
of disease mass of any size ted disappeared repeat biopsy;
if PET negative if
(b) Variably FDG-avid or rminate
PET negative; regression by
to normal size on CT morphology,
immunohisto-
chemistry
should be
Regression of 250% decrease in SPD of 250% Irrelevant if
measurable up to 6 largest dominant decrease in positive prior
e and no masses; no increase in size SPD of to therapy; cell
new sites of other nodes nodules (for type should be
(a) FDG-avid or PET single nodule specified
positive prior to therapy; in greatest
one or more PET positive transverse
at previously involved site diameter); no
(b) Variably FDG-avid or increase in
PET negative; regression size of liver
on CT or s oleen
Res 1 onse Definition Nodal Masses S leen, liver Bone Marrow
Failure to (a) FDG-aVid or PET
attain CIVPR positive prior to therapy;
or PD PET ve at prior sites
of disease and no new
sites on CT or PET
(b) Variably FDG-aVid or
PET negative; no change
in size of previous lesions
on CT
PD or Any new Appearance of a new 250% New or
relapsed lesion or lesion(s) 21.5 cm in any increase recurrent
disease increase by 2 axis, 250% se in from nadir in involvement
50% of SPD ofmore than one the SPD of
previously node, any previous
involved sites or 250% increase in lesions
from nadir longest diameter of a
previously identifed node
21 cm in short axis
Lesions PET positive if
FDG-aVid lymphoma or
PET positive prior to
therao
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron
on tomography; CT, computed tomography; PR, partial remission; SPD,
sum of the product of the ers; SD, stable disease; PD, progressive disease.
End noint ts Definition Measured from
Primary
Overall survival Death as a result of any cause Entry onto study
Progression-free Disease progression or death as a result of Entry onto study
al any cause
Secondary
Event-free survival Failure of treatment or death as result of Entry onto study
any cause
Time to progression All Time to ssion or death as a result of Entry onto study
lymphoma
End oint Patients Definition Measured from
Disease-free survival Time to e or death as a result of ntation
lymphoma or acute toxicity of ent of response
Response on Time to relapse or progression Documentation
of response
Lymphoma-specific All Time to death as a result of lymphoma Entry onto study
survival
Time to next treatment All Time to new treatment End of primary
treatment
iations: CR: complete remission; PR: partial remission.
In one embodiment, the end point for lymphoma is evidence of clinical benefit.
Clinical benefit may reflect improvement in quality of life, or reduction in patient symptoms,
transfusion requirements, frequent ions, or other parameters. Time to reappearance or
progression of ma-related symptoms can also be used in this end point.
In certain embodiments, the treatment of le myeloma may be assessed by
the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM,
Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma.
Leukemia, 2006; (10) 10: 1-7), using the response and endpoint definitions shown below:
Res n onse Subcate_or Res n onse Criteriaa
CR as defined below plus
Normal FLC ratio and
Absence of clonal cells in bone marrowb by
immunohistochemist or immunofluorescencec
Negative immunofixation on the serum and urine and
Disappearance of any soft tissue plasmacytomas and
<5% olasma cells in bone marrowb
VGPR Serum and urine ein detectable by immunofixation but
not on electrophoresis or 90% or greater reduction in serum
M-protein plus urine M-protein level <100mg per 24 h
Res n onse Subcateor Res n onse Criteriaa
250% reduction of serum M-protein and ion in 24-h
y M-protein by290% or to <200mg per 24 h
If the serum and urine M-protein are unmeasurable,d a 250%
decrease in the difference between involved and uninvolved
FLC levels is required in place of the M-protein criteria
If serum and urine M-protein are unmeasurable, and serum
free light assay is also unmeasurable, 250% reduction in
plasma cells is required in place of ein, provided
baseline bone marrow plasma cell percentage was 230%
In addition to the above listed criteria, if present at baseline, a
250% reduction in the size of soft tissue plasmacytomas is also
reuired
SD (not recommended for use Not meeting ia for CR, VGPR, PR or progressive disease
as an indicator of response;
stability of disease is best
described by providing the
time to progression estimates)
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable
disease; sCR, ent complete response; VGPR, very good partial response; aAll response
categories e two consecutive assessments made at anytime before the institution of any
new therapy; all categories also require no known evidence of progressive or new bone lesions
if radiographic studies were performed. Radiographic s are not required to satisfy these
response requirements; bConfirmation with repeat bone marrow biopsy not needed;
cPresence/absence of clonal cells is based upon the K/k ratio. An abnormal 1d?» ratio by
immunohistochemistry and/or fluorescence requires a minimum of 100 plasma cells for
analysis. An abnormal ratio reflecting presence of an abnormal clone is 1d)» of >4:1 or <1 :2.
dMeasurable disease defined by at least one of the following measurements: Bone marrow
plasma cells 230%; Serum M-protein 21 g/dl (210 gm/l)[10 g/l]; Urine ein
2200 mg/24 h; Serum FLC assay: Involved FLC level 210 mg/dl (2100 mg/l); provided serum
FLC ratio is abnormal.
The procedures, conventions, and definitions described below e guidance
for implementing the recommendations from the Response Assessment for Neuro-Oncology
(RANO) g Group regarding response criteria for rade gliomas (Wen P.,
Macdonald, DR., Reardon, DA., et al. Updated response ment criteria for highgrade
gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28:
1963-1972). Primary modifications to the RAND ia for Criteria for Time Point Responses
(TPR) can include the addition of operational conventions for defining changes in
glucocorticoid dose, and the removal of subjects’ clinical deterioration component to focus on
objective radiologic assessments. The baseline MRI scan is defined as the assessment
med at the end of the post-surgery rest period, prior to re-initiating compound treatment.
The baseline MRI is used as the reference for assessing complete response (CR) and partial
response (PR). Whereas, the smallest SPD (sum of the products of perpendicular diameters)
obtained either at baseline or at uent assessments will be designated the nadir assessment
and utilized as the reference for determining progression. For the 5 days preceding any
protocol-defined MRI scan, subjects receive either no glucocorticoids or are on a stable dose of
glucocorticoids. A stable dose is defined as the same daily dose for the 5 consecutive days
preceding the MRI scan. If the ibed glucocorticoid dose is changed in the 5 days before
the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria
described above. The following definitions will be used.
Measurable Lesions: able lesions are contrast-enhancing lesions that can
be measured bidimensionally. A ement is made of the maximal enhancing tumor
er (also known as the longest diameter, LD). The greatest perpendicular diameter is
measured on the same image. The cross hairs of bidimensional measurements should cross and
the product of these diameters will be calculated.
Minimal Diameter: Tl-weighted image in which the sections are 5 mm with
1 mm skip. The l LD of a able lesion is set as 5 mm by 5 mm. Larger diameters
may be required for inclusion and/or designation as target lesions. After ne, target s
that become smaller than the minimum requirement for ement or become no longer
amenable to bidimensional measurement will be recorded at the t value of 5 mm for each
diameter below 5 mm. Lesions that disappear will be recorded as 0 mm by 0 mm.
Multicentric Lesions: Lesions that are considered multicentric (as opposed to
continuous) are lesions where there is normal intervening brain tissue between the two (or
more) lesions. For multicentric lesions that are te foci of enhancement, the approach is to
separately measure each enhancing lesion that meets the inclusion ia. If there is no normal
brain tissue between two (or more) lesions, they will be considered the same lesion.
Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable
disease as defined above will be considered non-measurable lesions, as well as all
nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of
ement that are less than the specified st diameter (ie., less than 5 mm by 5 mm),
nonenhancing lesions (eg., as seen on Tl-weighted post-contrast, T2-weighted, or fluid-
attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or
necrotic lesions, and leptomeningeal tumor. Hemorrhagic s often have intrinsic
Tl-weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this
reason, the pre-contrast Tl-weighted image may be examined to exclude baseline or interval
sub-acute hemorrhage.
At baseline, lesions will be classified as follows: Target s: Up to
measurable lesions can be selected as target lesions with each measuring at least 10 mm by
mm, representative of the subject’s disease; Non-target lesions: All other lesions, including all
surable lesions (including mass effects and T2/FLAIR findings) and any measurable
lesion not selected as a target lesion. At baseline, target lesions are to be measured as bed
in the definition for measurable lesions and the SPD of all target s is to be determined.
The presence of all other lesions is to be documented. At all post-treatment evaluations, the
baseline classification of lesions as target and non-target lesions will be maintained and lesions
will be nted and described in a consistent fashion over time (eg., ed in the same
order on source documents and eCRFs). All measurable and nonmeasurable lesions must be
ed using the same technique as at baseline (e.g., subjects should be imaged on the same
MRI scanner or at least with the same magnet strength) for the duration of the study to reduce
difficulties in interpreting changes. At each evaluation, target lesions will be measured and the
SPD ated. Non-target lesions will be assessed qualitatively and new lesions, if any, will
be documented separately. At each evaluation, a time point se will be determined for
target lesions, rget lesions, and new lesion. Tumor progression can be established even if
2012/067172
only a subset of lesions is assessed. However, unless progression is observed, objective status
(stable disease, PR or CR) can only be determined when all lesions are assessed.
Confirmation assessments for overall time point responses of CR and PR will be
med at the next scheduled assessment, but confirmation may not occur if scans have an
interval of < 28 days. Best response, incorporating confirmation requirements, will be derived
from the series of time points.
The term “contacting” or “contact” is meant to refer to bringing er of a
therapeutic agent and cell or tissue such that a physiological and/or al effect takes place
as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one
embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine
the effect of the therapeutic agent on the cell. In r embodiment, the contacting of a
therapeutic agent with a cell or tissue es the administration of a therapeutic agent to a
t having the cell or tissue to be contacted.
The term “solid form” refers to a physical form which is not predominantly in a
liquid or a gaseous state. As used herein and unless otherwise ed, the term “solid form,”
when used herein to refer to nd A, refers to a physical form comprising Compound A
which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline
form, an amorphous form, or a mixture thereof. In certain embodiments, a solid form may be a
liquid crystal. In certain embodiments, the term “solid forms comprising nd A”
includes crystal forms comprising Compound A, amorphous forms comprising Compound A,
and mixtures thereof.
As used herein and unless otherwise specified, the term “crystalline” when used
to describe a compound, nce, modification, material, component or product, unless
otherwise specified, means that the compound, substance, modification, material, component or
product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington:
The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins,
Baltimore, MD (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
The term “crystal form” or alline form” refers to a solid form that is
crystalline. In certain ments, crystal forms include salts. In certain embodiments, a
crystal form of a substance may be substantially free of amorphous forms and/or other crystal
forms. In certain embodiments, a crystal form of a substance may contain less than about 1%,
less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about
6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than
about 15%, less than about 20%, less than about 25%, less than about 30%, less than about
%, less than about 40%, less than about 45%, or less than about 50% by weight of one or
more amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a
substance may be physically and/or chemically pure. In certain embodiments, a crystal form of
a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%,
about 93%, about 92%, about 91%, or about 90% physically and/or chemically pure.
The term “amorphous” or “amorphous form” means that the substance,
component, or product in question is not substantially crystalline as determined by X-ray
diffraction. In particular, the term “amorphous form” describes a disordered solid form, z'.e., a
solid form lacking long range crystalline order. In certain embodiments, an ous form of
a substance may be substantially free of other amorphous forms and/or crystal forms. In certain
ments, an ous form of a substance may contain less than about 1%, less than
about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 10%, less
than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about
%, less than about 40%, less than about 45%, or less than about 50% by weight of one or
more other amorphous forms and/or crystal forms on a weight basis. In certain embodiments,
an amorphous form of a substance may be physically and/or chemically pure. In certain
embodiments, an amorphous form of a substance be about 99%, about 98%, about 97%, about
96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% ally
and/or chemically pure.
The term “co-crystal” means a crystalline structure comprised of two or more
ents.
The term te” means a lline structure comprised of either
iometric or nonstoichiometric amounts of a solvent incorporated within the crystalline
structure.
The term “hydrate” means a crystalline structure comprised of either
iometric or nonstoichiometric s of water incorporated within the crystalline
structure.
Techniques for characterizing crystal forms and amorphous forms include, but
are not limited to, thermal graVimetric analysis (TGA), differential ng calorimetry (DSC),
X-ray powder diffractometry , -crystal X-ray diffractometry, Vibrational
spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear
magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical copy,
scanning electron microscopy (SEM), electron crystallography and quantitative analysis,
particle size analysis (PSA), surface area is, solubility measurements, dissolution
measurements, elemental analysis, and Karl Fischer analysis. Characteristic unit cell
parameters may be determined using one or more techniques such as, but not limited to, X-ray
diffraction and neutron diffraction, including single-crystal diffraction and powder ction.
Techniques useful for ing powder diffraction data include e refinement, such as
Rietveld refinement, which may be used, 6.g. to analyze diffraction peaks associated with a
single phase in a sample comprising more than one solid phase. Other methods useful for
analyzing powder diffraction data include unit cell indexing, which allows one of skill in the art
to determine unit cell parameters from a sample comprising crystalline powder.
The term “pharmaceutically acceptable salt(s)” means a salt prepared from a
pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an
organic acid and base. Suitable pharmaceutically acceptable base addition salts of Compound
A include, but are not limited to metallic salts made from aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc or organic salts made from lysine,
N,N’-dibenzylethylenediamine, procaine, choline, diethanolamine, ethylenediamine,
meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not
limited to, nic and organic acids such as , c, anthranilic, esulfonic,
benzoic, camphorsulfonic, citric, ethenesulfonic, formic, filmaric, furoic, galacturonic,
gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric,
propionic, salicylic, stearic, succinic, sulfanilic, sulfilric, tartaric acid, and p-toluenesulfonic
acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and
methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate
salts. Others are well-known in the art, see for example, Remington’s Pharmaceutical es,
18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of
Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).
The term “isotopologue” means any form of Compound A, including
metabolites thereof, in which at least one atom of natural isotopic abundance is ed with an
isotopically enriched form that s from natural abundance. An ologue can be based
on replacement of hydrogen for deuterium and/or tritium. Similarly, naturally abundant 12C can
be replaced with 13C or 14C, naturally abundant 14N can be replaced with 15N, and naturally
abundant 16O with 17O or 18O, and so on in any combination. Other isotopologues can be based
on isotopic enrichment of fluorine, sulfur, phosphorus, boron, and the like. Isotopologues can
include replacing any number atoms within the compound with isotopically enriched forms.
The isotopic enrichment can be effected to any degree, including, 1, 5, 10, 15, 20, 25, 30, 35,
40, 45, 50, 60, 70, 80, 90, 95, and 99, and 100% enrichment, including any value in between
and ons f.
The term “metabolite” means any form of Compound A ed upon
stration to a subject. In one embodiment, the metabolite of nd A is the
O-desmethyl metabolite (haVing the name ,4r)—4-hydroxycyclohexyl)(6-(2-
hydroxypropanyl)pyridinyl)-3 ,4-dihydropyrazino[2,3-b]pyrazin-2(1H)—one), haVing the
structure:
OH [1
|\ 2
N/ NNo
llf\
The term “about” or “approximately” means an acceptable error for a particular
value as determined by one of ordinary skill in the art, which depends in part on how the value
is measured or determined. In certain embodiments, the term “about” or ximately”
means within 1, 2, 3, or 4 rd deviations. In certain embodiments, the term “about” or
“approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,
0.5%, or 0.05% ofa given value or range.
As used herein and unless otherwise specified, a sample comprising a particular
crystal form or amorphous form that is “substantially pure,” e.g., substantially free of other
solid forms and/or of other chemical compounds, contains, in ular embodiments, less than
about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 9%,
less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about
4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.75%, less
than about 0.5%, less than about 0.25%, or less than about 0.1% by weight of one or more other
solid forms and/or of other chemical nds.
As used herein and unless ise specified, a sample or composition that is
“substantially free” of one or more other solid forms and/or other chemical compounds means
that the composition contains, in particular embodiments, less than about 25%, less than about
%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less
than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%,
less than about 2%, less than about 1%, less than about 0.75%, less than about 0.5%, less than
about 0.25%, or less than about 0.1% by weight of one or more other solid forms and/or other
chemical compounds.
As used herein, the term aceutically acceptable salt(s)” refers to a salt
prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid
and base and an c acid and base. Suitable pharmaceutically acceptable base on salts
of Compound A include, but are not limited to metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine,
N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not
limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic,
benzoic, camphorsulfonic, citric, ethenesulfonic, formic, filmaric, , galacturonic,
ic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric,
propionic, salicylic, stearic, succinic, ilic, sulfilric, tartaric acid, and p-toluenesulfonic
acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and
methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate
salts. Others are well-known in the art, see for example, Remington’s Pharmaceutical Sciences,
18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of
cy, 19th eds., Mack hing, Easton PA (1995).
The term “stereoisomer” or “stereomerically pure” means one stereoisomer of a
compound that is substantially free of other stereoisomers of that compound. For example, a
merically pure compound haVing one chiral center will be substantially free of the
opposite omer of the compound. A stereomerically pure nd having two chiral
centers will be substantially free of other diastereomers of the compound. In certain
embodiments, a stereomerically pure compound comprises greater than about 80% by weight of
one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of
the compound, greater than about 90% by weight of one stereoisomer of the compound and less
than about 10% by weight of the other stereoisomers of the compound, greater than about 95%
by weight of one stereoisomer of the compound and less than about 5% by weight of the other
isomers of the compound, or greater than about 97% by weight of one stereoisomer of the
compound and less than about 3% by weight of the other stereoisomers of the nd.
.2 SOLID FORMS OF COMPOUND A
In one embodiment, provided herein is a solid form of nd A or a
pharmaceutically acceptable salt thereof. In certain embodiments, the solid form is crystalline.
In certain embodiments, the solid form is a single-component solid form. In n
embodiments, the solid form is anhydrous.
WO 82344
While not intending to be bound by any particular , certain solid forms are
characterized by physical properties, e.g., ity, solubility and dissolution rate, appropriate
for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by
any particular theory, certain solid forms are characterized by physical properties (e.g., density,
ssibility, hardness, morphology, cleavage, stickiness, lity, water , electrical
properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability)
affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting,
flowability, dissolution, formulation, and lyophilization) which make certain solid forms
le for the manufacture of a solid dosage form. Such properties can be determined using
particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray
diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in
the art.
The solid forms provided herein (for example, Form A of Compound A) may be
characterized using a number of methods known to a person skilled in the art, including, but not
limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g.,
scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning metry
(DSC), thermal gravimetric analysis (TGA), and hot-stage microscopy), and oscopy (e.g.,
infrared, Raman, and solid-state nuclear magnetic resonance). The particle size and size
distribution of the solid form provided herein may be determined by conventional methods,
such as laser light scattering technique.
] The purity of the solid forms provided herein may be determined by standard
analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas
chromatography, high performance liquid chromatography (HPLC), and mass ometry
(MS).
It should be understood that the numerical values of the peaks of an X-ray
powder diffraction pattern may vary slightly from one machine to another or from one sample
to another, and so the values quoted are not to be ued as te, but with an allowable
variability, such as ::0.2 degrees two-theta (see United States Pharmacopoeia, page 2228
(2003)).
In one embodiment, ed herein is Form A of Compound A. In one
embodiment, Form A of Compound A has an X-ray powder ction pattern ntially as
shown in In one embodiment, Form A of Compound A has an X-ray powder diffraction
pattern comprised of one or more of the peaks set forth in Table 2. In r embodiment,
Form A of Compound A has one or more characteristic X-ray powder diffraction peaks at a
two-theta angle oximately 8.3, 8.8, 12.0, 13.2, 13.9, 14.4, 14.8, 16.5, 17.7, 18.2, 19.3,
19.5, 19.6, 21.0, 21.2, 21.7, 22.5, 24.1, 24.7, 25.0, 25.3, 26.5, 26.7, 28.3, 29.3, 29.5, 29.8, 30.5,
32.1, 33.3, 34.2 or 34.6 s. In a specific embodiment, Form A of Compound A has one,
two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a two-
theta angle of approximately 8.3, 8.8, 13.2, 16.5, 17.7, 18.2, 21.7 or 26.5 degrees. In another
embodiment, Form A of Compound A has one, two, three or four characteristic X-ray powder
diffraction peaks at a two-theta angle of approximately 8.3, 13.2, 18.2 or 21.7 degrees. In a
particular embodiment, Form A of Compound A has one or more characteristic X-ray powder
diffraction peaks at a two-theta angle of approximately 8.0, 9.0, 12.0, 13.0, 16.5, 17.5, 18.2,
21.5, 22.5, 25.0 or 26.5 degrees. In a specific embodiment, Form A of Compound A has one,
two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a two-
theta angle of approximately 8.0, 9.0, 13.0, 16.5, 17.5, 18.2, 21.5 or 26.5 s. In another
embodiment, Form A of Compound A has one, two, three or four characteristic X-ray powder
diffraction peaks at a two-theta angle of approximately 8.0, 13.0, 18.2 or 21.5 degrees. In
another embodiment, Form A of Compound A has one, two, three or four characteristic X-ray
powder diffraction peaks at a two-theta angle of approximately 13.0, 16.5, 18.2 or 21.5 degrees.
In another embodiment, Form A of Compound A has a thermogravimetric
thermogram substantially as shown in In certain embodiments, Form A of Compound
A shows less than about 10%, less than about 5%, less than about 3%, less than about 2%, less
than about 1%, less than about 0.5%, less than about 0.2%, less than about 0.1%, less than
about 0.05%, or less than about 0.03%, e.g., about 0.024%, weight loss between about 25 0C to
about 100 0C in a gravimetric thermogram. In certain embodiments, Form A of
Compound A shows less than about 0.1% weight loss between about 25 0C to about 100 0C in a
thermogravimetric thermogram. In n embodiments, Form A of Compound A shows about
0.025% weight loss between about 25 0C to about 100 0C in a thermogravimetric thermogram.
In certain embodiments, Form A of Compound A shows no weight loss until degradation at
about 260 0C in a thermogravimetric thermogram. In certain embodiments, Form A of
Compound A is anhydrous. In certain embodiments, Form A of Compound A is unsolvated.
In yet another embodiment, Form A of nd A has a differential scanning
calorimetric (DSC) thermogram substantially as shown in In certain embodiments,
Form A of Compound A has an endotherm with a peak temperature of about 201 0C in a DSC
thermogram. In n embodiments, Form A of Compound A has an endotherm with an onset
temperature of about 197 0C in a DSC thermogram. In certain embodiments, Form A of
Compound A has an endotherm with a peak ature of about 199 0C and an onset
temperature of about 197 0C in a DSC thermogram. In one embodiment, Form A of Compound
A has a melting temperature of about 197-199 0C. In certain embodiment, Form A of
Compound A has a melting temperature of about 199 0C. In one embodiment, Form A of
Compound A has an endotherm of about 195 0C in a DSC thermogram.
In yet another embodiment, Form A of Compound A is non-hygroscopic, e.g.,
ts a mass gain of less than about 0.1% w/w of when subjected to an se in ty
from about 0% to about 80% ve humidity (RH). In another embodiment, Form A of
Compound exhibits a mass gain of about 0.5% w/w ofwhen subjected to an increase in
humidity from about 80% to about 90% relative humidity. In certain embodiments, Form A of
Compound A exhibits no greater than about 2% w/w, no greater than about 1% w/w, no greater
than about 0.6% w/w, no greater than about 0.4% w/w, no greater than about 0.2% w/w, or no
greater than about 0.1% w/w weight gain in response to an increase in humidity from about 0%
to about 95% relative humidity at about 25 CC. In certain embodiments, Form A of Compound
A ts about 0.3% w/w weight gain in response to an increase in humidity from about 0%
to about 95% relative ty at about 25 CC. In certain embodiments, Form A of Compound
A ts no r than about 2% w/w, no greater than about 1% w/w, no greater than about
0.6% w/w, no greater than about 0.4% w/w, no greater than about 0.2% w/w, or no greater than
about 0.1% w/w weight gain in response to an increase in humidity from about 0% to about
50% relative humidity at about 25 CC. In n embodiments, Form A of Compound A
exhibits about 0.1% w/w weight gain in response to an se in humidity from about 0% to
about 50% relative humidity at about 25 0C.
In one embodiment, provided herein is Form B of Compound A. In one
embodiment, Form B of Compound A has an X-ray powder diffraction pattern substantially as
shown in In another embodiment, Form B of Compound A has one or more
characteristic X-ray powder diffraction peaks at a two-theta angle of imately 6.0, 7.0,
8.0, 10.0, 12.0, 14.0, 17.0, 18.0, 20.0, 20.5, 22.5, or 24.5 degrees. In a specific embodiment,
Form B of Compound A has one, two, three, four, five, six, or seven teristic X-ray
powder diffraction peaks at a two-theta angle of approximately 6.0, 7.0, 8.0, 10.0, 12.0, 14.0,
17.0, 18.0, 20.0, 20.5, 22.5, or 24.5 degrees. In another embodiment, Form B of Compound A
has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of
approximately 6.0, 7.0, 8.0, 10.0, 12.0, 14.0, 17.0, 18.0, 20.0, 20.5, 22.5, or 24.5 degrees.
In n embodiments, Form B of Compound A shows less than about 10% or
less than about 7%, e.g., about 6.4%, weight loss and an onset temperature of about 50 0C in a
gravimetric thermogram. In certain embodiments, Form B of Compound A is a hydrate.
In yet r embodiment, Form B of Compound A has a differential scanning
calorimetric (DSC) thermogram substantially as shown in . In certain embodiments,
Form B of nd A has an endotherm with a peak temperature of about 111.3 CC, and an
exotherm with a peak temperature of about 164.9 c’C in a DSC thermogram. In certain
embodiments, Form B of Compound A has an endotherm with a peak temperature of about 202
In one embodiment, provided herein is Form C of Compound A. In one
embodiment, Form C of Compound A has an X-ray powder diffraction pattern substantially as
shown in . In another embodiment, Form C of Compound A has one or more
characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 6.5, 9.0,
.0, 14.5, 16.5, 19.0, 23.0, or 23.5 degrees. In a specific embodiment, Form C of
Compound A has one, two, three, four, five, six, or seven characteristic X-ray powder
diffraction peaks at a two-theta angle of imately 6.5, 9.0, 10.0, 14.5, 16.5, 19.0, 23.0, or
23.5 degrees. In another embodiment, Form C of Compound A has one, two, three or four
characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 6.5, 9.0,
.0, 14.5, 16.5, 19.0, 23.0, or 23.5 degrees. In a particular embodiment, Form C of
nd A has one or more characteristic X-ray powder diffraction peaks at a two-theta
angle of approximately 6.5, 9.0, 10.0, 14.5, 16.5, 19.0, 23.0, or 23.5 degrees.
In certain embodiments, Form C of Compound A is anhydrous.
In yet another embodiment, Form C of Compound A has a differential scanning
calorimetric (DSC) thermogram substantially as shown in . In certain embodiments,
Form C of Compound A has an endotherm and exotherm of about 160 CC and an endothermof
about 200 CC in a DSC thermogram. In certain embodiments, Form C of Compound A has an
endotherm of about 162 CC and an endotherm of about 200 CC in a DSC thermogram.
In one embodiment, provided herein is Form D of Compound A. In one
ment, Form D of Compound A has an X-ray powder diffraction pattern substantially as
shown in . In another embodiment, Form D of nd A has one or more
characteristic X-ray powder ction peaks at a eta angle of approximately 6.0, 8.0,
9.0, 10.0, 12.5, 14.5, 16.5, 18.0, 19.0, 19.5, 20.5, 22.5, 23.5, or 27.5 degrees. In a specific
embodiment, Form D of Compound A has one, two, three, four, five, six, seven, eight, nine,
ten, eleven, or twelvecharacteristic X-ray powder diffraction peaks at a two-theta angle of
approximately 6.0, 7.5, 8.0, 9.0, 10.0, 12.5, 14.5, 16.5, 19.0, 19.5, 20.5, or 23.0 degrees. In
another embodiment, Form D of Compound A has one, two, three or four characteristic X-ray
powder ction peaks at a two-theta angle of approximately 6.0, 7.5, 8.0, 9.0, 10.0, 12.5,
14.5, 16.5, 19.0, 19.5, 20.5, or 23.0 degrees. In a particular embodiment, Form D of
Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta
angle oximately 6.0, 7.5, 8.0, 9.0, 10.0, 12.5, 14.5, 16.5, 19.0, 19.5, 20.5, or 23.0
degrees.
] In n embodiments, Form D of Compound A shows less than about 10% or
less than about 8%, e.g., about 7.4%, weight loss and an onset temperature of about 80 0C in a
thermogravimetric thermogram. In certain embodiments, Form D of Compound A is a solvate.
In yet another embodiment, Form D of Compound A has a ential scanning
calorimetric (DSC) thermogram substantially as shown in . In certain embodiments,
Form D of Compound A has an endotherm with a peak temperature of about 98.3 CC, and an
endotherm with a peak temperature of about 159.3 c’C in a DSC thermogram. In certain
embodiments, Form D of Compound A has an endotherm with a peak temperature of about
200.6 0C.
] In still another embodiment, Form A of Compound A is substantially pure. In
certain embodiments, the substantially pure Form A of Compound A is ntially free of
other solid forms, e.g., ous form. In certain embodiments, the purity of the
substantially pure Form A of Compound A is no less than about 95%, no less than about 96%,
no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about
99%, no less than about 99.5%, or no less than about 99.8%.
In still another embodiment, Form B of nd A is substantially pure. In
certain embodiments, the substantially pure Form B of Compound A is substantially free of
other solid forms, e.g., amorphous form. In certain embodiments, the purity of the
substantially pure Form B of nd A is no less than about 95%, no less than about 96%,
no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about
99%, no less than about 99.5%, or no less than about 99.8%.
In still another embodiment, Form C of Compound A is substantially pure. In
n embodiments, the substantially pure Form C of Compound A is substantially free of
other solid forms, e.g., ous form. In certain embodiments, the purity of the
substantially pure Form C of Compound A is no less than about 95%, no less than about 96%,
no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about
99%, no less than about 99.5%, or no less than about 99.8%.
In still another embodiment, Form D of Compound A is substantially pure. In
certain embodiments, the substantially pure Form D of Compound A is substantially free of
other solid forms, e.g., amorphous form. In certain embodiments, the purity of the
substantially pure Form D of Compound A is no less than about 95%, no less than about 96%,
no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about
99%, no less than about 99.5%, or no less than about 99.8%.
In one embodiment, provided herein is a pinacol co-crystal of Compound A. In
one embodiment, the pinacol co-crystal of Compound A has an X-ray powder diffraction
pattern ntially as shown in In another embodiment, the pinacol stal of
Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta
angle of approximately 5.0, 6.0, 12.5, 14.0, 15.0, 15.5, 17.5, 18.5, and 22.5 degrees. In a
specific embodiment, the pinacol co-crystal of Compound A has one, two, three, four, or five
characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 5.0, 6.0,
12.5, 14.0, 15.0, 15.5, 17.5, 18.5, and 22.5 degrees. In another embodiment, the l co-
crystal of Compound A has one, two, three or four characteristic X-ray powder diffraction
peaks at a two-theta angle of approximately 5.0, 6.0, 12.5, 14.0, 15.0, 15.5, 17.5, 18.5, and 22.5
degrees.
In yet another embodiment, the pinacol co-crystal of Compound A has a
differential ng calorimetric (DSC) gram substantially as shown in In
certain embodiments, the pinacol co-crystal of Compound A has an endotherm with a peak
ature of about 119 0C in a DSC thermogram. In certain embodiments, the pinacol co-
crystal of Compound A has an erm with an onset temperature of about 115 0C in a DSC
thermogram. In certain ments, the pinacol co-crystal of Compound A has an endotherm
with a peak ature of about 119 0C and an onset temperature of about 115 0C in a DSC
thermogram. In another embodiment, the pinacol co-crystal of Compound A is comprised of
about 20% by weight of pinacol.
In still another embodiment, the pinacol co-crystal of Compound A is
substantially pure. In certain embodiments, the substantially pure pinacol co-crystal of
Compound A is substantially free of other solid forms, e.g., amorphous form. In certain
embodiments, the purity of the substantially pure pinacol co-crystal of Compound A is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no
less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
The solid forms of Compound A ed herein (for example, Forms A, B, C or
D) can be prepared by the methods described herein.
In certain embodiments, Form A of Compound A can be prepared by solvent
evaporation of a solution or slurry of Compound A in e, MTBE l tert-butyl ether),
DIPE (diisopropyl ether), THF (tetrahydrofuran), DME (dimethoxyethane), IPAc opyl
acetate), EtOAc (ethyl acetate), MIBK (methyl isobutyl ketone), acetone, IPA (isopropyl
alcohol), ethanol, ACN (acetonitrile), nitromethane or IPA:water (for example, 95 :5).
In certain ments, Form A of Compound A can be prepared by subjecting
a solution or slurry of Compound A in toluene, MTBE (methyl tert-butyl ether), DIPE
(diisopropyl ether), THF (tetrahydrofilran), DME hoxyethane), IPAc (isopropyl acetate),
EtOAc (ethyl acetate), MIBK (methyl isobutyl ketone), acetone, IPA (isopropyl alcohol),
ethanol, ACN nitrile), nitromethane or IPA:water (95 :5) to cycles of heating to about 50
0C and cooling to room temperature, followed by solvent evaporation.
In certain embodiments, provided herein are methods for making Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, comprising dissolving amorphous 2—hydroxypropan-
2-yl)pyridin-3 -yl)- l ns)—4-methoxycyclohexyl)-3 ,4-dihydro-pyrazino [2,3 -b]pyrazin-2( 1H)-
one in toluene, MTBE (methyl tert-butyl ether), DIPE (diisopropyl ether), THF
hydrofuran), DME (dimethoxyethane), IPAc (isopropyl acetate), EtOAc (ethyl acetate),
MIBK (methyl yl ketone), acetone, IPA (isopropyl alcohol), ethanol, ACN nitrile),
nitromethane, or IPA:water (95 :5) and allowing the resulting solution to evaporate at room
temperature.
In certain embodiments, provided herein are methods for making Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT (butylated hydroxytoluene), IPA and water, heating and then cooling to room
temperature. In some embodiments, the methods further comprise collection by filtration,
washing with IPA and water and drying.
] In certain embodiments, provided herein are methods for making Form A of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l ns)—4-methoxycyclohexyl)-3 ,4-dihydro-
2012/067172
pyrazino[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT and MeOAc (methyl acetate), heating, cooling to room temperature, distilling
under vacuum and contacting with n-heptane. In certain embodiments, the methods filrther
comprise collection by filtration and washing with MeOAc and n-heptane and drying. In
certain ments, this process further comprises adding a small amount of Form A in
MeOAc to the mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in BHT and MeOAc. In
some ments, the methods further comprise filtration of the hot BHT and MeOAc
solution.
In certain embodiments, provided herein are methods for making Form B of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l ns)—4-methoxycyclohexyl)-3 ydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, sing dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT, IPA and water, heating the mixture and adding water, cooling the mixture,
collection by filtration, washing with IPA and water, and drying. In certain embodiments, this
process fiarther comprises adding a small amount of Form B in water to the mixture of 7-(6-(2-
hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -
b]pyrazin-2(lH)—one in BHT, IPA and water.
In certain embodiments, provided herein are s for making Form C of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT, MeOH, distilling to remove MeOH, further distillation with IPA, cooling the
mixture, collection by filtration, washing with IPA and drying.
In certain ments, ed herein are methods for making Form D of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydro-
pyrazino[2,3-b]pyrazin-2(lH)—one, comprising dissolving 7-(6-(2-hydroxypropanyl)pyridin-
3-yl)— l -((trans)—4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one in a
mixture of BHT in MeOH, heating, then cooling with stirring, collection by filtration, washing
and drying.
In certain embodiments, provided herein are methods for making a pinacol
co-crystal of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, comprising mixing 7-(6-(2-hydroxypropan
yl)pyridinyl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-
one with pinacol in solution (for example THF and toluene), heating until solids are ved,
distilling said solution and seeding with a pinacol co-crystal of 7-(6-(2-hydroxypropan
yl)pyridinyl)- l -((trans)methoxycyclohexyl)-3 ydropyrazino [2,3 -b]pyrazin-2( 1H)-
one. IN some embodiements, the s further comprise collection by filtration, washing
with THF/toluene and drying.
.3 PROCESS OF PREPARATION OF COMPOUND A
In certain embodiments, provided herein are methods for preparing nd
A, comprising: (1) contacting ethyl(3,5-dibromopyrazinylamino)acetate with
4-methoxycyclohexylamine hydrochloride and ylpyrrolidine and adding DIPEA to
produce ethyl 2-((5-bromo(((lr,4r)methoxycyclohexyl)amino)pyrazinyl)amino)acetate;
(2) contacting ethyl 2-((5-bromo-3 -(((lr,4r)methoxycyclohexyl)amino)pyrazin
yl)amino)acetate with an acid (such as a phosphoric acid on) to produce 7-bromo-l-
r)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one; and (3)
ting 7-bromo- l -(( l r,4r)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-
2(lH)—one with 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)pyridinyl)propanol and
PdC12(Amphos)2.
Provided herein are methods of preparing Compound A
\ ('1
| =
N / N N o
I l f
N N
CompoundA,
the method comprising contacting a compound of Formula b
BrNfio
with a compound of formula c
O"? /
in a solvent (e.g. THF), in the presence of a base (e.g. K2C03) and a palladium
catalyst (e.g. PdClz(Amphos)2), wherein said ting occurs under ions suitable to
provide Compound A. In some embodiments, the ting occurs at elevated temperature
(e.g. reflux).
WO 82344
] In some such embodiments, the methods further comprise preparing a compound
of formula b
1:1:1
the method comprising contacting a compound of formula (1
with an acid (e.g. phosphoric acid), wherein said contacting occurs under
conditions suitable to provide a compound of formula b. In some embodiments, the contacting
occurs at elevated ature (e.g. 80 0C).
In some such embodiments, the methods further comprise preparing a compound
of formula (1
the method comprising contacting a compound of formula e
with oxycyclohexylamine hydrochloride, in the ce of a base (e.g.
DIPEA), in a solvent (e.g. NMP), wherein said contacting occurs under conditions suitable to
provide a compound of formula b.
In some embodiments, the contacting occurs at elevated ature (e.g.
125 - l 3 0 0C).
Isotopologues of Compound A and metabolites thereof can be prepared by the
methods provided herein.
In one embodiment, provided herein are processes for preparing a nd
having the formula:
14\C/ (5
HO/ /| a
N\ N N O
I l T
N N
14C-Compound A
the method comprising contacting
With
Br N N O
N N
in the presence of a palladium catalyst (e.g. PdClz(Amphos)2) and a base (e.g.
K2C03) in a t (6.g. , THF, optionally with water), wherein said contacting occurs under
conditions suitable to produce
\ /
HO/ /
I i
N \ N\ N O
I l T
N N
mpound A
In some embodiments, the contacting occurs at elevated temperature (e.g. 73 0C).
In one embodiment, provided herein are processes for preparing a compound
having the formula:
\ /
HO/ /
I 5
N \ N N O
I l T
N N
14C—Compound A
the method comprising contacting
1‘4/C/ \
HO |
'HCl @3350
With
Br N r51 0
N N
in the presence of a palladium catalyst (e.g. PdClz(Amphos)2) and a base (e.g.,
K2C03) in a solvent (6.g. , THF, optionally with water), wherein said ting occurs under
conditions le to produce
/ /
HO | g
N \ N N O
N N
14C—Compound A
In some such embodiments, the contacting occurs at elevated temperature (e.g.
73 0C). In some such embodiments, the method further comprises addition of EtOAc, and
isolation of crude 14C-compound A using EtOAc, DCM, methanol, and silica gel and drying. In
some such ments, crude 14C-compound A is dissolved in BHT and ACN and isolated
using EtOAc.
In some embodiments, the methods fiarther comprise contacting
9J¥;f
\ /
140 N
TMSO/\
with an acid (e.g. HCl) in a solvent (e.g., oxane), wherein said contacting
occurs under conditions suitable to produce
H09? N’
In some embodiments, the s fiarther comprise contacting
i4 fj/Br/
TMSO/g N
with
q ,9
lB—B\
O O
in the presence of a palladium catalyst (e.g. PdClz(dppf)-DCM complex) and a
base (e.g. KOAc) in a solvent (e.g. l,4-dioxane), wherein said contacting occurs under
conditions le to produce
In some embodiments, the methods further comprise contacting
\ I
Ho/g14 N
with TMSCl in the presence of a base (e. g. TEA) in a solvent (e. g. DCM),
wherein said contacting occurs under conditions suitable to produce
i4 @81'/
c N
TMSO/\
In some embodiments, the s fiarther comprise contacting
| N
with
H3C \CH3
in the presence of a base (e. g. butyl lithium) in a solvent (e.g, DCM) wherein
said contacting occurs under conditions suitable to produce
Ho/g14 N
Further ed herein are processes for preparing a nd having the
formula:
HO\ 1fCH
H313C/ /
I l
N \ N ,o
the method comprising contacting
TMSO\13.CH3
H31SC/ / (V)
I ;
| NINSCfo
N/ N1’scHZ
with an acid us HCl) in a solvent (e.g. ACN) wherein said contacting
occurs under conditions suitable to produce
H0 13
1\30/CH
’ /
H 13C I 3
N \ N\
I “(Inf/30H2Nsan
In some ments, the methods fiarther comprise contacting
With
in the ce of a palladium catalyst (e.g. PdClz(Amphos)2) and a base (e.g.
K2C03) in a t (e.g. IPA, optionally in the presence of water), wherein said contacting
occurs under conditions suitable to produce
In some such embodiments, the contacting occurs at ted temperatures (e.g.
69-71 c’C).
In some embodiments, the methods further comprise contacting
With
in the presence of a palladium catalyst (e.g., PdClz(dppf)-DCM complex) and a
base (e. g. K2C03) in a solvent (e.g l,4-dioxane), wherein said contacting occurs under
conditions suitable to produce
In some such embodiments, the contacting occurs at elevated ature (e.g.
90-95 c’C).
] In some embodiments, the methods fiarther comprise contacting
Haws | \13CH3
with TMSCl in the presence of a base (e. g. TEA, optionally in the presence of
DMAP) in a t (e.g. in DCM), wherein said contacting occurs under conditions suitable to
produce
In some such embodiments, the contacting occurs at low temperature (e.g.
0 - 5 CC).
In some embodiments, the methods fiarther comprise contacting
With
WO 82344
in the presence of a base (e.g. n-butyllithium) in a solvent (e.g. DCM), n
said contacting occurs under conditions suitable to produce
Haws | 13%
In some such embodiments, the contacting occurs at low temperature (e.g.
- 78 CC).
In some embodiments, the methods fiarther comprise contacting
BrI21,
with a base (e.g. potassium tert—butoxide) in a solvent (e.g THF), wherein said
contacting occurs under conditions suitable to produce
'3erNIN3C’ONl/3CH2
In some embodiments, the methods fiarther comprise contacting
Br N Br
\E I 13(:H OEt
/ 2\13 /
With
OCH3
NHZ-HCI
in the presence of a base (e. g. DIPEA) in a solvent (e. g. NMP), wherein said
contacting occurs under ions suitable to produce
OCH3
Br1:1::CH1111111
In some such embodiments, the contacting occurs at elevated temperature (e.g.
124-129 c’C).
In some embodiments, the methods fiarther comprise contacting
Br N Br
\E I\
N NH2
With
13CH» OEt
Br/ 139/
in the presence of a base (e.g., K2C03) in a solvent e.g e), optionally in the
presence of tetrabutylammonium ensulfate, wherein said contacting occurs under
conditions suitable to produce
Br N Br
I IBCH CE:
N/ 2\ ’
M/ 130
In one embodiment, provided herein are methods of preparing a nd
having the formula:
HO 13.0“
\130
H31SC/ /
I l
N/ N9CH2
the methods comprising contacting
With
in the presence of a palladium catalyst (e.g. PdClz(Amphos)2) and a base (e.g.
K2C03) in a solvent (e.g., THF, ally with water), wherein said contacting occurs under
conditions le to produce
HO\13.CH3
H31SC/ /
I :
N \ NIMS(940
N/ N13CH2
In some such embodiments, the contacting occurs at elevated temperatures (e. g.
reflux).
In some embodiments, the methods fiarther comprise contacting
H313C\
TMSO—13C08N \ ,0
/ _ \0
H3130
with an acid (e.g. HCl) in a t (e.g. l,4-dioxane), wherein said contacting
occurs under conditions le to produce
H3130 l \1SCH3
In some embodiments, the methods fiarther comprise contacting
with
0‘ ,0
IB—B\
o o
in the presence of a palladium catalyst (e.g. PdClz(dppf)-DCM complex) and a
base (e.g., K2C03) in a solvent (e,g. l,4-dioxane), wherein said ting occurs under
conditions suitable to produce
In some embodiments, the contacting occurs at elevated temperature eflux).
In some embodiments, the methods fiarther comprise contacting
H3130 l \1SCH3
with TMSCl in the presence of a base (e.g., TEA, ally in the presence of
DMAP) in a solvent (e.g. DCM), wherein said contacting occurs under conditions suitable to
produce
In some embodiments, the methods filrther comprise contacting
With
H3130 \13CH3
in the presence of a base (e.g n-butyllithium) in a t (e. g. DCM), wherein
said contacting occurs under conditions suitable to produce
In some embodiments, the the contacting occurs at low ature (e. g. -78 ° to
-72 CC).
In some embodiments, the methods fiarther comprise contacting
Br N lilH
with an acid (e.g. aqueous phosphoric acid), wherein said contacting occurs
under ions suitable to produce
?Q/HZ130N/C/O
In some embodiments, the the contacting occurs at elevated temperature (e.g.
75-80 c’C).
In some embodiments, the s fiarther comprise ting
BrTT3942
with
fiHyHCI
in the presence of a base (e. g. DIPEA) in a solvent (e. g. NMP), wherein said
contacting occurs under conditions suitable to produce
BrTT
In some embodiments, the the contacting occurs at elevated temperature (e.g.
reflux).
In some embodiments, the methods fiarther comprise contacting
Br N Br
\E I\
N NH2
With
Br9|-|2\13C’OEt13
in the presence of a base (e. g. K2C03) in a t (e.g. acetone), optionally in
the presence of tetrabutylammonium hydrogensulfate, wherein said contacting occurs under
conditions suitable to produce
Br N Br
I IW2\N/ ,OEt
N/ 130
H n
In some embodiments, the the contacting occurs at elevated temperature (e.g.
reflux).
In one embodiment, the compound having the formula:
HO\13.CH3
H31SC/ /
I ;
N \ NINSC,,o
N/ N9CH2
is tallized from a e of 2-propanol and water in the presence of 2,6-
di-tert-butylmethylphenol.
In one embodiment, provided herein are methods ofpreparing a compound
having the formula:
DD3CC
Q12:
the methods sing contacting
3'1“1:1
with
in the presence of a palladium catalyst (e.g. Amphos)2) and a base
(e.g. K2C03) in a solvent (e.g., THF, optionally with water), wherein said contacting
occurs under conditions suitable to produce
D3CC
N \ IZI:I
In some such embodiments, the contacting occurs at ed temperatures
(e.g. reflux).
In some embodiments, the methods further comprise contacting
OTMS
D3C 003
, B\
O O
with an acid (e.g. HCl) in a solvent (e.g. oxane), wherein said
contacting occurs under conditions suitable to produce
030 ODCD3
In some embodiments, the methods r comprise contacting
OTMS
D30 003
With
0‘ lo
IB—B\
o o
in the presence of a palladium catalyst (e.g. PdClz(dppf)-DCM complex) and a
base (e.g., K2C03) in a solvent (e,g. l,4-dioxane), wherein said contacting occurs under
conditions le to produce
OTMS
030 003
In some embodiments, the contacting occurs at elevated temperature (e.g.reflux).
In some embodiments, the s fiarther comprise contacting
2012/067172
with TMSCl in the presence of a base (e.g., n-butyllithium) in a solvent (6.g. d6-
acetone), wherein said contacting occurs under conditions suitable to produce
OTMS
030 003
In some embodiments, the methods fiarther comprise contacting
Br N\ KIH
\[ I/ /32 CE:
N N j;
with an acid (e.g. aqueous oric acid), wherein said contacting occurs
under conditions suitable to produce
BrNKJo
TIE:/
NN’2
] In some embodiments, the the contacting occurs at elevated temperature (e.g.
75-80 c’C).
In some embodiments, the methods fiarther comprise contacting
Br N\ Br
I j:/ /32 CE
N M \[d/
With
0H2 - HCI
in the ce of a base (e. g. DIPEA) in a solvent (e. g. NMP), wherein said
contacting occurs under conditions suitable to produce
Br N\ 0H
\E I/ I32 CE
N M \[d/
In some embodiments, the the contacting occurs at elevated temperature (e.g.
In some embodiments, the methods fiarther comprise contacting
Br N Br
I I\
N NH2
With
D D
BrXCOZEt
in the presence of a base (e. g. K2C03) in a solvent (e.g. acetone), optionally in
the presence of tetrabutylammonium hydrogensulfate, wherein said contacting occurs under
conditions suitable to produce
\E IN\
/32 CE
N M WC]:
] In some embodiments, the the contacting occurs at elevated ature (e.g.
reflux).
In one embodiment, provided herein are s ofpreparing a compound
having the formula:
DSCC 0003
ILIIZI
the methods comprising contacting
0003
3'1:1
with
in the presence of a palladium catalyst (e.g. PdC12(Amphos)2) and a base
(e.g. K2C03) in a solvent (e.g., THF, optionally with , wherein said contacting
occurs under conditions suitable to produce
D3CC
/ 0003
N \ IZIZDFQ
] In some such embodiments, the contacting occurs at elevated temperatures
(e.g. reflux).
In some embodiments, the methods further comprise contacting
OTMS
D30 003
/ B\
O O
with an acid (e.g. HCl) in a solvent (e.g. oxane), wherein said
contacting occurs under conditions suitable to produce
030 00003
2012/067172
] In some embodiments, the methods fiarther comprise contacting
OTMS
030 003
With
0‘ lo
IB—B\
o o
in the presence of a palladium catalyst (e.g. PdClz(dppf)-DCM complex) and a
base (e.g., K2C03) in a solvent (e,g. l,4-dioxane), wherein said contacting occurs under
conditions suitable to produce
OTMS
030 003
In some ments, the contacting occurs at elevated temperature (e.g.reflux).
In some embodiments, the methods fiarther comprise contacting
with TMSCl in the ce of a base (e.g., n-butyllithium) in a solvent (6.g. d6-
acetone), wherein said contacting occurs under conditions suitable to e
OTMS
D30 003
In some embodiments, the methods fiarther comprise contacting
0003
Br N\ NH
\[Igzoa//
with an acid (e.g. aqueous phosphoric acid), wherein said contacting occurs
under conditions suitable to produce
0003
Br N N o
TIE/
N N’ 2
] In some embodiments, the the contacting occurs at elevated temperature (e.g.
75-80 c’C).
In some embodiments, the methods fiarther comprise contacting
Br N\ Br
I I/ I32 0E:
N m If
With
0003
in the ce of a base (e. g. DIPEA) in a solvent (e. g. NMP), wherein said
contacting occurs under conditions suitable to produce
0003
Br 0H
\E IN\/ /32 CE:
N N \[d/
In some embodiments, the the contacting occurs at elevated temperature (e.g.
reflux).
In some ments, the methods r comprise contacting
Br N Br
I I\
N NH2
With
D D
BrXCOZEt
in the presence of a base (e. g. K2C03) in a t (e.g. acetone), optionally in
the presence of tetrabutylammonium hydrogensulfate, wherein said contacting occurs under
conditions suitable to produce
I IN\
/32 CE
N m \[d/
In some embodiments, the the contacting occurs at elevated temperature (e.g.
reflux).
In one embodiment, the compound has the formula:
0030C / OCD3
N \ |2I2I
In one embodiment, provided herein are methods ofpreparing a
nd having the formula:
0003
|2I2I
the methods comprising contacting
N\ N u o
N N
with a base and CD31 to produce
0003
“\ 2121°
further contacting with a base and ROD/D20, n said contacting occurs
under conditions suitable to produce
0003
DO /
I ;
N \ N N o
I I TD
N N’ 2
In one embodiment, provided herein are methods of preparing a compound
haVing the formula:
DO /
| i
N\ N NY0
N/IN’CD2
the s comprising contacting
HOXaE :
N\ NNo
llf\
with a base and ROD/D20, wherein said contacting occurs under conditions
le to produce
DO /
| i
N\ N NO
“IfN/N’D2
.4 PHARMACEUTICAL COMPOSITIONS
In one embodiment, provided herein are pharmaceutical compositions
comprising Compound A and one or more pharmaceutically acceptable excipients or carriers.
In one embodiment, the pharmaceutical compositions provided herein comprise Form A of
Compound A and one or more pharmaceutically acceptable excipients or carriers. In one
embodiment, the pharmaceutical compositions provided herein comprise Form B (a hydrate) of
Compound A and one or more pharmaceutically able excipients or carriers. In one
embodiment, the pharmaceutical compositions provided herein comprise Form C (anhydrous)
of Compound A and one or more pharmaceutically able excipients or carriers. In one
embodiment, the pharmaceutical compositions ed herein comprise Form D (a methanol
solvate) of Compound A and one or more pharmaceutically able excipients or carriers.
In one embodiment, the pharmaceutical compositions provided herein comprise
an ologue of Compound A and one or more pharmaceutically acceptable excipients or
carriers. In one embodiment, the pharmaceutical compositions provided herein comprise a
metabolite of Compound A and one or more pharmaceutically acceptable excipients or carriers.
With respect to the pharmaceutical compositions provided herein, each reference to
“Compound A” is contemplated as ing pharmaceutically acceptable salts, solid forms,
ologues and lites of Compound A.
In one embodiment, the pharmaceutically able excipients and carriers are
selected from binders, diluents, disintegrants and lubricants.
In certain embodiments, the binders include, but are not limited to, cellulose
(e.g., microcrystalline cellulose, such as AVICEL® PH 101 and AVICEL® PH 102) and starch
(e.g., pregelatinized starch (STARCH 1500®)). In one embodiment, the binder is cellulose. In
another embodiment, the binder is microcrystalline cellulose. In yet another embodiment, the
binder is AVICEL® PH 101. In yet another embodiment, the binder is AVICEL® PH 102. In
yet another embodiment, the binder is starch. In yet another embodiment, the binder is
pregelatinized starch. In still another embodiment, the binder is STARCH 1500®.
In certain ments, the diluents include, but are not limited to, e
(e.g., lactose monohydrate (FAST FLO® 316) and lactose anhydrous), cellulose
(e.g., microcrystalline cellulose, such as AVICEL® PH 101 and ® PH 102). In one
ment, the diluent is lactose. In another embodiment, the diluent is lactose monohydrate.
In yet another embodiment, the diluent is FAST FLO® 316. In yet another embodiment, the
diluent is lactose anhydrous. In yet another embodiment, the diluent is cellulose. In yet
another embodiment, the diluent is rystalline cellulose. In yet r embodiment, the
diluent is AVICEL® PH 101. In still another ment, the diluent is AVICEL® PH 102).
In certain embodiments, the egrants include, but are not limited to, starch
(e.g., corn starch) and carboxymethyl cellulose (e.g., croscarmellose sodium, such as
AC-DI-SOL®). In one embodiment, the disintegrant is starch. In another ment, the
disintegrant is corn starch. In yet another embodiment, the disintegrant is carboxymethyl
cellulose. In yet another embodiment, the disintegrant is croscarmellose sodium. In still
another ment, the disintegrant is AC-DI-SOL®.
In certain embodiments, the lubricants include, but are not limited to, starch
(e.g., corn starch), magnesium stearate, and c acid. In one embodiment, the lubricant is
starch. In r embodiment, the lubricant is corn starch. In yet another embodiment, the
lubricant is ium stearate. In still another embodiment, the lubricant is stearic acid.
In another embodiment, the pharmaceutical itions provided herein
comprise Compound A and one or more pharmaceutically acceptable excipients or carriers,
each independently selected from carboxymethyl cellulose, cellulose, e, magnesium
stearate, starch, and stearic acid.
] In yet r embodiment, the pharmaceutical compositions provided herein
comprise Compound A and one or more pharmaceutically able excipients or carriers,
each independently selected from croscarmellose sodium, microcrystalline cellolose, lactose
ous, lactose monohydrate, magnesium stearate, corn starch, pregelatinized starch, and
stearic acid.
In yet r embodiment, the pharmaceutical compositions provided herein
comprise Compound A and one or more pharmaceutically acceptable excipients or carriers,
each independently selected from AC-DI-SOL®, AVICEL PH 101®, AVICEL PH 102®,
lactose anhydrous, FAST FLO 3 l6®, magnesium stearate, corn starch, STARCH 1500®, and
stearic acid.
In one embodiment, the pharmaceutical itions ed herein comprise
Compound A, a diluent(s)/binder(s), a disintegrant(s), and a ant(s).
In one embodiment, the pharmaceutical compositions provided herein comprise
Compound A, stearic acid and e monohydrate.
In one embodiment, the pharmaceutical itions provided herein comprise
Compound A, stearic acid, lactose monohydrate and microcyrstalline cellulose.
In another embodiment, the ceutical compositions provided herein
comprise Compound A, lactose monohydrate, microcrystalline cellulose, carboxymethyl
cellulose, and magnesium stearate.
In another embodiment, the pharmaceutical compositions ed herein
comprise Compound A, lactose monohydrate, microcrystalline cellulose, croscarmellose
sodium, stearic acid and magnesium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise Compound A, FAST FLO 316®, AVICEL PH 102®, AC-DI-SOL®, stearic acid and
magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 10-20% by weight of Compound A, about 70-90% by weight of diluent(s)/binder(s),
about l-5% by weight of disintegrant(s), and about 0.1-2% by weight of lubricant(s).
In one embodiment, the pharmaceutical compositions provided herein comprise
about 15% by weight of Compound A, about 80% by weight of diluent(s)/binder(s), about 3%
by weight of disintegrant(s), and about 1.4% by weight of 1ubricant(s).
In r embodiment, the pharmaceutical compositions provided herein
comprise about 10-20% by weight of Form A of Compound A, about 30-60% by weight of
lactose, about 20-40% by weight of microcrystalline ose, about 1-5% by weight of
carboxymethyl cellulose, about 0.1-2% by weight of stearic acid and about 0.5-3% by weight of
magnesium stearate.
In another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Form A of Compound A, about 49% by weight of lactose,
about 31% by weight of microcrystalline cellulose, about 3% by weight of carboxymethyl
ose, about 0.4% by weight of stearic acid and about 1% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
se about 10-20% by weight of Form A of Compound A, about 30-60% by weight of
lactose monohydrate, about 20-40% by weight of microcrystalline cellulose, about 1-5% by
weight of rmellose sodium, about 0.1-2% by weight stearic acid and about 0.5-3% by
weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions ed herein
comprise about 15% by weight of Form A of Compound A, about 49% by weight of e
monohydrate, about 31% by weight of microcrystalline cellulose, about 3% by weight of
croscarmellose sodium, about 0.4% by weight of stearic acid and about 1% by weight of
magnesium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise about 10-20% by weight of Form A of Compound A, about 30-60% by weight of
FAST FLO 316®, about 20-40% by weight ofAVICEL PH 102®, about 1-5% by weight of
AC-DI-SOL®, about 0.1-2% by weight of stearic acid and about 0.5-3% by weight of
magnesium te.
In still another embodiment, the pharmaceutical compositions ed herein
comprise about 15% by weight of Form A of Compound A, about 49% by weight of FAST
FLO 316®, about 31% by weight ofAVICEL PH 102®, about 3% by weight ofAC-DI-SOL®,
about 0.4% by weight of stearic acid and about 1% by weight of magnesium stearate.
In one ment, the pharmaceutical compositions provided herein se
Form A of Compound A, e, starch, ymethyl cellulose, stearic acid and magnesium
stearate.
In another embodiment, the pharmaceutical compositions provided herein
comprise Form A of Compound A, e monohydrate, pregelatinized starch, croscarmellose
sodium, stearic acid and magnesium stearate.
In still another embodiment, the ceutical itions provided herein
se Compound A, FAST FLO 316®, STARCH 1500®, AC-DI-SOL®, stearic acid and
magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 15% by weight of Compound A, from about 55% to about 80% by weight of
diluent(s)/binder(s), from about 20% to about 30% by weight of disintegrant(s), and about 1%
by weight of lubricant(s).
In another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 55% by weight of lactose, about 25% by
weight of starch, about 3% by weight of carboxymethyl ose, about 0.4% by weight of
stearic acid and about 1% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 55% by weight of lactose monohydrate,
about 25% by weight of pregelatinized starch, about 3% by weight of croscarmellose sodium,
about 0.4% by weight of stearic acid and about 1% by weight of magnesium stearate.
In still another embodiment, the pharmaceutical itions provided herein
comprise about 15% by weight of Compound A, about 55% by weight of FAST FLO 316®,
about 25% by weight of STARCH 1500®, about 3% by weight of AC-DI-SOL®, about 0.4%
by weight of stearic acid and about 1% by weight of magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
Compound A, lactose, microcrystalline cellulose, carboxymethyl cellulose, c acid and
magnesium stearate.
] In another embodiment, the pharmaceutical compositions provided herein
comprise Compound A, e monohydrate, microcrystalline cellulose, croscarmellose
sodium, stearic acid and magnesium stearate.
In still another embodiment, the pharmaceutical compositions ed herein
comprise Compound A, FAST FLO 316®, AVICEL PH 102®, AC-DI-SOL®, about 0.4% by
weight of stearic acid and magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 15% by weight of Compound A, about 80% by weight of diluent(s)/binder(s), about 3%
by weight of disintegrant(s), and about 1% by weight of lubricant(s).
In another embodiment, the pharmaceutical compositions ed herein
comprise about 15% by weight of nd A, about 50% by weight of lactose, about 30% by
weight of microcrystalline cellulose, about 3% by weight of carboxymethyl cellulose, about
0.4% by weight of stearic acid and about 1% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical itions provided herein
se about 15% by weight of Compound A, about 50% by weight of lactose monohydrate,
about 30% by weight of microcrystalline cellulose, about 3% by weight of croscarmellose
sodium, about 0.4% by weight of stearic acid and about 1% by weight of magnesium stearate.
In still another embodiment, the ceutical compositions provided herein
se about 15% by weight of Compound A, about 50% by weight of FAST FLO 316®,
about 30% by weight ofAVICEL PH 102®, about 3% by weight ofAC-DI-SOL®, about 0.4%
by weight of stearic acid and about 1% by weight of ium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
Compound A, lactose, microcrystalline cellulose, corn starch, carboxymethyl cellulose, stearic
acid and magnesium stearate.
In another embodiment, the pharmaceutical compositions ed herein
comprise Compound A, lactose monohydrate, microcrystalline cellulose, corn starch,
croscarmellose , c acid and magnesium stearate.
] In still another embodiment, the pharmaceutical compositions provided herein
comprise Compound A, FAST FLO 316®, AVICEL PH 102®, corn starch, AC-DI-SOL®,
stearic acid and magnesium stearate.
In one embodiment, the pharmaceutical compositions ed herein comprise
about 15% by weight of Compound A, from about 85% to about 90% by weight of
diluent(s)/binder(s), from about 1% to about 10% by weight of disintegrant(s), and from about
1% to about 6% by weight of lubricants.
In another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 45% by weight of lactose, about 30% by
weight of microcrystalline cellulose, about 3% by weight of corn starch, about 3% by weight of
carboxymethyl ose, about 0.4% by weight of stearic acid and about 1% by weight of
magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 88% by weight of lactose, about 25% by
weight of rystalline ose, about 4% by weight of corn starch, about 4% by weight of
ymethyl cellulose, about 0.4% by weight of stearic acid and about 1.5% by weight of
magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 45% by weight of lactose monohydrate,
about 30% by weight of microcrystalline cellulose, about 3% by weight of corn starch, about
3% by weight of croscarmellose sodium, about 0.4% by weight of stearic acid and about 1% by
weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 88% by weight of lactose monohydrate,
about 25% by weight of microcrystalline cellulose, about 4% by weight of corn starch, about
4% by weight of croscarmellose sodium, about 0.4% by weight of stearic acid and about 1.5%
by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of nd A, about 45% by weight of FAST FLO 316®,
about 30% by weight ofAVICEL PH 102®, about 3% by weight of corn starch, about 3% by
weight ofAC-DI-SOL®, about 0.4% by weight of c acid and about 1% by weight of
magnesium stearate.
In still another embodiment, the pharmaceutical itions provided herein
comprise about 15% by weight of Compound A, about 88% by weight of FAST FLO 316®,
about 25% by weight ofAVICEL PH 102®, about 4% by weight of corn starch, about 4% by
weight ofAC-DI-SOL®, about 0.4% by weight of stearic acid and about 1.5% by weight of
magnesium stearate.
In one embodiment, the pharmaceutical compositions ed herein comprise
Compound A, lactose, rystalline cellulose, corn starch, carboxymethyl cellulose, stearic
acid, and magnesium stearate.
In one embodiment, the pharmaceutical compositions ed herein comprise
about 5% by weight of Compound A, about 90% by weight of diluent(s)/binder(s), from about
3% to about 6% by weight of disintegrant(s), and from about 1.5% to about 5% by weight of
lubricants.
In another embodiment, the pharmaceutical compositions provided herein
comprise about 5% by weight of Compound A, about 60% by weight of e, about 30% by
weight of microcrystalline cellulose, about 3% by weight of corn starch, about 3% by weight of
carboxymethyl cellulose, about 0.5% by weight of stearic acid, and about 1% by weight of
magnesium stearate.
] In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 5% by weight of Compound A, about 60% by weight of lactose monohydrate,
about 30% by weight of microcrystalline ose, about 3% by weight of corn starch, about
3% by weight of croscarmellose sodium, about 0.5% by weight of stearic acid, and about 1% by
weight of magnesium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise about 5% by weight of Compound A, about 60% by weight of FAST FLO 3 l6®,
about 30% by weight ofAVICEL PH 102®, about 3% by weight of corn starch, about 3% by
weight ofAC-DI-SOL®, about 0.5% by weight of stearic acid, and about 1% by weight of
magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
Compound A, lactose, microcrystalline cellulose, carboxymethyl cellulose, c acid, and
magnesium stearate.
In another embodiment, the ceutical compositions ed herein
comprise Compound A, lactose monohydrate, microcrystalline cellulose, croscarmellose
sodium, stearic acid, and ium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise Compound A, FAST FLO 3 l6®, AVICEL PH 102®, AC-DI-SOL®, stearic acid, and
magnesium stearate.
] In one embodiment, the pharmaceutical compositions provided herein se
about 12% by weight of Compound A, from about 80% to about 85% by weight of
diluent(s)/binder(s), about 3% by weight of disintegrant(s), and about 1.5% by weight of
lubricant(s).
In another embodiment, the pharmaceutical compositions ed herein
comprise about 12% by weight of nd A, about 52.5% by weight of lactose, about 30%
by weight of microcrystalline cellulose, about 3% by weight of carboxymethyl cellulose, about
0.5% by weight of stearic acid, and about 1% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 12% by weight of Compound A, about 52.5% by weight of e
monohydrate, about 30% by weight of microcrystalline ose, about 3% by weight of
croscarmellose sodium, about 0.5% by weight of stearic acid, and about 1% by weight of
magnesium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise about 12% by weight of Compound A, about 52.5% by weight of FAST FLO 3 l6®,
WO 82344
about 30% by weight ofAVICEL PH 102®, about 3% by weight ofAC-DI-SOL®, about 0.5%
by weight of stearic acid, and about 1% by weight of magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 12% by weight of Compound A, about 80% by weight of diluent(s)/binder(s), about 3%
by weight of disintegrant(s), and about 4% by weight of 1ubricant(s).
In another ment, the pharmaceutical compositions provided herein
comprise about 12% by weight of nd A, about 63% by weight of lactose, about 18% by
weight of microcrystalline cellulose, about 3% by weight of carboxymethyl ose, about 3%
by weight of stearic acid, and about 1% by weight of magnesium stearate.
In yet another ment, the pharmaceutical compositions provided herein
comprise about 12% by weight of Compound A, about 63% by weight of lactose monohydrate,
about 18% by weight of microcrystalline cellulose, about 3% by weight of croscarmellose
sodium, about 3% by weight of stearic acid, and about 1% by weight of magnesium stearate.
] In still another embodiment, the ceutical compositions provided herein
comprise about 12% by weight of Compound A, about 63% by weight of FAST FLO 316®,
about 18% by weight ofAVICEL PH 102®, about 3% by weight ofAC-DI-SOL®, about 3%
by weight of stearic acid, and about 1% by weight of magnesium stearate.
In one ment, the pharmaceutical compositions provided herein comprise
about 15% by weight of Compound A, about 80% by weight of a diluent/binder, about 3% by
weight of a disintegrant, and about 1.5% by weight of lubricants.
In another embodiment, the ceutical compositions provided herein
comprise about 15% by weight of Compound A, about 50% by weight of lactose, about 30% by
weight of microcrystalline cellulose, about 3% by weight of carboxymethyl cellulose, about
0.5% by weight of stearic acid, and about 1% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 15% by weight of Compound A, about 50% by weight of lactose monohydrate,
about 30% by weight of microcrystalline cellulose, about 3% by weight of croscarmellose
, about 0.5% by weight of stearic acid, and about 1% by weight of magnesium stearate.
] In still another embodiment, the pharmaceutical compositions ed herein
comprise about 15% by weight of Compound A, about 50% by weight of FAST FLO 316®,
about 30% by weight ofAVICEL PH 102®, about 3% by weight ofAC-DI-SOL®, about 0.5%
by weight of stearic acid, and about 1% by weight of magnesium te.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 17% by weight of Form A of Compound A, about 80% by weight of dilent(s)/binder(s),
about 3% by weight of egrant(s), and about 1% by weight of lubricant(s).
In another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of nd A, about 50% by weight of lactose,
about 30% by weight of microcrystalline cellulose, about 3% by weight of carboxymethyl
cellulose, and about 1% by weight of magnesium stearate.
] In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 50% by weight of e
monohydrarte, about 30% by weight of microcrystalline cellulose, about 3% by weight of
croscarmellose sodium, and about 1% by weight of magnesium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 50% by weight of FAST
FLO 316®, about 30% by weight ofAVICEL PH 101®, about 3% by weight ofAC-DI-SOL®,
and about 1% by weight of magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 17% by weight of Form A of Compound A, from about 55% to about 80% by weight of
dilent(s)/binder(s), from about 20% to about 30% by weight of disintegrant(s), and about 1% by
weight of lubricant(s).
] In another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of nd A, about 55% by weight of lactose,
about 25% by weight of starch, about 3% by weight of carboxymethyl cellulose, and about 1%
by weight of magnesium stearate.
] In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 55% by weight of lactose
monohydrarte, about 25% by weight of pregelatinized starch, about 3% by weight of
croscarmellose sodium, and about 1% by weight of magnesium stearate.
In still another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 55% by weight of FAST
FLO 316®, about 25% by weight of STARCH l500®, about 3% by weight of AC-DI-SOL®,
and about 1% by weight of ium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 17% by weight of Form A of Compound A, about 80% by weight of dilent(s)/binder(s),
about 3% by weight of disintegrant(s), and about 1% by weight of lubricant(s).
In another embodiment, the ceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 50% by weight of lactose,
about 30% by weight of microcrystalline cellulose, about 3% by weight of carboxymethyl
cellulose, and about 1% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 50% by weight of lactose
monohydrarte, about 30% by weight of microcrystalline cellulose, about 3% by weight of
rmellose sodium, and about 1% by weight of magnesium te.
In still another embodiment, the pharmaceutical compositions provided herein
se about 17% by weight of Form A of Compound A, about 50% by weight of FAST
FLO 316®, about 30% by weight ofAVICEL PH 102®, about 3% by weight ofAC-DI-SOL®,
and about 1% by weight of magnesium stearate.
In one embodiment, the pharmaceutical compositions provided herein comprise
about 17% by weight of Form A of Compound A, from about 85% to about 90% by weight of
dilent(s)/binder(s), from about 3% to about 9% by weight of disintegrant(s), and from about 1%
to about 6% by weight of lubricants.
In another embodiment, the pharmaceutical itions provided herein
comprise about 17% by weight of Form A of Compound A, about 45% by weight of lactose,
about 30% by weight of microcrystalline cellulose, about 3% by weight of corn , about
3% by weight of carboxymethyl ose, and about 1% by weight of magnesium stearate.
In yet r embodiment, the pharmaceutical compositions provided herein
se about 17% by weight of Form A of Compound A, about 88% by weight of lactose,
about 25% by weight of microcrystalline cellulose, about 4% by weight of corn starch, about
4% by weight of carboxymethyl cellulose, and about 1.5% by weight of magnesium stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 45% by weight of lactose
monohydrarte, about 30% by weight of microcrystalline cellulose, about 3% by weight of corn
starch, about 3% by weight of croscarmellose sodium, and about 1% by weight of magnesium
stearate.
In yet another embodiment, the pharmaceutical compositions ed herein
comprise about 17% by weight of Form A of Compound A, about 88% by weight of lactose
monohydrarte, about 25% by weight of rystalline cellulose, about 4% by weight of corn
starch, about 4% by weight of croscarmellose sodium, and about 1.5% by weight of magnesium
stearate.
In yet another embodiment, the pharmaceutical compositions provided herein
comprise about 17% by weight of Form A of Compound A, about 45% by weight of FAST
FLO 3 l6®, about 30% by weight ofAVICEL PH 102®, about 3% by weight of corn starch,
about 3% by weight ofAC-DI-SOL®, and about 1% by weight ofmagnesium te.
In still another ment, the pharmaceutical compositions ed herein
comprise about 17% by weight of Form A of Compound A, about 88% by weight of FAST
FLO 3 l6®, about 25% by weight ofAVICEL PH 102®, about 4% by weight of corn starch,
about 4% by weight ofAC-DI-SOL®, and about 1.5% by weight ofmagnesium stearate.
In certain embodiments, provided herein are pharmaceutical compositions
comprising Compound A and stearic acid. In n embodiments, stearic acid is present in an
amount of about 0.1-5%, 0.1 to 1%, or 0.4% by weight. Without being d by theory, it was
found that the addition of stearic acid improved ation (reduced sticking) without
impacting disintegration and compressability.
In certain embodiments, provided herein are pharmaceutical itions
comprising Compound A and lactose monohydrate. In certain embodiments, lactose
monohydrate is present in an amount of about , 45-55%, or 49.2% by weight. t
being limited by theory, it was found that e monohydrate provided better flowability than
lactose anhydrous.
In certain embodiments, provided herein are pharmaceutical compositions
comprising nd A and AVICEL PH 102®. In certain embodiments, AVICEL PH 102®
is present in an amount of about 20-40%, , or 31% by weight. Without being limited by
theory, it was found that AVICEL PH 102® provided better flowability than AVICEL PH
1 0 1 ®.
In certain embodiments, provided herein are pharmaceutical itions
comprising Compound A, c acid, lactose monohydrate and AVICEL PH 102®. In certain
embodiments, provided herein are pharmaceutical compositions comprising Compound A,
stearic acid (in an amount of about 0.1-5%, 0.1 to 1%, or 0.4% by weight), lactose drate
(in an amount of about 40-60%, 45-55%, or 49.2% by weight) and AVICEL PH 102® (in an
amount of about 20-40%, 25-35%, or 31% by weight).
In certain embodiments, ed herein are ceutical compositions
comprising an opaque coating. Without being limited by theory, it was found that a more
opaque coating protected the drug product from degradation. In some embodiments, the
pharmaceutical composition is formulated as a tablet. In some such embodiments, the tablet is
film coated. In some embodiments, the tablet is film coated to a weight gain of 1-8%. In
others, the film coating is about 4% by weight of the tablet.
In certain embodiments, provided herein are pharmaceutical compositions as set
forth in Tables 3-11, 14-16, 23-25, 28 and 29, wherein the amounts of the recited components
can independently be varied by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or
%.
In certain embodiments, provided herein are liquid formulations comprising
Compound A, an alcohol and polyethylene glycol. In certain embodiments, the alcohol and
polyethylene glycol are present in a ratio of about 80:20 to about 20:80. In certain
embodiments, the alcohol and polyethylene glycol are present in a ratio of about 50:50. In
certain ments, the alcohol is ethanol. In certain embodiments, the polyethylene glycol is
PEG 400. In one embodiment, provided herein are capsules filled with a liquid formulation
sing nd A, an alcohol and polyethylene . In one ment, Compound
A is an isotopologue of 2-hydroxypropanyl)pyridinyl)-l-((trans)—4-
methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one. In some embodiments, the
isotopologue is enriched in 14C.
The pharmaceutical compositions ed herein can be provided in a unit-
dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically
discrete unit suitable for administration to a human and animal t, and packaged
individually as is known in the art. Each unit-dose contains a predetermined quantity of an
active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the
required pharmaceutical carriers or excipients. Examples of a unit-dosage form include an
individually packaged tablet or capsule. A unit-dosage form may be stered in fractions
or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms
packaged in a single container to be administered in segregated unit-dosage form. In certain
embodiments, the unit dosage forms provided herein comprise about 1 mg to about 100 mg of
Compound A. In other ments, the unit dosage forms provided herein comprise about 5
mg to about 50 mg of Compound A. In other embodiments, the unit dosage forms provided
herein comprise about 1 mg, about 5 mg, about 20 mg, about 45 mg, about 50 mg, about 75 mg
or about 100 mg of Compound A. In other embodiments, the unit dosage forms provided
herein comprise about 5 mg, about 20 mg, about 45 mg, and about 50 mg of Compound A.
In certain embodiments, provided herein are methods for preparing a
composition provided herein, comprising: (i) weighing out the desired amount of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form (such as Form A, Form B, Form C, or Form D) f and the desired
amount of excipients (such as lactose drate, croscarmellose sodium and
microcrystalline cellulose); (ii) mixing or blending 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a
pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof and the
excipients; (iii) passing the mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)
methoxycyclohexyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form thereof and excipients through a screen
(such as an 18 mesh or 1000 um screen); (iv) mixing or blending 7-(6-(2-hydroxypropan
yl)pyridinyl)- l -((trans)methoxycyclohexyl)-3 ydropyrazino [2,3 -b]pyrazin-2( 1H)-
one, or a pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof and
the excipients after passage through the screen; (V) weighing out the desired amount of
lubricating agents (such as stearic acid and ium stearate); (vi) passing the ating
agents through a screen (such as a 30 mesh or 600 um ); (vii) mixing or blending 7-(6-
(2-hydroxypropanyl)pyridin-3 -yl)— l -((trans)—4-methoxycyclohexyl)-3 ,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the ents and the lubricating agents; (viii) compressing
the mixture of 7-(6-(2-hydroxypropanyl)pyridinyl)-l-((trans)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the excipients and the ating agents (such as into a tablet
form); and (ix) coating the compressed mixture of 2-hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a
pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof, the excipients
and the lubricating agents with a g agent (such as Opadry pink, yellow or beige).
In certain embodiments, ed herein are methods for preparing a
composition provided herein, comprising: (i) weighing out the desired amount of
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-dihydropyrazino
[2,3-b]pyrazin-2(lH)—one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form f and the desired amount of ents (such as lactose
monohydrate, croscarmellose sodium and microcrystalline cellulose); (ii) passing the excipients
through a screen (such as an 18 mesh or 1000 um screen); (iii) mixing or blending (such as at
26 revolutions per minute for 20 minutes) 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)-l-((trans)-
4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically
acceptable salt, isotopologue, metabolite or solid form (such as Form A, Form B, Form C, or
Form D) f and the ents; (iv) passing the mixture of 2-hydroxypropan
yl)pyridinyl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-
one, or a ceutically acceptable salt, isotopologue, metabolite or solid form thereof and
excipients through a screen (such as an 18 mesh or 1000 um screen); (V) mixing or blending
(such as at 26 revolutions per minute for 10 minutes) 7-(6-(2-hydroxypropanyl)pyridinyl)-
l-((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a
pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof and the
excipients; (vi) weighing out the desired amount of lubricating agents (such as stearic acid and
ium stearate); (vii) passing the lubricating agents through a screen (such as a 30 mesh or
600 um screen); (viii) mixing or blending (such as at 26 revolutions per minute for 3 minutes)
7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3 ,4-
opyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the excipients and the lubricating agents; (ix) compressing the
mixture of 7-(6-(2-hydroxypropanyl)pyridin-3 -yl)- l -((trans)—4-methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, isotopologue,
metabolite or solid form thereof, the excipients and the lubricating agents (such as into a tablet
form); and (x) coating the compressed mixture of 2-hydroxypropanyl)pyridinyl)-l-
((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a
pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof, the excipients
and the lubricating agents with a coating agent (such as Opadry pink, yellow or beige).
In n embodiments, the pharmaceutical compositions provided herein
comprise Form A of Compound A, including substantially pure Form A.
In certain embodiments, the pharmaceutical compositions provided herein
comprise Form B of Compound A, ing substantially pure Form B.
In certain embodiments, the pharmaceutical compositions provided herein
se Form C of Compound A, including substantially pure Form C.
In certain embodiments, the ceutical compositions provided herein
comprise Form D of Compound A, including substantially pure Form D.
Further provided herein are kits comprising a pharmaceutical composition of
Compound A provided herein. In particular embodiments, provided herein are kits comprising
a unit dosage form of Compound A provided herein. In certain ments of the kits
provided herein, Compound A is provided as Form A. In certain embodiments of the kits
provided herein, Compound A is provided as Form B. In n embodiments of the kits
ed herein, Compound A is provided as Form C. In certain embodiments of the kits
provided herein, Compound A is provided as Form D. In certain embodiments of the kits
provided herein, Compound A is provided as a pinacol co-crystal. In some embodiments, of the
kits provided herein Compound A is provided as an isotopologue of 7-(6-(2-hydroxypropan
yl)pyridinyl)- l -((trans)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2(1H)-
one. In some such ments, the isotopologue is enriched in is ed in C, 14C
and/or 2H.
.5 METHODS OF USE
The solid forms of Compound A (e.g, Form A, Form B, Form C, or Form D),
ologues of Compound A, metabolites of nd A (e.g, O-desmethyl Compound A)
and the pharmaceutical compositions provided herein have utility as pharmaceuticals to treat or
prevent a disease in a subject, e.g., a proliferative disease. Further, the solid forms of
Compound A (e.g., Form A, Form B, Form C, or Form D), isotopologues of Compound A,
metabolites of Compound A (e.g, O-desmethyl Compound A) and the pharmaceutical
compositions ed herein ed herein are active against kinases (e.g, protein kinases),
including those involved in cancer, inflammatory conditions, immunological conditions,
neurodegenerative diseases, diabetes, obesity, neurological disorders, age-related diseases,
and/or cardiovascular conditions. Without being limited by theory, it is thought the solid forms
of Compound A (e.g., Form A, Form B, Form C, or Form D), ologues of Compound A,
metabolites of Compound A (e.g, O-desmethyl nd A) and the ceutical
itions provided herein are effective for treating and preventing diseases and conditions
due to its y to te (e.g. kinases that are involved in the etiology of the
, inhibit)
diseases and conditions. Accordingly, provided herein are uses of the solid forms of Compound
A (e.g., Form A, Form B, Form C, or Form D), isotopologues of Compound A, metabolites of
Compound A (e.g, O-desmethyl Compound A) and the pharmaceutical compositions provided
herein, including the treatment or prevention of those diseases set forth herein. In certain
embodiments, the methods provided herein comprise stering a solid form of Compound
A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite
of Compound A (e.g, O-desmethyl Compound A) or a pharmaceutical composition provided
herein, wherein the solid form of Compound A (e.g., Form A, Form B, Form C, or Form D),
isotopologue of nd A, metabolite of Compound A (e.g, O-desmethyl Compound A) or
the pharmaceutical composition provided herein is part of a kit provided herein.
In one embodiment, provided herein is a method of treating and preventing a
e or condition in a subject, comprising the stration of an effective amount of the
solid form of Compound A (e.g., Form A, Form B, Form C, or Form D), an ologue of
Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A) or a
pharmaceutical ition provided herein to the subject.
Representative immunological conditions that the solid forms of Compound A
(e.g., Form A, Form B, Form C, or Form D), isotopologues of Compound A, metabolites of
Compound A (e.g, O-desmethyl Compound A) and the ceutical compositions provided
herein are useful for treating or ting include, but are not limited to, rheumatoid arthritis,
rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel e,
ulcerative colitis, Crohn’s disease, myasthenia gravis, Graves disease, encephalomyelitis, Type
II diabetes, dermatomyositis, and transplant rejection (6.g. in the treatment of recipients
of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, or corneal transplants; or
graft-versus-host disease, such as following bone marrow transplantation).
Representative inflammatory conditions that the solid forms of nd A
(e.g., Form A, Form B, Form C, or Form D), isotopologues of Compound A, metabolites of
Compound A (e.g, ethyl Compound A) and the pharmaceutical compositions provided
herein are useful for treating or preventing include, but are not limited to, psoriasis, asthma and
allergic is, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory
bowel disease, irritable bowel syndrome, Crohn’s disease, mucous colitis, ulcerative colitis, and
obesity.
Representative cardiovascular es that the solids form of Compound A
(e.g., Form A, Form B, Form C, or Form D), isotopologues of Compound A, metabolites of
Compound A (e.g, O-desmethyl Compound A) and the pharmaceutical compositions ed
herein are useful for ng or preventing include, but are not d to, restenosis, Wolf-
Parkinson-White Syndrome, stroke, myocardial infarction or ischemic damage to the heart,
lung, gut, kidney, liver, pancreas, spleen or brain.
entative neurodegenerative diseases that the solid forms of Compound A
(e.g., Form A, Form B, Form C, or Form D), isotopologues of Compound A, metabolites of
Compound A (e.g, O-desmethyl Compound A) and the pharmaceutical compositions provided
herein are useful for treating or preventing include, but are not limited to, Huntington’s disease,
Alzheimer’s disease, Parkinson’s disease, dementias caused by tau mutations, spinocerebellar
ataxia type 3, motor neuron e caused by SODl ons, neuronal ceroid
lipofiJcinoses/Batten disease (pediatric neurodegene ration) and HIV-associated encephalitis.
entative age-related diseases that the solid forms of Compound A (e.g.,
Form A, Form B, Form C, or Form D), isotopologues of Compound A, metabolites of
Compound A (e.g, O-desmethyl Compound A) and the pharmaceutical compositions provided
herein are useful for treating or preventing include, but are not d to, cancer, obesity, type
II diabetes mellitus, autoimmune disease, cardiovascular diseases and neuronal degeneration.
In certain embodiments, the disease or condition is a fibrotic disease or disorder.
Thus, in one embodiment, provided herein is a method for treating or preventing a fibrotic
disease or disorder in a subject, sing the administration of an ive amount of the
solid form of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a metabolite of nd A (e.g, O-desmethyl Compound A) or a
pharmaceutical composition provided herein to the subject. In another embodiment, provided
herein is a method of treating or ting scleroderma, idiopathic pulmonary fibrosis, renal
fibrosis, cystic s, myelofibrosis, hepatic fibrosis, steatofibrosis or steatohepatitis in a
subject, comprising the administration of an effective amount of the solid form of Compound A
(e.g., Form A, Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of
Compound A (e.g, ethyl nd A) or a pharmaceutical composition provided
herein to the subject.
] Representative cancers that the solid forms of Compound A (e.g, Form A, Form
B, Form C, or Form D), isotopologues of Compound A, metabolites of Compound A (e.g, 0-
desmethyl Compound A) and the pharmaceutical itions provided herein are useful for
treating or preventing e, but are not limited to, s of the head, neck, eye, mouth,
throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach,
prostate, urinary bladder, uterine, cervix, , ovaries, testicles or other uctive organs,
skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.
The solid forms of Compound A (e.g., Form A, Form B, Form C, or Form D), isotopologues of
Compound A, metabolites of Compound A (e.g, O-desmethyl Compound A) and the
pharmaceutical compositions ed hereinare also useful for treating or preventing solid
tumors and bloodbome tumors.
In some embodiments, the cancers within the scope of the methods provided
herein include those associated with the pathways involving mTOR, PI3K, or Akt s and
mutants or isoforms thereof. In some embodiments, the cancers within the scope of the
methods provided herein include those ated with the pathways of the following kinases:
PI3K0L, PI3KB, PI3K8, KDR, GSK30L, GSK3B, ATM, ATX, ATR, cFMS, and/or DNA-PK
kinases and mutants or isoforms thereof In some embodiments, the cancers associated with
mTOlV PI3K/Akt pathways include solid and blood-bome tumors, for example, multiple
myeloma, mantle cell lymphoma, diffilsed large B-cell ma, acute myeloid lymphoma,
follicular lymphoma, chronic cytic leukemia; breast, lung, endometrial, ovarian, gastric,
cervical, and prostate cancer; glioblastoma; renal carcinoma; hepatocellular carcinoma; colon
carcinoma; neuroendocrine tumors; head and neck tumors; and sarcomas.
In one embodiment, provided herein is a method for treating or preventing a
disease or er associated with activation ofmTOR signaling, comprising the
administration of an effective amount of the solid form of Compound A (e.g. Form A, Form B,
Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g, 0-
desmethyl Compound A) or a ceutical composition provided herein to a subject in need
thereof. Examples of diseases or disorders associated with activation ofmTOR signaling
include, but are not limited to, tumor mes resulting ly or ctly from c
defects in PTEN (Phosphatase and tensin homologue deleted on chromosome 10), TSCl
(Tuberous sclerosis l), TSC2 (Tuberous sclerosis 2), NFl (Neurof1bromin l), AMPK (AMP-
dependent n kinase STKl l, serine/threonine kinase ll), LKBl, VHL (von Hippel-Lindau
disease) and PKDl (polycystin-l). Without being limited by theory, it is thought that genetic
s associated with these proteins results in hyperactivation of the BK/Akt
pathway. In certain embodiments, the diseases which are treatable or preventable through
inhibition of the mTOlVPBK/Akt pathway include, but are not limited to, Cowden’s disease,
Cowden syndrome, Cowden-like syndrome, Bannayan-Zonana me, Bannayan-Riley-
Ruvalcaba syndrome, tte-Duclos disease, endometrial carcinoma, tuberous sclerosis
complex, lymphangioleiomyomatosis, neurof1bromatosis l, Peutz-Jeghers syndrome, renal cell
carcinoma, von Hippel-Lindau disease, s me, and polycystic kidney disease.
In another embodiment, provided herein is a method for treating or preventing a
disease or disorder associated with mTOR, PI3K, Akt, and/or DNA-PK signaling, comprising
the administration of an effective amount of the solid form of Compound A (e.g. Form A,
Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A
(e. g, O-desmethyl Compound A) or a pharmaceutical composition provided hereinto a t
in need thereof. Examples of diseases which are treatable or preventable by inhibiting mTOR,
PI3K, Akt and/or DNA-PK signaling, include, but are not limited to, rheumatoid arthritis;
rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic is; chronic
obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel
syndrome; mucous colitis; ulcerative colitis; Crohn’s e; gton’s disease; gastritis;
esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus;
atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial
infarction; stroke; ischemic damages of heart, lung, gut, kidney, liver, pancreas, spleen and
brain; acute or chronic organ transplant rejection; preservation of the organ for transplantation;
organ failure or loss of limb (e.g. , including, but not limited to, that resulting from ischemia-
reperfilsion injury, , gross bodily , car accident, crush injury or transplant e);
graft versus host disease; endotoxin shock; multiple organ e; psoriasis; burn from
exposure to fire, chemicals or radiation; eczema; dermatitis; skin graft; ischemia; ischemic
conditions associated with surgery or traumatic injury (e.g., vehicle accident, gunshot wound or
limb crush); epilepsy; Alzheimer’s disease; Parkinson’s disease; immunological response to
bacterial or viral infection; cachexia; angiogenic and proliferative diseases (including retinitis
pigmentosa), solid tumors, and cancers of a variety of tissues such as colon, rectum, prostate,
liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx,
esophagus, mouth, pharynx, urinary bladder, ovary or uterine.
] In yet another embodiment, provided herein is a method of inhibiting a kinase in
a cell expressing the , comprising contacting the cell with an effective amount of the solid
form of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A) or a
pharmaceutical ition provided herein ed herein. In one embodiment, the kinase is
TOR kinase. In certain embodiments, the cell is in a t. In n embodiments, the cell
is from a subject.
In yet another embodiment, provided herein is a method of treating or ting
a condition treatable or preventable by the inhibition of a kinase pathway, in one embodiment,
the mTOlVPI3K/Akt and/or DNA-PK pathway, comprising administering to a subject in need
thereof an effective amount of the solid form of nd A (e.g., Form A, Form B, Form C,
or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g, O-desmethyl
Compound A) or a pharmaceutical composition provided herein. Conditions ble or
preventable by the inhibition of the mTOlV PI3K/Akt pathway include, but are not limited to,
solid and blood-bome tumors, for example, multiple myeloma, mantle cell lymphoma, diffused
large B-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, c lymphocytic
leukemia; breast, lung, endometrial, ovarian, gastric, cervical, and te cancer;
glioblastoma; renal carcinoma; hepatocellular carcinoma; colon carcinoma; neuroendocrine
tumors; head and neck ; sarcomas; tumor syndromes resulting directly or indirectly from
c defects in PTEN (Phosphatase and tensin homologue deleted on chromosome 10),
TSCl ous sclerosis l), TSC2 (Tuberous sclerosis 2), NFl (Neurofibromin l), AMPK
(AMP-dependent protein kinase STKl l, serine/threonine kinase ll), and LKB l , VHL (von
Hippel-Lindau disease) and PKDl (polycystin-l); ’s disease, Cowden me,
Cowden-like syndrome, Bannayan-Zonana me, Bannayan-Riley-Ruvalcaba syndrome,
Lhermitte-Duclos disease, endometrial carcinoma, tuberous sclerosis complex,
lymphangioleiomyomatosis, neurof1bromatosis l, Jeghers syndrome, renal cell
carcinoma, von Hippel-Lindau disease, Proteus syndrome, and polycystic kidney disease;
rheumatoid arthritis; rheumatoid spondylitis; rthritis; gout; asthma, bronchitis; allergic
rhinitis; chronic obstructive ary disease; cystic fibrosis; inflammatory bowel disease;
ble bowel syndrome; mucous colitis; ulcerative colitis; Crohn’s disease; Huntington’s
disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sis; lupus
erythematosus; atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy;
myocardial infarction; stroke; ischemic damages of heart, lung, gut, kidney, liver, pancreas,
spleen and brain; acute or chronic organ transplant rejection; preservation of the organ for
transplantation; organ failure or loss of limb (e.g. , including, but not limited to, that resulting
from ischemia-reperfusion injury, trauma, gross bodily injury, car accident, crush injury or
transplant failure); graft versus host disease; endotoxin shock; multiple organ e; psoriasis;
burn from exposure to fire, als or ion; eczema; dermatitis; skin graft; ischemia;
ischemic conditions associated with surgery or traumatic injury (e.g., vehicle accident, gunshot
wound or limb crush); epilepsy; Alzheimer’s disease; Parkinson’s disease; immunological
response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases,
including retinitis pigmentosa, solid tumors, and cancers of a variety of tissues such as colon,
rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney,
cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterine.
Provided herein are methods for ng or preventing a solid tumor, non-
Hodgkin lymphoma or multiple myeloma, comprising administering an effective amount of the
solid form of nd A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a lite of Compound A (e.g, ethyl Compound A) or a
pharmaceutical composition provided , to a subject having a solid tumor, non-Hodgkin
ma or multiple myeloma. In one embodiment, the solid tumor, non-Hodgkin lymphoma
or le myeloma, is rapamycin resistant.
In one embodiment, the non-Hodgkin lymphoma is diffuse large B-cell
lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), mantle cell
lymphoma (MCL), or ALK+ anaplastic large cell lymphoma. In one embodiment, the non-
Hodgkin lymphoma is advanced solid non-Hodgkin lymphoma.
In one embodiment, the solid tumor is a neuroendocrine tumor. In certain
embodiments, the neuroendocrine tumor is a neuroendocrine tumor of gut origin. In certain
embodiments, the neuroendocrine tumor is of non-pancreatic origin. In certain embodiments,
the neuroendocrine tumor is non-pancreatic of gut origin. In certain embodiments, the
neuroendocrine tumor is ofunknown primary origin. In certain embodiments, the
neuroendocrine tumor is a symptomatic endocrine ing tumor or a ctional tumor.
In certain embodiments, the neuroendocrine tumor is locally unresectable, metastatic moderate,
well differentiated, low (grade 1) or intermediate (grade 2).
In one embodiment, the solid tumor is non-small cell lung cancer (NSCLC).
In r embodiments the solid tumor is glioblastoma multiforme (GBM).
In another ment, the solid tumor is hepatocellular carcinoma (HCC).
In another embodiment, the solid tumor is breast cancer. In one embodiment,
the breast cancer is estrogen receptor positive (ER+, r2- or ER+/Her2+). In one
embodiment, the breast cancer is en receptor negative (ER-/Her2+). In one embodiment,
the breast cancer is triple negative (TN) (breast cancer that does not express the genes and/or
protein corresponding to the en receptor (ER), progesterone or (PR), and that does
not overexpress the Her2/neu protein).
In another embodiment, the solid tumor is colorectal cancer.
] In another embodiment, the solid tumor is salivary cancer.
] In another embodiment, the solid tumor is pancreatic cancer.
In another embodiment, the solid tumor is adenocystic cancer.
In another ment, the solid tumor is adrenal cancer.
In another embodiment, the solid tumor is geal cancer.
In r embodiment, the solid tumor is renal cancer.
In another embodiment, the solid tumor is leiomyosarcoma.
In another embodiment, the solid tumor is paraganglioma.
In one embodiment, the solid tumor is an ed solid tumor.
In one embodiment, the advanced solid tumor is a neuroendocrine tumor. In
certain embodiments, the neuroendocrine tumor is a neuroendocrine tumor of gut origin. In
certain embodiments, the neuroendocrine tumor is of non-pancreatic origin. In certain
embodiments, the neuroendocrine tumor is non-pancreatic of gut origin. In certain
embodiments, the neuroendocrine tumor is ofunknown y . In certain
embodiments, the neuroendocrine tumor is a symptomatic endocrine producing tumor or a
nonfunctional tumor. In certain embodiments, the neuroendocrine tumor is y
ctable, metastatic moderate, well differentiated, low (grade 1) or intermediate (grade 2).
In one embodiment, the ed solid tumor is non-small cell lung cancer
(NSCLC).
In another embodiments the advanced solid tumor is glioblastoma multiforme
(GBM).
In another embodiment, the advanced solid tumor is hepatocellular carcinoma
(HCC).
] In another embodiment, the advanced solid tumor is breast cancer. In one
embodiment, the advanced solid tumor is estrogen receptor positive (ER+, ER+/Her2- or
r2+) breast . In one embodiment, the advanced solid tumor is ER+/Her2- breast
cancer. In one embodiment, the advanced solid tumor is ER+/Her2+ breast cancer. In one
embodiment, the advanced solid tumor is r2+ breast cancer. In one embodiment, the
advanced solid tumor is triple negative (TN) breast cancer.
In another embodiment, the advanced solid tumor is colorectal cancer.
In another embodiment, the advanced solid tumor is salivary cancer.
In another embodiment, the advanced solid tumor is pancreatic cancer.
In another embodiment, the advanced solid tumor is adenocystic cancer.
] In another embodiment, the advanced solid tumor is adrenal cancer.
In another embodiment, the advanced solid tumor is esophageal .
In r embodiment, the advanced solid tumor is renal cancer.
In another embodiment, the advanced solid tumor is leiomyosarcoma.
In another embodiment, the advanced solid tumor is or paraganglioma.
In one embodiment, the non-Hodgkin lymphoma is diffuse large B-cell
lymphoma (DLBCL).
In one embodiment, provided herein are methods for achieving a Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Eisenhauer E.A., Therasse P., Bogaerts
J., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version
1.1). European J. Cancer; 2009; (45) 228—247) of complete response, partial response or stable
disease in a patient comprising administering an effective amount of the solid form of
Compound A (e.g., Form A, Form B, Form C, or Form D) or a pharmaceutical composition
comprising the solid form of nd A (e.g, Form A, Form B, Form C, or Form D)
provided herein, to a subject having a solid tumor, such as an advanced solid tumor.
In one embodiment, ed herein are methods for preventing or delaying a
se Evaluation Criteria in Solid Tumors (RECIST 1.1) of ssive disease in a subject,
comprising administering an effective amount of the solid form of Compound A (e.g., Form A,
Form B, Form C, or Form D) or a pharmaceutical composition comprising the solid form of
Compound A (e.g., Form A, Form B, Form C, or Form D) provided herein, to a subject having
a solid tumor, such as an advanced solid tumor. In one embodiment the prevention or delaying
of progressive disease is characterized or ed by a change in overall size of the target
lesions, of for example, between -30% and +20% compared to pre-treatment. In another
embodiment, the change in size of the target lesions is a reduction in overall size of more than
%, for example, more than 50% reduction in target lesion size compared to pre-treatment. In
another, the tion is characterized or ed by a reduction in size or a delay in
progression of non-target s compared to pre-treatment. In one embodiment, the
prevention is achieved or characterized by a reduction in the number of target lesions compared
to pre-treatment. In another, the prevention is ed or characterized by a reduction in the
number or quality of non-target lesions compared to pre-treatment. In one embodiment, the
prevention is achieved or characterized by the absence or the disappearance of target lesions
compared to pre-treatment. In another, the prevention is achieved or characterized by the
absence or the disappearance of non-target lesions compared to pre-treatment. In another
embodiment, the prevention is achieved or characterized by the prevention ofnew lesions
compared to pre-treatment. In yet another embodiment, the prevention is ed or
characterized by the prevention of clinical signs or symptoms of disease progression compared
to pre-treatment, such as -related cachexia or increased pain.
] In certain embodiments, provided herein are s for decreasing the size of
target lesions in a subject compared to pre-treatment, comprising stering an ive
amount of the solid form of nd A (e.g., Form A, Form B, Form C, or Form D), an
isotopologue of Compound A, a metabolite of Compound A (e.g, O-desmethyl nd A)
or a ceutical composition provided herein, to a subject having a solid tumor, such as an
advanced solid tumor.
In certain embodiments, provided herein are methods for decreasing the size of a
non-target lesion in a subject compared to pre-treatment, comprising administering an effective
amount of the solid form of Compound A (e.g., Form A, Form B, Form C, or Form D), an
isotopologue of Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A)
or a pharmaceutical composition provided herein, to a subject having a solid tumor, such as an
advanced solid tumor.
] In certain ments, provided herein are methods for achieving a reduction
in the number of target lesions in a subject compared to pre-treatment, comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g,
O-desmethyl Compound A) or a pharmaceutical composition provided herein, to a subject
having a solid tumor, such as an advanced solid tumor.
In certain embodiments, provided herein are methods for achieving a ion
in the number of non-target lesions in a t compared to pre-treatment, comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an ologue of Compound A, a metabolite of Compound A (e.g, 0-
hyl Compound A) or a pharmaceutical composition ed , to a subject having
a solid tumor, such as an advanced solid tumor.
In certain embodiments, provided herein are methods for achieving an absence
of all target lesions in a subject, comprising administering an effective amount of the solid form
of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of Compound A,
a metabolite of Compound A (e.g, O-desmethyl Compound A) or a pharmaceutical composition
provided herein, to a subject having a solid tumor, such as an advanced solid tumor.
In certain embodiments, provided herein are methods for achieving an absence
of all non-target s in a subject, comprising administering an effective amount of the solid
form of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A) or a
pharmaceutical ition provided herein, to a subject having a solid tumor, such as an
advanced solid tumor.
A method of treating a solid tumor, such as an advanced solid tumor, the method
comprising administering an effective amount of the solid form of Compound A (e.g., Form A,
Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A
(e. g, O-desmethyl Compound A) or a pharmaceutical composition provided herein, to a subject
having a solid tumor, such as an advanced solid tumor, wherein the treatment results in a
complete response, partial response or stable disease, as ined by Response tion
Criteria in Solid Tumors (RECIST 1.1).
A method of treating a solid tumor, such as an advanced solid tumor, the method
comprising administering an effective amount of the solid form of Compound A (e.g., Form A,
Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A
(e. g, O-desmethyl Compound A) or a pharmaceutical ition provided herein, to a subject
having a solid tumor, such as an advanced solid tumor, wherein the ent results in a
reduction in target lesion size, a reduction in non-target lesion size and/or the absence of new
target and/or non-target s, compared to pre-treatment.
A method of treating a solid tumor, such as an advanced solid tumor, the method
comprising administering an effective amount of the solid form of Compound A (e.g., Form A,
Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A
(e. g, O-desmethyl Compound A) or a pharmaceutical composition provided herein, to a subject
having a solid tumor, such as an advanced solid tumor, n the treatment results in
tion or ing of clinical progression, such as -related cachexia or increased
pain.
In another embodiment, provided herein are methods for improving the
International Workshop Criteria (IWC) for NHL (see Cheson BD, er B, Juweid, ME, et.
al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-5 86.) of
a subject comprising administering an effective amount of the solid form of Compound A (e.g.,
Form A, Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of
Compound A (e.g, O-desmethyl Compound A) or a pharmaceutical composition provided
herein, to a subject having non-Hodgkin lymphoma. In another embodiment, provided herein
are methods to increase Progression Free Survival rates, as determined by -Meier
estimates. In one embodiment, the ent results in a complete remission, partial remission
or stable disease, as determined by the International Workshop ia (IWC) for NHL. In
another embodiment, the treatment results in an se in overall survival, ssion-free
survival, event-free survival, time to progression, disease-free survival or lymphoma-free
survival.
In another embodiment, provided herein are s for inducing a eutic
response characterized with the International Uniform Response Criteria for Multiple Myeloma
(IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response
criteria for multiple myeloma. Leukemia, 2006; (10) 10: l-7) of a subject comprising
stering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g,
O-desmethyl Compound A) or a ceutical composition provided , to a subject
having multiple myeloma. In one embodiment, the treatment results in a stringent complete
response, complete response, or very good partial response, as determined by the the
International Uniform Response ia for Multiple Myeloma (IURC). In another
ment, the treatment results in an increase in overall survival, progression-free survival,
event-free survival, time to progression, or disease-free survival.
In another embodiment, ed herein are s for inducing a therapeutic
response ed with Response ment for Neuro-Oncology (RANO) Working Group for
GBM (see Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria
for highgrade gliomas: Response assessment in neuro-oncology working group. J. Clin. Oncol.
2010; 28: 1963-1972) of a subject comprising administering an effective amount of the solid
form of nd A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A) or a
pharmaceutical composition provided herein, to a subject having gliobastoma multiforme.
In r embodiment, provided herein are methods for improving the Eastern
Cooperative Oncology Group Performance Status (ECOG) of a subject comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an ologue of Compound A, a metabolite of Compound A (e.g,
O-desmethyl Compound A) or a pharmaceutical composition provided herein, to a t
having a tumor, such as an ed solid tumor.
In another embodiment, provided herein are methods for inducing a therapeutic
se assessed by Positron Emission Tomography (PET) outcome of a subject comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g,
O-desmethyl Compound A) or a pharmaceutical composition provided herein, to a subject
having a tumor, such as an advanced solid tumor. In certain embodiments, provided herein are
methods for treating a solid tumor, such as an advanced solid tumor, the methods comprising
administering an effective amount of a TOR kinase inhibitor to a patient having a solid tumor,
such as an advanced solid tumor, wherein the treatment results in a ion in tumor
lic activity, for example, as measured by PET g.
] In another embodiment, provided herein are methods for inducing a therapeutic
response assessed by a reduction in carcinoid syndrome-related symptoms, such as diarrhea
and/or flushing, and/or a reduction in endocrine hormone markers, such as granin,
n, nin, and/or glucagon.
In one embodiment, provided herein are methods for inhibiting phosphorylation
of S6RP, 4E-BPl and/or AKT in a subject having a solid tumor (for example, a neuroendocrine
tumor, non-small cell lung cancer, glioblastoma multiforme, hepatocellular carcinoma, breast
cancer, colorectal cancer, ry cancer, pancreatic cancer, adenocystic cancer, adrenal
cancer, esophageal cancer, renal cancer, leiomyosarcoma, or paraganglioma), non-Hodgkin
lymphoma or multiple myeloma, comprising administering an effective amount of the solid
form of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A) or a
pharmaceutical composition provided herein to said subject. In some such embodiments, the
inhibition of phosphorylation is assessed in a biological sample of the subject, such as in
circulating blood and/or tumor cells, skin biopsies and/or tumor biopsies or aspirate. In such
ments, the amount of inhibition of phosphorylation is assessed by comparison of the
amount of o- S6RP, 4E-BPl and/or AKT before and after administration of the solid
form of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a metabolite of Compound A (e.g, O-desmethyl Compound A) or a
pharmaceutical composition provided herein. In certain embodiments, ed herein are
methods for measuring tion of phosphorylation of S6RP, 4E-BPl or AKT in a subject
having a solid tumor (for example, a neuroendocrine tumor, non-small cell lung ,
glioblastoma multiforme, hepatocellular carcinoma, breast , colorectal cancer, salivary
cancer, pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal , renal cancer,
leiomyosarcoma, or paraganglioma), non-Hodgkin lymphoma or multiple myeloma, comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g, 0-
desmethyl Compound A) or a ceutical composition provided herein to said t,
measuring the amount of phosphorylated S6RP, 4E-BPl and/or AKT in said subject, and
comparing said amount of phosphorylated S6RP, 4E-BPl and/or AKT to that of said subject
prior to administration of an effective amount of the solid form of Compound A (e.g. , Form A,
Form B, Form C, or Form D), an ologue of Compound A, a metabolite of Compound A
(e. g, O-desmethyl Compound A) or a pharmaceutical composition provided . In some
embodiments, the inhibition of phosphorylation of S6RP, 4E-BPl and/or AKT is ed in
B-cells, T-cells and/or monocytes.
] In certain ments, provided herein are methods for inhibiting
phosphorylation of S6RP, 4E-BPl and/or AKT in a biological sample of a subject having a
solid tumor (for e, a neuroendocrine tumor, non-small cell lung cancer, glioblastoma
multiforme, hepatocellular carcinoma, breast cancer, colorectal cancer, salivary cancer,
pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal cancer, renal cancer,
leiomyosarcoma, or paraganglioma), non-Hodgkin lymphoma or multiple myeloma, comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an isotopologue of Compound A, a metabolite of Compound A (e.g,
O-desmethyl Compound A) or a pharmaceutical composition ed herein to said subject
and ing the amount of phosphorylated S6RP, 4E-BPl and/or AKT in a biological
sample of a subject obtained prior to and after administration of said solid form of Compound A
(e.g., Form A, Form B, Form C, or Form D), isotopologue of Compound A, metabolite of
nd A (e.g, O-desmethyl Compound A) or pharmaceutical composition provided herein,
wherein less phosphorylated S6RP, 4E-BPl and/or AKT in said ical sample obtained
after administration of said solid form of Compound A (e.g., Form A, Form B, Form C, or
Form D), isotopologue of Compound A, metabolite of Compound A (e.g, O-desmethyl
Compound A) or a pharmaceutical ition provided herein relative to the amount of
phosphorylated S6RP, 4E-BPl and/or AKT in said biological sample obtained prior to
administration of said solid form of Compound A (e.g., Form A, Form B, Form C, or Form D),
isotopologue of Compound A, metabolite of Compound A (e.g, O-desmethyl Compound A) or
pharmaceutical composition provided herein indicates inhibition. In some embodiments, the
inhibition of orylation of S6RP, 4E-BPl and/or AKT is assessed in B-cells, T-cells
and/or monocytes.
In one embodiment, ed herein are methods for inhibiting DNA-dependent
protein kinase (DNA-PK) activity in a subject having a solid tumor (for example, a
neuroendocrine tumor, non-small cell lung cancer, glioblastoma multiforme, hepatocellular
carcinoma, breast cancer, colorectal cancer, salivary cancer, pancreatic cancer, adenocystic
cancer, adrenal cancer, esophageal cancer, renal cancer, leiomyosarcoma, or paraganglioma),
non-Hodgkin lymphoma or multiple myeloma, comprising administering an effective amount of
the solid form of Compound A (e.g., Form A, Form B, Form C, or Form D), an isotopologue of
Compound A, a lite of nd A (e.g, O-desmethyl Compound A) or a
pharmaceutical composition provided herein to said t. In some embodiments, DNA-PK
inhibition is assessed in the skin of the subject having a solid tumor (for example, a
neuroendocrine tumor, non-small cell lung cancer, glioblastoma multiforme, hepatocellular
carcinoma, breast cancer, colorectal cancer, salivary cancer, pancreatic cancer, adenocystic
cancer, adrenal , esophageal cancer, renal cancer, leiomyosarcoma, or paraganglioma),
non-Hodgkin lymphoma or le a, in one example in a UV light-irradiated skin
sample of said subject. In another embodiment, DNA-PK inhibition is assessed in a tumor
biopsy or aspirate of a subject haVing a solid tumor (for example, a neuroendocrine tumor, non-
small cell lung , glioblastoma multiforme, hepatocellular carcinoma, breast cancer,
ctal cancer, salivary cancer, pancreatic cancer, adenocystic cancer, adrenal cancer,
esophageal cancer, renal cancer, leiomyosarcoma, or paraganglioma), non-Hodgkin lymphoma
or multiple myeloma. In one embodiment, inhibition is assessed by measuring the amount of
phosphorylated DNA-PK 82056 (also known as pDNA-PK 82056) before and after
administration of the solid form of Compound A (e.g., Form A, Form B, Form C, or Form D),
an isotopologue of Compound A, a metabolite of Compound A (e.g, O-desmethyl nd
A) or a ceutical composition ed herein. In certain embodiments, provided herein
are methods for measuring inhibition of phosphorylation of DNA-PK 82056 in a skin sample of
a subject haVing a solid tumor (for example, a ndocrine tumor, non-small cell lung
cancer, glioblastoma multiforme, hepatocellular carcinoma, breast cancer, ctal cancer,
salivary cancer, pancreatic , adenocystic cancer, adrenal cancer, esophageal cancer, renal
, leiomyosarcoma, or paraganglioma), non-Hodgkin ma or multiple myeloma,
comprising administering an effective amount of the solid form of Compound A (e.g., Form A,
Form B, Form C, or Form D), an isotopologue of nd A, a metabolite of Compound A
(e. g, O-desmethyl Compound A) or a pharmaceutical composition ed herein to said
subject, measuring the amount of phosphorylated DNA-PK 82056 present in the skin sample
and comparing said amount of orylated DNA-PK 82056 to that in a skin sample from
said subject prior to administration of an effective amount of the solid form of Compound A
(e.g., Form A, Form B, Form C, or Form D), an isotopologue of Compound A, a metabolite of
Compound A (e.g, O-desmethyl Compound A) or a pharmaceutical ition provided
herein. In one embodiment, the skin sample is irradiated with UV light.
In certain embodiments, provided herein are methods for inhibiting
DNA-dependent n kinase (DNA-PK) activity in a skin sample of a subject having a solid
tumor (for example, a neuroendocrine tumor, non-small cell lung cancer, glioblastoma
multiforme, hepatocellular carcinoma, breast , colorectal cancer, salivary cancer,
pancreatic , adenocystic , adrenal cancer, esophageal cancer, renal cancer,
leiomyosarcoma, or paraganglioma), non-Hodgkin lymphoma or multiple myeloma, comprising
administering an effective amount of the solid form of Compound A (e.g., Form A, Form B,
Form C, or Form D), an ologue of Compound A, a metabolite of Compound A (e.g,
O-desmethyl Compound A) or a pharmaceutical composition provided hereinto said subject and
comparing the amount of phosphorylated DNA-PK in a biological sample of a subject obtained
prior to and after administration of said solid form of Compound A (e.g. , Form A, Form B,
Form C, or Form D), isotopologue of Compound A, metabolite of Compound A (e.g,
ethyl Compound A) or pharmaceutical composition provided herein, n less
phosphorylated DNA-PK in said ical sample obtained after administration of said solid
form of Compound A (e.g., Form A, Form B, Form C, or Form D), isotopologue of Compound
A, lite of nd A (e.g, O-desmethyl Compound A) or pharmaceutical composition
provided herein relative to the amount of phosphorylated DNA-PK in said biological sample
obtained prior to administration of said solid form of Compound A (e.g. Form A, Form B,
Form C, or Form D), isotopologue of Compound A, metabolite of Compound A (e.g,
O-desmethyl Compound A) or pharmaceutical composition provided herein indicates
inhibition.
The solid form of Compound A (e.g., Form A, Form B, Form C, or Form D),
isotopologues of Compound A, metabolites of Compound A (e.g, ethyl Compound A)
and pharmaceutical itions provided herein can be combined with radiation therapy or
surgery. In certain embodiments, the solid form of Compound A (e.g., Form A, Form B, Form
C, or Form D), isotopologues of Compound A, metabolites of Compound A (e.g, O-desmethyl
Compound A) and pharmaceutical compositions provided herein are administered to subject
who is undergoing radiation therapy, has previously one radiation therapy or will be
undergoing radiation therapy. In certain embodiments, the solid form of Compound A (e.g.,
Form A, Form B, Form C, or Form D), isotopologues of nd A, metabolites of
Compound A (e.g, O-desmethyl Compound A) and pharmaceutical compositions provided
herein are administered to a subject who has undergone tumor removal y (e.g., surgery to
remove a GBM tumor).
Further provided herein are methods for treating subjects who have been
usly treated for a solid tumor (for example, a ndocrine tumor, non-small cell lung
cancer, glioblastoma multiforme, hepatocellular carcinoma, breast cancer, colorectal cancer,
salivary cancer, pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal cancer, renal
cancer, leiomyosarcoma, or paraganglioma), non-Hodgkin lymphoma or multiple myeloma, but
are non-responsive to standard therapies, as well as those who have not previously been treated.
Further provided herein are methods for treating subjects who have undergone surgery in an
attempt to treat the condition at issue, as well as those who have not. Because subjects with a
solid tumor (for example, a neuroendocrine tumor, non-small cell lung cancer, glioblastoma
multiforme, cellular carcinoma, breast cancer, colorectal cancer, salivary cancer,
pancreatic cancer, adenocystic cancer, l cancer, esophageal cancer, renal ,
leiomyosarcoma, or nglioma), non-Hodgkin lymphoma or le myeloma have
genous clinical manifestations and varying clinical es, the treatment given to a
subject may vary, depending on his/her prognosis.
In certain embodiments, the pharmaceutical compositions provided herein
comprising Compound A can be used for the treatment or prevention of a disease disclosed in
US. Pat. Appl. Publ. No. 2010/0216781 (see, e.g., paragraphs [04 l 5]-[0437]), the disclosure of
which is incorporated herein by reference in its entirety.
Further provided herein are methods for achieving certain pharmacokinetic (PK)
parameters with respect to nd A in a subject, comprising administering a
pharmaceutical composition provided herein to said subject. In certain embodiments, provided
herein are methods for achieving a PK parameter set forth in the examples provided herein with
t to Compound A in a subject, comprising administering a pharmaceutical composition
provided herein to said subject. In certain ments, the s for achieving a PK
parameter described herein r comprise measuring the amount of Compound A in a
biological sample (e.g., urine, blood, serum or plasma) of a subject after administration of
Compound A.
In certain embodiments, provided herein are methods for achieving a Tmax of
about 0.5 to about 2 hours of Compound A in a t, comprising administering a
pharmaceutical composition provided herein to said subject. In specific embodiments, provided
herein are methods for achieving a Tmax of about 1 hour, about 1.5 hours or about 2 hours of
Compound A in a subject, comprising administering a pharmaceutical composition ed
herein to said subject.
In certain embodiments, ed herein are s for achieving a tug of
about 4 to about 8 hours of Compound A in a subject, comprising administering a
pharmaceutical composition provided herein to said subject. In specific embodiments, provided
herein are methods for achieving a tug of about 4 hours, about 4.5 hours, about 5 hours, about
.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours or about 8 hours of
Compound A in a subject, comprising stering a pharmaceutical composition provided
herein to said t.
In certain ments, ed herein are methods for achieving a Cmax of
about 150 to about 500 ng/mL of Compound A in a subject, comprising administering a
pharmaceutical composition provided herein to said subject. In specific embodiments, provided
herein are methods for achieving a Cmax of about 150 ng/mL, about 175 ng/mL, about
200 ng/mL, about 225 ng/mL, about 250 ng/mL, about 275 ng/mL, about 300 ng/mL, about
325 ng/mL, about 350 ng/mL, about 375 ng/mL, about 400 ng/mL, about 425 ng/mL, about
450 ng/mL, about 475 ng/mL or about about 500 ng/mL of Compound A in a subject,
comprising administering a pharmaceutical composition provided herein to said subject. In one
embodiment, provided herein are methods for achieving a steady state Cmax of about 485 ng/mL
of Compound A in a subject, comprising administering a pharmaceutical composition provided
herein to said subject.
In n embodiments, provided herein are methods for achieving an AUC0_24
of about 900 to about 2500 ng*h/mL of Compound A in a t, comprising administering a
ceutical composition provided herein to said subject. In specific embodiments, provided
herein are methods for achieving an AUC0_24 of about 900 ng*hr/mL, about 950 ng*hr/mL,
about 1000 ng*hr/mL, about 1050 ng*hr/mL, about 1100 ng*hr/mL, about 1150 ng*hr/mL,
about 1200 ng*hr/mL, about 1250 mL, about 1300 ng*hr/mL, about 1350 ng*hr/mL,
about 1400 ng*hr/mL, about 1450 ng*hr/mL, about 1500 ng*hr/mL, about 1550 ng*hr/mL,
about 1600 ng*hr/mL, about 1650 ng*hr/mL, about 1700 mL, about 1750 ng*hr/mL,
about 1800 ng*hr/mL, about 1850 ng*hr/mL, about 1900 ng*hr/mL, about 1950 ng*hr/mL,
about 2000 ng*hr/mL, about 2050 ng*hr/mL, about 2100 ng*hr/mL, about 2150 ng*hr/mL,
about 2200 ng*hr/mL, about 2250 ng*hr/mL, about 2300 ng*hr/mL, about 2350 ng*hr/mL,
about 2400 ng*hr/mL, about 2450 ng*hr/mL or about 2500 ng*hr/mL of Compound A in a
subject, comprising administering a pharmaceutical composition provided herein to said
subject.
In certain embodiments, ed herein are methods for achieving an AUC00 of
about 900 to about 1100 mL of nd A in a subject, comprising administering a
pharmaceutical ition provided herein to said subject. In specific embodiments, provided
herein are methods for ing an AUC00 of about 900 ng*hr/mL, about 950 ng*hr/mL, about
1000 ng*hr/mL, about 1050 ng*hr/mL or about 1000 ng*hr/mL of Compound A in a subject,
comprising administering a pharmaceutical composition provided herein to said subject.
In certain ments, provided herein are methods for achieving a CL/F of
about 19 to about 22 L/hr of nd A in a subject, comprising administering a
pharmaceutical composition provided herein to said subject. In specific embodiments, provided
herein are methods for ing a CL/F of about 19 L/hr, about 19.5 L/hr, about 20 L/hr, about
.5 L/hr, about 21 L/hr, about 21.5 L/hr or about 22 L/hr of Compound A in a subject,
comprising administering a pharmaceutical composition provided herein to said subject.
In certain embodiments, provided herein are methods for achieving a Vz/F of
about 150 to about 180 L of Compound A in a subject, comprising administering a
ceutical composition provided herein to said subject. In specific ments, provided
herein are methods for achieving a Vz/F of about 150 L, about 155 L, about 160 L, about 165 L,
about 170 L, about 175 L or about 180 L of Compound A in a subject, comprising
administering a pharmaceutical composition provided herein to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a lite of Compound A.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a metabolite of nd A in a t,
wherein the metabolite has one or more of the pharmacokinetic parameters selected from a Cmax
of about 100 to about 200 ng/mL (e.g., 143 , a Tmax of about 7 to about 9 hours (e.g.,
8 , an AUC0_24 of about 2500 to about 3000 ng*h/mL (e.g., 2744 ng*h/mL), an AUC0_00 of
about 7750 to about 8250 ng*h/mL (e.g., 7948 ng*h/mL) and a tug of about 30 to about
40 hours (e.g., 35 hours) on day l of administration of about 7.5 mg of Compound A or a
pharmaceutical composition thereof to said subject or wherein the metabolite has one or more
of the pharmacokinetic parameters selected from a Cmax of about 300 to about 400 ng/mL (e.g.,
363 ng/mL), a Tmax of about 1 to about 3 hours (e.g., 2 hours), an AUC0_24 of about 6250 to
about 6750 ng*h/mL (e.g., 6404 ng*h/mL), an AUC0_OO of about 42500 to about 47500 L
(e.g., 45602 ng*h/mL) and a Cmugh of about 200 to about 300 ng/mL (e.g., 267 ng/mL) on day
of once a day administration of about 7.5 mg of Compound A or a pharmaceutical
composition thereof to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a lite of Compound A in a subject,
wherein the metabolite has one or more of the pharmacokinetic ters selected from a Cmax
of about 250 to about 350 ng/mL (e.g., 309 ng/mL), a Tmax of about 1 to about 3 hours (e.g.,
2 hours), an AUC0_24 of about 3500 to about 4000 ng*h/mL (e.g., 3828 ng*h/mL), an O of
about 5500 to about 6000 ng*h/mL (e.g., 5821 ng*h/mL) and a tug of about 10 to about
14 hours (e.g., 12 hours) on day 1 of administration of about 15 mg of Compound A or a
ceutical composition f to said subject or wherein the metabolite has one or more
of the pharmacokinetic parameters selected from a Cmax of about 400 to about 500 ng/mL (e.g.,
458 ng/mL), a Tmax of about 2 to about 4 hours (e.g., 3 hours), an AUC0_24 of about 5500 to
about 6000 ng*h/mL (e.g., 5677 L), an AUC0_OO of about 9500 to about 10000 ng*h/mL
(e.g., 9753 ng*h/mL) and a Cuough of about 100 to about 200 ng/mL (e.g., 145 ng/mL) on day
of once a day administration of about 15 mg of Compound A or a pharmaceutical
composition thereof to said subject.
In certain embodiments, the methods of use and ceutical compositions
provided herein comprise in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has one or more of the cokinetic parameters selected from a Cmax
of about 700 to about 800 ng/mL (e.g., 776 ng/mL), a Tmax of about 6 to about 8 hours (e.g.,
7 hours), an AUC0_24 of about 13000 to about 13500 ng*h/mL (e.g., 13288 ng*h/mL), an AUC0_
00 of about 25000 to about 30000 ng*h/mL (e.g., 27672 ng*h/mL) and a tug of about 18 to about
24 hours (e.g., 21 hours) on day 1 of administration of about 30 mg of Compound A or a
pharmaceutical composition thereof to said subject or wherein the metabolite has one or more
of the pharmacokinetic parameters selected from a Cmax of about 1600 to about 2000 ng/mL
(e.g., 1768 ng/mL), a Tmax of about 1 to about 3 hours (e.g., 2 , an AUC0_24 of about
27500 to about 32500 ng*h/mL (e.g., 29423 L), an AUC0_OO of about 110000 to about
130000 L (e.g., 117697 ng*h/mL) and a Cuough of about 1000 to about 1200 ng/mL (e.g.,
1102 ng/mL) on day 15 of once a day administration of about 30 mg of nd A or a
pharmaceutical composition thereof to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has one or more of the pharmacokinetic parameters selected from a Cmax
of about 1100 to about 1200 ng/mL (e.g., 1153 ng/mL), a Tmax of about 2 to about 4 hours (e.g.,
3 hours), an AUC0_24 of about 15500 to about 16000 ng*h/mL (e.g., 15854 ng*h/mL), an
AUC0_OO of about 25000 to about 30000 ng*h/mL (e.g., 27274 ng*h/mL) and a tug of about 14 to
about 20 hours (e.g., 17 hours) on day 1 of administration of about 45 mg of Compound A or a
ceutical ition thereof to said subject or wherein the lite has one or more
of the pharmacokinetic parameters selected from a Cmax of about 2000 to about 2500 ng/mL
(e.g, 2243 ng/mL), a Tmax of about 1 to about 3 hours (e.g., 2 hours), an AUC0_24 of about
30000 to about 35000 ng*h/mL (e.g., 32705 ng*h/mL), an AUC0_00 of about 75000 to about
80000 ng*h/mL (e.g., 77722 L) and a Cuough of about 1100 to about 1200 ng/mL (e.g,
1181 ng/mL) on day 15 of once a day administration of about 45 mg of Compound A or a
pharmaceutical composition thereof to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has one or more of the pharmacokinetic parameters selected from a Cmax
of about 1400 to about 1500 ng/mL (e.g., 1438 ng/mL), a Tmax of about 4 to about 6 hours (e.g.,
hours), an 4 of about 21000 to about 22000 ng*h/mL (e.g, 21454 ng*h/mL), an
AUC0_OO of about 35000 to about 40000 ng*h/mL (e.g., 37490 ng*h/mL) and a tug of about 12 to
about 20 hours (e.g., 16 hours) on day 1 of stration of about 60 mg of Compound A or a
pharmaceutical ition thereof to said subject or wherein the metabolite has one or more
of the pharmacokinetic ters selected from a Cmax of about 2250 to about 2750 ng/mL
(e.g, 2521 , a Tmax of about 2 to about 4 hours (e.g., 3 hours), an AUC0_24 of about
45000 to about 50000 ng*h/mL (e.g., 46852 ng*h/mL), an AUC0_OO of about 135000 to about
145000 ng*h/mL (e.g., 138418 ng*h/mL) and a Cuough of about 1400 to about 1500 ng/mL (e.g.,
1467 ng/mL) on day 15 of once a day administration of about 60 mg of Compound A or a
pharmaceutical composition thereof to said subject.
In n embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has a Tmax of about 2 to about 4 hours (e.g., 3 hours) upon
administration of about 20 mg of Compound A or a pharmaceutical composition thereof or
about 45 mg of Compound A or a pharmaceutical composition thereof to said subject.
In certain embodiments, the s of use and pharmaceutical compositions
provided herein se in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has a Cmax of about 450 to about 550 ng/mL (e.g., 503 ng/mL) upon
administration of about 20 mg of Compound A or a ceutical composition f or a
Cmax of about 1100 to about 1200 ng/mL (e.g., 1153 ng/mL) upon administration of about
45 mg of Compound A or a pharmaceutical composition thereof to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein se in viva production of a metabolite of Compound A in a subject,
n the metabolite has an AUC00 of about 10000 to about 15000 ng/mL (e.g.,
11928 ng*h/mL) upon administration of about 20 mg of Compound A or a pharmaceutical
composition thereof or an AUC00 of about 25000 to about 30000 ng/mL (e.g., 27274 ng*h/mL)
upon administration of about 45 mg of Compound A or a ceutical composition thereof
to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has an AUC0_24 of about 7000 to about 8000 ng/mL (e.g.,
7484 ng*h/mL) upon administration of about 20 mg of Compound A or a pharmaceutical
ition thereof or an AUC0_24 of about 12500 to about 17500 ng/mL (e.g.,
15854 ng*h/mL) upon administration of about 45 mg of Compound A or a pharmaceutical
composition thereof to said subject.
In certain embodiments, the methods of use and pharmaceutical compositions
provided herein comprise in viva production of a metabolite of Compound A in a subject,
wherein the metabolite has a tug of about 12 to about 16 hours (e.g., 14.3 hours) upon
administration of about 20 mg of Compound A or a ceutical composition thereof or a tug
of about 12 to about 16 hours (e.g., 14.7 hours) upon stration of about 45 mg of
nd A or a pharmaceutical composition thereof to said subject.
In certain embodiments, the pharmacokinetic parameters in connection with the
metabolite of Compound A produced via stration of 7.5 mg, 15 mg, 30 mg, 45 mg and
60 mg of Compound A are obtained using the protocol set forth in Section 5.2.1 (paragraphs
-[00520]) of US. provisional application no. 61/653,436, filed May 31, 2012, which is
orated by reference herein in its entirety.
In certain embodiments, the pharmacokinetic ters in connection with the
metabolite of Compound A produced Via administration of 20 mg of Compound A were
obtained using the protocol set forth in Section 6.5.1, below.
In certain embodiments, the cokinetic parameters set forth herein are
mean values obtained from multiple subjects.
In certain ments, the metabolite of Compound A is the O-desmethyl
metabolite.
6. EXAMPLES
D Draw (ChemInnovation Software, Inc., San Diego, CA) or
ChemDraw Ultra (Cambridgesoft, Cambridge, MA) was used to generate names for chemical
structures.
The following abbreViations were used in descriptions and examples:
ACN Acetonitrile
Amphos t—butyl(4-dimethylaminophenyl)phosphine
BHT Butylated hydroxytoluene
Boc utoxycarbonyl
dba Dibenzylideneacetone
DCM Dichloromethane
DIBE Diisobutyl hexahydrophthalate
DIPEA N,N—Diisopropylethylamine
DIPE Diisopropyl ether
DME Dimethoxyethane
DMAP 4-Dimethylaminopyridine
DMSO Dimethylsulfoxide
dppf l,l'- Bis( diphenylphosphino)ferrocene
DSC Differential scanning calorimetry
ESI Electronspray ionization
EtOAc Ethyl acetate
DVS Dynamic vapor sorption
HPLC High performance liquid chromatography
IPA Isopropyl alcohol
IPAc Isopropyl e
MeOAc Methyl acetate
MIBK Methyl isobutyl ketone
mp Melting point
MS Mass spectrometry
MTBE Methyl tert—butyl ether
NBS N—Bromosuccinimide
NMR Nuclear ic resonance
NMP N—methyl-2—pyrrolidinone
PEG Polyethylene glycol
PFL Protect from light
REF Refrigerated
RTmp Room temperature
TEA Triethylamine
TFA Trifluoroacetic acid
TGA ThermograVimetric analysis
THF Tetrahydrofuran
TLC Thin layer tography
TMS Trimethylsilyl
XRPD X-ray powder ction
The following Examples are presented by way of illustration, not limitation.
6.1 SOLID FORM SCREEN
6.1 . l CHARACTERIZATION METHODOLOGY
6. l . l .1 X-ray Powder Diffraction (XRPD)
All of solid s generated in the solid form screen were analyzed by XRPD.
XRPD analysis was conducted on a Bruker AXS C2 GADDS or Bruker AXS D8 Advance
X-ray powder diffractometer.
Certain X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2
GADDS ctometer using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser
video cope for auto-sample oning and a HiStar 2-dimensional area or. X-ray
optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
A weekly performance check is d out using a certified standard NIST 1976 Corundum
(flat plate). The beam divergence, i.e. the effective size of the X-ray beam on the sample, was
approximately 4 mm. A 0-0 continuous scan mode was employed with a sample — detector
distance of 20 cm which gives an effective 20 range of 3.2 O — 29.7 0. Typically the sample
would be exposed to the X-ray beam for 120 seconds. The software used for data collection
was GADDS for WNT 4.1.16 and the data were analyzed and presented using Diffrac Plus
EVA vl 1.0.0.2 or vl3.0.0.2. Ambient conditions: s run under ambient conditions were
ed as flat plate specimens using powder as received without grinding. Approximately
l-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface. Non-ambient
conditions: Samples run under non-ambient conditions were mounted on a silicon wafer with
heatconducting compound. The sample was then heated to the appropriate ature at
°C/min and subsequently held isothermally for 1 minute before data collection was initiated.
Certain X-Ray Powder Diffraction patterns were collected on a Bruker D8
diffractometer using CuKa radiation (40 kV, 40 mA), 0-2 0 goniometer, and divergence ofV4
and receiving slits, a Ge monochromator and a Lynxeye detector. The instrument is
performance d using a ed Corundum standard (NIST 1976). The software used for
data collection was Diffrac Plus XRD Commander v2.5.0 and the data were analyzed and
presented using Diffrac Plus EVA vl 1.0.0.2 or vl3.0.0.2. Samples were run under ambient
WO 82344
conditions as flat plate specimens using powder as received. The sample was gently packed into
a cavity cut into polished, ackground (510) silicon wafer. The sample was d in its
own plane during analysis. The details of the data collection are: Angular range: 2 to 42 c’20;
Step size: 0.05 02 0; Collection time: 0.5 s/step.
6. 1.1.2 Differential Scanning Calorimetry (DSC)
Modulated DSC data were collected on a TA Instruments Q2000 equipped with
a 50 position auto-sampler. The calibration for thermal capacity was carried out using sapphire
and the calibration for energy and temperature was carried out using certified indium.
Typically 3—1.5 mg of each sample, in a pin-holed aluminum pan, was heated at 2 c’C/min from
-80 0C to 300 0C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
Modulated temperature DSC was carried out using an underlying heating rate of 2 c’C/min and
temperature tion parameters of :: 1.272 0C (amplitude) every 60 seconds (period). The
instrument control software was Advantage for Q Series v2.8.0.392 and Thermal Advantage
v4.8.3 and the data were analyzed using Universal Analysis v4.4A.
Non-modulated DSC data were collected on a TA ments Q2000 equipped
with a 50 position auto-sampler. The calibration for thermal capacity was carried out using
sapphire and the calibration for energy and temperature was carried out using certified .
Typically l to 5 mg of each sample, in an aluminum pan, was heated at 10 c’C/min from 20 CC
to 300 °C. A purge of dry nitrogen at 50 mL/min was maintained over the sample. The
instrument control software was Advantage for Q Series .392 and Thermal Advantage
v4.8.3 and the data were analyzed using Universal Analysis v4.4A.
6.1.1.3 Thermogravimetric Analysis (TGA)
TGA data were collected on a Mettler TGA/SDTA 85 l e equipped with a
34 position autosampler. The ment was temperature calibrated using ied indium.
Typically 5-15 mg of each sample was loaded onto a pre-weighed aluminum crucible and was
heated at 10 c’C/min from ambient ature to 350 CC. A nitrogen purge at 50 ml/min was
maintained over the . The instrument l and data analysis software was
STARe v9.20.
6. l . l .4 Polar Light copy
Samples were studied on a Leica LM/DM polarized light microscope with a
digital video camera for image capture. A small amount of each sample was placed on a glass
slide, mounted in immersion oil and covered with a glass slip, the individual particles being
separated as well as le. The sample was viewed with appropriate cation and
partially polarised light, coupled to a 7t false-colour filter.
6. l . l .5 Gravimetric Vapour Sorption (GVS)
Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption
analyser, controlled by DVS Intrinsic Control software vl 0.0.30. The sample temperature was
maintained at 25 CC by the instrument controls. The humidity was controlled by mixing
streams of dry and wet nitrogen, with a total flow rate of 200 mL/min. The relative ty
was measured by a ated Rotronic probe (dynamic range of 1.0—100 %RH), located near
the sample. The weight change, (mass relaxation) of the sample as a function of %RH was
constantly monitored by the microbalance (accuracy :0005 mg). Typically 5—20 mg of sample
was placed in a tared mesh stainless steel basket under ambient conditions. The sample was
loaded and unloaded at 40 %RH and 25 CC (typical room conditions). The rd rm
was med at 25 CC at 10 %RH intervals over a 0—90 %RH range. Data analysis was
undertaken in Microsoft Excel using DVS Analysis Suite v6.0.0.7.
6.1.2 SOLID FORM SCREEN EXPERIMENTS
] The solvents used in the rph screen were either HPLC or reagent grade,
including toluene, MTBE (methyl tert-butyl ether), DIPE (diisopropyl ether), THF
(tetrahydrofuran), DME (dimethoxyethane), IPAc (isopropyl e), EtOAc (ethyl acetate),
MIBK (methyl isobutyl ketone), acetone, IPA (isopropyl alcohol), ethanol, ACN (acetonitrile),
nitromethane, or IPA:water (for example, 95 :5).
The solid form generated from the screen was characterized by X-ray powder
diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis
(TGA), optical microscopy, and gravimetric vapor sorption (GVS).
6.1.2.1 Equilibration/Slurry and Evaporation
Amorphous Compound A (~10 mg per experiment) was treated with the stated
solvent. Solutions were d to slowly evaporate at room temperature and the residual solids
were ed by XRPD. Suspensions were subjected to heat/cool cycles (50°C/room
temperature, 8 hour cycle) for 16 hours; the solvent was then allowed to evaporate and the
al solids were analyzed by XRPD.
] The results of slurry experiments are summarized in Table 1. All of the solids
obtained from filtration of the slurries were confirmed to be Form A by XRPD.
Table l. Slurry Experiments of Form A of Compound A at Room Temperature
MTBE Form A
IPAc Form A
MIBK Form A
Acetone Form A
Ethanol Form A
ACN Form A
6.1.3 TERIZATION OF FORM A OF COMPOUND A
6.1.3.1 XRPD, TGA, and DSC Characterization
] Form A has a crystalline XRPD pattern as shown in and an irregular plate
crystal habit as shown in The XRPD pattern of Form A of Compound A shows that
Form A is crystalline. Some XRPD peaks of crystalline Form A are summarized in Table 2.
Table 2. X-Ray Diffraction Peaks for Form A of Compound A
Two-theta angle (°) d Space (A) Intensity (%)
8.3 10.648 58.3
8.8 9.984 26.8
12.0 7.342 8.1
13.2 6.708 100.0
13.9 6.357 8.0
14.4 6.125 3.3
14.8 5.961 8.7
16.5 5.352 50.2
17.7 4.996 35.4
18.2 4.872 50.7
19.3 4.586 8.2
19.5 4.560 7.7
19.6 4.526 7.3
21.0 4.230 4.4
21.2 4.185 3.9
21.7 4.094 50.9
22.5 3.942 13.6
24.1 3.684 8.4
24.7 3.603 7.1
.0 3.560 12.8
.3 3.512 5.6
26.5 3.363 35.7
26.7 3.332 5.7
28.3 3.147 11.4
29.3 3.051 5.5
29.5 3.022 9.9
29.8 2.992 7.9
Two-theta angle (°) d Space (A) Intensity (%)
.5 2.924 3.2
32.1 2.782 2.9
33.3 2.690 3.4
34.2 2.621 3.5
34.6 2.587 4.4
TGA and DSC thermograms of Form A are shown in Form A was found
to lose up to 0.02 % volatiles during TGA analysis upon 100 0C, which indicates that Form A is
unsolvated and anhydrous. Form A exhibited a single melting peak at 199.3 0C (onset).
6.1.3.2 Hygroscopicity
Hygroscopicity of Form A was determined by moisture adsorption and
desorption. The moisture sorption/desorption or of Form A was determined by DVS and
the results are ized in Form A showed no significant water uptake (<0.1% w/w)
between 0 and 80% relative ty, which indicates that Form A is not hygroscopic. After
undergoing the full adsorption/desorption cycle, the XRPD diffractogram of the sample showed
that the material was unchanged from the l Form A. Based on the characterization results,
Form A was found to be an anhydrous and non-hygroscopic crystalline material.
6.1.4 ALTERNATIVE METHODS FOR THE PREPARATION OF
FORM A OF COMPOUND A
ation 1: Compound A was combined with BHT (0.001 equiv) in IPA
and water (3x:5x vol). The mixture was heated 65 CC and while maintaining this temperature,
water (5x vol) heated to 65 0C was added. A small amount of the title compound (0.02 equiv)
in water heated to 65 0C was added. The mixture was held for 2 h, cooled to room ature
over 4 h, and stirred for an additional 2 h. The resulting solids were collected by filtration,
washed with 20% IPA in water and dried to give Compound A as a white to yellow solid.
1H NMR (400 MHz, DMSO-d6) 8 (ppm) 9.03 (d, J: 1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd,
J: 2.34, 8.20 Hz, 1H), 7.74 (d, J: 7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, J= 3.71,
WO 82344
12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20 (tt, J= 4.00, 10.84 Hz, 1H), 2.58 (qd, J= 2.93,
12.82 Hz, 2H), 2.14 (d, J: 10.15 Hz, 2H), 1.68 (d, J: 10.93 Hz, 2H), 1.47 (s, 6H), 1.17 - 1.35
(m, 2H); MS (ESI) m/Z 398.3 ‘ DSC endotherm at 201.9 c’C. XRPD ctogram (top
peaks :05 °) two-theta angle (°): 8.0, 9.0, 12.0, 13.0, 16.5, 17.5, 18.2, 21.5, 22.5, 25.0, 26.5.
Preparation 2: Compound A was combined with BHT (0.02 equiv) in MeOAc
(25X vol) and heated to 55 oC. The solution was cooled to 25 OC and a small amount of the title
compound (0.02 equiv) in MeOAc was added. The slurry was held for 1 h, distilled under
vacuum to a d volume and treated with n-heptane (10x vol). The slurry was held for 2 h,
and the resulting solids were collected by filtration, washed with 50% MeOAc in n-heptane and
dried to give Compound A as a white to yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 (ppm)
9.03 (d, .1: 1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, .1: 2.34, 8.20 Hz, 1H), 7.74 (d, .1: 7.81 Hz,
1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, .1: 3.71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20
(tt, .1: 4.00, 10.84 Hz, 1H), 2.58 (qd, .1: 2.93, 12.82 Hz, 2H), 2.14 (d, .1: 10.15 Hz, 2H), 1.68
(d, .1: 10.93 Hz, 2H), 1.47 (s, 6H), 1.17 - 1.35 (m, 2H); MS (ESI) m/z 398.3 [M+1]+' DSC
endotherm at 201.9 0C. XRPD diffractogram (top peaks, :05 °) eta angle (°): 8.0, 9.0,
12.0, 13.0, 16.5, 17.5, 18.2, 21.5, 22.5, 25.0, 26.5
Preparation 3: Compound A was combined with BHT (0.02 equiv), and
MeOAc, and heated to 55 CC, forming a clear solution. The solution was filtered while hot,
cooled to 30 oC and a small amount of the title compound (0.02 equiv). The slurry was agitated
for at least 1 h, distilled under vacuum to a reduced volume and treated with n-heptane. The
resulting solid was collected through filtration, washed with a 1:1 mixture of MeOAc in
n-heptane and dried to give Compound A as a white to yellow solid 1H NMR (400 MHz,
DMSO-d6) 8 (ppm) 9.03 (d, .1: 1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, J: 2.34, 8.20 Hz, 1H),
7.74 (d, .1: 7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, J: 3.71,12.10 Hz,1H),4.13(s,
2H), 3.28 (s, 3H), 3.20 (tt, .1: 4.00, 10.84 Hz, 1H), 2.58 (qd, J: 2.93, 12.82 Hz, 2H), 2.14 (d,
.1: 10.15 Hz, 2H), 1.68 (d, .1: 10.93 Hz, 2H), 1.47 (s, 6H), 1.17 - 1.35 (m, 2H); MS (ESI) m/z
398.3 [M+l]+‘ DSC endotherm at 201.9 c’C. XRPD diffractogram (top peaks, ::0.5 0) two-theta
angle (°): 8.0, 9.0, 12.0, 13.0, 16.5, 17.5, 18.2, 21.5, 22.5, 25.0, 26.5.
Preparation 4: A 1:1 wt/wt mixture Of Compound A (Form A) and Compound
A (pinacol stal) was d with IPA (6X vol) with agitation for 4 days at ambient
temperature. The solids were collected by filtration and and dried under reduced pressue at
40-50 0C to give Compound A (Form A) as a yellow solid. DSC endotherm Of 195 OC. XRPD
diffractogram (top peaks, ::0.5 0) two-theta angle (°): 8.0, 9.0, 12.0, 13.0, 16.5, 17.5, 18.2, 21.5,
22.5, 25.0, 26.5
6.1.5 PREPARATION OF PINACOL CO-CRYSTAL OF
ND A
Compound A, pinacol (2.4 equiv), and THF (5x vol) were combined and heated
to 45- 50 oC, and toluene (1x vol) was added. The solution was led under reduced
pressure (300- 350 Torr) keeping the temperature between 40-45 0C to 4x vol. The solution
was cooled, and toluene (5x vol) was added while continuously removing t under
reduced re (300-350 Torr), until 15% THF in toluene composition was achieved. The
batch was seeded with pinacol co-crystal (0.02 equiv) at 25 OC, and the batch was held for 72 h.
The solids were filtered, rinsed with THF/toluene and dried at 45- 50 0C under vacuum to
afford Compound A pinacol stal (71% yield, 20 wt% pinacol by 1H NMR). DSC melt at
119.0 °C. XRPD diffractogram (top peaks, ::0.5 0) two-theta angle (°): 5.0, 6.0, 12.5, 14.0,
.0, 15.5, 17.5, 18.5, 22.5.
6.1.6 PREPARATION OF HYDRATE OF COMPOUND A
(FORM B)
Compound A was combined with BHT (0.001 equiv) in IPA and water (3x:5x
vol). The mixture was heated to 55 °C, and water (5x vol) was added. A small amount Of the
title compound (0.02 equiv) in water was added. The mixture was cooled to room temperature
over 1 h and stirred for an additional 48 h at room temperature. The resulting solids were
ted by filtration, washed with 20% IPA in water and dried tO give Compound A hydrate
as a pink solid. The solid had a DSC endotherm Of 111.3 C’C, exotherm Of 164.9 CC, and
endotherm Of201.6 oC. TGA analysis showed 6.4% weight loss and an onset temperature of 50
c’C. XRPD diffractogram (tOp peaks, :05 °) two-theta angle (°): 6.0, 7.0, 8.0, 10.0, 12.0, 14.0,
17.0, 18.0, 20.0, 20.5, 22.5, 24.5.
6.1.7 PREPARATION OF ANHYDROUS FORM OF COMPOUND A
(FORM C)
Preparation 1: Compound A was combined with BHT (0.001 equiv) in MeOH
(10X VOl). The mixture was distilled tO a reduced volume (5X) and further distilled with the
addition Of IPA until an additional 50 mL Of distillate was collected, and the solution was
cooled to room temperature. The resulting solids were collected by filtration, washed with IPA,
(2X vol) and dried tO give nd A as an Off-white solid. DSC analysis Of the solid
showed an endotherm Of 161 OC and an endotherm Of 200 OC. XRPD diffractogram (top peaks,
:05 °) two-theta angle (°): 6.5, 9.0, 10.0, 14.5, 16.5, 19.0, 23.0, 23.5.
Preparation 2: Compound A (pinacol co-crystal) and BHT (0.01X wt) were
treated with IPA (8X vol) with agitation for 4 days at ambient ature. The solids were
ted by filtration, washed with IPA, and dried under reduced pressue at 40-50 0C to give
Compound A (Form C) as a solid. DSC is Of the solid showed an endotherm and
exotherm at 160 CC and an endotherm at 200 CC. XRPD diffractogram (tOp peaks, :05 °) two-
theta angle (°): 6.5, 9.0, 10.0, 14.5, 16.5, 19.0, 23.0, 23.5.
6.1.8 ATION OF METHANOL SOLVATE OF
COMPOUND A (FORM D)
] nd A was combined with BHT (0.001 equiv) in MeOH (20x vol) and
heated to 65 oC. The solution was cooled to room temperature and stirred for an additional
18 h. The resulting solids were collected by filtration, washed and dried at 40-45 0C to give
Compound A as a pink solid. The solid had a DSC endotherm Of 98.3 0C, an exotherm Of 159.3
0C, and an endotherm Of 200.6 0C. TGA analysis showed 7.4% weight loss and an onset
temperature Of 80 oC. XRPD diffractogram (top peaks, :05 °) two-theta angle (°): 6.0, 7.5,
8.0, 9.0, 10.0, 12.5, 14.5, 16.5, 19.0, 19.5, 20.5, 23.0.
6.2 SIS
6.2.1 LARGE SCALE SYNTHESIS OF COMPOUND A
6.2.1.1 Synthesis 1
Bug;A0023 +66 DIPEA (5
NMP 125 °c Br NH
fiHz-HC| (:1?ACOZEt
Ethyl(3,5-dibromopyrazinylamino)acetate (70.0 kg), trans
methoxycyclohexylamine hydrochloride, (51.5 kg) and NMP (360.1 kg) were combined and
treated with DIPEA (93.5 kg). The batch was heated to 125-130 0C until completion was
reached. The resulting on mixture was cooled to 20-35 0C and ed into a mixture of
% sodium chloride solution and EtOAc. The c layer was washed three times with a 5%
sodium chloride solution followed by a water wash. The c phase was concentrated by
distillation, causing the solid product to form. The solid was collected h filtration,
washed with MTBE and dried (40% yield).
OMe OMe
: 1. H3PO4, 80 °C (5
B1:1:: 2. aq. K2003 ”11;01
Ethyl 2-((5-bromo(((lr,4r)methoxycyclohexyl)amino)pyrazin
yl)amino)acetate (35.0 kg) was treated with a 21% phosphoric acid solution (147.4 kg) at 80 °C
for at least 12 h. The resuling suspension was cooled to room temperature an d the solid was
collected through filtration and washed with water. The solid was slurried in water and treated
with a l M potassium carbonate solution (1 equiv, 12.6 kg). The resulting solid was collected
through filtration, washed with water, and dried (85.0% yield).
OMe OMe
(5 HO /
. N\ 8/0 WHO / GO
(57% _
,A =
Br |N\ N O ,aq. 2 3 N\
-HC|
/ 'ZI;
7-Bromo- l -(( l r,4r)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-
2(1H)—one (27.5 kg), 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)pyridinyl)propan
ol hydrochloride (26.2 kg), and PdC12(Amphos)2 (137.5 g) in THF (219.8 kg) were combined
with a potassium carbonate solution (27.5 kg),and heated to reflux until reaction completion
was d. The mixture was cooled, treated with toluene, and the s layer was
removed. The organic solution was washed with an aqueous potassium dihydrogen phosphate
solution, and the aqueous layer was removed. The organic layer was treated with SiliaBond®
Thiol (4.2 kg) and twice with activated carbon (2 x 2.8 kg). The organic solution was distilled
to a reduced volume followed by continuous lation with the addition of toluene until a 15%
THF in e solution was reached, at which time the batch was cooled and the product was
left to precipitate. The resulting solid was ted through filtration, washed with e, and
dried (70.0% yield).
2 Synthesis 2
Bug;A0023 +66 DIPEA (5
NMP 125 °c Br KIH
0H2-HC| T:IfACOZEt
A mixture of ethyl(3,5-dibromopyrazinylamino)acetateH(69.1 kg), trans
methoxycyclohexylamine hydrochloride, (50.8 kg) and NMP (360 kg) was heated to
125-130 0C until completion was achieved. The mixture was cooled to 20-30 0C, and treated
with 5% sodium chloride solution (5 vol) and EtOAc (8 vol). The aqueous layer was removed,
and the organic layer was washed three times with 5% sodium chloride (3 X 5 vol) and once
with water (5 vol). The c layer was concentrated by vacuum distillation to a reduced
volume, cooled to 25 CC, and agitated at this temperature for 19 h. The slurry was d and
the wet cake was washed with MTBE. The product was dried in a vacuum oven at to obtain
ethyl 2-((5-bromo-3 -((( l r,4r)methoxycyclohexyl)amino)pyrazinyl)amino)acetate (44. l%
yield).
OMe OMe
: 1. H3PO4, 80 °C (5
B11:: 2. aq. K2003 31:1;1,3]
] Ethyl bromo(((lr,4r)methoxycyclohexyl)amino)pyrazin
yl)amino)acetate (35 kg) was d with a 21% phosphoric acid solution (410 kg) at 80 °C
until completion was achived. The suspension was cooled to 30-35 0C and filtered, and the wet
cake was washed with water (5X vol), charged to a reactor, and suspended in water (3X vol).
The slurry was treated with 1M postassium carbonate solution (1 equiv), filtered and washed
with water (2 x 5x vol). The product was dried at 50-55 0C in a vacuum oven to deliver
7-Bromo- l -(( l r,4r)methoxycyclohexyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( l H)-one (91%
yield).
OMe OMe
“EGO +|—|o><l\:j\Boo PdAmphosZCIZ HO / (j
fTHF aq. K2003, A E
N\ fligof
A mixture of 7-bromo-l-((lr,4r)methoxycyclohexyl)-3,4-
dihydropyrazino[2,3-b]pyrazin-2(lH)-one (27.7 kg), 2-(5-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolanyl)pyridinyl)propanol hydrochloride (26.3 kg) and PdClz(Amphos)2
(137.6 g) in THF (1227 kg) was combined with a solution of potassium carbonate (27.5 kg) in
water (220 kg). The mixture was heated to reflux and held until reaction completion. The batch
was cooled to 45 oC, toluene (71.4 kg) was added, and the aqueous phase was removed. The
organic solution was treated with aqueous potassium dihydrogen phosphate solution,
SiliaBond® Thiol, and twice with activated . The resulting organic solution was distilled
under atmospheric re to a reduced volume and continuously distilled with toluene
addition until a composition of ~15 wt% THF in toluene was reached. The batch was cooled to
OC, d, and the solids were washed with toluene, and dried under vacuum to deliver
Compound A as a light yellow solid (87% yield).
OMe OMe
/ MeOAc HO / (j
N \ [NIN[ifo n—heptane N \
BHT '21gof
Compound A (27.1 kg), BHT, (270 g) and MeOAc (604 kg) were combined,
heated to 50-55 0C, and filtered. A slurry of small amount of Compound A (540 g) in MeOAc
(2.6 kg) was added, and the batch was held for 1 h. The batch was led under vacuum to
10X vol, and treated with heptane while maintaining the batch temperature at 25-30 c’C until the
composition is 1:1 (v/v/) MeOAc / heptane. The batch was held at 20-25 0C for 14 h, filtered,
and the wet cake was washed twice with 1:1 MeOAc / heptane and dried at 50- 55 0C under
vacuum to deliver Compound A (78% yield) as an off-white to light yellow solid. DSC
confirmed the crystal Form A. 1H NMR (DMSO-d6) was tent with the ed structure.
WO 82344 2012/067172
6.2.2 LARGE SCALE SYNTHESIS OF METABOLITE OF
COMPOUND A
A metabolite of Compound A was prepared as follows:
OH OH
DIPEA H3PO4
/\+C02Et NMP, 125 °C Br 80°C Br
fiHz-HCI \[NNIZHA \[NNE::0]?
ACOZEt
1 2 3 4
A vessel was charged with 1 (2.15 kg), 2 (1.44 kg), and NMP (6.5 L), and the
resulting slurry was agitated at 20-30 CC and treated with DIPEA (3.87 L). The batch was
heated to 125-130 0C, held for 20 hours until completion was achieved, cooled to 20-35 °C, and
transferred to a vessel containing a e of EtOAc (17.2 L) and 5% aq. NaCl (10.7 L). The
batch was agitated for 10-15 minutes, allowed to settle for 10-15 minutes, and the aqueous layer
was removed. The batch was washed an additional three times with 5% aq. NaCl (10.7 L) and
once with water (10.7 L). The batch was distilled under reduced pressure (50-60 0C; 250-300
Torr) until reaching 2X volume. The resulting slurry was treated with ane (6.3 L) while
maintaining a batch temperature of 50-60 0C. The batch was cooled to 20-30 °C, held for 17
hours, and filtered. The filter cake was washed with n-heptane and dried at 50-60 0C under
vacuum to afford 3 (66% yield) as a solid.
The solid 3 (1.56 kg) and a 10% aq. H3PO4 solution (16 L) were heated to
75-85°C, held for 15 hours, cooled to 20-30 °C, and filtered. The filter cake was washed with
water (5 L) and dried on the filter for 1 hour. The filter cake was charged to a vessel, treated
with water (15 L), and agitated at 20-30 CC for 2 hours. The batch was filtered, washed with
water (2 x 4.7 L), dried in a vacuum oven at 50-60 0C to obtain 4 (54% for two steps) as solid.
MS: Calc: 327.0 [M+H]; Obsd: 309.0 [M-OH], 329.0 [M+3].
OH OH
6 H0 /
| G
N\ PdCl2(Amphos)2 /
+ B/O HO
aq KCO THF I
BrTN\ N O ' 2 3’
~HCI (‘3 N\ N\ N O
| I ' I
N N N N
H H
4 5 6
] A vessel was charged with 4 (447 g), 5 (425 g), PdAmphoszClz (0.00023 eq.),
and THF (2.2 L) that had been sparged with N2 for 30 min. The slurry was agitated and treated
with a solution of K2C03 (2.4 eq.) in water (3.6 L), that had been sparged with N2 for 30 min.
The batch was heated to reflux, held for 15 h, cooled to just below the reflux point, and an
additional charge of PdAmphos2C12 46 eq.) was added. The e was heated to
reflux, held for 20 h, cooled to 40-50 0C, treated with e (447 mL), and the aqueous layer
was removed. The batch was treated with toluene (447 mL) at which time precipitation of
solids began. The batch was distilled under atmospheric pressure to 6X vol and distilled at
constant volume with addition of toluene until the composition reached ~30% THF in toluene.
The supernatant was removed, and the remaining solids were treated with THF
(447 mL), heated to 60-65 CC, and treated with THF (447 mL). The batch was held at 60-65 °C
for 30 minutes, cooled to 20-30 0C over 45 minutes, and aged for 15 hours at 20-30 0C. The
batch was treated with THF (447 mL) and filtered. The filter cake was dried under vacuum at
40-50 0C to obtain crude 6 (59% yield) as a solid. MS: Calcd: 384.2 [M+H]; Obsd: 384.2.
The THF filtrate was concentrated under reduced pressure, slurried in IPA
(500 mL) for 4 hours and filtered. The filtered solids were dried under vacuum at 40-50 0C to
obtain crude 6 (23% yield) as a solid. MS: Calcd: 384.2 [M+H]; Obsd: 384.2.
1. THF, water
HO / <1
= SiliaBond®-Thio| 50°C Ho /
N \ of 2 IPA/water, BHT N \ IZINNfo‘30
6 (Crude)
6 (Purified)H
A vessel was charged with crude 6 (310 g), BHT (155 mg), SiliaBond® Thiol
(47 g), THF (1 1.8 L), and water (620 mL) and agitated to form a slurry. The batch was heated
to C, held for 4 hours, cooled to 30-40 0C, and filtered. The filtrate was charged to a
vessel distilled under reduced pressure (27-30 0C, 200 mmHg) until reaching 5-6X vol. The
batch was cooled to 20-30 0C, agitated for 2 hours, and filtered. The filter cake was washed
with THF (300 mL) and dried under vacuum at 45-50 c’C. The resulting solid (153 g), BHT
(75 mg), IPA (l .l L), and water (380 mL), were combined and agitated to form a slurry. The
slurry was heated at elevated temperature (reflux) for 18 h, cooled to 20-30 0C, held for
3-4 hours, and filtered. The filter cake was dried at 50 0C under vacuum to deliver purified 6
(66% yield) as a solid. MS: Calcd: 384.2 [M+H]; Obsd: 384.2.
6.3 SYNTHESIS OF ISOTOPOLOGUES OF COMPOUND A
6.3.1 SYNTHESIS OF 14C ENRICHED COMPOUND A
] 14C-radiolabeled Compound A was prepared as follows.
Br Br
\ n-BULI \
I I
/ H30 /
i N o 1:‘c N
| | HQ l
14 CH3
/C\ 7
H30 CH3
5-Bromoiodopyridine (1 equiv) in DCM was cooled to -78 oC and treated
sequentially with n-BuLi (1.05 equiv of 2.5M in hexane) and 14C-labeled acetone (3 equiv).
The mixture was slowly warmed to ambient ature, stirred for 30 min, and treated with
water (10 mL). The organic layer was dried with Na2S04, filtered, and concentrated under
reduced pressure. The crude product was taken to the next step with no additional ation.
Br Br
\ \
H30 |
/ TMSCI, TEA H30 |
‘fC —’
N 14c N
HO | TMSO
CH3 CH3
7 8
Crude 7 in DCM at ambient temperature was sequentially treated with TEA
(3 equiv) and TMSCl (2 equiv) and stirred for 18 h. The reaction mixture was treated with
saturated NaHCOg (15 mL), and extracted with DCM. The organic layer was dried with
Na2S04, filtered, and concentrated under reduce pressure.. The oil was purified by column
chromatography (5% EtOAc/hexane) to deliver 8 as an oil (52% over 2 .
WU133‘33$314C\ HCCE?/
TMSO CH3N
8 Pd(dppf)2C|2 TMSO’C 9
Dioxane CH3
Compound 8, bis(pinacolato)diborane (1.1 equiv), KOAc (3 equiv), and
dppf)-DCM complex (0.03 equiv) were combined in l,4-dioxane, heated to 90 oC, and
held for ~18 h. The mixture was cooled to t temperture, d with MTBE, filtered,
and concentrated under reduced pressure. The crude material was purified by column
chromatography (l:l hexane) to obtain Compound 9 as a solid (27% yield).
H30 H30
mCH3 3%CH3
\ 0 CH3 0 CH3
| HCIDioxane
H C3
/ H3C {T3140 /
N -HC|
TMSO14C 9
6:143 HO
CH3 1o
2012/067172
Compound 9 in l,4-dioxane was treated with 4 M HCl in l,4-dioxane (2 equiv)
at ambient temperature and stirred for 2 h. The mixture was concentrated under a flow ofN2 to
give an off white solid, which was treated with MTBE for l h and filtered to obtain Compound
as a solid (98% yield).
PdC|2(Amphos)2 :
3140' N N N N O \
Br K2003, THF/water
HO’I T1“T\ I
N/j: jN
N N
H 14C—Compound A
Compound 10, Compound 11 (1.08 equiv), PdClz(Amphos)2 (0.02 equiv), THF,
and an aqueous K2C03 solution (2.5 equiv K2C03) were heated in a sealed tube at 70-75 0C for
16 h. The tube was cooled to 25 oC, and the mixture was extracted with toluene and
concentrated under reduced pressure. The crude oil was purified by column chromatography
(1 :l THF/DCM) and isocratic semi-preparative HPLC. The isolated fiactionswere concentrated
under reduced pressure, dissolved in EtOAc, dried with , filtered, and concentrated
under reduced pressure. The material was dissolved in THF and trated under a flow of
nitrogen followed by high vacuum. The isolated oil was treated with ACN and concentrated
with a stream ofN2 to induce crystallization. The contents of were concentrated under high
vacuum to obtain 14C-labeled Compound A as a solid.
Alternatively, 14C-Compound A can be prepared from 10 and 11 as s:
Compound 10 and 11 (1.1 , THF, and aqueous K2C03 (2.5 equiv ,
were ed with PdAmphoszClz (0.02 equiv) and heated to 70-75 0C until reaction
completion (about 18 h). The mixture was cooled, treated with EtOAc and brine and the layers
separated. The organic layer was dried over Na2S04, filtered, and concentrated to a residue.
The residue was purified by column chromatography on silica gel (CH2C12:EtOAc 1:3;
followed by tOAc 2:98) and concentrated to a e. The residue was then purified
by preparative HPLC using 0.015 M KH2P04 and MeCN. The collected fractions were
extracted with EtOAc, dried over NaZSO4, d, and concentrated to obtain 14C-labeled
Compound A as a solid.
6.3.2 SYNTHESIS OF 13c ENRICHED COMPOUND A
13C-labeled Compound A was prepared as follows.
Br13/CHZ\13¢,0 Br
Br N Br
\E \/
N NH2 —O>|N:[Br1SCH2\1SC’OEtK2003
Bu4NHSO4 o
acetone
K2C03 (1.5 eq,) and ethyl bromoacetate-13C2 (1.3 eq) were added to a solution of
3,5-dibromopyrazinamine (1.0 eq) in acetone (10x vol). The slurry was heated to 30 oC,
Bu4NHSO4 (0.074 eq) was added, and the mixture was stirred for 2 d at reflux . The reaction
slurry was cooled to t temperature, filtered h celite, and the cake was washed with
acetone (10 vol). The filtrate was concentrated under reduced re, dissolved in EtOAc
(11.4 vol), and the organic phase was washed with water (2 x 3.2 vol) and saturated aqueous
NaCl (2 x 3.2 vol). The ed aqueous phase was extracted with EtOAc, and the combined
organic phase was dried over MgSO4, filtered, and washed with EtOAc. Ecosorb-906 (0.11 wt)
was added, and the mixture was stirred 13 h. The slurry was filtered washed with EtOAc, and
the filtrate was concentrated under reduced pressure to a slurry to which was added a 2%
EtOAc in e solution (7.9 vol). The slurry was filtered after stirring for 3 h at ambient
temperature. The collected solid was washed with heptane (3 vol) and dried in a vacuum oven
at 35 0C to provide (12) as a solid (57% yield). 1H NMR(CDC13, 300 MHz): 8 = 8.05 (s, l H),
.77 (br. s., l H), 4.41 (t, J=5.7 Hz, 1 H), 4.26 (qd, J=7.1, 3.0 Hz, 2 H), 3.94 (t, 1 H), 1.31 (t,
J=7.1 Hz, 3 H) ppm. LC/MS: Calculated: 340.9, Found: ES+ (M+l) 341.9.
NMP N N’ 13c
H II
12 O
A reaction flask was sequentially charged with (1 ,4-trans)
methoxycyclohexanamine hydrochloride (1.5 eq), compound (12) (1.0 eq), NMP (5.0 vol) and
DIPEA (3.5 eq). The solution was heated to 125 0C for 24 h and then cooled to 25 oC. EtOAc
(10 vol) and 5% s NaCl (15 vol) were added, and the layers were separated. The organic
layer was washed with a 5% aqueous NaCl (2 X 15 vol) and concentrated under reduced
pressure. The residue was treated with MTBE (4.0 vol), stirred 1 hour at t temperature
and filtered. The solid was washed with MTBE and dried in a vacuum oven at 20-30 0C to
provide (13) as a solid (61% yield). 1H NMR (DMSO-d6 ,300 MHz): 8 = 7.21 (s, 1 H), 6.98 (t,
J=4.8 Hz, 1 H), 6.48 (d, J=6.8 Hz, 1 H), 4.26 (t, J=5.5 Hz, 1 H), 4.09 (qd, J=7.1, 3.1 Hz, 2 H),
3.79 (t, J=5.6 Hz, 1 H), 3.73 (br. s., 1 H), 3.25 (s, 3 H), 3.05 - 3.22 (m, 1 H), 1.89 - 2.14 (m,
4 H), 1.21 - 1.37 (m, 4 H), 1.18 (t, J=7.1 Hz, 3 H) ppm. LC/MS: ated: 388.1; Found ES+
389.1 (M+1) 391.1 (M+1+2).
OCH3
OCH3
:H KOt—Bu é
3\[NINscz/O
BrI:1:413,0H2 THF
N/ JECHZ
130’O H
A 1 M on of KOt—Bu in THF (0.20 eq) was added to a stirred mixture of
(13) (1.0 eq) in THF (8.0 vol) over 4 min at ambient temperature. The mixture was stirred for
2 h and quenched into a 9% aqueous KH2P04 solution (4.0 vol). IPAc (5 vol) was added, and
WO 82344
the layers were separated. The organic layer was washed with 5% aqueous NaCl (4 vol) and
concentrated under reduced re with azeotropic removal of THF with IPAc. The solid was
dissolved in IPAc (10 vol), passed through silica gel, eluted with IPAc, and concentrated under
reduced pressure. The solids were dried at 20-25 0C under vacuum to afford (14) as a solid
(70% yield). 1H NMR (DMSO-d6 ,300 MHz): 8 = 7.70 (s, l H), 7.57 (d, J=7.6 Hz, 1 H),
4.55 - 4.77 (m, l H), 4.22 - 4.36 (m, l H), 3.76 - 3.86 (m, l H), 3.25 (s, 3 H), 3.04 - 3.19 (m,
l H), 2.33 - 2.47 (m, 2 H), 1.98 - 2.20 (m, 2 H), 1.61 (d, J=ll.l Hz, 2 H), 1.07 - 1.33 (m, 3 H).
LC/MS: Calculated:342.l; found: ES+ (M+l) 343.0; (M + 2+ l)345.l.
1. n—BuLi, DCM —78 °C
R Br
13 §C\
/ H3 C 13CH3 I
2. TMSCI, DMAP,TEA, DCM 130
I H313C/ l \1SCH
OTMS
A mixutre of 5-bromoiodopyridine (l .0 eq) in DCM (12 vol) was cooled to -
78 CC and treated with n-BuLi (2.5 M solution in s, l.0 eq). The mixture was treated
with acetone-13C3 (10 eq) while maintaining the temperature below -55 oC, cooled to -78 oC,
and held for 30 min. The reaction mixture was warmed to -40 0C over 1 h, warmed to -15 oC,
quenched with water (10 vol), warmed to 10 0C over 10 minutes, and the layers were separated.
The aqueous phase was extracted with DCM, and the organic layers were washed with water,
saturated aqueous NaCl, dried over Na2S04, and filtered. The cake was washed with DCM, and
the filtrate was concentrated under reduced pressure to obtain an oil. The oil was dissolved in
DCM (120 vol), and DMAP (0.05 eq) and TEA (3.0 eq) were added. The solution was cooled
to 0-5 OC and treated with TMSCl (2.5 eq) over 15 minutes keeping the ture below 5 oC.
The mixture was stirred for 1.5 h, quenched with 5% aqueous NaHCOg (6.5 vol) maintaining
the temperature at 10-15 c’C. The layers were separated, and the c layer was washed with
water and saturated aqueous NaCl. The organic layer was dried over Na2S04, filtered, and
2012/067172
concentrated under d pressure. Hexanes (2 x 9 vol) waere charged and the mixture was
concentrated under reduced pressure to afford an oil. The oil was purified by column
chromatography on silica gel (5% EtOAc in hexanes) to afford (15) (63% yield). 1H NMR
(MeOD, 300 MHz): 8 = 8.38 (d, J=2.1 Hz, 1 H), 7.78 (dd, J=8.6, 2.4 Hz, 1 H), 7.48 (d,
J=8.5 Hz, 1 H), 1.61 - 1.70 (m, 3 H), 1.18 - 1.27 (m, 3 H), 0.00 (s, 9 H).
0‘ ,0
| ’B—B\ 13
N \ \ N
\ /O
—>TMSO—l3C—<:>—B\
13g PoICI2 (dppf)'DCM / — o
/ H 130
H3130 I l3CH3 3
KZCOS,1,4—Dioxane
OTMS
Compound (15) (1.0 eq), bis(pinacolato)diboron (1.0 eq) and KOAc (3.0 eq)
were stirred in 1,4-dioxane (8 vol) and treated with PdClz(dppf)°DCM complex (0.015 eq). The
mixture was heated to 90-95 0C and stirred for 4.5 h. The reaction mixture was cooled to
-25 c’C over 1 h, diluted with MTBE (5 vol), filtered on a celite plug, and the cake was
washed with MTBE. The filtrate was washed with water, and the aqueous layer was extracted
with MTBE. The organic layers were washed with saturated s NaCl, dried over ,
and filtered. The filtrate was concentrated under reduced pressure to an oil, treated with MTBE
and conentrated to an oil three times. The oil was dried under high vacuum at 20-25 °C to
afford a solid. This solid was dissolved in THF (7.5 vol), treated with SiliaBond® Thiol
(lx wt), stirred for 20 min, filtered, and the cake washed with THF. The e was
concentrated under reduced pressure to afford a solid, which was dried under high vacuum.
The solid was dissolved in MTBE, treated with silica gel (lx wt), and concentrated under
reduced pressure. The silica gel ning the crude product was purified by column
chromatography on silica gel (eluent: MTBE) and concentrated under reduced re to
obtain the product (16) as a solid (72% yield). 1H NMR (CDClg, 300 MHZ): 5 = 8.71 (s, l H),
7.90 (d, J=7.6 Hz, 1 H), 7.45 - 7.55 (m, 1 H), 1.64 - 1.72 (m, 3 H), 1.25 (d, J=4.0 Hz, 3 H), 1.20
2012/067172
(s, 12 H), 1.13 (s, 1 H), 1.10 (s, l H), 0.00 (s, 9 H) ppm. MS ated: 410.2, found ES+ 257
(as boric acid).
0\ ,o
/ 16
| OCH3
OCH3 13
130 TMSO\ 9H3
13 / 130
H3 C | 13CH3 H3130 /
| =
r '
é PdCI Am
\ 3C 2 phos2 / lECHZ
| 2 , IPA N N
H 17
A slurry of compound (14) (1.0 eq) and nd (16) (1.20 eq) in IPA (10 vol)
was treated with 2 M aqueous N32C03 (2.5 eq) and PdClemphosz (0.0135 eq). The reaction
mixture was heated to 70 CC, stirred for 2 h, cooled to ambient temperature, and treated with
EtOAc (38 vol) and water (13 vol). The organic layer was washed with 2% aqueous NaCl to
reach pH 6 and concentrated under reduced pressure. EtOAc (13 vol) was added to the
concentrate, the aqueous layer was extracted with EtOAc, and the combined organic phases
were concentrated under reduced pressure. The residue was dissolved in EtOAc and purified by
column chromatography on silica gel (EtOAc/hexanes), concentrated under reduced pressure
and cooled to 0 oC. The solids were dissolved in IPA, concentrated under reduced pressure,
and dried under high vacuum to provide (17) as a solid (73% yield). 1H NMR (DMSO-d6,
300MHz): 5 = 9.03 (d, J=1.9 Hz, 1 H), 8.28 (s, 1 H), 8.25 (dd, J=8.4, 2.2 Hz, 1 H), 7.68 (d,
J=8.3 Hz, 1 H), 7.61 (d, J=7.7 Hz, 1 H), 4.81-4.99 (m, J=11.8, 7.9, 3.9, 3.9 Hz, 1 H), 4.35 (d,
J=6.2 Hz, 1 H), 3.88 (d, J=6.4 Hz, 1 H), 3.25 - 3.31 (m, 3 H), 3.13 - 3.24 (m, 1 H), 2.52 - 2.67
(m, 2 H), 2.13 (d, J=10.4 Hz, 2 H), 1.79 (d, J=3.8 Hz, 3 H), 1.67 (d, J=10.6 Hz, 2 H), 1.36 (d,
J=4.0 Hz, 3 H), 1.18 - 1.33 (m, 2 H), 0.06 - 0.18 (m, 9 H). Calculated 402.2; ES+ (M+1-TMS)
403.2.
OCHs OCH3
(5 1:21:51“ Hm
H313C’C / 3. EtOAc, ACN
—>H313330 / (:3
N \ |:INl§CH2N30 N \ '13:]: 2N300 17
A slurry of (17) (1.0 eq), ACN (10.0 vol) and water (2.5 vol) was treated with
1 M HCl (0.185 eq) for 20 h and neutralized to pH 4-6 with 1 M NaOH. The mixture was
treated with water (50 vol) and EtOAc (75 vol) and the layers were separated. The s
layer was extracted with EtOAc and the combined c layers were concentrated under
reduced pressure. The residue was again treated with water (50 vol) and EtOAc (75 vol) and
the layers were separated and the aqueous layer extracted with additional EtOAc. The organic
fractions were concentrated under reduced pressure with replacement of EtOAc by ACN
addition. The residue was dissolved in ACN (2.5 vol), and a small amount (0.02 eq) of the
target product was added followed by additional ACN (0.8 vol). The solids were filtered,
washed with ACN, and dried under a N2 . The solid was dissolved in EtOAc and silica
gel (1.9 wt) was added and the e concentrated under reduced pressure. The silica gel
containing the crude product was purified by column chromatography on silica gel (eluent:
EtOAc) and concentrated under reduced pressure with replacement of EtOAc by ACN addition.
The al was dried under high vacuum, slurried in ACN (2.5 vol) for 20 h, and filtered to
obtain (18) as a solid (34% yield). 1H NMR (DMSO-d6, 300 MHz): 5 = 9.02 (d, J=l.9 Hz,
1 H), 8.28 (s, 1 H), 8.23 (dd, J=8.3, 2.1 Hz, 1 H), 7.73 (d, J=8.5 Hz, 1 H), 7.59 (d, J=7.7 Hz,
1 H), 5.24 (d, J=2.3 Hz, 1 H), 4.80 - 5.00 (m, J=11.9, 8.0, 3.9, 3.9 Hz, 1 H), 4.36 (d, J=6.2 Hz,
1H), 3.88 (d, J=6.2 Hz, 1 H), 3.25 - 3.31 (m, 3 H), 3.14 - 3.25 (m, 1 H), 2.53 - 2.67 (m, 2 H),
2.14 (d, J=10.4 Hz, 2 H), 1.68 (d, J=4.0 Hz, 5 H), 1.18 — 1.35 (m, 5 H). 13C NMR (DMSO-d6,
75MHz): 8 = 168.7, 168.0, 167.0, 166.6, 166.3, 165.7, 164.9, 162.9, 162.1, 157.4, 156.9, 156.4,
155.9, 154.9, 145.7, 145.7, 145.0, 137.0, 135.6, 133.6, 133.3, 131.3, 119.9, 119.8, 86.4, 85.6,
79.2, 76.5, 75.7, 74.3, 74.0, 73.8, 73.5, 73.2, 73.0, 56.3, 53.3, 47.6, 47.3, 47.0, 41.6, 41.3, 41.0,
40.7, 40.5, 40.2, 39.9, 32.5, 32.1, 31.8, 31.6, 31.0, 27.1. Calculated 402.2, found ES+ (M+1)
403.2.
6.3.3 SYNTHESIS OF 13C ENRICHED LITE OF
COMPOUND A
13C5-labeled metabolite of Compound A was prepared as follows.
13CH
Br/ OEt
Br\[l\k Br ('3' Br N\ Br
—> I
N/ NH2 K2003 / CH2\ ,OEt
BU4NHSO4 H II
acetone
A slurry of 3,5-dibromopyrazinamine (1 eq) in acetone (10 vol) was treated
with K2C03 (0.8x wt) and ethyl bromoacetate'13C2 (0.87x wt) were added, and the mixture was
heated to 30 0C. O4 (0.1x wt) was added, and the e was stirred for 46 h at reflux.
Additional ethyl bromoacetate-13C2 was added in portions and the e was held at reflux
until completion was achieved (~24 h). The reaction mixture was cooled to 20-25 0C, filtered,
and the filter cake was washed twice with acetone. The filtrate was concentrated under reduced
pressure, dissolved in EtOAc, washed twice with water and then with a 5% aqueous NaCl. The
combined aqueous washes were extracted with EtOAc, and the combined organic fractions
were treated with MgSO4 (0.3x wt) and b C-906 (0.1x wt) for 13 h at 30 oC. The
mixture was cooled to 20 oC and filtered. The collected solids were washed twice with EtOAc,
and the filtrate was concentrated to a solid which was dissolved in EtOAc (0.9 vol) and d
with heptane (5.7 volumes) over 40 min at 20-25 0C. The suspension was stirred for 4 h and
filtered. The isolated solids were washed with heptane and dried under reduced pressure at
-40 0C to provide 11.8 g of(12) as a solid (46% yield). LC/MS: Calculated [M+1] 342.3;
Observed 342, 344.
OH OH
Br (5 (5
T:3:8:CH2\ 2
NH -HC| Br N NH
OEt—2>
130 | I.3
DIPEA / H2\ OEt
12H N N’ 130’
O NMP
19 c”)
A slurry of compound 12 (1 eq) and transaminocyclohexanol hydrochloride
(1.5 eq) in NMP (5 vol) at ambient temperature was d with DIPEA (3.5 eq). The mixture
was heated to 125-130 0C and held for 18 h. The solution was cooled to 20-25 0C, treated with
EtOAc (10 vol), and washed three times with 5% aqueous NaCl and once with water. The
on was trated under reduced pressure to 2 vol and the slurry was stirred for 18 h at
ambient temperature. The solids were collected by filtration and dried to obtain compound (19)
(24% yield). The filtrate was concentrated under reduced pressure, d for 18 h at ambient
temperature, treated with EtOAc (1-2 vol) and filtered. The solids were dried under reduced
re to obtain compound (19) (14% yield). LC/MS: Calculated [M+1] 375; Observed 375,
377.
OH OH
C; (5
Br\[N:INHHN/130\1 21%aq H3PO4 Br N300
NOE \[N:1QSCHZ
19 20
nd (19) (1X wt) and a 21% H3PO4 solution (10 vol) were combined at
ambient temperature and heated to 75-80 0C and stirred for 16 h. The batch was cooled to
-25 0C and then filtered, and the filter cake was washed with water. The solid was suspended
in water (10 vol) and stirred for 2 h at 20-25 0C. The product was filtered, washed twice with
water, and dried under reduced pressure at 45-50 0C (20) as a solid (65% yield). LC/MS:
Calculated [M+1] 329; Observed 329, 331.
2012/067172
1) n—BuLi,
DCM —78°C
/ 1303—»—2) acetone
I H13C/’1/30\CIDH\3130H
5-bromoiodopyridine (1.0 eq) in DCM (12 vol) was cooled to -78 oC and
treated with n-BuLi (1.4 vol of 2.5 M in hexanes) over 45 min. After 40 min, 13Cg-acetone
(2.0 eq) was added over 50 s keeping the reaction e below -70 OC. The mixture
was stirred for 2 h below -70 oC, warmed to -14 0C over 2 h, quenched with water (10 vol)
between -15 ° and 10 oC, and warmed to 10 oC. The aqueous layer was extracted with DCM,
and the combined organic layers were washed with water and saturated aqueous NaCl, dried
over MgSO4, filtered, and washed with DCM. The filtrate was concentrated under reduced
pressure to obtain (21) as a liquid (62% yield). LC/MS: ated [M+1] 219; Observed 219,
221.
TMSCI
DMAP EgN
DCM Nx
1/30\ 1/SC\\1
H130/\1SCH3 313C/ l 3CH3>
OTMS
21 15
A solution of compound (21) (1 eq) in DCM (395 mL) was treated with DMAP
(0.01 eq) and the solution was cooled to 0 oC. TEA (1 eq) and TMSCl (1.5 eq) were added and
the on mixture was stirred at 0-5 0C for 2 h, quenched by addition of saturated aqueous
NaHCO3 (2.3 vol) and water (2.3 vol). DCM was added and the layers were separated. The
c layer was washed with water and saturated aqueous NaCl, dried over MgSO4, and
filtered. The cake was rinsed with DCM and the filtrate was concentrated under reduced
pressure, treated with hexanes, and concentrated under reduce pressure to obtain crude (15).
The crude product was purified by column chromatography on silica gel (eluent: 5% EtOAc in
hexanes) and concentrated to a residue. The residue was treated with s and concentrated
to an oil to provide compound (15) as an oil (61% yield). LC/MS: Calculated [M+l] 291;
Observed 291, 293. 1H NMR(CDC13, 300 MHz): 5 = 8.39 (d, J=2.1 Hz, 1 H), 7.61 (dd, J=2.3,
8.5 Hz, 1 H), 7.41 (d, J=8.5 Hz, 1 H), 1.57 - 1.73 and 1.17 - 1.28 (2 m, 6 H, , 0.00 (s,
9 H). 13C NMR(CDC13, 75 MHz) 5 = 164.63 (d, JC-C=6 Hz), 146.57 (d, JC-C=6 Hz), 136.44
(d, JC-C=2 Hz), 118.48 (d, JC-C=4 Hz), 115.94, 74.59 (t, JC-C=39 Hz), 28.80 (d,
JC-C=39 Hz), 0.50.
0‘ ,0
| [Ia—3‘ 13
N \ o 0 “S C\ N o
—>TMSO—1SC~<}B:
fic\ PdCI2 (dppf)'DCM 130/ — 0
H3130 | 13CH3 3
KOAC, 1,4—Dioxane
OTMS
A solution of compound (15) (1 eq) in 1,4-dioxane (8 vol) was treated with
KOAc (2.2 eq), bis(pinacolato)diboron (1 eq), and PdClz(dppf)°DCM complex (0.02 eq). The
ts were heated to reflux, held for 4 h, cooled to ambient temperature and treated with
MTBE (10 vol). The slurry was filtered and the filter cake was washed with MTBE. The
filtrate was passed through a 0.45 mm filter, transferred to a separatory filnnel, and washed with
water. The aqueous phase was extracted with MTBE and treated with aqueous NaCl. The
combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, and
filtered. The e was concentrated under reduced pressure. The e was dissolved in
ACN (1.1 vol) at 45 OC, and transferred with ACN (3.9 vol) to a flask. The crude product was
heated to 40-50 0C, cooled to ambient temperature, agitated for 14.5 h, cooled to 0-5 oC, and
stirred for 2 h. The product was d, washed with cold ACN, and dried under vacuum at
40-55 0C to provide (16) as a solid (65% yield). 1H NMR (DMSO-d6, ): 8 = 9.03 (d,
J=1.9 Hz, 1 H), 8.28 (s, 1 H), 8.25 (dd, J=8.4, 2.2 Hz, 1 H), 7.68 (d, J=8.3 Hz, 1 H), 7.61 (d,
J=7.7 Hz, 1 H), 4.81 - 4.99 (m, J=11.8, 7.9, 3.9, 3.9 Hz, 1 H), 4.35 (d, J=6.2 Hz, 1 H), 3.88 (d,
J=6.4 Hz, 1 H), 3.25 - 3.31 (m, 3 H), 3.13 - 3.24 (m, 1 H), 2.52 - 2.67 (m, 2 H), 2.13 (d,
J=10.4 Hz, 2 H), 1.79 (d, J=3.8 Hz, 3 H), 1.67 (d, J=10.6 Hz, 2 H), 1.36 (d, J=4.0 Hz, 3 H),
1.18 — 1.33 (rm, 2 H), 0.06- 0.18 (rm, 9 H). 1H NMR(CDC13, 300 MHz): 5 = 8.71 (s, 1 H), 7.89
(dd, J=0.8, 7.9 Hz, 1 H), 7.49 (d, J=7.7 Hz, 1 H), 1.61 — 1.75 and 1.23 - 1.32 (2 H1, 6 H, 13CH3),
1.21 (s, 12 H), 0.00 (s, 9 H). 13C NMR(CDC13, 75 MHz) 5 = 168.76, 15171 (d, JC-C=6 Hz),
140.21, 11597 (d, JC-C=4 Hz), 81.55, 74.69 (t, JC—C=39 Hz), 28.60 (d, JC-C=39 Hz), 22.41,
0.087. LC/MS: LC/MS: Calculated [M+1] 339.2; ed 257.2 (as boric acid).
4.0MHCI/
1,4—dioxane /
| |
—>N\
1,4—dioxane
A solution of (16) (1 eq) in oxane (4 vol) was cooled to 15-20 0C and
treated with 4 M HCl in 1,4-dioxane (2.1 eq). The slurry was treated with heptane (3.75 vol),
cooled to 0-5 oC, stirred for 1-2 h, and filtered. The t was washed with heptane and
dried under vacuum at 50-60 0C to obtain (22) as a solid (94% yield). 1H NMR(CDC13,
300 MHz): 8 = 16.56 (br. s., 1 H), 9.05 (s, 1 H), 8.54 (d, J=7.9 Hz, 1 H), 7.78 (dd, J=1.4,
8.0 Hz, 1 H), 4.1-6.3 (br. s., 1 H), 1.95-1.98 and 1.52-1.56 (2 H1, 6 H, 13CH3), 1.30 (s, 12 H).
13C NMR (CDC13,75MHz): 5 = 164.79 (d, JC-C=47 Hz), 15091 (d, JC-C=2.4 Hz), ,
122.26 (d, JC-C=2.8 Hz), 85.66, 71.92 (t, JC-C=38 Hz), 29.89 (d, JC-C=38 Hz), 24.83.
LC/MS: Calculated [M+1] 303; Observed 185 (as boric acid).
o, ,o
HCI 22
OH I
HO\ 9H3
13c 130
/ (1)
H 130/l lSCH H3130
I =
i N \ N /0
Br N\ NSCI/O L. \
I NISQ/
| I 13' 1. PdCIZAmphosz / 13*CH2
/ ,CH2 N N
N N K2C03, THF/water H
2. IPA/water, BHT
23
Compound (20) (1 eq), Compound (22) (1.1 eq), PdCl2Amphos2 (0.009 eq), and
THF (5 vol) were combined and treated with a solution of K2CO3 (2.1 eq) in water (3.75 vol).
The mixture was heated to reflux, held for 6 h, cooled to ambient temperature, stirred for 11 h,
and filtered. The filter cake was washed twice with 1 vol of ter (5:8) and the filtrate
was diluted with THF (6.75 vol). The e was heated to 40-45 CC and treated with toluene
(6.75 vol). The organic layer was washed with a solution of KH2PO4 in water (0.04 w/w) and
the layers were separated. The organic layer was heated to 40-45 CC and treated with
SiliaBond® Thiol for 2 h. The slurry was cooled to ambient ature, filtered, and the filter
cake was washed with THF. The filtrate was treated with ted carbon (decolorizing) for
4 h at ambient temperature, filtered, and the filter cake was washed with THF. The filtrate was
concentrated under reduced pressure, dissolved in DCM, and concentrated under reduce
pressure. The residue was dried under vacuum, treated with THF, heated to 40-45 0C, and
treated with silica gel. The slurry was concentrated under reduced re and the silica gel
containing the crude product was purified by column chromatography on silica gel (eluent
0-41% THF in DCM), concentrated under reduced pressure, and dried under vacuum at
-40 0C to obtain crude (23). The crude (23) and BHT (0.0005X wt) were treated with
IPA/water (l : 1.65), heated to 60 CC, held for 1 h, cooled to ambient temperature, and held for
16 h. The slurry was heated t050-60 oC, treated with IPA (0.8 vol) and water (23 vol). The
slurry was cooled to t temperature and filtered. The product was washed with IPA/water
(10 : 90) and dried under vacuum at 50-60 0C to afford (23) as a solid (85% yield). 1H NMR
(CDClg, 300 MHz): 8 = 9.03 (d, J=1.9 Hz, 1 H), 8.27 (s, 1 H), 8.23 (dd, J=2.1, 8.3 Hz, 1 H),
7.72 (d, J=8.3 Hz, 1 H), 7.59 (d, J=7.6 Hz, 1 H), 5.23 (m, 1 H), 4.81-4.92 (m, 1 H), 4.65 (d,
J=4.3 Hz, 1 H), 4.36 (d, J=6.4 Hz, 1 H), 3.88 (d, J=6.2 Hz, 1 H), 3.41-3.57 (m, 1 H), 2.53-2.71
(m, 2 H), 1.95 (d, J=10.4 Hz, 2 H), 1.66-1.69 and 1.24-1.27 (2 m, 6 H, 13CH3), 1.29-1.37 (m,
2 H). 13C NMR ,75MHz): 8 = 165.34 (d, JC-C=52 Hz), 144.46 (d, JC-C=5.6 Hz),
143.74 (d, JC-C=2 Hz), 135.78, 134.28, 132.28, 132.01, 130.02, 118.54 (d, 2 Hz), 72.18
(d, JC-C=38 Hz), 68.54, 52.03, 45.85 (d, JC-C=52 Hz), 35.09, 30.53 JC-C=39 Hz), 26.11.
, (d,
LC/MS: Calculated [M+1] 388; Observed 389.
6.3.4 SIS OF 2H ENRICHED COMPOUND A
Deuterium-enriched Compound A can be prepared as follows.
QMe OMe
OH/OD
Deuterium source \Z
\' O,Solvent Base
:I:I \ :IZI:
H/NDD
Compound A 24
QMe OMe
D20 ch03 /N
\ N\ N THF, 60 °C \
I I I
N N
H IZI”If?
Compound A
nd 24 can be made using the route above wherein all of the
exchangeable protons are replaced with deuterium. Starting with Compound A, the acidic
protons can be exchanged in the ce of base (such as sodium tert—butoxide, potassium
carbonate and 1,8-diazabicyclo[5,4,0]undecene) and a deuterium source (such as tert—BuOD,
MeOD, EtOD, iPrOD, AcOD, D20) to give Compound 24. A solvent (such as tetrahydrofuran,
dimethylformamide, or dimethylsulfoxide) can be used to facilitate the reaction. The hydrogen
isotopes on the alcohol and the secondary amine could be either hydrogen or deuterium
depending on the workup. A workup solvent with an exchangeable proton (such as H20,
MeOH or EtOH) will provide 25, while a workup solvent with an exchangeable deuterium (e.g.
D20, MeOD, EtOD) will afford 24.
For example, Compound A (10 g, 25.2 mmol) was treated with K2C03 (3.48 g,
.2 mmol) in 20% THF/DZO at 50 — 60 CC for 15 h. After cooling to room temperature, the
mixture was extracted with HF, and the c layer was washed 3 times with water to
allow proton exchange of the alcohol and the pyrazine groups. The c layer was
concentrated to a crude oil and llization from IPA/water to afford Compound 25 (7.6 g,
76%) as an off-white solid; 1H NMR (300 MHz, CDClg) 5 9.02 (d, J: 1.5 Hz, 1 H), 8.27 - 8.05
(m, 2 H), 7.49 (d, J: 8.3 Hz, 1 H), 5.51 (s, 1 H), 5.15 - 4.97 (m, 1 H), 4.93 (s, 1 H), 3.40 (s, 3
H), 3.37 - 3.23 (m, 1 H), 2.79 - 2.53 (m, 2 H), 2.43 - 2.11 (m, 2 H), 1.92 - 1.70 (m, 2 H), 1.60
(s, 6 H), 1.52 - 1.29 (m, 2 H); 13C NMR (300 MHz, CDC13)5 165.6, 164.8, 144.6, 143.1, 136.7,
136.5, 133.6, 132.0, 130.8, 118.7, 78.5, 71.9, 55.9, 53.2, 46.4, 31.6, 30.6, 26.4; LCMS (E1) m/z
calcd. for C21H25D2N503 [M + H]+, 400.2; found 400.2
6.3.5 SYNTHESIS OF 2H ENRICHED METABOLITE OF
COMPOUND A
A deuterium-enriched metabolite of Com ound A can bep prepared as follows.
OH gH/OD QH
E =
OH/OD
OH OH
N N
1 Deuterium source /N
/ - I /
l Solvent Base \ N O I
\ N N O N\ \ N N O
I I f 2. Workup conditions I I ID | I ID
’ N/ N D
N N/
fl N D
H/ND H
6 26 27
nd 26 can be made using the route above wherein all of the
exchangeable protons are replaced with deuterium. Starting with nd 6, the acidic
protons can be exchanged in the presence of base (such as sodium tert—butoxide, ium
carbonate and l,8-diazabicyclo[5,4,0]undecene) and a deuterium source (such as tert—BuOD,
MeOD, EtOD, iPrOD, AcOD, D20) to give nd 26. A solvent (such as tetrahydrofuran,
dimethylformamide, or dimethylsulfoxide) can be used to facilitate the reaction. The hydrogen
isotopes on the two alcohols and the secondary amine could be either hydrogen or deuterium
depending on the workup. A workup solvent with an exchangeable proton (such as H20,
MeOH or EtOH) will provide 27, while a workup solvent with an geable deuterium (e.g.
D20, MeOD, EtOD) will afford 26.
6.4 PHARMACEUTICAL COMPOSITIONS
6.4.l TABLETS
Compound A was formulated as tablets containing about 5 mg, 20 mg, and
50 mg of Compound A as an active pharmaceutical ingredient. The excipients and carriers that
were used in the tablet formulations are ized in Table 3, along with their ed
functions .
Table 3. ceutical Acceptable Excipients and Carriers
Lactose drate, NF (Fast Flo 316) Diluent
Microcrystalline cellulose, NF (Avicel pH 101) Diluent/binder
Microcrystalline cellulose, NF (Avicel pH 102) Diluent/binder
Corn starch, NF Disintegrant/lubricant
Pregelatinized starch, NF (Starch 1500) /Disintegrant
Lactose anhydrous, NF Diluent
Croscarmellose sodium, NF -Sol) Disintegrant
Stearic acid, NF Lubricant
Magnesium Stearate, NF Lubricant
General for tabletpreparation. Tablets were produced at batch size
ranging from 0.5 to 2.2 kg. Form A of compound A was first blended with binders,
diluent(s), and/or disintegrant (e.g., lactose monohydrate (NF), croscarmellose sodium (NF),
and/or microcrystalline cellulose (NF)) using a Globepharma 4-8" Bin Blender. The mixture
was then sieved via 18 mesh screen. The sieved e was further mixed/blended with a
Globepharma 4-8" Bin Blender. After lubricant(s) (e.g., stearic acid (NF) and/or magnesium
te (NF)) were sieved via 30 mesh screen, the lubricant(s) were then added to the mixture.
The resulting mixture was then mixed/blended with a Globepharma 4-8” Bin Blender. The
mixture was then compressed into tablets with a Globepharma Korsch XL100, and then coated
in an Ohara 8" pan. The tablets thus produced were evaluated for their powder characteristics,
tablet characteristics, drug product photostability/short term stability, and manufacturing
process.
Tablet formulations I to VIII of Compound A are summarized in Tables 4 to 11.
The process parameters for tablet preparation (blending/compression) are summarized in
Tables 12 and 13. It was observed that the tablets of ations I to VIII showed
discoloration. Picking was ed when compressing Formulations I to IV. The addition of
stearic acid in Formulations V to VIII ed lubrication t impacting disintegration
and compressibility. Compressibility of Formulation II was not acceptable when replacing
lactose by pregelatinized starch and tablet ss could not exceed 4.1 kp (average). Lactose
monohydrate, NF (Fast Flo 316) was used as an alternate t and was preferred over lactose
anhydrous lation III) for its flowability properties. Both Avicel PH 101 and PH 102
were tested for binding properties (Formulations III and IV). Avicel PH 102’s larger particle
size, and more spherical particle shape provided better flow than Avicel PH 101.
Table 4. Tablet Formulation I
Amounts
Ingredients
Compound A
Lactose monohydrate, NF (Fast Flo 316)
Microcrystalline cellulose, NF (Avicel pH 101)
Croscarmellose , NF (Ac-Di-Sol)
Magnesium Stearate, NF
Table 5. Tablet Formulation II
Amounts
Ingredients
mg %
Compound A 50.0 16.7
Lactose monohydrate, NF (Fast Flo 316) 168.0 56.0
Pregelatinized starch, NF (Starch 1500)
Croscarmellose sodium, NF (Ac-Di-Sol)
Magnesium Stearate, NF 3.0 1.0
Total 300.0 100
Table 6. Tablet Formulation III
Ingredients
mg %
Compound A 50.0
Lactose anhydrous, NF 145.1
Microcrystalline cellulose, NF (Avicel pH 101) 93.1
Croscarmellose sodium, NF (Ac-Di-Sol) 9.0
Magnesium Stearate, NF 3.0
Total 300.0
Table 7. Tablet Formulation IV
Amounts
ients
mg /
Compound A 50.0
Lactose monohydrate, NF (Fast Flo 316) 145.0
Microcrystalline cellulose, NF (Avicel pH 102) 93.0
Croscarmellose sodium, NF (Ac-Di-Sol) 9.0
Magnesium Stearate, NF 3.0
Table 8. Tablet Formulation V
Amounts
Ingredients
mg %
Compound A 50.0 11.9
e monohydrate, NF (Fast Flo 316) 220.48 52.5
Microcrystalline cellulose, NF (Avicel pH 102) 130.20 31.0
Croscarmellose sodium, NF (Ac-Di-Sol) 12.6 3.0
Amounts
Ingredients
c acid, NF 2.52 0.6
Magnesium Stearate, NF 4.20 l 0
Table 9. Tablet Formulation VI
Ingredients
mg %
Compound A 50.0 11.9
Lactose monohydrate NF (Fast Flo 316) 182.20 63.1
Microcrystalline cellulose, NF (Avicel pH 102) 54.0 18.0
Magnesium Stearate, NF 3.0 1.0
Total 300.0 100
Table 10. Tablet Formulation VII
Amounts
Ingredients
Mg %
Compound A 50.0 16.7
Lactose drate NF (Fast Flo 316) 265.0 88.3
Microcrystalline cellulose NF (AV1cel pH 102) 75.60 25.2
Corn starch NF 12.6 4.2
Croscarmellose sodium NF -Sol) 12.6 4.2
Magnesium Stearate, NF 4.20 1 .4
420.0 100
Table 11 Tablet Formulation VIII
Amounts
Ingredients
Compound A 500
Lactose monohydrate, NF (Fast Flo 3 16) 136.0
Microcrystalline cellulose, NF (Avicel pH 102) 93.0
Corn starch, NF
Croscarmellose sodium, NF (Ac-Di-Sol)
Magnesium Stearate, NF
Table 12. Tablet Process Parameters
Equipment/Process Parameters—n“-
Batcmkgw
Bin blender (quart)
Pre-blending time (min)
Lubrication time (min) 3 3 3 3
ACtual welght (mg)
291-309 295-310 1 290-300
Bulk density (g/cc) 0.4 0.53 0.37 0.42
Tooling , SC)
ss (average in Kp)
Thickness (averagein mm) 395 386 398 386
Friability (4 min) (%) .-
Observation Picking Picking g Picking
Table 13. Tablet s Parameters
Equipment/Process Parameters V VI VII VIII
Bin blender used (quart)
Pre-blending time (min) 20/10 20/10 20/10 20/10
Lubrication time (min)
418 299 419 301
Actual weight (mg)
413-421 293-307 413-426 5
Bulk density (g/cc) 0.45 0.43 0.48 0.43
Tooling (round, SC)
Hardness (average in Kp) 9.1 8.5 9.0 8.4
Thickness (average in mm)
Friability (4 min) (%) .3
Disintegration time (max) (sec) 31 30 29 20
Observation None None None None
Tablet formulations IX to XI of Compound A are ized in Tables 14 to
16. The process parameters for their preparation are summarized in Tables 17 and 18.
Table 14. Tablet ation IX
Amounts
Ingredients
Compound A 50.0 15.4
Lactose monohydrate, NF (Fast Flo 316) 151.5 46.6
Microcrystalline cellulose, NF (Avicel pH 102) 100.75 31.0
Corn starch, NF 9.75 3.0
Croscarmellose sodium, NF (Ac-Di-Sol) 9.75 3.0
Magnesium Stearate, NF 1.0
Ingredients
Total 325.0 100
Opadry pink 03Kl40004 4% weight gain
Table 15. Tablet Formulation X
Amounts
ients
Microcrystalline cellulose, NF (Avicel pH 102) 100.75 31.0
Table 16. Tablet Formulation XI
Amounts
Ingredients
Compound A 5.0 3.85
Lactose monohydrate, NF (Fast Flo 316) 74.82 57.55
Microcrystalline cellulose, NF (Avicel pH 102) 40 30 31.00
Corn starch, NF 3.90 3.00
Croscarmellose sodium, NF (Ac-Di-Sol) 3.90 3.00
Stearic acid, NF 0.60
Magnesium Stearate, NF 1.30 1.00
Amounts
Ingredients
Total 130.0 100
Opadry beige 03K170001 4% weight gain
Table 17. Tablet Process Parameters
Equipment/Process Parameters
IX X XI
Blending/Compression
Bin r used (quart) 4 4 4
Pre-blending time (min) 20/10 20/10 20/10
323 326 131
Actual weight (mg)
318-328 316-333 130-134
Tooling (round, SC) 12/32 12/32 1/4
Hardness (average in Kp) 9.3 9.1 5.9
Friability (4 min) (%) 0.1 0.1 0.1
Disintegration time (max) (sec) 39 27 24
Table 18. Tablet Process Parameters
Equipment/Process Parameters
IX X XI
Coating
Batch size (kg) 0.27 0.27 0.30
Weight gain (%) 4 4 4
Equipment/Process Parameters
IX X XI
Coating
Pan (inch)
Nozzle size (mm) 08 08 08
Atomizing air re (PSI) lO
Pattern (PSI) 12-13 12-13 11-12
Pan speed (RPM) l6-l8 14-17 14-17
Inlet temperature (0C) 72-73
Exhaust ature (0C) 51-53 51-53 49-50
The 5 mg and 50 mg tablets (core and ) were subjected to short term
stability and photo-stability evaluations. The short term stability of the 50 mg tablets was tested
by storing for 2 weeks at 40 0C/75%RH in an open bottle. The results are summarized in
Table 19.
Table 19 Tablet Formulation X (50 mg) Tablet Short Term Stability
Compound A (%) Total Impurities (%)
Tablet After 2 wks at After 2 wks at
Imtial. Initial
40 0C/75% RH 40 0C/75% RH
Coated 100.1 99.9 0.25 0.29
The photo-stabiity of the 50 mg tablets was also tested and the results are
summarized in Table 20.
Table 20. Tablet Formulation X (50 mg) Tablet Photo-Stability
nd A (%) Total Impurities (%)
Tablet stability Photo-stability
Control Control
Sample Sample
The short term stability of the 5 mg tablets was tested by storing them for
2 weeks at 40 0C/75%RH in an open bottle. The results are summarized in Table 21. No major
increase of impurity was observed for the 50 mg coated s after two weeks at 40 0C/75%
RH and light exposure. The coating appears to offer acceptable protection against moisture and
light.
Table 21. Tablet Formulation X (5 mg) Tablet Short Term Stability
Compound A (%) Total Impurities (%)
Tablet After 2 wks at After 2 wks at
Initial Initial
40 0C/75% RH 40 0C/75% RH
Coated 101.1 100.7 0.21 1.11
The photo-stabiity of the 5 mg s was also tested and the results are
summarized in Table 22.
Table 22. Tablet (5 mg) Tablet Photo-Stability
Compound A (%) Total Impurities (%)
Photo-stability Photo-stability
Control
Sample Sample
Core 99.5 97.9 0.27 2.85
Coated 99.0 101.0 0.23 0.84
Tablet formulations XII (50 mg), X111 (20 mg), and XIV (5 mg) are summarized
in Tables 23, 24, and 25.
Table 23. Tablet Formulation XII (50 mg)
Ingredients
mg ‘V0
Compound A 50.0 15 38
Opadry pink 03K140004 4% weight gain
Table 24. Tablet Formulation X111 (20 mg)
Amounts
Ingredients
Compound A 15.38
Lactose monohydrate, NF (Fast Flo 316) 49.22
Microcrystalline cellulose, NF l pH
31 00'
102)
Croscarmellose , NF (Ac-Di—Sol) 3.00
Stearic acid, NF 0.52
Magnesium Stearate, NF 1.30 l 00
Total 130.0 10
Opadry yellow 03Kl2429 4% weight gain_
WO 82344
Table 25. Tablet Formulation XIV (5 mg)
Amounts
Ingredlents
nd A 5.0
Lactose monohydrate, NF (Fast Flo 316) 78.98
Microcrystalline cellulose, NF (Avicel pH
40.30
102)
Croscarmellose sodium, NF (Ac-Di-Sol) 3.90
Stearic acid, NF
Magnesium Stearate, NF
Opadry 11 pink 85F942ll 5.2 4% weight gain
No event was ed during the ation of the tablets of Formulations XII,
XIII, or XIV. The 20 mg and 50 mg tablets were compressed at various compression forces to
assess compressibility and define a ss range. The parameters for the preparation of the
tablets to assess compressibility are summarized in Tables 26 (blending/compression) and 27
(coating). The 20 mg tablets were coated with Opadry Yellow 03Kl2429, whereas the 50 mg
tablets were not coated. The core and coated tablets (20 mg) were tested for dissolution. It was
found that there is no significant difference between the dissolution of the core and coated
tablets (.
Table 26. Process Parameters for 50 mg and 20 mg Tablet Formulations
(Blending/Compression)
Batch Size (kg) 221 (Common Blend)
Pre-blending time (min) 20/10
Equipment/Process Parameter 50 mg 20 mg
Lubrication time (min)
327 129
Actual weight (mg)_
313-339 124-135
Bulk density (g/cc) 0.41
Tooling (round, SC) 1%:
Hig High-3.6 High-9.0
ss (average in Kp) Low-5. Low-3.87
-9.9 Target-6.1
Thickness (average in mm) 4.26 3.76
Friability (4 min) (%) 0.04
Disinegration time (max) (sec) 39 22
Observations None None
Table 27. Process Parameters for Formulation XIII (Coating)
Equipment/Process ter 20 mg
Exhaust temperature (C) 45-47
Equipment/Process Parameter 20 mg
Observation Acceptable coating
Batch tablet formulations of Compound A are summarized in Table 28.
Table 28. Batch Tablet Formulations
mg mg
45-0 180-0
“0-82 575-82
362-70 362-70
3510 35-10
4-68 4-68
“-70 “-70
“7-0 “7-0
65-52 -
' 65-52
Tablet formulation XV (45 mg) is summarized in Table 29. Tablet formulation
XV can be ed using ology provided herein or other methods known to one skilled
in the art.
Table 29. Tablet Formulation XV (45 mg)
Amounts
Ingredients
Lactose monohydrate, NF (Fast Flo 316) 143.955
Microcrystalline cellulose, NF (Avicel pH 102) 90.675
Croscarmellose sodium, NF (Ac-Di-Sol) 8.775
Stearic acid, NF l.l70
Amounts
Ingredients
Magnesium te, NF 2.925 1.00
Total 292.50 100
Opadry pink 03K140004 4.0% weight gain
The batch size of the current 45 mg strength tablet is approx. 10,000 tablets or
approximately 3.5 kg (approximately. 20% overage is dispensed to allow for losses during
manufacturing).
6.4.2 DEVELOPMENT OF AN ORAL DOSE VEHICLE OF 14C ENRICHED
COMPOUND A
A solution was prepared using appropriate amounts of 50:50 (v:v)
EG 400, [14C]-Cornp0und A, and Compound A to achieve a final concentration of
28.6 mg/mL. An aliquot of the solution was transferred to a white Size 00 Capsugel® V Caps
Plus Hyprornellose capsule for dose administration. Preliminary ity data indicated that the
in-process bulk solution is stable for at least 48 hours when stored at refrigerated conditions and
protected from light.
Compound A drug substance was dissolved in five different solvent
combinations of EtOH and PEG 400. The t ations selected were 100% EtOH,
80:20 (v:v) EtOH:PEG 400, 50:50 (v:v) EtOH:PEG 400, 20:80 (v:v) EtOH:PEG 400 and 100%
PEG 400. Due to solubility and viscosity , the 100% EtOH and 100% PEG 400
formulations were not analyzed.
The 80:20 (v:v) EtOH:PEG 400, 50:50 (v:v) EtOH:PEG 400 and 20:80 (v:v)
EtOH:PEG 400 solutions were prepared at a concentration of 28.6 mg/mL and diluted to
257 ug/mL for analysis. These samples were analyzed at T=0 and stored at RTmp/PFL and
REF/PFL until is at T=72 hours post-preparation.
WO 82344
Solution stability was performed on the final [14C]-Compound A dosing solution
to establish ity for at least 48 hours protected from light at refrigerated and room
temperature ions. Following analysis at T=0, T=24 hours and T=48 hours, it was
ined that the [14C]-Compound A dosing on was stable for at least 48 hours
protected from light at refrigerated conditions. Degradation was observed at 48 hours for the
[14C]-Compound A solution that was stored at room temperature and protected from light.
The final formulation for the [14C]-Compound A dosing solution was developed
to deliver a single capsule containing a solution of 20 mg of Compound A with a microtracer of
[14C]-Compound A (200 nCi).
The formulation was prepared using 50:50 (v:v) EtOH:PEG 400,
[14C]-Compound A, and Compound A drug nce to e a final concentration of
28.6 mg/mL. Preliminary stability data indicates that this formulation was stable for at least
48 hours when stored at refrigerated conditions and protected from light.
6.5 BIOLOGICAL ES
6.5.1 A PHASE 1, OPEN-LABEL, RANDOMIZED, CROSSOVER
STUDY TO EVALUATE THE PHARMACOKINETICS OF COMPOUND A AFTER A
SINGLE ORAL DOSE OF TABLET AND CAPSULE FORMULATIONS IN HEALTHY
MALE ADULT SUBJECTS.
Certain formulations provided herein were evaluated in a Phase 1, abel,
ized, crossover study. The study had a Screening phase, three Treatment and Sample
Collection periods, and a follow-up visit.
Within no more than 21 days (Day -21) and no less than 2 days (Day -2) prior to
the start of Period 1, subjects underwent routine screening procedures including physical
examination, lZ-lead electrocardiogram (ECG), assessment of vital signs, clinical laboratory
safety tests (serum chemistry, hematology, and urinalysis), serology , fasting glucose
levels and drug/alcohol screen.
Eligible subjects returned to the study center on Day -1 of Period 1 for baseline
assessments. During each study period, subjects were domiciled at the study center from Day
-l through Day 5. Subjects were rged from the study center on the morning of Day 5
upon satisfactory safety review and completion of study-related procedures.
On Day 1 of Period 1, following an overnight fast of at least 8 hours, subjects
were randomized to one of the following 3 sequences to receive Treatment A, B or C
(Table 30).
Table 30. Treatment Sequences
————
Sequence 1 A B C
Sequence 2 B C A
————
In Treatment A, one 20-mg reference Compound A API-in-capsule was
administered orally after at least 8 hour fast with 240 mL of non-carbonated, room temperature
water. In ent B, one 20-mg tablet of Compound A (Tablet Formulation XIII) was
administered under fasted conditions. In Treatment C, four 5-mg tablets of Compound A
(Tablet Formulation XIV) were administered under fasted conditions. The 20-mg tablet and
four 5-mg tablets were administered orally after at least 8 hour fast with 240 mL of non-
carbonated, room temperature water.
The periods were separated by a washout period of at least 7 days (no more than
days) from the prior dose to the next dose. In certain instances, a longer washout is
acceptable.
For each period, serial blood samples were ted before dosing (zero hour)
and at 0.5, l, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after dosing. Plasma
trations of nd A were determined for ining PK parameters, such as
AUC0_t, O, Cmax, Tmax, t1/2, CL/F, and Vz/F for Compound A. Plasma PK parameters
were ated using non compartmental methods. Analyses of ce (ANOVA) were
performed on the natural log-transformed AUC0_t, AUCOM, and Cmax for Compound A. The
geometric mean ratios (test/reference) and their 90% confidence intervals were also calculated.
For Tmax, non parametric analysis was used to produce median differences.
Blood samples to assess PD were collected at Baseline (Day -1) in Period 1 for
all subjects. After randomization, serial PD blood samples were collected only in each period
in which Treatment B (20 mg tablet ation) was administered. Samples were collected
prior to dosing (zero hour) and at 1.5, 3, 6, 8, 12, 24, and 48 hours after administration of
Treatment B. The samples were used for biomarker analysis which involve measuring levels of
pAKT (mTORC2), p4EB-Pl, and/or pS6RP (mTORCl); and/or and pAKT (mTORC2) by flow
cytometry using whole blood samples and/or other exploratory biomarkers in pre- and post-
treatment samples at different time . The biomarker data were used for exploration of
PK-PD onships.
Safety was monitored throughout the study. Safety evaluations included AE
reporting, physical examinations, vital sign measurements, ECGs, and al laboratory safety
tests. Concomitant medications were ed and recorded throughout the study from the time
ed consent was obtained until the follow-up visit.
] All subjects returned to the clinic within 7 to 10 days after the last dose in Period
3 for -up safety assessments. In the event that a t discontinued prematurely from
the study, every reasonable effort was made (and documented) to ensure that all procedures and
evaluations scheduled for the follow-up visit were performed at time of discontinuation or a
follow-up visit was scheduled within 7 to 10 days from the discontinuation day.
Results: The major PK parameters are summarized in Tables 31 and 32 (see
for plasma concentration-time profiles).
Table 3 l. Pharmacokinetic Parameters (Geometric Mean (Geometric CV%))
Parameter Treatment A Treatment B Treatment C
(n = 18) (n = 17) (n = 17)
Cmpd. A O-Desmethyl
metabolite
cmaxmg/mm <2222>
2012/067172
Parameter Treatment A Treatment B Treatment C
(n = 18) (n = 17) (n = 17)
838808888883 88888
AUCAAgmmm 338833
<83 <38
CL/F (L/h) 20.3 (23) ND 20.2 (27) 20.4 (30)
tm (h) 5.7 (24) 14.3 (20) 5.6 (22) 5.4 (23)
*Tmax presented as median (range).
Table 32
90% CI of
Geometric Ratio of Ratio (%) of
Mean Means Means
99.7 (B vs A) 94.7-105.0
99.3 (C vs A) 94.3-104.6
99.3 (B vs A) 94.8-104.0
98.4 (C vs A) 94.0-103.l
103.8 (B vs A) 93.6-115.0
111.6(CvsA) lOO.7-l23.7
Abbreviations: AUC00 = area under the plasma tration versus time curve from time zero
to infinity; AUC04 = area under the plasma concentration versus time curve from time 0 to the
last quantifiable concentration; CI = confidence interval.
Conclusions: Compound A pharmacokinetics are comparable after single dose
administration of 20 mg Compound A tablet formulations and API in capsule in healthy adult
male subjects.
6.5.2 A PHASE 1, OPEN-LABEL STUDY TO EVALUATE THE
METABOLISM AND EXCRETION OF COMPOUND A AND THE EFFECT OF FOOD
ON THE PHARMACOKINETICS OF COMPOUND A IN HEALTHY MALE ADULT
SUBJECTS.
The primary ives of this study are: to characterize the nsformation
and excretion of Compound A following a single 20 mg oral dose of Compound A capsule
containing a racer of [14C]-Compound A solution in healthy male subjects (Part 1) and to
evaluate the effect of a at meal on the pharmacokinetics (PK) of Compound A following a
single oral 20-mg dose of Compound A tablet (Part 2).
The secondary objectives of this study are to evaluate the tolerability of
Compound A after a single 20-mg oral dose of Compound A capsule containing a microtracer
of Compound A solution in healthy male adult subjects (Part I), to evaluate the effect of a
high-fat meal on the PK of the O-desmethyl metabolite of Compound A following a single
-mg oral dose of Compound A tablet (Part 2) and to evaluate the tolerability of Compound A
after a single 20-mg oral dose of Compound A tablet in healthy male adult subjects (Part 2).
The primary nts of Part 1 are : Total [14C]-radioactivity in whole blood,
plasma, urine and feces; cumulative excretion of Total [14C]-radioactivity (as fraction of
radioactive dose) in urine and feces; total [14C]-radioactivity whole to-plasma ratios;
concentration of Compound A and the O-desmethyl metabolite of Compound A in plasma,
urine, and feces samples collected up to 14 times from the day prior to dosing to 8 days after
dosing; and metabolite characterization and profiling in plasma, urine and fecal samples.
Plasma PK parameters for total radioactivity, nd A and the O-desmethyl metabolite of
Compound A (e. g., Cmax, Tmax, AUC0_t, AUCOO, tl/z) will be ined provided ent data
are available.
The primary endpoints of Part 2 are: Plasma PK parameters (e.g., Cmax, Tmax,
AUC0_OO, tm) for nd A and the O-desmethyl metabolite of Compound A under fed and
fasted conditions.
The shared ary endpoints of Part 1 and Part 2 are: Adverse event (AE)
reporting (includes serious AE [SAE] reporting); Complete physical examinations; Clinical
laboratory safety tests; Vital sign measurements; l2-lead electrocardiograms (ECGs); and
Concomitant medications.
The secondary endpoint of Part 2 is: Plasma PK parameters (e. g., Cmax, Tmax,
AUC0_t, AUCOO, t1/2) for the O-desmethyl lite of Compound A under fed and fasted
conditions.
This will be a single-center, 2-part, open-label, ized (Part 1 only),
2-treatment study in healthy adult males (11 = 18). Within no more than 28 days (Day - 28)
prior to the start of Part 1 or Part 2, subjects will undergo routine screening procedures
including physical examination, 12- lead electrocardiograms (ECGs), vital signs, clinical
laboratory safety tests (plasma or serum chemistry, logy, and urinalysis), serology
screen, fasting glucose levels (including HbAlC) and drug and l screen.
On Day 1 of Part 1, subjects who continue to be qualified for participation in the
study will be enrolled ing an overnight fast of at least 8 hours. For Part 2 and on Day 1
of Period 1, subjects who continue to be ed for participation in the study will be
randomly ed to l of 2 ent sequences (Cohort 2 or Cohort 3) and enrolled in Part 2
following an overnight fast of at least 8 hours. Subjects will be enrolled in Part 1) and Part 2) to
e Treatment A or B in one of the following 3 cohorts:
Part 1 Cohort l (n = 6) Treatment A (fasted) NA
Part 2 Cohort 2 n = 6 Treatment B fasted Treatment B fed
Cohort 3 n = 6 Treatment B fed Treatment B fasted
Treatment A: A single 20-mg oral dose of Compound A capsule containing a microtracer of
[14C]-Compound A solution under fasted conditions.
Treatment B: A single 20-mg oral dose of Compound A tablet under fasting or fed conditions.
Part 1 : After screening, ts (n =6) eligible for participation in the
study will return to the study center on Day —1 for baseline assessments. Subjects who continue
to be qualified for participation in the study will be enrolled in the study on the morning of Day
1. Subjects will receive Treatment A after fasting overnight for at least 8 hours and will
ue fasting (not consume any food) until 4 hours after dosing on the morning of Day 1.
Water will be allowed during the fasting period. Subjects will be domiciled at the study center
from Day —1 until the g of Day 8. Subjects will be discharged from the study center on
the morning of Day 8 upon satisfactory safety review and completion of study-related
procedures.
Serial blood samples (10 mL) will be collected at predose (0 hour) and at 0.5, l,
2, 3, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours post dose. Total [14C]-radioactivity will be
determined in blood, plasma, urine and feces. Blood-to-plasma ratios will be calculated to
determine partitioning for total [l4C]-radioactivity. Urine samples will be collected at predose
(within 2 hours prior to dose administration) and at the following post dose collection als:
0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168 hours.
Total urine volume collected in each interval will be recorded for determination of the fraction
of dose excreted in urine. All fecal samples will be collected daily from Day —1 through Day 8
and weight of daily fecal collections will be pooled and recorded.
Part 2 design: Part 2 will be a 2-period crossover study; in Period 1, subjects
(n = 12) will be randomized to receive either an oral 20 mg dose of nd A tablet
(Treatment B) under fed (11 = 6) or fasted (n = 6) conditions. In Period 2, subjects will receive
Treatment B under converse conditions based on treatment assignment in Period 1. After
screening, ts (n = 12) eligible for participation in the study will return to the study center
on Day —1 for baseline assessments. Subjects who continue to be ed for participation in
the study will be randomized and enrolled in the study on the morning of Day 1. Subjects (n =
6) will be enrolled and randomized to receive Treatment B under fed or fasted conditions on the
morning of Day 1 after fasting for at least 8 hours. Fed subjects will be served a standard high
fat meal breakfast, or its equivalent, that must be consumed within 30 s from serving.
Dosing must occur 30 minutes (:5 s) after serving a subject breakfast. All subjects (fed
and fasted) will fast (not to consume any food) until 4 hours post dose. Water will be allowed
during the g period. Subjects will be domiciled at the study center from Day —1 until the
morning of Day 5 of each period. Subjects will be rged from the study center on the
morning of Day 5 upon satisfactory safety review and completion of study-related procedures.
Safety and tolerability data will be monitored and collected following each dosing period.
Periods l and 2 will be separated by a washout period of at least 7 days (no more than 10 days)
from prior dose to the next dose. In certain instances, a longer washout may be acceptable if
previously agreed to.
Serial blood s (10 mL) will be collected at predose (0 hour) and at 0.5, l,
2, 3, 6, 12, 24, 48, 72 and 96 hours post dose for the determination of plasma concentrations of
Compound A and the O-desmethyl metabolite of Compound A. Safety will be monitored
throughout the study; safety evaluations will include AE reporting, al examinations, vital
sign measurements, ECG, and clinical tory safety tests. Concomitant medications will be
assessed and recorded throughout the study as well. In addition, during the subjects’ stay-in-the
clinic (i.e., confinement period), fasting plasma glucose levels will be monitored as part of the
clinical laboratory safety tests. For Parts 1 and 2, all subjects will return to the clinic within 7 to
days after the last dose for follow up safety assessments. In the event that a subject
discontinues prematurely from the study, every reasonable effort should be made (and
documented) to ensure that all ures and evaluations scheduled for the follow-up visit are
performed at the time of discontinuation or a follow-up visit should be scheduled within 7 to
days from the discontinuation day.
Part 1 dosing: Subjects will fast overnight for at least 8 hours prior to Compound
A administration. On the morning of Day 1, each subject will be dosed under g conditions
with a single20-mg oral dose of Compound A capsule containing microtracer of [14C]-
nd A in an ethanol/polyethylene glycol solution. The exact ic activity, chemical
purity and radiochemical purity will be determined prior to dosing. After , subjects will
continue to fast until 4 hours after dosing; thereafter, they will be served standard meals and
snacks. Dosing time will be recorded in the source documents and CRF. Dosing instruction
and calculation for actual dose stered to each subject will be provided at or before study
initiation. The actual dose of the [14C]-Compound A racer administered to each subject
will be calculated based on the ed radioactivity concentration (dpm/g) of the solution in
the capsule.
Part 2 dosing: In Part 2, subjects will fast overnight for at least 8 hours prior to
Compound A administration. On the morning of Day 1, each subject will receive a 20-mg tablet
of Compound A . Subjects randomized to receive Compound A under fed conditions will
be a served a standard high fat meal (breakfast).
The standard high fat meal or its equivalent must be consumed within
s of serving. Dosing must occur 30 minutes (:5 minutes) after serving the meal. The
tablet will be administered with approximately 240 mL of rbonated, room temperature
water. After dosing, subjects will continue to fast until 4 hours after dosing.
Subjects enrolled in the study will spend a total of approximately 8 weeks on the
study.
ts must satisfy all of the following inclusion criteria to be eligible for
enrollment into the study: 1. Must understand and voluntarily sign a written ICD prior to any
study-related procedures being med and be able to adhere to restrictions and examination
schedules; 2. Must be able to communicate with the investigator and clinical staff and to
understand and comply with the requirements of the study; 3. Must be a male 18 to 55 years of
age (inclusive) at the time of signing, with a BMI t (kg)/(height (m2)) between 18 and
33 kg/m2 (inclusive) and weight between 60 and 100 kg (132 to 220 lbs; ive); 4. Must be
healthy (at ing and Day —l) as determined by the investigator on the basis of medical
history, physical examination, clinical laboratory safety test results, vital signs, and 12 lead
ECG (Vital signs (systolic and diastolic blood pressure, pulse rate, and oral body ature)
will be assessed in the supine position after the subject has rested for at least 5 minutes, Subject
must be afebrile (febrile is defined as 2 38.5 0C or 101.3 Fahrenheit), Systolic blood pressure in
the range of 90 to 140 mmHg, diastolic blood pressure in the range of 60 to 90 mmHg, and
pulse rate in the range of 45 to 100 bpm, Screening g plasma glucose value within the
normal limits of the institution and HbAlC < 6%); 5. Subjects (with or without vasectomy)
must agree to use barrier contraception (i.e., latex condom or any non-latex condom not made
out of natural (animal) membrane (e.g., polyurethane)) and one other method (e.g., spermicide)
when engaging in sexual activity with woman of child-bearing potential during study conduct,
and for 90 days after the last dose of study medication; and 6. Must agree to refrain from
donating blood or plasma (other than for this study) while ipating in this study and for at
least 28 days after the last dose of study drug.
] The ce of any of the following will exclude a subject from enrollment into
the study: 1. Recent history (i.e., within 3 years) of any clinically significant neurological,
gastrointestinal, hepatic, renal, atory, vascular, metabolic, endocrine, hematological,
dermatological, psychological, or other major disorders; 2. Any condition, including the
presence of laboratory abnormalities, which places the subject at unacceptable risk if he were to
participate in the study, or confounds the ability to ret data from the study; 3. Use of any
ibed systemic or topical medication within 30 days of the first dose; 4. Use of any non-
prescribed systemic or topical tion (including herbal medicines) within 7 days of the first
dose administration (with the exception of vitamin/mineral supplements); 5. Subject used any
metabolic enzyme inhibitors or inducers (i.e., CYP3A inducers and inhibitors or St. John’s
Wort) within 30 days of the first dose administration; 6. Presence of any surgical or medical
conditions possibly affecting drug tion, distribution, metabolism, and excretion, or plans
to have elective or medical procedures during the conduct of the trial; 7. Exposure to an
investigational drug (new chemical entity) within 90 days prior to the first dose administration;
8. Donation of blood or plasma within 60 days prior to the first dose administration; 9. History
of multiple (i.e., 2 or more) drug allergies; 10. Any clinical significant allergic disease
(excluding non-active hay fever), excluding nonactive seasonal allergies and childhood asthma
d for at least 3 years; ll. History of drug abuse within 2 years prior to first dosing, or
positive urine drug screening test due to illicit drugs; 12. History of l abuse within
2 years prior to dosing, or positive alcohol screen; 13. Smokes more than 10 cigarettes, or
consumes the equivalent in tobacco, per day; 14. Known to have, or tests positive for, active or
chronic hepatitis B or hepatitis C, or HIV antibodies; 15. Received vaccination (excluding
seasonal flu vaccination) within 90 days of the study drug administration; or 16. For Part 1
only: Prior exposure to radioactive investigational drugs within 6 months prior to check in, and
prior exposure to work-related, diagnostic or therapeutic ion within 12 months prior to
check in.
Inclusion / exclusion criteria will be assessed at screening. Subject ility
will be confirmed again on the admission day (Day —l) of the first period and/or prior to
randomization on Day 1 by physical examination, drug screen, clinical tory safety tests
Vital signs and ECGs.
Preliminary Results: 1 l/ 12 enrolled subjects completed Part 2. The results are
set forth in Table 33, below.
Table 33. Geometric Mean CV%) Pharmacokinetic Parameters After Single
-mg Oral Dose
Parameter Fasted
(n = 11)
Cmpd. A O-Desmethyl Cmpd. A O-Desmethyl
metabolite lite
Tm; (h) 1.00 (1—2) 3.00 (1—3) 3.00 (1—3) 6.00 (3—12)
among/mm <20
AUCinf(ng*h/mL) 1005 (38) 9834 (38) 1195 (38) 10131 (35)
AUC0.24 (ng*h/mL) 955 (35) 6401 (30) 1131 (34) 6271 (29)
Vz/F (L) 151 (28) 34.7 (28) 125 (20) 42.6 (30)
CL/F (L/h) 19.9 (38) 2.0 (38) 16.7 (38) 2.0 (36)
tm (h) 5.3 (33) 14.8 (25) 5.2 (27) 14.9 (29)
*Tmax ted as median (range).
Conclusions: After administration of Compound A with a high fat meal to
healthy adult males, there is an approximate 17% decrease in Compound A Cmax and an
approximate 20% increase in overall exposure (AUCinf). There is also a 2 hour delay in Tmax.
After administration of Compound A with a high fat meal to healthy adult males, there is an
approximate 17% decrease in O-desmethyl metabolite Cmax and an approximate 3% increase in
overall exposure (AUCinf). There is also a 3 hour delay in Tmax.
The embodiments sed herein are not to be limited in scope by the specific
embodiments disclosed in the examples which are intended as illustrations of a few aspects of
the disclosed embodiments and any ments that are onally equivalent are
encompassed by the present disclosure. Indeed, various modifications of the embodiments
disclosed herein are in addition to those shown and described herein will become apparent to
those skilled in the art and are ed to fall within the scope of the appended claims.
A number of references have been cited, the disclosures of which are
incorporated herein by reference in their entirety.
-180—
Claims (30)
- Claims What is claimed is: l. A pharmaceutical composition comprising an ive amount of 7-(6-(2-hydroxypropanyl)pyridinyl)-1 -((trans)methoxycyclohexyl)-3 ,4- dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a ceutically acceptable salt, ologue, metabolite or solid form thereof, stearic acid and lactose monohydrate, wherein the the lite is the O-desmethyl metabolite having the structure: 0.. (5 m. N / N N o I l T N N
- 2. The pharmaceutical composition of claim 1, comprising about 0.1-5% by weight of stearic acid.
- 3. The pharmaceutical ition of claim 2, comprising about 0.4% by weight of stearic acid.
- 4. The pharmaceutical composition of claim 1, comprising about 40-60% by weight of lactose monohydrate.
- 5. The pharmaceutical composition ofclaim 4, comprising about 49.2% by weight of lactose monohydrate.
- 6. The pharmaceutical composition of claim 1, further comprising microcrystalline cellulose.
- 7. The pharmaceutical composition of claim 1, further comprising microcrystalline cellulose (AVICEL PH 102®). -181—
- 8. The ceutical composition of claim 7, comprising about 20-40% by weight ofmicrocrystalline cellulose L PH 102®).
- 9. The pharmaceutical composition of claim 8, comprising about 31% by weight of microcrystalline cellulose (AVICEL PH 102®).
- 10. The pharmaceutical composition of claim 1, further comprising a egrant.
- 11. The pharmaceutical composition of claim 10, n the disintegrant is croscarmellose sodium.
- 12. The pharmaceutical composition of claim 10, wherein the disintegrant is croscarmellose sodium (AC-DI-SOL®).
- 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises from about 1-5% by weight ofcroscarmellose sodium (AC-DI-SOL®).
- 14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 40-60% by weight of 7-(6-(2-hydroxypropanyl)py1idinyl) ((trans)methoxycyclohexyl)-3,4—dihydropyrazino[2,3-b]pyrazin-2(lH)-one, or a pharmaceutically acceptable salt, ologue, or solid form thereof.
- 15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition ses about 15% by weight of 7-(6-(2-hydroxypropanyl)pyridinyl)-l- ((trans)methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, isotopologue, or solid form thereof.
- 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition comprises Form A of 7-(6—(2-hydroxypropanyl)pyridin—3-yl)-l-((trans)—4- ycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)—one, wherein Form A has an X-ray powder diffraction pattern comprising peaks at approximately 13.0, 18.2 and 21.5 °29.
- 17. The pharmaceutical composition of claim 1, further comprising magnesium stearate.
- 18. The ceutical composition of claim 17, wherein the pharmaceutical composition comprises from about 0.5-3% by weight of magnesium stearate.
- 19. The pharmaceutical ition of claim 18, wherein the pharmaceutical composition comprises from about 1% by weight of ium te.
- 20. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a tablet.
- 21. The pharmaceutical ition of claim 20, wherein the tablet is film coated.
- 22. The pharmaceutical composition of claim 21, wherein the film coating is about 4% by weight of the tablet.
- 23. Use of a pharmaceutical composition of claim 1 in the cture of a medicament for treating or preventing cancer, an inflammatory condition, an logical condition, a neurodegenerative disease, diabete, obesity, a neurological disorder, an age-related disease, a cardiovascular condition, or a conditions treatable or preventable by inhibition of a kinase pathway.
- 24. The use of claim 23, wherein the kinase pathway is the TOR kinase pathway.
- 25. Use of a pharmaceutical ition of claim 1 in the manufacture of a medicament for achieving a Response Evaluation Criteria in Solid Tumors T 1.1) of complete response, partial response or stable disease in a subject having a solid tumor.
- 26. Use of a pharmaceutical composition of claim 1 in the manufacture of a medicament for improving International Workshop Criteria (IWC) for non-Hodgkin lymphoma (NHL), International m Response Criteria for Multiple Myeloma (IURC), Eastern Cooperative Oncology Group Performance Status (ECOG) or Response Assessment for Neuro- Oncology (RANO) Working Group for astoma multiforme (GBM) in a subject in need thereof.
- 27. A pharmaceutical composition according to claim 1, ntially as herein described or exemplified.
- 28. A use according to claim 23, substantially as herein described or exemplified.
- 29. A use according to claim 25, substantially as herein described or exemplified.
- 30. A use according to claim 26, substantially as herein described or exemplified.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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NZ711123A NZ711123B2 (en) | 2011-12-02 | 2012-11-30 | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use |
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
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US201161566109P | 2011-12-02 | 2011-12-02 | |
US61/566,109 | 2011-12-02 | ||
US201261647288P | 2012-05-15 | 2012-05-15 | |
US61/647,288 | 2012-05-15 | ||
US201261653439P | 2012-05-31 | 2012-05-31 | |
US61/653,439 | 2012-05-31 | ||
US201261670419P | 2012-07-11 | 2012-07-11 | |
US61/670,419 | 2012-07-11 | ||
PCT/US2012/067172 WO2013082344A1 (en) | 2011-12-02 | 2012-11-30 | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use |
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NZ625511B2 true NZ625511B2 (en) | 2016-07-01 |
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