U.S. patent application number 15/320656 was filed with the patent office on 2017-07-13 for sodium (2r,5s,13ar)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,- 5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa- zepin-8-olate.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Ernest A. Carra, Irene Chen, Vahid Zia.
Application Number | 20170197985 15/320656 |
Document ID | / |
Family ID | 53674269 |
Filed Date | 2017-07-13 |
United States Patent
Application |
20170197985 |
Kind Code |
A1 |
Carra; Ernest A. ; et
al. |
July 13, 2017 |
SODIUM
(2R,5S,13AR)-7,9-DIOXO-10-((2,4,6-TRIFLUOROBENZYL)CARBAMOYL)-2,3,4,-
5,7,9,13,13A-OCTAHYDRO-2,5-METHANOPYRIDO[1',2':4,5]PYRAZINO[2,1-B][1,3]OXA-
ZEPIN-8-OLATE
Abstract
The present Invention relates to sodium
(2R,5S,13aR)-7,9-dioxo-10
((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-metha-
nopyrido[1',2':4,5] pyrazino[2,1-b][1,3]oxazepin-8-olate Form
I.
Inventors: |
Carra; Ernest A.; (Foster
City, CA) ; Chen; Irene; (San Mateo, CA) ;
Zia; Vahid; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
53674269 |
Appl. No.: |
15/320656 |
Filed: |
June 19, 2015 |
PCT Filed: |
June 19, 2015 |
PCT NO: |
PCT/US2015/036757 |
371 Date: |
December 20, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62015245 |
Jun 20, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07D 498/14 20130101; A61K 31/553 20130101; A61P 31/00 20180101;
A61P 31/18 20180101; A61K 31/685 20130101; A61K 31/513 20130101;
A61P 43/00 20180101; C07D 498/18 20130101; A61K 9/20 20130101; A61K
31/537 20130101; A61K 31/675 20130101; A61K 45/06 20130101; A61K
31/683 20130101; A61K 9/2054 20130101; A61K 31/553 20130101; A61K
2300/00 20130101; A61K 31/675 20130101; A61K 2300/00 20130101; A61K
31/683 20130101; A61K 2300/00 20130101; A61K 31/513 20130101; A61K
2300/00 20130101 |
International
Class: |
C07D 498/18 20060101
C07D498/18; A61K 31/513 20060101 A61K031/513; A61K 9/20 20060101
A61K009/20; A61K 31/685 20060101 A61K031/685; A61K 45/06 20060101
A61K045/06; A61K 31/537 20060101 A61K031/537 |
Claims
1. A compound of Formula II: ##STR00004##
2. The compound of claim 1, characterized by being crystalline.
3. The compound of claim 2, characterized by an x-ray powder
diffraction (XRPD) pattern having peaks at about 5.5.degree.,
16.1.degree., and
23.3.degree.2-.theta..+-.0.2.degree.2-.theta..
4. The compound of claim 3, wherein the x-ray powder diffraction
(XRPD) pattern has further peaks at about 22.1.degree., and
28.5.degree.2-.theta..+-.0.2.degree.2-.theta..
5. The compound of claim 4, wherein the x-ray powder diffraction
(XRPD) pattern has further peaks at about 22.5 and
19.5.degree.2-.theta..+-.0.2.degree.2-.theta..
6. The compound of claim 5, wherein the x-ray powder diffraction
(XRPD) pattern has further peaks at about 26.6.degree. and
17.9.degree.2-.theta..+-.0.2.degree.2-.theta..
7. The compound of claim 2, characterized by an x-ray powder
diffraction (XRPD) pattern substantially as set forth in FIG.
1.
8. The compound of claim 2, characterized by differential scanning
calorimetry (DSC) pattern substantially as set forth in FIG. 2.
9. The compound of claim 2, characterized by a dynamic vapor
sorption (DVS) pattern substantially as set forth in FIG. 4.
10. The compound of any one of claims 1 to 9, Characterized in
being partially or fully hydrated.
11. The compound of any one of claims 1 to 9, characterized in
being anhydrous or essentially anhydrous.
12. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of any one of claims 1 to 11, and a
pharmaceutically acceptable carrier or excipient.
13. The pharmaceutical composition of claim 12, further comprising
one to three additional therapeutic agents.
14. The pharmaceutical composition of claim 13, wherein the
additional therapeutic agents are each anti-HIV drugs.
15. The pharmaceutical composition of claim 13 or claim 14, wherein
the additional therapeutic agents are each independently selected
from the group consisting of HIV protease inhibitors, HIV
non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside
inhibitors of reverse transcriptase, HIV nucleotide inhibitors of
reverse transcriptase, and other drugs for treating HIV.
16. The pharmaceutical composition of any one of claims 12 to 14,
wherein at least two of the additional therapeutic agents are each
HIV nucleoside inhibitors of reverse transcriptase.
17. The pharmaceutical composition of claim 12, further comprising
tenofovir disoproxil fumarate and emtricitabine.
18. The pharmaceutical composition of claim 12, further comprising
tenofovir alafenamide and emtricitabine.
19. The pharmaceutical composition of claim 12, further comprising
tenofovir alafenamide hemifumarate and emtricitabine.
20. The pharmaceutical composition of any one of claims 12 to 18,
wherein the pharmaceutical composition is in a unit dosage
form.
21. The pharmaceutical composition of claim 20, wherein the unit
dosage form is a tablet.
22. Use of a compound of any one of claims 1 to 11 for treating or
prophylactically preventing an HIV infection.
23. Use of a compound of any one of claims 1 to 11 for the
manufacture of a medicament for treating or prophylactically
preventing an HIV infection.
24. A compound of any one of claims 1 to 11 for use in a method for
treating or prophylactically preventing an HIV infection.
25. A method for treating or prophylactically preventing an HIV
infection in a human in need thereof, comprising administering to
the human a therapeutically effective amount of a compound of any
one of claims 1 to 11.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit under 35
U.S.C. 119(e) of U.S. Provisional Patent Application Ser. No.
62/015,245, filed Jun. 20, 2014, the disclosure of which is hereby
incorporated by reference in its entirety.
FIELD
[0002] The present invention relates to sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4;5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, the crystalline forms, the pharmaceutical formulations,
and the therapeutic uses thereof.
BACKGROUND
[0003] Human immunodeficiency virus infection and related diseases
are a major public health problem worldwide. Human immunodeficiency
virus type 1 (HIV-1) encodes three enzymes which are required for
viral replication: reverse transcriptase, protease, and integrase.
Although drugs targeting reverse transcriptase and protease are in
wide use and have shown effectiveness, particularly when employed
in combination, toxicity and development of resistant strains have
limited their usefulness (Palella, et al. N. Engl. J Med. (1998)
338:853-860; Richman, D. D. Nature (2001) 410:995-1001).
[0004] A goal of antiretroviral therapy is to achieve viral
suppression in the HIV infected patient. Treatment guidelines
published by the United States Department of Health and Human
Services provide that achievement of viral suppression requires the
use of combination therapies, i.e., several drugs from at least two
or more drug classes. In addition, decisions regarding the
treatment of HIV infected patients are complicated when the patient
requires treatment for other medical conditions. Because the
standard of care requires the use of multiple different drugs to
suppress HIV, as well as to treat other conditions the patient may
be experiencing, the potential for drug interaction is a criterion
for selection of a drug regimen. As such, there is a need for
antiretroviral therapies having a decreased potential for drug
interactions.
[0005] As discussed in co-pending application U.S. Ser. No.
14/133,855, filed Dec. 19, 2013 entitled
"POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL
USE",
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-1,3]oxazepine-10-c-
arboxamide demonstrates anti-viral activity. As discussed in
co-pending application PCT Serial No. US2013/076367, filed Dec. 19,
2013 entitled "POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR
PHARMACEUTICAL USE",
(2R5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,-
13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-
-carboxamide demonstrates anti-viral activity.
[0006]
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,-
7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaze-
pine-10-carboxamide, (Formula I), has the following structure:
##STR00001##
[0007] It is desired to have physically stable forms of the
compound that are suitable for the therapeutic use and the
manufacturing process.
BRIEF SUMMARY
[0008] In certain embodiments, the present invention is directed to
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, having the following structure (Formula II):
##STR00002##
[0009] In a still further embodiment, the present invention is
directed to crystalline sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate.
[0010] In a still further embodiment, the present invention is
directed to sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate Form I.
[0011] In a certain embodiment, the present invention is directed
to pharmaceutical formulations comprising sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate.
[0012] In another embodiment, the present invention is directed to
methods of treating or prophylactically preventing an HIV infection
by administering sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate.
[0013] In another embodiment, the present invention is directed to
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate for use in methods of treating or prophylactically
preventing an HIV infection.
[0014] In another embodiment, the present invention is directed to
the use of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,-
3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3-
]oxazepin-8-olate in the manufacture of a medicament for treating
or prophylactically preventing an HIV infection.
DESCRIPTION OF THE FIGURES
[0015] FIG. 1: XRPD pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I.
[0016] FIG. 2: DSC for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I.
[0017] FIG. 3: TGA for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I.
[0018] FIG. 4: DVS for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I.
[0019] FIG. 5: Dissolution profiles of Formula I Form I, Formula I
Form III, and Formula II Form I.
[0020] FIG. 6: Solubility profiles of Formula I Form III and
Formula II Form I in Fasted-State Simulated Gastric Fluid
(FaSSGF).
[0021] FIG. 7: Solubility profiles of Formula I Form III and
Formula II Form I in Fed-State Simulated Intestinal Fluid (FeSSIF)
and Fasted-State Simulated Intestinal Fluid (FaSSIF).
[0022] FIG. 8: Calculated and Experimental XRPD pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I.
DETAILED DESCRIPTION
[0023] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments of the invention. However, one skilled in the art will
understand that the invention may be practiced without these
details. The description below of several embodiments is made with
the understanding that the present disclosure is to be considered
as an exemplification of the claimed subject matter, and is not
intended to limit the appended claims to the specific embodiments
illustrated. The headings used throughout this disclosure are
provided for convenience only and are not to be construed to limit
the claims in any way. Embodiments illustrated under any heading
may be combined with embodiments illustrated under any other
heading.
Definitions
[0024] Unless the context requires otherwise, throughout the
present specification and claims, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is as "including, but
not limited to".
[0025] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present invention. Thus,
the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
[0026] The invention disclosed herein is also meant to encompass
all pharmaceutically acceptable compounds of Formulas (I) and (II)
being isotopically-labeled by having one or more atoms replaced by
an atom having a different atomic mass or mass number. Examples of
isotopes that can be incorporated into the disclosed compounds
include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, chlorine, and iodine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively. These
radiolabeled compounds could be useful to help determine or measure
the effectiveness of the compounds, by characterizing, for example,
the site or mode of action, or binding affinity to
pharmacologically important site of action. Certain
isotopically-labeled compounds of Formulas (I) and (II), for
example, those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e., .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0027] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability. For example, in vivo half-life may
increase or dosage requirements may be reduced. Thus, heavier
isotopes may be preferred in some circumstances.
[0028] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of Formulas (I)
and (II) can generally be prepared by conventional techniques known
to those skilled in the art or by processes analogous to those
described in the Examples as set out below using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0029] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0030] "Optional" or "optionally" means that the subsequently
described event or circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0031] "Pharmaceutically acceptable carrier, diluent or excipient"
includes without limitation any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isotonic agent, solvent, or
emulsifier which has been approved by the United States Food and
Drug Administration as being acceptable for use in humans or
domestic animals.
[0032] A "pharmaceutical composition" refers to a formulation of a
compound of the invention and a medium generally accepted in the
art for the delivery of the biologically active compound to
mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients therefor.
[0033] "Effective amount" or "therapeutically effective amount"
refers to an amount of a compound according to the invention, which
when administered to a patient in need thereof, is sufficient to
effect treatment for disease-states, conditions, or disorders for
which the compounds have utility. Such an amount would be
sufficient to elicit the biological or medical response of a tissue
system, or patient that is sought by a researcher or clinician. The
amount of a compound according to the invention which constitutes a
therapeutically effective amount will vary depending on such
factors as the compound and its biological activity, the
composition used for administration, the time of administration,
the route of administration, the rate of excretion of the compound,
the duration of the treatment, the type of disease-state or
disorder being treated and its severity, drugs used in combination
with or coincidentally with the compounds of the invention, and the
age, body weight, general health, sex and diet of the patient. Such
a therapeutically effective amount can be determined routinely by
one of ordinary skill in the art having regard to their own
knowledge, the state of the art, and this disclosure.
[0034] The term "treatment" as used herein is intended to mean the
administration of a compound or composition according to the
present invention to alleviate or eliminate symptoms of HIV
infection and/or to reduce viral load in a patient. The term
"treatment" also encompasses the administration of a compound or
composition according to the present invention post-exposure of the
individual to the virus but before the appearance of symptoms of
the disease, and/or prior to the detection of the virus in the
blood, to prevent the appearance of symptoms of the disease and/or
to prevent the virus from reaching detectible levels in the blood,
and the administration of a compound or composition according to
the present invention to prevent perinatal transmission of HIV from
mother to baby, by administration to the mother before giving birth
and to the child within the first days of life. In certain
embodiments, the term "treatment" as used herein is intended to
mean the administration of a compound or composition according to
the present invention to alleviate or eliminate symptoms of HIV
infection and/or to reduce viral load in a patient. In certain
embodiments, the term "treatment" as used herein is further or
alternatively intended to mean the administration of a compound or
composition according to the present invention to maintain a
reduced viral load in a patient. The term "treatment" also
encompasses the administration of a compound or composition
according to the present invention post-exposure of the individual
to the virus but before the appearance of symptoms of the disease;
and/or prior to the detection of the virus in the blood, to prevent
the appearance of symptoms of the disease and/or to prevent the
virus from reaching detectible levels in the blood, and the
administration of a compound or composition according to the
present invention to prevent perinatal transmission of HIV from
mother to baby, by administration to the mother before giving birth
and to the child within the first days of life. In certain
embodiments, the term "treatment" as used herein is further or
alternatively intended to mean the administration of a compound or
composition according to the present invention post-exposure of the
individual to the virus as a subsequent or additional therapy to a
first-line therapy (e.g., for maintenance of low viral load).
[0035] "Prevention" or "preventing" means any treatment of a
disease or condition that causes the clinical symptoms of the
disease or condition not to develop. The term "prevention" also
encompasses the administration of a compound or composition
according to the present invention pre-exposure of the individual
to the virus (e.g., pre-exposure prophylaxis), to prevent the
appearance of symptoms of the disease and/or to prevent the virus
from reaching detectible levels in the blood.
[0036] The terms "Subject" or "patient" refer to an animal, such as
a mammal (including a human), that has been or will be the object
of treatment, observation or experiment. The methods described
herein may be useful in human therapy and/or veterinary
applications. In some embodiments, the subject is a mammal (or the
patient). In some embodiments the subject (or the patient) is
human, domestic animals (e.g., dogs and cats), farm animals (e.g.,
cattle, horses, sheep, goats and pigs), and/or laboratory animals
(e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and
monkeys). In one embodiment, the subject (or the patient) is a
human, "Human (or patient) in need thereof" refers to a human who
may have or is suspect to have diseases or conditions that would
benefit from certain treatment; for example, being treated with the
compounds disclosed herein according to the present
application.
[0037] The term "antiviral agent" as used herein is intended to
mean an agent (compound or biological) that is effective to inhibit
the formation and/or replication of a virus in a human being,
including but not limited to agents that interfere with either host
or viral mechanisms necessary for the formation and/or replication
of a virus in a human being.
[0038] The term "inhibitor of HIV replication" as used herein is
intended to mean an agent capable of reducing or eliminating the
ability of HIV to replicate in a host cell, whether in vitro, ex
vivo or in vivo.
[0039] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule. The present
invention includes tautomers of any said compounds.
[0040] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X". Also, the singular forms "a" and "the"
include plural references unless the context clearly dictates
otherwise. Thus, e.g., reference to "the compound" includes a
plurality of such compounds and reference to "the assay" includes
reference to one or more assays and equivalents thereof known to
those skilled in the art.
[0041] "Pharmaceutically acceptable" or "physiologically
acceptable" refer to compounds, salts, compositions, dosage forms
and other materials which are useful in preparing a pharmaceutical
composition that is suitable for veterinary or human pharmaceutical
use.
[0042] "Unit dosage forms" are physically discrete units suitable
as unitary dosages for subjects (e.g., human subjects and other
mammals), each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical carrier.
Crystalline Form
[0043] Formula II
[0044] It is desirable to develop a crystalline form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate that may be useful in the synthesis of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate. A form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate may be an intermediate to the synthesis of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate. A form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate may be the final product in the synthesis of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate. A polymorphic form or polymorph or cocrystal may have
properties such as bioavailability and stability at certain
conditions that may be suitable for medical or pharmaceutical
uses.
[0045] A crystalline form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate may provide the advantage of bioavailability and stability,
suitable for use as an active ingredient in a pharmaceutical
composition. In certain embodiments, a crystalline form sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate provides an advantage of improved bioavailability (Table 3)
and/or stability (Table 4). Variations in the crystal structure of
a pharmaceutical drug substance or active ingredient may affect the
dissolution rate (which may affect bioavailability, etc.),
manufacturability (e.g., ease of handling, ability to consistently
prepare doses of known strength) and stability (e.g., thermal
stability, shelf life, etc.) of a pharmaceutical drug product or
active ingredient. Such variations may affect the preparation or
formulation of pharmaceutical compositions in different dosage or
delivery forms, such as solid oral dosage form including tablets
and capsules. Compared to other forms such as non-crystalline or
amorphous forms, crystalline forms may provide desired or suitable
hygroscopicity, particle size controls, dissolution rate,
solubility, purity, physical and chemical stability,
manufacturability, yield, and/or process control. Thus, crystalline
forms of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,-
3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3-
]oxazepin-8-olate may provide advantages such as: improving the
manufacturing process of an active agent or the stability or
storability of a drug product form of the compound or an active
ingredient, and/or having suitable bioavailability and/or stability
as an active agent.
[0046] The use of certain solvents has been found to produce
different polymorphic forms of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, including polymorphic. Form I, which may exhibit one or
more favorable characteristics described above. In certain
embodiments, Form I of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,-
3,4,5,7,9,13,1.3a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,-
3]oxazepin-8-olate provides an advantage of improved
bioavailability (Table 3) and/or stability (Table 4). The processes
for the preparation of the polymorphs described herein and
characterization of these polymorphs are described in greater
detail below.
[0047] The compound name provided above is named using ChemBioDraw
Ultra and one skilled in the art understands that the compound
structure may be named or identified using other commonly
recognized nomenclature systems and symbols. By way of example, the
compound may be named or identified with common names, systematic
or non-systematic names. The nomenclature systems and symbols that
are commonly recognized in the art of chemistry including but not
limited to Chemical Abstract Service (CAS) and international Union
of Pure and Applied Chemistry (IUPAC). Accordingly, the compound
structure provided above may be named or identified as sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate under IUPAC.
[0048] In particular embodiments, crystalline forms of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate are disclosed.
[0049] Formula II Form I
[0050] In a certain embodiment, novel forms of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin8-
-olate, having the following structure (Formula II) are
disclosed:
##STR00003##
[0051] In a further embodiment, crystalline forms of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate are disclosed.
[0052] In a certain embodiment, sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I is disclosed.
[0053] In one embodiment, provided is polymorphic Form I of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, wherein the polymorph exhibits an X-ray powder diffraction
(XRPD) pattern substantially as shown in FIG. 1 and/or FIG. 8.
Polymorphic sodium Form I may exhibit a differential scanning
calorimetry (DSC) thermogram substantially as shown in FIG. 2.
Polymorphic sodium Form I may exhibit a thermographic analysis
(TGA) graph substantially as shown in FIG. 3. Polymorphic sodium
Form I may exhibit dynamic vapour sorption (DVS) graphs
substantially as shown in FIG. 4.
[0054] The term "substantially as shown in" when referring, for
example, to an XRPD pattern, a DSC thermogram, or a TGA graph
includes a pattern, thermogram or graph that is not necessarily
identical to those depicted herein, but that falls within the
limits of experimental error or deviations when considered by one
of ordinary skill in the art.
[0055] Polymorphic sodium Form I may have a unit cell as determined
by crystal X-ray crystallography of the following dimensions:
a=8.9561 (10) .ANG.; b=1.39202 (14) .ANG.; c=31.115 (3) .ANG.;
.alpha.=90.degree.; .beta.=90.degree.; and .gamma.=90.degree..
[0056] In some embodiments of polymorphic sodium Form I, at least
one, at least two, at least three, at least four, at least five, at
least six, at least seven, at least eight, at least nine, or all of
the following (a)-(j) apply: (a) polymorphic Form I has an XRPD
pattern substantially as shown in FIG. 1 and/or FIG. 8; (b)
polymorphic sodium Form I has a DSC thermogram substantially as
shown in FIG. 2; (c) polymorphic sodium Form I has a TGA graph
substantially as shown in FIG. 3; (d) polymorphic sodium Form I has
DVS graphs substantially as shown in FIG. 4; (e) polymorphic sodium
Form I has a unit cell, as determined by crystal X-ray
crystallography, of the following dimensions: a=8.9561 (10) .ANG.;
b=13.9202 (14) .ANG.; c=31.115 (3) .ANG.; .alpha.=90.degree.;
.beta.90.degree.; and .gamma.=90.degree.; (f) polymorphic sodium
Form I has an orthorhombic crystal system; (g) polymorphic sodium
Form I has a P212121 space group; (h) polymorphic sodium Form I has
a volume of 3879.2(7) .ANG..sup.3; (i) polymorphic Form I has a Z
value of 4; and ( )polymorphic Form I has a density of 1.614
Mg/m.sup.3.
[0057] In some embodiments, polymorphic sodium Form I has at least
one, at least two, at least three, at least four, or all of the
following properties: [0058] a. an XRPD pattern substantially as
shown in FIG. 1 and/or FIG. 8; [0059] b. a DSC thermogram
substantially as shown in FIG. 2; [0060] c. TGA graphs
substantially as shown in FIG. 3; [0061] d. DVS graphs
substantially as shown in FIG. 4; and [0062] e. a unit cell, as
determined by crystal X-ray crystallography, of the following
dimensions a=8.9561 (10) .ANG.; b=13.9202 (14) .ANG.; c=31.115 (3)
.ANG.; .alpha.=90.degree.; .beta.=90.degree.; and
.gamma.=90.degree.;
[0063] In some embodiments, polymorphic sodium Form I has an XRPD
pattern displaying at least two, at least three, at least four, at
least five, or at least six of the degree 2.theta.-reflections with
the greatest intensity as the XRPD pattern substantially as shown
in FIG. 1 and/or FIG. 8.
[0064] In certain embodiments, polymorphic sodium Form I has an
XRPD pattern comprising degree 2.theta.-reflections (+/-0.2 degrees
2.theta.) at 5.5, 16.1, and 23.3. In one embodiment, polymorphic
sodium Form I has an XRPD pattern comprising degree
2.theta.-reflections (+/-0.2 degrees 2.theta.) at 5.5, 16.1, and
23.3 and one or more of the degree 2.theta.-reflections (+/-0.2
degrees 2.theta.) at 22.1, 28.5, and 22.5. In one embodiment,
polymorphic sodium Form I has an XRPD pattern comprising degree
2.theta.-reflections (+/-0.2 degrees 2.theta.) at 5.5, 16.1, and
23.3 and one of the degree 2.theta.-reflections (+/-0.2 degrees
2.theta.) at 22.1, 28.5, and 22.5. In one embodiment, polymorphic
sodium Form I has an XRPD pattern comprising degree
2.theta.-reflections (+/-0.2 degrees 2.theta.) at 5.5, 16.1, and
23.3 and two of the degree 2.theta.-reflections (+/-0.2 degrees
2.theta.) at 22.1, 28.5, and 22.5. In one embodiment, polymorphic
sodium Form I has an XRPD pattern comprising degree
2.theta.-reflections (+/-0.2 degrees 2.theta.) at 5.5, 16.1, and
23.3 and three of the degree 2.theta.-reflections (+/-0.2 degrees
2.theta.) at 22.1, 28.5, and 22.5. In one embodiment, polymorphic
sodium Form I has an XRPD pattern comprising degree
2.theta.-reflections (+/-0.2 degrees 2.theta.) at 5.5, 16.1, 23.3,
22.1, 28.5, and 22.5. In one embodiment, polymorphic sodium Form I
has an XRPD pattern comprising degree 2.theta.-reflections (+/-0.2
degrees 2.theta.) at 5.5, 16.1, 23.3, 22.1, 28.5, 22.5, 19.5, and
26.6. In one embodiment, polymorphic sodium Form I has an XRPD
pattern comprising any three degree 2.theta.-reflections (+/-0.2
degrees 2.theta.) selected from the group consisting of 5.5, 16.1,
23.3, 22.1, 28.5, 22.5, 19.5, 26.6, and 17.9.
Pharmaceutical Compositions
[0065] For the purposes of administration, in certain embodiments,
the compounds described herein are administered as a raw chemical
or are formulated as pharmaceutical compositions. Pharmaceutical
compositions of the present invention comprise a compound of
Formula (II), including forms and co-crystals thereof, and a
pharmaceutically acceptable carrier, diluent or excipient. The
compound of Formula (II) is present in the composition in an amount
which is effective to treat a particular disease or condition of
interest. The activity of compounds of Formula (II) can be
determined by one skilled in the art, for example, as described in
co-pending application Ser. No. 14/133,855, filed Dec. 19, 2013
entitled "POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR
PHARMACEUTICAL USE". The activity of compounds of Formula (II) can
also be determined by one skilled on the art, for example, as
described in co-pending PCT Serial No. US2013/076367, filed Dec.
19, 2013 entitled, "POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND
THEIR PHARMACEUTICAL USE." Appropriate concentrations and dosages
can be readily determined by one skilled in the art. In certain
embodiments, a compound of Formula (II) is present in the
pharmaceutical composition in an amount from about 25 mg to about
500 mg. In certain embodiments, a compound of Formula (II) is
present in the pharmaceutical composition in an amount of about 100
mg to about 300 mg. In certain embodiments, a compound of Formula
(II) is present in the pharmaceutical composition in an amount of
about 5 mg to about 100 mg. In certain embodiments, a compound of
Formula (II) is present in the pharmaceutical composition in an
amount of about 25 mg to about 100 mg. In certain embodiments, a
compound of Formula (II) is present in the pharmaceutical
composition in an amount of about 50 mg to about 100 mg. In certain
embodiments, a compound of Formula (II) is present in the
pharmaceutical composition in an amount of about 5 mg to about 100
mg. In certain embodiments, a compound of Formula (II) is present
in the pharmaceutical composition in an amount of about 5 mg, 25
mg, 50 mg, 75, mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500
mg.
[0066] Formula II
[0067] Provided are also compositions comprising at least one
polymorph (e.g., any one or more of Formula II polymorphic Forms I)
as described herein, in a particular embodiment, a composition
comprising Formula II polymorphic Form I, described herein is
provided. In other embodiments, the compositions described herein
may comprise substantially pure polymorphic forms, or may be
substantially free of other polymorphs and/or impurities.
[0068] In some embodiments, the composition comprises a polymorphic
form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,-
3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3-
]oxazepin-8-olate. In certain embodiments are provided compositions
comprising a polymorphic form as described herein, wherein the
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate within the composition is substantially pure (i.e.,
substantially pure Form I). In particular embodiments of
compositions comprising a polymorphic form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, at least about 50%, at least about 60%, at least about
70%, at least about 80%, at least about 85%, at least about 90%, at
least about 95%, at least about 96%, at least about 97%, at least
about 98%, or at least about 99% of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate present in the composition is Formula II, Form I, disclosed
herein. In certain embodiments, the composition includes at least
about 50%, at least about 60%, at least about 70%, at least about
80%, at least about 85%, at least about 90%, at least about 95%, at
least about 96%, at least about 97%, at least about 98%, or at
least about 99% of Form I of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate.
[0069] In other embodiments of compositions comprising a
polymorphic form disclosed herein, less than about 50%, less than
about 40%, less than about 30%, less than about 20%, less than
about 10%, less than about 5%, less than about 4%, less than about
3%, less than about 2% or less than about 1% of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate present in the composition are other polymorphs of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate and/or impurities.
[0070] In yet other embodiments of compositions comprising the
polymorphic forms disclosed herein, impurities make up less than
about 5%, less than about 4%, less than about 3%, less than about
2% or less than about 1% of the total mass relative to the mass of
the polymorphic forms present. Impurities may, for example, include
by-products from synthesizing sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, contaminants, degradation products, other polymorphic
forms, amorphous form, water, and solvents. In certain embodiments,
impurities include by-products from the process of synthesizing
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate. In certain embodiments, impurities include contaminants
from the process of synthesizing sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate. In certain embodiments, impurities include degradation
products of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,-
3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3-
]oxazepin-8-olate. In certain embodiments, impurities include other
polymorphic forms of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate. In certain embodiments, impurities include water or
solvent. In certain embodiments of compositions comprising a
polymorphic form disclosed herein, impurities are selected from the
group consisting of by-products from synthesizing sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, contaminants, degradation products, other polymorphic
forms, water, solvents and combinations thereof.
[0071] In yet other embodiments, the composition comprising Formula
II, Form I disclosed herein has less than about 5%, less than about
4%, less than about 3%, less than about 2%, or less than about 1%
by weight of amorphous or non-crystalline sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate.
[0072] In some embodiments, the term "substantially pure" or
"substantially free" with respect to a particular polymorphic form
of a compound means that the composition comprising the polymorphic
form contains less than 95%, less than 90%, less than 80%, less
than 70%, less than 65%, less than 60%, less than 55%, less than
50%, less than 40%, less than 30%, less than 20%, less than 15%,
less than 10%, less than 5%, or less than 1% by weight of other
substances, including other polymorphic forms and/or impurities. In
certain embodiments, "substantially pure" or "substantially free
of" refers to a substance free of other substances, including other
polymorphic forms and/or impurities. Impurities may, for example,
include by-products or left over reagents from chemical reactions,
contaminants, degradation products, other polymorphic forms, water,
and solvents.
Administration
[0073] Administration of the compounds disclosed herein in pure
form or in an appropriate pharmaceutical composition, can be
carried out via any of the accepted modes of administration of
agents for serving similar utilities. The pharmaceutical
compositions described herein can be prepared by combining a
compound disclosed herein with an appropriate pharmaceutically
acceptable carrier, diluent or excipient, and may be formulated
into preparations in solid, semi.-solid, liquid or gaseous forms,
such as tablets, capsules, powders, granules, ointments, solutions,
suppositories, injections, inhalants, gels, microspheres, and
aerosols. The pharmaceutical compositions of the invention can be
prepared by combining a compound of the invention with an
appropriate pharmaceutically acceptable carrier, diluent or
excipient, and may be formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as solid dispersions and
solid solutions. Typical routes of administering such
pharmaceutical compositions include, without limitation, oral,
topical, transdermal, inhalation, parenteral, sublingual, buccal,
rectal, vaginal, and intranasal. In one embodiment, the
pharmaceutical compositions is prepared for oral administration, in
a specific embodiment, the pharmaceutical compositions is a tablet.
Pharmaceutical compositions of the invention are formulated so as
to allow the active ingredients contained therein to be
bioavailable upon administration of the composition to a patient.
Compositions that will be administered to a subject or patient take
the form of one or more dosage units, where for example, a tablet
may be a single dosage unit, and a container of a compound of the
invention in aerosol form may hold a plurality of dosage units.
Actual methods of preparing such dosage forms are known, or will be
apparent, to those skilled in this art; for example, see Remington:
The Science and Practice of Pharmacy, 20th Edition (Philadelphia
College of Pharmacy and Science, 2000). The composition to be
administered will, in any event, contain a therapeutically
effective amount of a compound of the invention for treatment of a
disease or condition of interest in accordance with the teachings
of this disclosure.
[0074] The pharmaceutical compositions disclosed herein may be
prepared by methodology well known in the pharmaceutical art. For
example, a pharmaceutical composition intended to be administered
by injection can be prepared by combining a compound of the
invention with sterile, distilled water so as to form a solution. A
surfactant may be added to facilitate the formation of a
homogeneous solution or suspension. Surfactants are compounds that
non-covalently interact with the compound of the invention so as to
facilitate dissolution or homogeneous suspension of the compound in
the aqueous delivery system.
[0075] For example, a solid pharmaceutical composition intended for
oral administration can be prepared by mixing a compound of the
invention with at least one suitable pharmaceutical excipient to
form a solid preformulation composition, which then may be readily
subdivided into equally effective unit dosage forms such as
tablets, pills and capsules. Accordingly, in one embodiment, a
pharmaceutical composition is provided, which includes a compound
of Formula (II) and a pharmaceutical excipient.
[0076] The compounds disclosed herein are administered in a
therapeutically effective amount, which will vary depending upon a
variety of factors including the activity of the specific compound
employed; the metabolic stability and length of action of the
compound; the age, body weight, general health, sex, and diet of
the patient; the mode and time of administration; the rate of
excretion; the drug combination; the severity of the particular
disorder or condition; and the subject undergoing therapy. In some
embodiments, the compounds of the invention can be administered
alone or in combination with other antiviral agents once or twice
daily for as long as the patient is infected, latently infected, or
to prevent infection (e.g. for multiple years, months, weeks, or
days).
Combination Therapy
[0077] In one embodiment, a method for treating or preventing an
HIV infection in a human having or at risk of having the infection
is provided, comprising administering to the human a
therapeutically effective amount of a compound disclosed herein in
combination with a therapeutically effective amount of one or more
(e.g., one, two, three, one or two, or one to three) additional
therapeutic agents. In one embodiment, a method for treating an HIV
infection in a human having or at risk of having the infection is
provided, comprising administering to the human a therapeutically
effective amount of a compound disclosed herein in combination with
a therapeutically effective amount of one or more (e.g., one, two,
three, one or two, or one to three) additional therapeutic
agents.
[0078] In one embodiment, a method for treating an HIV infection in
a human having or at risk of having the infection is provided,
comprising administering to the human a therapeutically effective
amount of a compound or composition disclosed herein in combination
with a therapeutically effective amount of one or more (e.g., one,
two, three, one or two, or one to three) additional therapeutic
agents.
[0079] In certain embodiments, the present invention provides a
method for treating an HIV infection, comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound or composition disclosed herein in combination with a
therapeutically effective amount of one or more additional
therapeutic agents which are suitable for treating an HIV
infection.
[0080] One embodiment provides a compound disclosed herein in
combination with one or more (e.g., one, two, three, one or two, or
one to three) additional therapeutic agents for use in a method for
treating or preventing an HIV infection in a human having or at
risk of having the infection. One embodiment provides a compound
disclosed herein in combination with one or more (e.g., one, two,
three, one or two, or one to three) additional therapeutic agents
for use in a method for treating an HIV infection in a human having
or at risk of having the infection. One embodiment provides a
compound disclosed herein for use in a method for treating or
preventing an HIV infection in a human having or at risk of having
the infection, wherein the compound is administered in combination
with one or more (e.g., one, two, three, one or two, or one to
three) additional therapeutic agents. One embodiment provides a
compound disclosed herein for use in a method for treating an HIV
infection in a human having or at risk of having the infection,
wherein the compound is administered in combination with one or
more (e.g., one, two, three, one or two, or one to three)
additional therapeutic agents. In certain embodiments, the present
invention provides a compound disclosed herein in combination with
one or more additional therapeutic agents which are suitable for
treating an HIV infection, for use in a method for treating an HIV
infection. In certain embodiments, the present invention provides a
compound disclosed herein for use in a method for treating an HIV
infection, wherein the compound is administered in combination with
one or more additional therapeutic agents which are suitable for
treating an HIV infection.
[0081] One embodiment provides the use of a compound disclosed
herein thereof, in combination with one or more (e.g., one, two,
three, one or two, or one to three) additional therapeutic agents
in the manufacture of a medicament for treating or preventing an
HIV infection in a human having or at risk of having the infection.
One embodiment provides the use of a compound disclosed herein in
combination with one or more (e.g., one, two, three, one or two, or
one to three) additional therapeutic agents in the manufacture of a
medicament for treating an HIV infection in a human having or at
risk of having the infection. One embodiment provides the use of a
compound disclosed herein in the manufacture of a medicament for
treating or preventing an HIV infection in a human having or at
risk of having the infection, wherein the compound is administered
in combination with one or more (e.g., one, two, three, one or two,
or one to three) additional therapeutic agents. One embodiment
provides the use of a compound disclosed herein thereof; in the
manufacture of a medicament for treating an HIV infection in a
human having or at risk of having the infection, wherein the
compound is administered in combination with one or more (e.g.,
one, two, three, one or two, or one to three) additional
therapeutic agents. In certain embodiments, the present invention
provides the use of a compound disclosed herein thereof, in
combination with one or more additional therapeutic agents which
are suitable for treating an HIV infection, in treating an HIV
infection. In certain embodiments, the present invention provides
the use of a compound disclosed herein thereof for treating an HIV
infection, wherein the compound is administered in combination with
one or more additional therapeutic agents which are suitable for
treating an HIV infection.
[0082] A compound as disclosed herein (e.g., any compound of
Formula (II)) may be combined with one or more additional
therapeutic agents in any dosage amount of the compound of Formula
II (e.g., from 50 mg to 1000 mg of compound).
[0083] In one embodiment, pharmaceutical compositions comprising a
compound disclosed herein in combination with one or more (e.g.,
one, two, three, one or two, or one to three) additional
therapeutic agents, and a pharmaceutically acceptable carrier,
diluent or excipient are provided.
[0084] In one embodiment, combination pharmaceutical agents
comprising a compound disclosed herein in combination with one or
more (e.g., one, two, three, one or two, or one to three)
additional therapeutic agents are provided.
[0085] In one embodiment, kits comprising a compound disclosed
herein in combination with one or more (e.g., one, two, three, one
or two, or one to three) additional therapeutic agents are
provided.
[0086] In the above embodiments, the additional therapeutic agent
may be an anti-HIV agent. For example, in some embodiments, the
additional therapeutic agent is selected from the group consisting
of HIV protease inhibitors, HIV non-nucleoside inhibitors of
reverse transcriptase, HIV nucleoside or nucleotide inhibitors of
reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic
site (or allosteric) integrase inhibitors, entry inhibitors (e.g.,
CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4
attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD
and NADH-oxidase inhibitors, compounds that target the HIV capsid
("capsid inhibitors"; e.g., capsid polymerization inhibitors or
capsid disrupting compounds such as those disclosed in WO
2013/006738 (Gilead Sciences), US 2013/0165489 (University of
Pennsylvania), and WO 2013/006792 (Pharma Resources),
pharmacokinetic enhancers, and other drugs for treating HIV, and
combinations thereof.
[0087] In other embodiments, the additional therapeutic agent may
be an anti-HIV agent. For example, in some embodiments, the
additional therapeutic agent is selected from the group consisting
of HIV protease inhibitors, non-nucleoside or non-nucleotide
inhibitors of reverse transcriptase, HIV nucleoside or nucleotide
inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV
non-catalytic site (or allosteric) integrase inhibitors, HIV entry
inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion
inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120
inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV
maturation inhibitors, latency reversing agents (e.g., histone
deacetylase inhibitors, proteasome inhibitors, protein kinase C
(PKC) activators, and BRD4 inhibitors), compounds that target the
HIV capsid ("capsid inhibitors"; e.g., capsid polymerization
inhibitors or capsid disrupting compounds, HIV nucleocapsid p7
(NCp7) inhibitors, HEY p24 capsid protein inhibitors),
pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1
modulators, Pd-L1 modulators, toll like receptors modulators IL-15
agonists,), HIV antibodies, bispecific antibodies and
"antibody-like" therapeutic proteins (e.g., DARTs.RTM.,
Duobodies.RTM., Bites.RTM., XmAbs.RTM., TandAbs.RTM., Fab
derivatives) including those targeting HIV gp120 or gp41,
combination drugs for HIV, HIV p17 matrix protein inhibitors, IL-13
antagonists, Peptidyl-prolyl cis-trans isomerase A modulators,
Protein disulfide isomerase inhibitors, Complement C5a receptor
antagonists, DNA methyltransferase inhibitor, HIV vif gene
modulators, Vif dimerization antagonists, HIV-1 viral infectivity
factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators,
Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3)
inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,
Integrin antagonists, Nucleoprotein inhibitors, Splicing factor
modulators, COMM domain containing protein 1 modulators, HIV
Ribonuclease H inhibitors, Retrocyclin modulators, CDK-9
inhibitors, Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV
GAG protein inhibitors, HIV POL protein inhibitors, Complement
Factor H modulators, Ubiquitin ligase inhibitors, Deoxycytidine
kinase inhibitors, Cyclin dependent kinase inhibitors Proprotein
convertase PC9 stimulators, ATP dependent RNA helicase DDX3X
inhibitors, reverse transcriptase priming complex inhibitors, HIV
gene therapy, PI3K inhibitors, compounds such as those disclosed in
WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of
Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO
2009/062285 (Boehringer Ingelheim), US2014/0221380 (Japan Tobacco),
US2014/0221378 (Japan Tobacco), WO 2010/130034 (Boehringer
Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728
(Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323
(Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064
(Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO
2013/006792 (Pharma Resources), and other drugs for treating HIV,
and combinations thereof.
[0088] In certain embodiments, the additional therapeutic is
selected from the group consisting of HIV protease inhibitors, HIV
non-nucleoside or non.-nucleotide inhibitors of reverse
transcriptase, HIV nucleoside or nucleotide inhibitors of reverse
transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or
allosteric) integrase inhibitors, pharmacokinetic enhancers, and
combinations thereof.
[0089] In certain embodiments a compound of Formula (II) is
formulated as a tablet, which may optionally contain one or more
other compounds useful for treating HIV. In certain embodiments,
the tablet can contain another active ingredient for treating HIV,
such as HIV protease inhibitors, HIV non-nucleoside or
non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside
or nucleotide inhibitors of reverse transcriptase, HIV integrase
inhibitors, HIV non-catalytic site (or allosteric) integrase
inhibitors, pharmacokinetic enhancers, and combinations thereof. In
certain embodiments, the tablet can contain one or more active
ingredients for treating HIV, such as HIV nucleoside or nucleotide
inhibitors of reverse transcriptase. In certain embodiments, such
tablets are suitable for once daily dosing.
[0090] In further embodiments, the additional therapeutic agent is
selected from one or more of: [0091] (1) HIV protease inhibitors
selected from the group consisting of amprenavir, atazanavir,
fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir,
saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114,
mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,
KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG
1859; [0092] (2) HIV non-nucleoside or non-nucleotide inhibitors of
reverse transcriptase selected from the group consisting of
capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)
calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963,
MIV-150, TMC-120, rilpivirine, BILR 355 BS, VRX 840773, lersivirine
(UK-453061), RDEA806, KM023 and MK-1439; [0093] (3) HIV nucleoside
or nucleotide inhibitors of reverse transcriptase selected from the
group consisting of zidovudine, emtricitabine, didanosine,
stavudine, zalcitabine, lamivudine, abacavir, abacavir sulfate,
amdoxovir, elvucitabine, alovudine, MIV-210, .+-.-FTC, D-d4FC,
emtricitabinc, phosphazide, fozivudine tidoxil, apricitibine
(AVX754), KP-1461, GS-9131 (Gilead Sciences), fosalvudine tidoxil
(formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate,
tenofovir alafenamide, tenofovir alafenamide hemifumarate,
tenofovir alafenamide fumarate (Gilead Sciences), GS-7340 (Gilead
Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil,
CMX-001 (Chimerix) and CMX-157 (Chimerix); [0094] (4) HIV integrase
inhibitors selected from the group consisting of curcumin,
derivatives of curcumin, chicoric acid, derivatives of chicoric
acid, 3,5-dicaffeoylquinic acid, derivatives of
3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of
aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives
of caffeic acid phenethyl ester, tyrphostin, derivatives of
tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177,
L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C,
BMS-707035, MK-2048, BA 011, elvitegravir, dolutegravir,
dolutegravir sodium, and GSK-744; [0095] (6) HIV non-catalytic
site, or allosteric, integrase inhibitors (NCINI) including, but
not limited to, BI-224436, CX0516, CX05045, CX14442, compounds
disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034
(Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO
2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO
2012/003498 (Gilead Sciences) each of which is incorporated by
references in its entirety herein; [0096] (7) gp41 inhibitors
selected from the group consisting of enfuvirtide, sifuvirtide,
albuvirtide, FB006M, and TRI-1144; [0097] (8) the CXCR4 inhibitor
AMD-070; [0098] (9) the entry inhibitor SP01A; [0099] (10) the
gp120 inhibitor BMS-488043; [0100] (11) the G6PD and NADH-oxidase
inhibitor immunitin; [0101] (12) CCR5 inhibitors selected from the
group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc,
PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004; [0102] (13)
CD4 attachment inhibitors selected from the group consisting of
ibalizumab (TMB-355) and BMS-068 (BMS-663068); [0103] (14)
pharmacokinetic enhancers selected from the group consisting of
cobicistat and SPI-452; and [0104] (15) other drugs for treating
HIV selected from the group consisting of BAS-100, SPI-452, REP 9,
SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat),
HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025,
BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040
(PA-040), [0105] and combinations thereof.
[0106] In certain embodiments, the additional therapeutic agent is
selected from one or more of: [0107] (1) Combination drugs selected
from the group consisting of ATRIPLA.RTM. (efavirenz+tenofovir
disoproxil fumarate+emtricitabine), COMPLERA.RTM. or EVIPLERA.RTM.
(rilpivirine+tenofovir disoproxil fumarate+emtricitabine),
STRIBILD.RTM. (elvitegravir+cobicistat+tenofovir disoproxil
fumarate+emtricitabine), dolutegravir+abacavir sulfate+lamivudine,
TRIUMEQ.RTM. (dolutegravir+abacavir+lamivudine)
lamivudine+nevirapine+zidovudine, dolutegravir+rilpivirine,
dolutegravir+rilpivirine hydrochloride, atazanavir
sulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat,
efavirenz+lamivudine+tenofovir disoproxil fumarate, tenofovir
alafenamide hemifumarate+emtricitabine+cobicistat+elvitegravir,
tenofovir alafenamide hemifumarate+emtricitabine, tenofovir
alafenamide+emtricitabine, tenofovir alafenamide
hemifumarate+emtricitabine+rilpivirine, tenofovir
alafenamide+emtricitabine+rilpivirine Vacc-4x+romidepsin,
darunavir+tenofovir alafenamide
hemifumarate+emtricitabine+cobicistat, APH-0812,
raltegravir+lamivudine, KALETRA.RTM. (ALUVIA.RTM.,
lopinavir+ritonavir), atazanavir sulfate+ritonavir, COMBIVIR.RTM.
(zidovudine+lamivudine, AZT+3TC), EPZICOM.RTM. (Kivexa.RTM.,
abacavir sulfate+lamivudine, ABC+3TC), TRIZIVIR.RTM. (abacavir
sulfate+zidovudine+lamivudine, ABC+AZT+3TC), TRUVADA.RTM.
(tenofovir disoproxil fumarate+emtricitabine, TDF+FTC),
doravirine+lamivudine+tenofovir disoproxil fumarate,
doravirine+lamivudine+tenofovir disoproxil, tenofovir+lamivudine
and lamivudine+tenofovir disoproxil fumarate; [0108] (2) HIV
protease inhibitors selected from the group consisting of
amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium,
indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir,
nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir,
brecanavir, darunavir, DG-17, TIMB-657 (PPL-100) and TMC-310911;
[0109] (3) HIV non-nucleoside or non-nucleotide inhibitors of
reverse transcriptase selected from the group consisting of
delavirdine, delavirdine mesylate, nevirapine, etravirine,
dapivirine, doravirine, rilpivirine, efavirenz, KM-023, VM-1500,
lentinan and AIC-292; [0110] (4) HIV nucleoside or nucleotide
inhibitors of reverse transcriptase selected from the group
consisting of VIDEX.RTM. and VIDEX.RTM. EC (didanosine, dd1),
zidovudine, emtricitabine, didanosine, stavudine, zalcitabine,
lamivudine, cerisavudine, abacavir, abacavir sulfate, amdoxovir,
elvucitabine, alovudine, phosphazid fozivudine tidoxil,
apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir,
tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir
disoproxil hemifumarate, tenofovir alafenamide, tenofovir
alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir,
adefovir dipivoxil, and festinavir; [0111] (5) HIV integrase
inhibitors selected from the group consisting of curcumin,
derivatives of curcumin, chicoric acid, derivatives of chicoric
acid, 3,5-dicaffeoylquinic acid, derivatives of
3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of
aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives
of caffeic acid phenethyl ester, tyrphostin, derivatives of
tyrphostin, quercetin, derivatives of quercetin, raltegtavir,
elvitegravir, dolutegavir and cabotegravir; [0112] (6) HIV
non-catalytic site, or allosteric, integrase inhibitors (NCINI)
selected from the group consisting of CX-05168, CX-05045 and
CX-14442; [0113] (7) HIV gp41 inhibitors selected from the group
consisting of enfuvirtide, sifuvirtide and albuvirtide; [0114] (8)
HIV entry inhibitors selected from the group consisting of
cenicriviroc; [0115] (9) HIV gp120 inhibitors selected from the
group consisting of Radha-108 (Receptol) and BMS-663068; [0116]
(10) CCR5 inhibitors selected from the group consisting of
aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir
(RAP-101), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu); [0117]
(11) CD4 attachment inhibitors selected from the group consisting
of ibalizumab; [0118] (12) CXCR4 inhibitors selected from the group
consisting of plerixafor, ALT-1188, vMIP and Haimipu; [0119] (13)
Pharmacokinetic enhancers selected from the group consisting of
cobicistat and ritonavir; [0120] (14) Immune-based therapies
selected from the group consisting of dermaVir, interleukin-7,
plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2),
interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated
interferon alfa, interferon gamma, hydroxyurea, mycophenolate
mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF),
WF-10, ribavirin, IL-2, IL-12, polymer polyethyleneimine (PEI),
Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators
(tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10,
tlr11, tlr12 and tlr13), rintatolimod and IR-103; [0121] (15) HIV
vaccines selected from the group consisting of peptide vaccines,
recombinant subunit protein vaccines, live vector vaccines, DNA
vaccines, virus-like particle vaccines (pseudovirion vaccine),
CD4-derived peptide vaccines, vaccine combinations, rgp120
(AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144),
monomeric gp120 HIV-1 subtype C vaccine (Novartis), Remune, ITV-1,
Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409,Vacc-4x,
Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5),
Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201,
HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC
adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), AGS 004,
gp140[delta]V2,TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag
vaccine, AT-20, DN-4, Ad35-GRIN/ENV, TBC-M4, HIVAX , HIVAX-2,
NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11,
GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade
C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001,
AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, ETV-01,
CDX-1401, rcAd26.MOS1.HIV-Env and DNA-Ad5 gag/pol/nef/nev
(HVTN505); [0122] (16) HIV antibodies, bispecific antibodies and
"antibody-like" therapeutic proteins (such as DARTs.RTM.,
Duobodies.RTM., Bites.RTM., XmAbs.RTM., TandAbs.RTM., Fab
derivatives) including BMS 936559, TMB-360 and those targeting HIV
gp120 or gp41 selected from the group consisting of bavituximab,
UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145,
PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523 and
VRC07; [0123] (17) latency reversing agents selected from the group
consisting of Histone deacetylase inhibitors such as Romidepsin,
vorinostat, panobinostat; Proteasome inhibitors such as Velcade;
protein kinase C (PKC) activators such as Indolactam, Prostratin,
Ingenol B and DAG-lactones, lonomycin, GSK-343, PMA, SAHA, BRD4
inhibitors, IL-15, JQ1, disulfram, and amphotericin B; [0124] (18)
HIV nucleocapsid p7 (NCp7) inhibitors selected from the group
consisting of azodicarbonamide; [0125] (19) HIV maturation
inhibitors selected from the group consisting of BMS-955176 and
GSK-2838232; [0126] (20) PI3K inhibitors selected from the group
consisting of idelalisib, AZD-8186, buparlisib, CLR-457,
pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342,
TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765,
gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666,
GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458,
CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439,
puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474,
MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and
CLR-1401; [0127] (21) the compounds disclosed in WO 2004/096286
(Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2006/015261
(Gilead Sciences), WO 2013/006738 (Gilead Sciences), US
2013/0165489 (University of Pennsylvania), US2014/0221380 (Japan
Tobacco), US2014/0221378 (Japan Tobacco), WO 2013/006792 (Pharma
Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034
(Boehringer Ingelheim), WO 2013/091096A1 (Boehringer WO 2013/159064
(Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497
(Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728
(Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO
2012/003498 (Gilead Sciences); and [0128] (22) other drugs for
treating HIV selected from the group consisting of BanLec, MK-8507,
AG-1105, TR-452, MK-8591, REF 9, CYF-107, alisporivir, NOV-205,
IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, Prolastin,
1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral,
IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376,
rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464,
SCY-635, naltrexone, AAV-eCD4-Ig gene therapy and PA-1050040
(PA-040); [0129] and combinations thereof.
[0130] In certain embodiments, a compound disclosed herein is
combined with two, three, four or more additional therapeutic
agents. In certain embodiments, a compound disclosed herein is
combined with two additional therapeutic agents. In other
embodiments, a compound disclosed herein is combined with three
additional therapeutic agents. In further embodiments, a compound
disclosed herein is combined with four additional therapeutic
agents. The two, three four or more additional therapeutic agents
can be different therapeutic agents selected from the same class of
therapeutic agents, or they can be selected from different classes
of therapeutic agents. In a specific embodiment, a compound
disclosed herein is combined with an HIV nucleoside or nucleotide
inhibitor of reverse transcriptase and an HIV non-nucleoside
inhibitor of reverse transcriptase. In another specific embodiment,
a compound disclosed herein is combined with an HIV nucleoside or
nucleotide inhibitor of reverse transcriptase, and an HIV protease
inhibiting compound. In a further embodiment, a compound disclosed
herein is combined with an HIV nucleoside or nucleotide inhibitor
of reverse transcriptase, an HIV non-nucleoside inhibitor of
reverse transcriptase, and an HIV protease inhibiting compound. In
an additional embodiment, a compound disclosed herein is combined
with an HIV nucleoside or nucleotide inhibitor of reverse
transcriptase, an HIV non-nucleoside inhibitor of reverse
transcriptase, and a pharmacokinetic enhancer. In another
embodiment, a compound disclosed herein is combined with two HIV
nucleoside or nucleotide inhibitors of reverse transcriptase.
[0131] In certain embodiments, a compound disclosed herein, is
combined with one, two, three, four or more additional therapeutic
agents. In certain embodiments, a compound disclosed herein is
combined with one additional therapeutic agent. In certain
embodiments, a compound disclosed herein is combined with two
additional therapeutic agents. In other embodiments, a compound
disclosed herein is combined with three additional therapeutic
agents. In further embodiments, a compound disclosed herein is
combined with four additional therapeutic agents. The one, two,
three, four or more additional therapeutic agents can be different
therapeutic agents selected from the same class of therapeutic
agents, and/or they can be selected from different classes of
therapeutic agents. In a specific embodiment, a compound disclosed
herein is combined with an HIV nucleoside or nucleotide inhibitor
of reverse transcriptase and an HIV non-nucleoside inhibitor of
reverse transcriptase. In another specific embodiment, a compound
disclosed herein is combined with an HIV nucleoside or nucleotide
inhibitor of reverse transcriptase, and an HIV protease inhibiting
compound. In a further embodiment, a compound disclosed herein is
combined with an HIV nucleoside or nucleotide inhibitor of reverse
transcriptase, as HIV non-nucleoside inhibitor of reverse
transcriptase, and an HIV protease inhibiting compound. In an
additional embodiment, a compound disclosed herein is combined with
an HIV nucleoside or nucleotide inhibitor of reverse transcriptase,
an HIV non-nucleoside inhibitor of reverse transcriptase, and a
pharmacokinetic enhancer. In certain embodiments, a compound
disclosed herein is combined with at least one HIV nucleoside
inhibitor of reverse transcriptase, an integrase inhibitor, and a
pharmacokinetic enhancer. In another embodiment, a compound
disclosed herein is combined with two HIV nucleoside or nucleotide
inhibitors of reverse transcriptase.
[0132] In certain embodiments, a compound disclosed herein is
combined with at least one HIV nucleoside inhibitor of reverse
transcriptase, an integrase inhibitor, and a pharmacokinetic
enhancer.
[0133] In a particular embodiment, a compound disclosed herein is
combined with abacavir, abacavir sulfate, tenofovir, tenofovir
disoproxil fumarate, tenofovir alafenamide, or tenofovir
alafenamide hemifumarate.
[0134] In a particular embodiment, a compound disclosed herein is
combined with tenofovir, tenofovir disoproxil fumarate, tenofovir
alafenamide, or tenofovir alafenamide hemifumarate.
[0135] In a particular embodiment, a compound disclosed herein is
combined with a first additional therapeutic agent selected from
the group consisting of: abacavir, abacavir sulfate, tenofovir,
tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir
alafenamide hemifumarate and a second additional therapeutic agent
selected from the group consisting of emtricitibine and
lamivudine.
[0136] In a particular embodiment, a compound disclosed herein is
combined with a first additional therapeutic agent selected from
the group consisting of: tenofovir, tenofovir disoproxil fumarate,
tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a
second additional therapeutic agent, wherein the second additional
therapeutic agent is emtricitibine.
[0137] In a particular embodiment, a compound disclosed herein is
combined with one, two, three, four or more additional therapeutic
agents selected from Triumeq.RTM.
(dolutegravir+abacavir+lamivudine), dolutegravir+abacavir
sulfate+lamivudine, raltegravir, raltegravir+lamivudine,
Truvada.RTM. (tenofovir disoproxil fumarate+emtricitabine,
TDF+FTC), maraviroc, enfuvirtide, Epzicom.RTM. (Livexa.RTM.,
abacavir sulfate+lamivudine, ABC+3TC), Trizivir.RTM. (abacavir
sulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovir
dipivoxil, Stribild.RTM. (elvitegravir+cobicistat+tenofovir
disoproxil fumarate+emtricitabine), rilpivirine, rilpivirine
hydrochloride, Complera.RTM. (Eviplera.RTM., rilpivirine+tenofovir
disoproxil fumarate+emtricitabine), Cobicistat, atazanavir
sulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat,
Atripla.RTM. (efavirenz+tenofovir disoproxil
fumarate+emtricitabine), atazanavir, atazanavir sulfate,
dolutegravir, elvitegravir, Aluvia.RTM. (Kaletra.RTM.,
lopinavir+ritonavir), ritonavir emtricitabine,
atazanavir_sulfate+ritonavir, datunavir, lamivudine, Prolastin,
fosamprenavir, fosamprenavir calcium, efavirenz, Combivir.RTM.
(zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir,
nelfinavir mesylate, interferon, didanosine, stavudine, indinavir,
indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine,
saquinavir, saquinavir mesylate, aldesleukin, zalcitabine,
tipranavir, amprenavir, delavirdine, delavirdine mesylate,
Radha-108 (Receptor), Hlviral, lamivudine+tergofovir disoproxil
fumarate, efavirenz+lamivudine+tenofovir disoproxil fumarate,
phosphazid, lamivudine+nevirapine+zidovudine, abacavir, abacavir
sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil
fumarate, darunavir+cobicistat, atazanavir sulfate+cobicistat,
atazanavir+cobicistat, tenofovir alafenamide and tenofovir
alafenamide hemifumarate.
[0138] In a particular embodiment, a compound disclosed herein is
combined with abacavir, abacavir sulfate, tenofovir, tenofovir
disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil
hemifumarate, tenofovir alafenamide or tenofovir alafenamide
hemifumarate.
[0139] In a particular embodiment, a compound disclosed herein is
combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil
fumarate, tenofovir alafenamide, or tenofovir alafenamide
hemifumarate.
[0140] In a particular embodiment, a compound disclosed herein is
combined with a first additional therapeutic agent selected from
the group consisting of abacavir sulfate, tenofovir, tenofovir
disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide,
and tenofovir alafenamide hemifumarate and a second additional
therapeutic agent selected from the group consisting of
emtricitabine and lamivudine.
[0141] In a particular embodiment, a compound disclosed herein is
combined with a first additional therapeutic agent selected from
the group consisting of: tenofovir, tenofovir disoproxil, tenofovir
disoproxil fumarate, tenofovir alafenamide, and tenofovir
alafenamide hemifumarate and a second additional therapeutic agent,
wherein the second additional therapeutic agent is
emtricitabine.
[0142] In certain embodiments, a compound disclosed herein is
combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir
alafenamide hemifumarate, or tenofovir alafenamide and 200 mg
emtricitabine. In certain embodiments, a compound disclosed herein
is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or
10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, tenofovir alafenamide and 200 mg emtricitabine. In
certain embodiments, a compound disclosed herein is combined with
10 mg tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In
certain embodiments, a compound disclosed herein is combined with
25 mg tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. A
compound as disclosed herein (e.g., a compound of formula (II)) may
be combined with the agents provided herein in any dosage amount of
the compound (e.g., from 50 mg to 500 mg of compound) the same as
if each combination of dosages were specifically and individually
listed.
[0143] In certain embodiments, a compound disclosed herein is
combined with 200-400 mg tenofovir disproxil, tenofovir disoproxil
fumarate, or tenofovir disoproxil hemifumarate and 200 mg
emtricitabine. In certain embodiments, a compound disclosed herein
is combined with 200-250; 200-300; 200-350; 250-350; 250-400;
350-400; 300-400; or 250-400 mg tenofovir disoproxil, tenofovir
disoproxil fumarate, or tenofovir disoproxil hemifumarate and 200
mg emtricitabine. In certain embodiments, a compound disclosed
herein is combined with 300 mg tenofovir disoproxil fumarate,
tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200
mg emtricitabine. A compound as disclosed herein (e.g., a compound
of formula (II)) may be combined with the agents provided herein in
any dosage amount of the compound (e.g., from 50 mg to 500 mg of
compound) the same as if each combination of dosages were
specifically and individually listed.
[0144] In certain embodiments, when a compound disclosed herein is
combined with one or more additional therapeutic agents as
described above, the components of the composition are administered
as a simultaneous or sequential regimen. When administered
sequentially, the combination may be administered in two or more
administrations.
[0145] In certain embodiments, a compound disclosed herein is
combined with one or more additional therapeutic agents in a
unitary dosage form for simultaneous administration to a patient,
for example as a solid dosage form for oral administration.
[0146] In certain embodiments, a compound disclosed herein is
administered with one or more additional therapeutic agents.
Co-administration of a compound disclosed herein with one or more
additional therapeutic agents generally refers to simultaneous or
sequential administration of a compound disclosed herein and one or
more additional therapeutic agents, such that therapeutically
effective amounts of the compound disclosed herein and one or more
additional therapeutic agents are both present in the body of the
patient.
[0147] Co-administration includes administration of unit dosages of
the compounds disclosed herein before or after administration of
unit dosages of one or more additional therapeutic agents, for
example, administration of the compound disclosed herein within
seconds, minutes, or hours of the administration of one or more
additional therapeutic agents. For example, in some embodiments, a
unit dose of a compound disclosed herein is administered first,
followed within seconds or minutes by administration of a unit dose
of one or more additional therapeutic agents. Alternatively, in
other embodiments, a unit dose of one or more additional
therapeutic agents is administered first, followed by
administration of a unit dose of a compound disclosed herein within
seconds or minutes. In some embodiments, a unit dose of a compound
disclosed herein is administered first, followed, alter a period of
hours (e.g., 1-12 hours), by administration of a unit dose of one
or more additional therapeutic agents. In other embodiments, a unit
dose of one or more additional therapeutic agents is administered
first, followed., after a period of hours (e.g., 1-12 hours), by
administration of a unit dose of a compound disclosed herein.
XRPD Data
[0148] In certain embodiments, the crystalline forms are
characterized by the interlattice plane intervals determined by an
X-ray powder diffraction pattern (XRPD). The diffractogram of XRPD
is typically represented by a diagram plotting the intensity of the
peaks versus the location of the peaks, i.e., diffraction angle
2.theta. (two-theta) in degrees. The intensities are often given in
parenthesis with the following abbreviations: very strong=vst;
strong=st; medium=m; weak=w; and very weak=vw. The characteristic
peaks of a given XRPD can be selected according to the peak
locations and their relative intensity to conveniently distinguish
this crystalline structure from others.
[0149] Those skilled in the art recognize that the measurements of
the XRPD peak locations and/or intensity for a given crystalline
form of the same compound will vary within a margin of error. The
values of degree 2.theta. allow appropriate error margins.
Typically, the error margins are represented by ".+-.". For
example, the degree 2.theta. of about "8.7+0.3" denotes a range
from about 8.7+0.3, i.e., about 9.0, to about 8.7-0.3, i.e., about
8.4. Depending on the sample preparation techniques, the
calibration techniques applied to the instruments, human
operational variation, and etc., those skilled in the art recognize
that the appropriate error of margins for a XRPD can be .+-.0.5;
.+-.0.4; .+-.0.3; .+-.0.2; .+-.0.1; .+-.0.05; or less. In certain
embodiments of the invention, the XRPD margin of error is
.+-.0.2.
[0150] Additional details of the methods and equipment used for the
XRPD analysis are described in the Examples section.
[0151] The XRPD peaks for the crystalline forms of sodium.
(2R,5S,13aR)-7,9-dioxo-10-(2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,
7,9,13,13
a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa-
zepin-8-olate (Formula II) of the present invention can be found
below in Table 1
TABLE-US-00001 TABLE 1 XRPD peaks for crystalline forms of Formula
II Form I Formula II Form I Peak Relative Position Intensity
[.degree.2.theta.] [%] 5.5 100.0 16.1 87.3 17.9 22.4 19.5 38.0 22.1
61.8 22.5 42.2 23.3 60.4 26.6 27.3 28.5 42.9
Preparation of the Polymorphs
[0152] One method of synthesizing
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide (e.g. a compound of Formula (I)) has been previously
described in PCT Publication No. WO2014/100323. This reference is
hereby incorporated herein by reference in its entirety, and
specifically with respect to the synthesis of
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide. One method of synthesizing sodium
(2R5S,13aR)7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8--
olate (e.g., a compound of Formula (II)) is described herein.
[0153] For example, in one aspect, provided is a method of
producing a composition comprising one or more polymorphs of sodium
(2R,5,S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-
,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-
-8-olate, wherein the method comprises combining a compound of
Formula (II) with a suitable solvent or a mixture of suitable
solvents to produce a composition comprising one or more polymorphs
of the compound of Formula (II). In another aspect, provided is
another method of producing a composition comprising one or more
polymorphs of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, wherein the method comprises combining sodium
(2R5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,1-
3,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-
-olate with a suitable solvent or a mixture of suitable
solvents.
[0154] The choice of a particular solvent or combination of
solvents affects the formation favoring one polymorphic form of
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate over another. Solvents suitable for polymorph formation may
include, for example, methanol, ethanol, water, isopropyl acetate,
acetonitrile, tetrahydrofuran, methyl isobutyl ketone, and any
mixtures thereof.
[0155] In another aspect, provided is also one or more polymorphs
of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate produced according to any of the methods described
herein.
[0156] It should be understood that the methods for preparing the
polymorphs described herein (including any polymorphic Form I) may
yield quantity and quality differences compared to the methods for
preparing sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate produced on laboratory scale.
[0157] Formula II Form I
[0158] In one embodiment, provided is a method of producing a
composition comprising polymorphic Form I of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, wherein the method comprises combining
(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide with a sodium base (e.g. sodium hydroxide) in a
solvent to produce a composition comprising polymorphic Form I of
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, wherein the solvent is selected from the group consisting
of ethanol, dimethylformamide, and any mixture thereof. In an
embodiment, the solvent is a mixture of ethanol and
dimethylformamide.
[0159] Provided is also polymorphic Form I of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate prepared by combining
(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide with a sodium base (e.g. sodium hydroxide) in a
solvent, wherein the solvent is selected from the group consisting
of ethanol, dimethylformamide, and any mixture thereof. In an
embodiment, the solvent is a mixture of ethanol and
dimethylformamide.
Uses in Manufacturing of Drug Product
[0160] Formula II
[0161] Provided are also a use of the polymorphs described herein
in the manufacture of a drug product. The one or more of the
polymorphic forms described herein (e.g., polymorphic Form I) may
be used as an intermediate in the manufacturing process to produce
the drug product.
[0162] In certain embodiments, Form I of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate are used in the manufacture of an active pharmaceutical
ingredient.
Articles of Manufacture and Kits
[0163] Compositions comprising one or more of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate and formulated in one or more pharmaceutically acceptable
carriers, excipients or other ingredients can be prepared, placed
in an appropriate container, and labeled for treatment of an
indicated condition. Accordingly, there also is contemplated an
article of manufacture, such as a container comprising a dosage
form of one or more of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,-
3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3-
]oxazepin-8-olate, and a label containing instructions for use of
the compound(s).
[0164] In some embodiments, the article of manufacture is a
container comprising a dosage form of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, and one or more pharmaceutically acceptable carriers,
excipients or other ingredients. In one embodiment of the articles
of manufacture described herein, the dosage form is a tablet.
[0165] Kits also are contemplated. For example, a kit can comprise
a dosage form of a pharmaceutical composition and a package insert
containing instructions for use of the composition in treatment of
a medical condition. The instructions for use in the kit may be for
treating HIV. In certain embodiments, the instructions for use in
the kit may be for treating HIV.
[0166] In certain embodiments, the polymorphic and solvate forms
described herein may potentially exhibit improved properties. For
example, in certain embodiments, the polymorphic and solvate forms
described herein may potentially exhibit improved stability. Such
improved stability could have a potentially beneficial impact on
the manufacture of the Compound of Formula I, such as for example
offering the ability to store process intermediate for extended
periods of time. Improved stability could also potentially benefit
a composition or pharmaceutical composition of the Compound of
Formula II. In certain embodiments, the polymorphic and solvate
forms described herein may also potentially result in improved
yield of the Compound of Formula II. Or potentially result in an
improvement of the quality of the Compound of Formula II. In
certain embodiments, the polymorphic and solvate forms described
herein may also exhibit improved pharmacokinetic properties and/or
potentially improved bioavailability.
Methods
[0167] Synthesis
Sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,-
5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa-
zepin-8-olate (Formula II)
[0168]
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,-
7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaze-
pine-10-carboxamide (20 g) and ethanol (80 mL) were added to a
reaction vessel and warmed to about 75.degree. C. Aqueous sodium
hydroxide (22 mL 2 M solution) was added over approximately 30
minutes, after which the slurry was cooled to approximately
20.degree. C. over approximately one hour. Sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I was collected by filtration, washed with EtOH (50
mL) and dried under vacuum.
[0169] .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.63 (t, J=5.8 Hz,
1H), 7.88 (s, 1H), 7.29-7.07 (m, 2H), 5.20 (dd, J=8.6, 3.6 Hz, 1H),
5.09 (t, J=4.1 Hz, 1H), 4.52 (m, 3H), 4.35 (dd, J=12.8, 3.6 Hz,
1H), 3.87 (dd, J=12.7, 8.7 Hz, 1H), 2.03-1.80 (m, 3H), 1.76-1.64
(m, 2H), 1.50-1.40 (m, 1H).
[0170] Characterization
[0171] Sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I was characterized by various analytical techniques,
including X-ray powder diffraction pattern (XPPD), differential
scanning calorimetry (DSC), thermographic analysis (TGA), and
dynamic vapor sorption (DVS) using the procedures described
below.
[0172] X-Ray Powder Diffraction: XRPD analysis was conducted on a
diffractometer (PANanalytical XPERT-PRO, PANanalytical B.V.,
Almelo, Netherlands) using copper radiation (Cu K.alpha.,
.lamda.=1.5418 .ANG.). Samples were prepared for analysis by
depositing the powdered sample in the center of an aluminum holder
equipped with a zero background plate. The generator was operated
at a voltage of 45 kV and amperage of 40 mA. Slits used were Soller
0.02 rad., antiscatter 1.0.degree., and divergence. The sample
rotation speed was 2 sec. Scans were performed from 2 to 40.degree.
2.theta. during 5-15 min with a step size of 0.0167.degree.
2.theta.. Data analysis was performed by X'Pert Highscore version
2.2c (PANalytical B.V., Almelo, Netherlands) and X'Pert data viewer
version 1.2d (PANalytical B.V., Almelo, Netherlands).
[0173] The XRPD pattern for sodium
(2R5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,1-
3,13a-octahydro-2,5-methanopyrido[1,',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I is represented in FIG. 1. The calculated XRPD
pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate Form I represented in FIG. 1 was calculated by using
Mercury 3.1 Development (Build RC5). Single crystal data for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I was input into Mercury 3.1 Development (Build RC5)
to calculate the XRPD pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I. Bulk material, such as stoichiometry arity between
the temperature was obtained on a Rigaku Miniflex II XRD using
power settings of 40 kV, 15 mA, scan speed of 2.0000 degrees per
minute, a Miniflex 300/600 goniometer and an ASC-6 attachment, a
scan range of 3.000 to 40.000 degrees, an incident slit of 1.250
degrees, a length limiting slit of 10.0 mm, and SC-70 detector, a
receiving slit #1 of 1.250 degrees, continuous scan mode, and a
receiving slit #2 of 0.3 mm. The sample was prepared by smoothing
about 20 mg of solids on a silicon disk mounted in a metal holder.
Acquisition temperature was .about.21.degree. C.
[0174] The XRPD pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I is further represented in FIG. 8. The calculated
XRPD pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I represented in FIG. 8 was calculated by using
Mercury 3.1 Development (Build RC5). Single crystal data for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I was input into Mercury 3.1 Development (Build RC5)
to calculate the XRPD pattern for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I. Bulk material, such as stoichiometry arity between
the temperature was obtained on a Rigaku Miniflex II XRD using
power settings of 40 kV, 15 mA, scan speed of 2.0000 degrees per
minute, a Miniflex 300/600 goniometer and an ASC-6 attachment, a
scan range of 3.000 to 40.000 degrees, an incident slit of 1.250
degrees, a length limiting slit of 10.0 mm, and SC-70 detector, a
receiving slit #1 of 1.250 degrees, continuous scan mode, and a
receiving slit #2 of 0.3 mm. The sample was prepared by smoothing
about 20 mg of solids on a silicon disk mounted in a metal holder.
Acquisition temperature was .about.21.degree. C.
[0175] FIG. 8 compares the calculated XRPD pattern of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I to the experimental XRPD pattern of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I. The comparison shows the degree to which the
calculated XRPD and experimental XRPD agree. Strong agreement
indicates the solved crystal structure is also the crystal
structure of the material analyzed directly by XRPD. This
determination can support orthogonal data about the composition of
the bulk material, such as stoichiometry.
[0176] XRPD peaks are found in Table 1 above.
[0177] Differential scanning calorimetry: Thermal properties of
sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I were evaluated using a Differential Scanning
calorimetry (DSC) instrument (TA Q1000, TA Instruments, New Castle,
Del., USA). Approximately 1 to 10 mg of solid sample was placed in
a standard aluminum pan vented with a pinhole for each experiment
and heated at a rate of 10.degree. C./min under a 50 mL/min
nitrogen purge. Data analysis was conducted using Universal
Analysis 2000 Version 4.7A (TA Instruments, New Castle, Del., USA).
Heat of fusion analysis was conducted by sigmoidal integration of
the endothermic melting peak.
[0178] The DSC for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I is represented in FIG. 2.
[0179] Thermogravimetric analysis: Thermogravimetric analysis (TGA)
of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4-
,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox-
azepin-8-olate Form I was performed on a TGA instrument (TA Q500,
TA Instruments, New Castle, Del., USA). Approximately 1 to 10 mg of
solid sample was placed in an open aluminum pan for each experiment
and heated at a rate of 10.degree. C./min under a 60 mL/min
nitrogen purge using. Data analysis was conducted using Universal
Analysis 2000 Version 4.7A (TA Instruments, New Castle, Del.,
USA).
[0180] The TGA for sodium
(2R5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,1-
3,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-
-olate Form I is represented in FIG. 3.
[0181] Dynamic vapor sorption: The hygroscopicity of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I was evaluated at about 25.degree. C. using a dynamic
vapor sorption (DVS) instrument (TGA Q5000 TA Instruments, New
Castle, Del.). Water adsorption and desorption were studied as a
function of relative humidity (RH) over the range of 0 to 90% at
room temperature. The humidity in the chamber was increased from
the initial level 50% RH to 60% RH and held until the solid and
atmosphere reached equilibration. The equilibrium test was
continued until passed or expired after 10 hours. At this point, RH
was raised 10% higher and the process was repeated until 90% RH was
reached and equilibrated. During this period, the water sorption
was monitored. For desorption, the relative humidity was decreased
in a similar manner to measure a full sorption/desorption cycle.
The cycle was optionally repeated. All experiments were operated in
dm/dt mode (mass variation over time) to determine the
equilibration endpoint. Approximately 3 mg of solid sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13
a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-
-8-olate was used. Data analysis was conducted using Universal
Analysis 2000 Version 4.7A (TA Instruments, New Castle, Del.,
USA).
[0182] The DVS for sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I is represented in FIG. 4.
[0183] The indexing data for Formula II Form I is summarized in
Table 2 below.
TABLE-US-00002 TABLE 2 Indexing Data for Formula II Form I Unit
Cell Dimensions Form and Distance (.ANG.) Angle (.degree.)
Identification Solvent a b c .alpha. .beta. .gamma. Formula II
methanol 9.105 13.986 31.384 90 90 90 Form I
[0184] The single crystal X-ray diffraction studies were carried
out on a Bruker APEX II Ultra diffractometer equipped with Mo
K.sub..alpha. radiation (.lamda.=0.71073 .ANG.). Crystals of the
subject compound were cut into a 0.22.times.0.18.times.0.04 mm
section and mounted on a Cryoloop with Paratone-N oil. Data were
collected in a nitrogen gas stream at 100 (2) K. A total of 15725
reflections were collected covering the indices, -9<=h<=10,
-13<=k<=16, -37<=l<=36. 7163 reflections were found to
be symmetry independent, with a R.sub.int of 0.682. Indexing and
unit-cell refinement indicated an orthorhombic lattice. The space
group, which was uniquely defined by the systematic absences in the
data, was found to be P2.sub.12.sub.12.sub.1. The data were
integrated using the Bruker SAINT software program and scaled using
the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model compatible with the proposed
structure.
[0185] All nonhydrogen atoms were refined anisotropically by
full-matrix least-squares (SHELXL-2014). All hydrogen atoms were
placed using a riding model. Their positions were constrained
relative to their parent atom using the appropriate HFIX command in
SHELXL-2014. Crystallographic data are summarized in Table 2A. The
absolute stereochemistry was set to conform to previously studied
samples of the same compound.
[0186] The single crystal X-ray crystallography data for Formula II
Form I is summarized in Table 2A below.
TABLE-US-00003 TABLE 2A Single Crystal Data for Formula II, Form I
C42 H34 F6 N6 Acquisition Space Group Z Unit Cell Dimensions Na2
O10 Temp. P212121 4 Form and 100(2) K Solvent in Density Distance
(.ANG.) Angle (.degree.) Identification Solvent lattice
(Mg/m.sup.3) a b c .alpha. .beta. .gamma. Formula II Ethanol/DMF
none 1.614 8.9561 13.9202 31.115 90 90 90 Form I (10) (14) (3)
[0187] Dissolution Profile
[0188] The intrinsic dissolution profile of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate (Formula II) Form I of the present invention and the
intrinsic dissolution profiles of Form I and Form III of Formula I,
the free acid,
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide (disclosed in the co-pending U.S. Provisional
Application 62/015,238 filed on Jun. 20, 2014 titled CRYSTALLINE
FORMS OF
(2R,5S,13AR)-8-HYDROXY-7,9-DIOXO-N-(2,4,6-TRIFLUOROBENZYL)-2,3,4,5,7,9,13-
,13A-OCTAHYDRO-2,5-METHANOPYRIDO[1',2':4,5]PYRAZINO[2,1-B][1,3]OXAZEPINE-1-
0-CARBOXAMIDE), were measured by characterizing API dissolution
from a constant surface area. Approximately 150 mg of the drug
substance was compressed at 1500 psi for approximately 3 seconds
using a hydraulic press (Carver Press, Fred Carver, N.J., USA). The
compressed drug substance formed a flat disk (surface area
.about.0.49 cm.sup.2), which was mounted onto a dissolution
apparatus (VanKel Industries Inc., Edison, N.J., VK7000,
W1120A-0288). The rotating disk (100 rpm) was then lowered into the
dissolution medium (500 mL, of 0.01N HCl) which was equilibrated to
37.+-.1.degree. C. Samples were pulled at pre-determined time
points and drug concentrations were measured using an appropriate
UPLC-UV method. The intrinsic dissolution rate constant (K) was
calculated using the following equation;
C = KA V t ##EQU00001##
[0189] Where C is the concentration of the active at time t, A is
the surface area of the tablet (.about.0.49 cm.sup.2) and V is the
volume of the media (500 mL). Note that the term active as used
herein refers to the parent molecule, whose structure is shared by
both Formula I and Formula II.
[0190] The dissolution profiles can be found in FIG. 5.
[0191] Solubility
[0192] The solubility of the sodium form of the present invention
and the free acid,
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide Form III in biorelevant media was determined at room
temperature as a function of time. Solubility was determined in the
following biorelevant media: 0.1 mM Fasted-State Simulated Gastric
Fluid (FaSSGF) pH 1.6 (0.08 mM taurocholate, 0.02 mM lecithin, 34.2
mM NaCl); 18.75 mM Fed-State Simulated Intestinal Fluid (FeSSIF) pH
5 (15 mM taurocholate, 3.75 mM lecithin, 0.12 M NaCl); and 3.75 mM
Fasted-State Simulated Intestinal Fluid (FaSSIF) pH 5 (3 mM
taurocholate, 0.75 mM lecithin, 0.10 M NaCl). Approximately 20 mg
of the drug substance was mixed on a magnetic stir-plate in 50 mL
of biorelevant media. Samples (.about.1 mL) were pulled every 5-10
min for 2 hours. The samples were immediately filtered/centrifuged
for 10 min in a Spin-X tube equipped with a 0.45 .mu.m nylon
filter. The resulting filtrate was analyzed using an appropriate
ULC-UV method.
[0193] The solubility profiles in FaSSGF can be found in FIG. 6.
The solubility profiles in FeSSIF and FaSSIF can be found in FIG.
7.
[0194] Bioavailability
[0195] The bioavailability of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate (Formula II) Form I was compared to the bioavailability of
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide (Formula I) Form III.
[0196] Each dosing group consisted of 6 male, non-naive purebred
beagle dogs. At dosing, the animals weighed between 10 to 13 kg.
The animals were fasted overnight prior to dose administration and
up to 4 hr after dosing. Each subject was pre-treated with
pentagastrin (6 .mu.g/kg) and dosed 30 minutes later with a single
25 mg strength tablet of Formula II Form I or Formula I Form III.
Each subject was given 10 mL of water to aid in swallowing.
[0197] Serial venous blood samples (approximately 1 mL each) were
taken from each animal at 0, 0.250, 0.483, 0.583, 0.750, 1.00,
1.50, 2.00, 4.00, 8.00, 12.0, and 24.0 hours after dosing. The
blood samples were collected into Vacutainer.TM. tubes containing
EDTA-K2 as the anti-coagulant and were immediately placed on wet
ice pending centrifugation for plasma. An LC/MS/MS method was used
to measure the concentration of the test compound in plasma. An
aliquot of 100 .mu.L of each plasma sample was added to a clean 96
well plate, and 400 .mu.L of cold acetonitrile/internal standard
solution (ACN)/(ISTD) was added. After protein precipitation, an
aliquot of 110 .mu.L of the supernatant was transferred to a clean
96-well plate and diluted with 300 .mu.L of water. An aliquot of 25
.mu.L of the above solution was injected into a TSQ Quantum Ultra
LC/MS/MS system utilizing a Hypersil Gold C.sub.18 HPLC column
(50.times.3.0 mm, 5 .mu.m; Thermo-Hypersil Part #25105-053030). An
Agilent 1200 series binary pump (P/N G1312A Bin Pump) was used for
elution and separation, and an HTS Pal autosampler (LEAP
Technologies, Carrboro, N.C.) was used for sample injection. A TSQ
Quantum Ultra triple quadrupole mass spectrometer was utilized in
selective reaction monitoring mode (Thermo Finnigan, San Jose,
Calif.). Liquid chromatography was performed using two mobile
phases: mobile phase A contained 1% acetonitrile in 2.5 mM ammonium
formate aqueous solution with pH of 3.0, and mobile phase B
contained 90% acetonitrile in 10 mM ammonium formate with pH of
4.6. Non-compartmental pharmacokinetic analysis was performed on
the plasma concentration-time data. The resulting data are shown in
Table 3: F (%) refers to oral bioavailability; AUC refers to area
under the curve and is a measure of total plasma exposure of the
indicated compound; C.sub.max refers to the peak plasma
concentration of the compound after administration.
TABLE-US-00004 TABLE 3 Bioavailability of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-
trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-
methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate Form I
and (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-
trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido
[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide Form III.
AUC.sub.last C.sub.max Form Formulation % F (uM .times. hr) (nM)
Formula I Dry Granulation.sup.1 10 .+-. 6 27 .+-. 13 6 .+-. 2 Form
III Formula II Dry Granulation.sup.2 28 .+-. 7 71 .+-. 16 13 .+-. 1
Form I .sup.1Tablet: 30% active, 56% microcrystalline cellulose,
13% croscarmellose sodium, 1% magnesium stearate .sup.2Tablet: 30%
active, 56% microcrystalline cellulose, 13% croscarmellose sodium,
1% magnesium stearate
[0198] Stability
[0199] The stability of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate Form I was tested. As seen in Table 4, below, the compound
is stable after four weeks of storage under accelerated conditions.
In Table 5, AN refers to area normalization and is the relative
peak area of the active with respect to other impurities and
components contained in the sample. LS refers to labile strength
and is the amount of active present relative to the theoretical
amount.
TABLE-US-00005 TABLE 4 Stability of sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-
trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-
methanopyrido[1',2':4,5]pyrazino[2,1- b][1,3]oxazepin-8-olate Form
I Storage Conditions Storage Time (weeks) % AN % LS Starting
material 0 94.4 .+-. 0.1 99.8 .+-. 0.1 40.degree. C. (closed) 1
95.2 .+-. 0.3 108.0 .+-. 0.2 2 94.4 .+-. 0.1 102.4 .+-. 0.1 4 94.4
.+-. 0.0 97.0 .+-. 0.0 40.degree. C./75% RH (open) 1 94.9 .+-. 0.1
103.3 .+-. 6.9 2 94.4 .+-. 0.0 108.5 .+-. 0.4 4 94.4 .+-. 0.0 102.9
.+-. 0.1 25.degree. C./60% RH (open) 1 95.0 .+-. 0.2 104.8 .+-. 0.1
2 94.4 .+-. 0.1 101.6 .+-. 0.1 4 94.4 .+-. 0.0 103.0 .+-. 0.8
[0200] Each of the references including all patents, patent
applications and publications cited in the present application is
incorporated herein by reference in its entirety, as if each of
them is individually incorporated. Further, it would be appreciated
that, in the above teaching of invention, the skilled in the art
could make certain changes or modifications to the invention, and
these equivalents would still be within the scope of the invention
defined by the appended claims of the application. Each of the
references including all patents, patent applications and
publications cited in the present application is incorporated
herein by reference in its entirety, as if each of them is
individually incorporated. Further, it would be appreciated that,
in the above teaching of invention, the skilled in the art could
make certain changes or modifications to the invention, and these
equivalents would still be within the scope of the invention
defined by the appended claims of the application.
* * * * *